Asperger's Disorder, Asperger Syndrome, Autism, Autism Spectrum Disorders, Autistic Disorder, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)
Conditions
Keywords
Asperger's, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Memantine, Pediatric Disorder, Randomized Controlled Trial
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).
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
Interventions
Extended Release Dose ranging from 3-15mg/day; administered orally
DRUGPlacebo capsules
Once daily, oral administration.
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| 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. |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
Countries
Belgium, Colombia, Estonia, France, Hungary, Iceland, Italy, New Zealand, Poland, Serbia, South Africa, South Korea, Spain, Ukraine, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Dose-matched placebo, oral administration, once per day. | 160 |
| 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. | 160 |
| Memantine Full-Dose Memantine, 3mg, 6mg, 9mg, 12mg or 15mg depending on weight group and tolerability. Oral administration, once per day. | 157 |
| Total | 477 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Inclusion/Exclusion criteria not met | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Loss of Therapeutic Response | 107 | 108 | 100 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Other Reasons | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 4 | 0 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Memantine Reduced Dose | Memantine Full-Dose | Total |
|---|---|---|---|---|
| Age, Continuous | 8.9 years STANDARD_DEVIATION 2 | 9.2 years STANDARD_DEVIATION 1.9 | 9.2 years STANDARD_DEVIATION 1.9 | 9.1 years STANDARD_DEVIATION 1.9 |
| Autism Spectrum Disorder Subtype Asperger's Disorder | 30 Participants | 30 Participants | 27 Participants | 87 Participants |
| Autism Spectrum Disorder Subtype Autism | 101 Participants | 99 Participants | 100 Participants | 300 Participants |
| Autism Spectrum Disorder Subtype PDD-NOS | 29 Participants | 31 Participants | 30 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 22 Participants | 15 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 137 Participants | 138 Participants | 142 Participants | 417 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 5 Participants | 8 Participants | 20 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants | 9 Participants | 7 Participants | 26 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 138 Participants | 141 Participants | 140 Participants | 419 Participants |
| Region of Enrollment Belgium | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Colombia | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Estonia | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment France | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Region of Enrollment Hungary | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Region of Enrollment Iceland | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Italy | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Korea, Republic of | 6 Participants | 3 Participants | 5 Participants | 14 Participants |
| Region of Enrollment New Zealand | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Poland | 5 Participants | 6 Participants | 10 Participants | 21 Participants |
| Region of Enrollment Serbia | 3 Participants | 6 Participants | 5 Participants | 14 Participants |
| Region of Enrollment South Africa | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Spain | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Ukraine | 2 Participants | 4 Participants | 0 Participants | 6 Participants |
| Region of Enrollment United States | 134 Participants | 125 Participants | 126 Participants | 385 Participants |
| Sex: Female, Male Female | 18 Participants | 28 Participants | 25 Participants | 71 Participants |
| Sex: Female, Male Male | 142 Participants | 132 Participants | 132 Participants | 406 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 160 | 5 / 160 | 4 / 157 |
| serious Total, serious adverse events | 0 / 160 | 1 / 160 | 0 / 157 |
Outcome results
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.
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases) | 69.0 Percentage of patients with LTR |
| Memantine Reduced Dose | Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases) | 67.5 Percentage of patients with LTR |
| Memantine Full-Dose | Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases) | 66.7 Percentage of patients with LTR |
Comparison: Cochran-Mantel-Haenszel test was performed controlling for Autism Spectrum Disorder (ASD) subtype. Odds ratio was calculated for placebo vs. memantine full dose.p-value: 0.65995% CI: [0.7, 1.8]Cochran-Mantel-Haenszel
Comparison: Cochran-Mantel-Haenszel test was performed controlling for Autism Spectrum Disorder (ASD) subtype. Odds ratio was calculated for placebo vs. Memantine reduced dosep-value: 0.783995% CI: [0.7, 1.7]Cochran-Mantel-Haenszel
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12 | 0.7 units on a scale | Standard Error 0.3 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12 | 1.0 units on a scale | Standard Error 0.3 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12 | 1.0 units on a scale | Standard Error 0.3 |
p-value: 0.414495% CI: [-0.4, 1.1]ANCOVA
p-value: 0.421295% CI: [-0.4, 1]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12 | 0.9 units on a scale | Standard Error 0.3 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12 | 0.8 units on a scale | Standard Error 0.3 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12 | 0.8 units on a scale | Standard Error 0.3 |
p-value: 0.718295% CI: [-0.8, 0.6]ANCOVA
p-value: 0.83995% CI: [-0.8, 0.6]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12 | 1.4 units on a scale | Standard Error 0.3 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12 | 1.6 units on a scale | Standard Error 0.3 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12 | 1.2 units on a scale | Standard Error 0.3 |
p-value: 0.623895% CI: [-0.9, 0.5]ANCOVA
p-value: 0.595795% CI: [-0.5, 0.9]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12 | 0.9 units on a scale | Standard Error 0.3 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12 | 1.3 units on a scale | Standard Error 0.3 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12 | 1.2 units on a scale | Standard Error 0.3 |
p-value: 0.371395% CI: [-0.4, 1]ANCOVA
p-value: 0.285595% CI: [-0.3, 1.1]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12 | 1.2 units on a scale | Standard Error 0.3 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12 | 1.5 units on a scale | Standard Error 0.3 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12 | 1.8 units on a scale | Standard Error 0.3 |
p-value: 0.081395% CI: [-0.1, 1.4]ANCOVA
p-value: 0.436595% CI: [-0.4, 1]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12 | 0.8 units on a scale | Standard Error 0.2 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12 | 1.1 units on a scale | Standard Error 0.2 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12 | 0.9 units on a scale | Standard Error 0.2 |
p-value: 0.86495% CI: [-0.6, 0.7]ANCOVA
p-value: 0.436295% CI: [-0.4, 0.9]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12 | 0.3 units on a scale | Standard Error 0.2 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12 | 0.7 units on a scale | Standard Error 0.2 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12 | 0.3 units on a scale | Standard Error 0.2 |
p-value: 0.90295% CI: [-0.5, 0.6]ANCOVA
p-value: 0.127995% CI: [-0.1, 1]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12 | 1.5 units on a scale | Standard Error 0.3 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12 | 1.8 units on a scale | Standard Error 0.3 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12 | 1.8 units on a scale | Standard Error 0.3 |
p-value: 0.421395% CI: [-0.4, 1]ANCOVA
p-value: 0.426795% CI: [-0.4, 1]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12 | 0.1 units on a scale | Standard Error 0.2 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12 | 0.1 units on a scale | Standard Error 0.2 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12 | 0.2 units on a scale | Standard Error 0.2 |
p-value: 0.813695% CI: [-0.5, 0.7]ANCOVA
p-value: 0.924495% CI: [-0.6, 0.5]ANCOVA
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).
Time frame: Baseline (Visit 1) to week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12 | 0.0 units on a scale | Standard Error 0.2 |
| Memantine Reduced Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12 | 0.3 units on a scale | Standard Error 0.2 |
| Memantine Full-Dose | Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12 | 0.1 units on a scale | Standard Error 0.2 |
p-value: 0.761195% CI: [-0.5, 0.7]ANCOVA
p-value: 0.317695% CI: [-0.3, 0.9]ANCOVA
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.
Time frame: Baseline to week 12
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Loss of Therapeutic (LTR) Response | 29 Days |
| Memantine Reduced Dose | Time to First Loss of Therapeutic (LTR) Response | 33 Days |
| Memantine Full-Dose | Time to First Loss of Therapeutic (LTR) Response | 30 Days |