Withdrawal Study of Memantine in Pediatric Patients With... | NCT01592747

NCT01592747

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Memantine 1	Experimental	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)
Memantine 2	Experimental	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)
Placebo	Placebo Comparator	Dosing will be once daily for up to 12 weeks.	Drug: Placebo capsules

Name	Type	Description	Arm Group Labels	Other Names
Memantine Hydrochloride (HCl)	Drug	Extended Release Dose ranging from 3-15mg/day; administered orally	Memantine 1

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

Measure	Description	Time Frame
Time to First Loss of Therapeutic (LTR) Response	Time to the first visit when a patient shows LTR following randomization to memantine or placebo.	Baseline to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Completed at least 12 weeks of exposure to study drug in lead-in study MEM-MD-91 (NCT01592786)
Met responder criterion at two consecutive visits separated by at least two weeks in lead-in study MEM-MD-91
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
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
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
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
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
Females who are 9 years and older or who have had onset of menses must have a negative urine pregnancy test at Visit 1
Age of 6 years to 12 years at the time of entry into lead in study MEM-MD-91

Exclusion Criteria:

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
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.
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
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
Patients requiring treatment with prohibited concomitant medications
Patients who, in the opinion of the Investigator, might not be suitable for the study
Employee or immediate relative of an employee of Forest Laboratories, Inc., any of its affiliates or partners, or the study center

Name	Affiliation	Role
Jordan Lateiner, MS, MBA	Forest Research Institute, Inc.- A Subsidiary of Forest Laboratories, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Forest Investigative Site 068		Dothan	Alabama	36303	United States
Forest Investigative Site 005

PubMed Identifier	Type	Citation	Retractions
37811711	Derived	Iffland M, Livingstone N, Jorgensen M, Hazell P, Gillies D. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2023 Oct 9;10(10):CD011769. doi: 10.1002/14651858.CD011769.pub2.
36006807	Derived	Brignell A, Marraffa C, Williams K, May T. Memantine for autism spectrum disorder. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013845. doi: 10.1002/14651858.CD013845.pub2.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Dose-matched placebo, oral administration, once per day.
FG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration once per day.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG0008.9± 2.0 BG0019.2± 1.9 BG0029.2± 1.9 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00018 BG00128 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00023 BG00122 BG002

Race/Ethnicity, Customized

Number

Participants

Title

Denominators

Categories

White

Title	Measurements
	BG000138 BG001141 BG002

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

United States

Title	Measurements
	BG000134 BG001125 BG002

Autism Spectrum Disorder Subtype

Count of Participants

Participants

Title

Denominators

Categories

Autism

Title	Measurements
	BG000101 BG00199 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases)

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.

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.)

Posted

Number

Percentage of patients with LTR

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg; oral administration. Once per day.

Units	Counts
Participants	OG000158 OG001160 OG002153

Title

Denominators

Categories

Title	Measurements
	OG00069.0 OG00167.5 OG00266.7

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002	Cochran-Mantel-Haenszel test was performed controlling for Autism Spectrum Disorder (ASD) subtype. Odds ratio was calculated for placebo vs. memantine full dose.	Cochran-Mantel-Haenszel		0.6590		Odds Ratio (OR)	1.1			2-Sided	95	0.7	1.8					Superiority or Other
OG000 OG001

Secondary

Time to First Loss of Therapeutic (LTR) Response

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

Posted

Median

95% Confidence Interval

Days

Baseline to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at 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).

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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

Secondary

Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at 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).

Posted

Least Squares Mean

Standard Error

units on a scale

Baseline (Visit 1) to week 12

ID	Title	Description
OG000	Placebo	Dose-matched placebo, oral administration, once per day.
OG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration, once per day.
OG002	Memantine Full-Dose

ID	Term
D001321	Autistic Disorder
D020817	Asperger Syndrome
D000067877	Autism Spectrum Disorder

ID	Term
D002659	Child Development Disorders, Pervasive
D065886	Neurodevelopmental Disorders
D001523	Mental Disorders

ID	Term
D000547	Amantadine
D000218	Adamantane
D001952	Bridged-Ring Compounds
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals

ID	Title	Description
BG000	Placebo	Dose-matched placebo, oral administration, once per day.
BG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day depending on weight group and tolerability. Oral administration once per day.
BG002	Memantine Full-Dose	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day.
BG003	Total	Total of all reporting groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Dose-matched placebo, oral administration, once per day.	0	160	8	160
EG001	Memantine Reduced Dose	Memantine, 3mg every other day, 3mg per day, or 6mg per day. Oral administration.	1	160	5	160
EG002	Memantine Full-Dose	Memantine, 3mg, 6mg, 9mg, 12mg or 15mg; oral administration. Once per day.	0	157	4	157