Withdrawal Study of Memantine in Pediatric Patients With Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified Previously Treated With Memantine

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01592747
• Collaborator: (none)
• Enrollment: 479
• Locations: 94
• Arms: 3
• Duration (Months): 13
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this randomized withdrawal study is to evaluate the safety, tolerability, and efficacy of memantine compared with placebo in pediatric patients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS).

Condition or Disease	Intervention/Treatment	Phase
Autistic Disorder; Autism; Asperger's Disorder; Asperger Syndrome; Autism Spectrum Disorders; Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)	Drug: Memantine Hydrochloride (HCl); Drug: Memantine Hydrochloride (HCl); Drug: Placebo capsules	Phase 2

Detailed Description

This clinical study was a 12-week, multicenter, double-blind, placebo-controlled, randomized withdrawal study in pediatric outpatients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Patients who completed at least 12 weeks of study drug exposure and met protocol specified responder criterion in lead in Study MEM-MD-91 (NCT01592786) at two consecutive visits separated by at least two weeks were eligible to transition to this study. The responder criterion was defined as having 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 in Study MEM-MD-91.

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 NOAEL(No observed adverse effect level) 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

Study Design

• Study Type: Interventional
• Actual Enrollment: 479 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study of the Safety and Efficacy of Memantine in Pediatric Patients With Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) Previously Treated With Memantine
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Memantine 1 Patients randomized to the full dose arm will continue taking memantine at the same tolerability and weight-based dose achieved in lead-in Study MEM-MD-91. Dosing will be once daily for up to 12 weeks.	Drug: Memantine Hydrochloride (HCl); Extended Release Dose ranging from 3-15mg/day; administered orally
Experimental: Memantine 2 Patients randomized to the reduced dose arm will take memantine at the tolerability and weight based dose that they received in lead in Study MEM-MD-91 reduced by at least 50%. Dosing will be once daily for up to 12 weeks.	Drug: Memantine Hydrochloride (HCl); Extended Release Dose ranging from 3mg every other day to 6mg/day; administered orally.
Placebo Comparator: Placebo Dosing will be once daily for up to 12 weeks.	Drug: Placebo capsules; Once daily, oral administration.

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases) [Baseline (Visit 1) to week 12]

   Loss of Therapeutic response is defined as a worsening (increase) of at least 10 points in Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 (randomization) score. The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment with total raw score 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. Time to First Loss of Therapeutic (LTR) Response [Baseline to week 12]

   Time to the first visit when a patient shows LTR following randomization to memantine or placebo.

2. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

3. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

4. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

5. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

6. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

7. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

8. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

9. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12 [Baseline (Visit 1) to week 12]

   The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

10. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12 [Baseline (Visit 1) to week 12]

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

11. Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12 [Baseline (Visit 1) to week 12]

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Completed at least 12 weeks of exposure to study drug in lead-in study MEM-MD-91 (NCT01592786)

2. Met responder criterion at two consecutive visits separated by at least two weeks in lead-in study MEM-MD-91

3. Provide written informed assent, when developmentally appropriate, to participate in the study before conduct of any study-specific procedures. The parent/guardian/LAR must provide written informed consent before the patient's participation in the study. A separate written informed consent for the caregiver must also be obtained before the conduct of any study specific procedures

4. Have a knowledgeable caregiver who is capable of providing reliable information about the patient's condition, attending all clinic visits with the patient, and overseeing the administration of study drug. Every effort should be made to maintain the same caregiver as used in the lead-in study throughout this study

5. Have normal results from the physical examination, laboratory tests, ECG, and vital signs at Visit 1 of this study (last visit of Study MEM-MD-91). Any abnormal findings must be deemed not clinically significant by the Investigator and documented

6. Be able to speak and understand English sufficiently (or their native language if this can be accommodated by the site), as well as have a caregiver and parent/guardian/LAR who is able to speak and understand English sufficiently (or their native language if this can be accommodated by the site), to comprehend the nature of the study and to allow for the completion of all study assessments

7. 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

8. Females who are 9 years and older or who have had onset of menses must have a negative urine pregnancy test at Visit 1

9. Age of 6 years to 12 years at the time of entry into lead in study MEM-MD-91

Exclusion Criteria:

1. Patients with a concurrent medical condition that might interfere with the conduct of the study, confound interpretation of the study results, or endanger the patient's well being

2. Significant risk of suicidality based on the Investigator's judgment, the Aberrant Behavior Checklist-Irritability subscale (ABC-I), or if appropriate, as indicated by a response of "yes" to questions 4 or 5 in the suicidal ideation section of the Children's C-SSRS (Columbia-Suicide Severity Rating Scale) or any suicidal behavior.

3. Patients with evidence or history of malignancy (other than excised basal cell carcinoma) or any significant hematologic, endocrine, cardiovascular (including any rhythm disorder), neurologic, respiratory, renal, hepatic, or gastrointestinal disease

4. Female patients of child-bearing potential who are not using or not willing to use a conventional method of contraception approved by the PI. Abstinence is an acceptable method of contraception

5. Patients requiring treatment with prohibited concomitant medications

6. Patients who, in the opinion of the Investigator, might not be suitable for the study

7. Employee or immediate relative of an employee of Forest Laboratories, Inc., any of its affiliates or partners, or the study center

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 068	Dothan	Alabama	United States	36303
2	Forest Investigative Site 005	Phoenix	Arizona	United States	85006
3	Forest Investigative Site 055	Tucson	Arizona	United States	85718
4	Forest Investigative Site 077	Little Rock	Arkansas	United States	72202-3591
5	Forest Investigative Site 054	Glendale	California	United States	91206
6	Forest Investigative Site 109	Imperial	California	United States	92251
7	Forest Investigative Site 096	Los Angeles	California	United States	90024
8	Forest Investigative Site 021	San Francisco	California	United States	94143-0984
9	Forest Investigative Site 026	Santa Ana	California	United States	92701
10	Forest Investigative Site 002	Stanford	California	United States	94305-5719
11	Forest Investigative Site 078	Boulder	Colorado	United States	80304
12	Forest Investigative Site 073	Centennial	Colorado	United States	80112
13	Forest Investigative Site 052	Washington	District of Columbia	United States	20010-2970
14	Forest Investigative Site 075	Bradenton	Florida	United States	32751
15	Forest Investigative Site 080	Gainesville	Florida	United States	32607
16	Forest Investigative Site 117	Jacksonville	Florida	United States	32216
17	Forest Investigative Site 065	Maitland	Florida	United States	32751
18	Forest Investigative Site 118	Miami	Florida	United States	33155
19	Forest Investigative Site 085	Oakland Park	Florida	United States	33334
20	Forest Investigative Site 115	Orange City	Florida	United States	32763
21	Forest Investigative Site 125	Orlando	Florida	United States	32803
22	Forest Investigative Site 062	Orlando	Florida	United States	32806
23	Forest Investigative Site 067	Tampa	Florida	United States	33612
24	Forest Investigative Site 101	Wellington	Florida	United States	33414
25	Forest Investigative Site 102	Libertyville	Illinois	United States	60048
26	Forest Investigative Site 023	Naperville	Illinois	United States	60563
27	Forest Investigative Site 082	Evansville	Indiana	United States	47713
28	Forest Investigative Site 056	Indianapolis	Indiana	United States	46260
29	Forest Investigative Site 106	Wichita	Kansas	United States	67214-3199
30	Forest Investigative Site 061	Louisville	Kentucky	United States	40202
31	Forest Investigative Site 095	Lake Charles	Louisiana	United States	70605
32	Forest Investigative Site 086	Rockville	Maryland	United States	20852
33	Forest Investigative Site 059	Newton	Massachusetts	United States	02459
34	Forest Investigative Site 108	Springfield	Massachusetts	United States	01199
35	Forest Investigative Site 116	Lincoln	Nebraska	United States	68516
36	Forest Investigative Site 097	Lincoln	Nebraska	United States	68526
37	Forest Investigative Site 130	Henderson	Nevada	United States	89052
38	Forest Investigative Site 104	Las Vegas	Nevada	United States	89128
39	Forest Investigative Site 136	Neptune	New Jersey	United States	07753
40	Forest Investigative Site 127	Toms River	New Jersey	United States	08755
41	Forest Investigative Site 081	Albuquerque	New Mexico	United States	87108-5129
42	Forest Investigative Site 107	Albuquerque	New Mexico	United States	87109
43	Forest Investigative Site 072	Chapel Hill	North Carolina	United States	27514
44	Forest Investigative Site 069	Avon Lake	Ohio	United States	44012
45	Forest Investigative Site 001	Columbus	Ohio	United States	43210
46	Forest Investigative Site 019	Oklahoma City	Oklahoma	United States	73116
47	Forest Investigative Site 092	Tulsa	Oklahoma	United States	74104
48	Forest Investigative Site 053	Gresham	Oregon	United States	97030
49	Forest Investigative Site 132	Johnstown	Pennsylvania	United States	15904
50	Forest Investigative Site 131	McMurray	Pennsylvania	United States	15317
51	Forest Investigative Site 100	Media	Pennsylvania	United States	19063
52	Forest Investigative Site 105	Charleston	South Carolina	United States	29407
53	Forest Investigative Site 090	Memphis	Tennessee	United States	38119
54	Forest Investigative Site 057	Nashville	Tennessee	United States	37232
55	Forest Investigative Site 051	Houston	Texas	United States	77090
56	Forest Investigative Site 070	The Woodlands	Texas	United States	77381
57	Forest Investigative Site 028	Clinton	Utah	United States	84015
58	Forest Investigative Site 141	Ogden	Utah	United States	84405
59	Forest Investigative Site 029	Salt Lake City	Utah	United States	84106
60	Forest Investigative Site 064	Charlottesville	Virginia	United States	22903
61	Forest Investigative Site 113	Norfolk	Virginia	United States	23507
62	Forest Investigative Site 071	Bothell	Washington	United States	98011
63	Forest Investigative Site 119	Charleston	West Virginia	United States	25304
64	Forest Investigative Site 063	Middleton	Wisconsin	United States	53562
65	Forest Investigative Site 204	Brussel		Belgium	1020
66	Forest Investigative Site 203	Bruxelles		Belgium	1090
67	Forest Investigative Site 228	Bello		Colombia
68	Forest Investigative Site 226	Bogotá		Colombia
69	Forest Investigative Site 276	Tallinn		Estonia	10617
70	Forest Investigative Site 329	Bron Cedex		France	69677
71	Forest Investigative Site 381	Budapest		Hungary	1026
72	Forest Investigative Site 376	Budapest		Hungary	1083
73	Forest Investigative Site 378	Budapest		Hungary	1089
74	Forest Investigative Site 401	Kopavogur		Iceland	200
75	Forest Investigative Site 453	Roma		Italy	165
76	Forest Investigative Site 452	Siena		Italy	53100
77	Forest Investigative Site 704	Yangsan-si	Gyeongsangnam-do	Korea, Republic of	626-770
78	Forest Investigative Site 702	Seoul		Korea, Republic of	110744
79	Forest Investigative Site 703	Seoul		Korea, Republic of	120-752
80	Forest Investigative Site 701	Seoul		Korea, Republic of	138-736
81	Forest Investigative Site 526	Wellington		New Zealand	6012
82	Forest Investigative Site 579	Gdansk		Poland	80-542
83	Forest Investigative Site 578	Gdansk		Poland	80-952
84	Forest Investigative Site 576	Kobierzyce		Poland	55-040
85	Forest Investigative Site 577	Warszawa		Poland	02-957
86	Forest Investigative Site 626	Belgrade		Serbia	11000
87	Forest Investigative Site 627	Belgrade		Serbia	11000
88	Forest Investigative Site 629	Nis		Serbia	18000
89	Forest Investigative Site 628	Novi Sad		Serbia	21000
90	Forest Investigative Site 676	Cape Town	Western Cape	South Africa	7530
91	Forest Investigative Site 728	Sabadell	Barcelona	Spain	8208
92	Forest Investigative Site 807	Kharkiv		Ukraine	61153
93	Forest Investigative Site 802	Kherson,Vil. Stepanivka		Ukraine	73488
94	Forest Investigative Site 804	Kyiv		Ukraine	04080

Sponsors and Collaborators

• Forest Laboratories

Investigators

• Study Director: Jordan Lateiner, MS, MBA, Forest Research Institute, Inc.- A Subsidiary of Forest Laboratories, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01592747
• Other Study ID Numbers: MEM-MD-68
• First Posted: May 7, 2012
• Last Update Posted: Apr 24, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Forest Laboratories: Asperger's; Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS); Memantine; Pediatric Disorder; Randomized Controlled Trial
• Additional relevant MeSH terms: Disease; Autistic Disorder; Autism Spectrum Disorder; Developmental Disabilities; Child Development Disorders, Pervasive; Asperger Syndrome; Memantine

Study Results

Participant Flow

Recruitment Details	Patient recruitment occurred over a ten month period, from September of 2012 to June of 2013, at 92 study sites, located in the Untied States and 14 other countries.
Pre-assignment Detail	Patients who completed at least 12 weeks of exposure to open-label memantine and met the responder criterion at 2 consecutive visits separated by at least 2 weeks during lead-in study MEM-MD-91 were eligible to enroll into this study.

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg, depending on weight group and tolerability. Oral administration, once per day.
Period Title: Overall Study
STARTED	160	161	158
COMPLETED	44	50	50
NOT COMPLETED	116	111	108

Baseline Characteristics

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose	Total
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.	Total of all reporting groups
Overall Participants	160	160	157	477
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.9 (2.0)	9.2 (1.9)	9.2 (1.9)	9.1 (1.9)
Sex: Female, Male (Count of Participants)
Female	18 11.3%	28 17.5%	25 15.9%	71 14.9%
Male	142 88.8%	132 82.5%	132 84.1%	406 85.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 14.4%	22 13.8%	15 9.6%	60 12.6%
Not Hispanic or Latino	137 85.6%	138 86.3%	142 90.4%	417 87.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
White	138 86.3%	141 88.1%	140 89.2%	419 87.8%
Black or African American	10 6.3%	9 5.6%	7 4.5%	26 5.5%
Asian	7 4.4%	5 3.1%	8 5.1%	20 4.2%
American Indian or Alaska Native	0 0%	1 0.6%	0 0%	1 0.2%
Native Hawaiian or Other Pacific Islander	1 0.6%	1 0.6%	0 0%	2 0.4%
Other	4 2.5%	3 1.9%	2 1.3%	9 1.9%
Region of Enrollment (Count of Participants)
United States	134 83.8%	125 78.1%	126 80.3%	385 80.7%
Belgium	2 1.3%	1 0.6%	1 0.6%	4 0.8%
Colombia	1 0.6%	2 1.3%	2 1.3%	5 1%
Estonia	0 0%	1 0.6%	0 0%	1 0.2%
France	1 0.6%	4 2.5%	2 1.3%	7 1.5%
Hungary	3 1.9%	3 1.9%	2 1.3%	8 1.7%
Iceland	0 0%	3 1.9%	0 0%	3 0.6%
Italy	2 1.3%	1 0.6%	1 0.6%	4 0.8%
Korea, Republic of	6 3.8%	3 1.9%	5 3.2%	14 2.9%
New Zealand	0 0%	1 0.6%	1 0.6%	2 0.4%
Poland	5 3.1%	6 3.8%	10 6.4%	21 4.4%
Serbia	3 1.9%	6 3.8%	5 3.2%	14 2.9%
South Africa	0 0%	0 0%	1 0.6%	1 0.2%
Spain	1 0.6%	0 0%	1 0.6%	2 0.4%
Ukraine	2 1.3%	4 2.5%	0 0%	6 1.3%
Autism Spectrum Disorder Subtype (Count of Participants)
Autism	101 63.1%	99 61.9%	100 63.7%	300 62.9%
Asperger's Disorder	30 18.8%	30 18.8%	27 17.2%	87 18.2%
PDD-NOS	29 18.1%	31 19.4%	30 19.1%	90 18.9%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases)
Description	Loss of Therapeutic response is defined as a worsening (increase) of at least 10 points in Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 (randomization) score. The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment with total raw score 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	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

All efficacy analyses were based on the Intent-to-treat (ITT) Population. Of the 479 randomized patients, 471 patients were in the ITT Population (ie, had at least 1 dose of double-blind investigational product and at least 1 assessment of the Social Responsiveness Scale (SRS) total raw score during the double-blind treatment period.)

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg; oral administration. Once per day.
Measure Participants	158	160	153
Number [Percentage of patients with LTR]	69.0	67.5	66.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments	Cochran-Mantel-Haenszel test was performed controlling for Autism Spectrum Disorder (ASD) subtype. Odds ratio was calculated for placebo vs. memantine full dose.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6590
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments	Cochran-Mantel-Haenszel test was performed controlling for Autism Spectrum Disorder (ASD) subtype. Odds ratio was calculated for placebo vs. Memantine reduced dose
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7839
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to First Loss of Therapeutic (LTR) Response
Description	Time to the first visit when a patient shows LTR following randomization to memantine or placebo.
Time Frame	Baseline to week 12

Outcome Measure Data

Analysis Population Description

All efficacy analyses were based on the Intent-to-treat (ITT) Population. Of the 479 randomized patients, 471 patients were in the ITT Population (ie, had at least 1 dose of double-blind investigational product and at least 1 assessment of the Social Responsiveness Scale (SRS) total raw score during the double-blind treatment period.)

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	158	160	153
Median (95% Confidence Interval) [Days]	29	33	30

3. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.1 (0.2)	0.1 (0.2)	0.2 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8136
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9244
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.0 (0.2)	0.3 (0.2)	0.1 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7611
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3176
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.3 (0.2)	0.7 (0.2)	0.3 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9020
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1279
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -0.1 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.7 (0.3)	1.0 (0.3)	1.0 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4144
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4212
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	1.4 (0.3)	1.6 (0.3)	1.2 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6238
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.9 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5957
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.8 (0.2)	1.1 (0.2)	0.9 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8640
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4362
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.9 (0.3)	0.8 (0.3)	0.8 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7182
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8390
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	1.2 (0.3)	1.5 (0.3)	1.8 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0813
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -0.1 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4365
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	1.5 (0.3)	1.8 (0.3)	1.8 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4213
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4267
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12
Description	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).
Time Frame	Baseline (Visit 1) to week 12

Outcome Measure Data

Analysis Population Description

Of the 479 randomized patients, 471 patients were included in the Intent to Treat (ITT) Population. Within the ITT population, 466 patients had post-baseline assessment of the Children's Communication Checklist-2 (CCC-2).

Arm/Group Title	Placebo	Memantine Reduced Dose	Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
Measure Participants	154	159	153
Least Squares Mean (Standard Error) [units on a scale]	0.9 (0.3)	1.3 (0.3)	1.2 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Full-Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3713
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.3
	Confidence Interval	() 95%; -0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Memantine Reduced Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2855
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -0.3 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected for a 14 month period from September of 2012 to October of 2013 at 92 study centers in the United States and 14 other countries.
Adverse Event Reporting Description	Safety results are based on Safety Population (ie, all randomized patients who took at least 1 dose of double-blind study drug).
Arm/Group Title	Placebo		Memantine Reduced Dose		Memantine Full-Dose
Arm/Group Description	Dose-matched placebo, oral administration, once per day.		Memantine, 3mg every other day, 3mg per day, or 6mg per day. Oral administration.		Memantine, 3mg, 6mg, 9mg, 12mg or 15mg; oral administration. Once per day.
All Cause Mortality
	Placebo		Memantine Reduced Dose		Memantine Full-Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Memantine Reduced Dose		Memantine Full-Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/160 (0%)		1/160 (0.6%)		0/157 (0%)
Infections and infestations
Furuncle	0/160 (0%)		1/160 (0.6%)		0/157 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Memantine Reduced Dose		Memantine Full-Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/160 (5%)		5/160 (3.1%)		4/157 (2.5%)
General disorders
Irritability	8/160 (5%)		5/160 (3.1%)		4/157 (2.5%)

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, Inc. 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, Inc.