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

Autism Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01592747
• Other study ID #: MEM-MD-68
• Status: Completed
• Phase: Phase 2
• Start date: September 2012
• Est. completion date: October 2013

Study information

• Verified date: March 2019
• Source: Forest Laboratories
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 479
• Est. completion date: October 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 12 Years

Eligibility

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

Related Conditions & MeSH terms

• Asperger Syndrome
• Asperger's Disorder
• Autism
• Autism Spectrum Disorder
• Autism Spectrum Disorders
• Autistic Disorder
• Child Development Disorders, Pervasive
• Developmental Disabilities
• Disease
• Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)

Intervention

Drug:
• Memantine Hydrochloride (HCl)
Extended Release Dose ranging from 3-15mg/day; administered orally
• Memantine Hydrochloride (HCl)
Extended Release Dose ranging from 3mg every other day to 6mg/day; administered orally.
• Placebo capsules
Once daily, oral administration.

Locations

Country	Name	City	State
Belgium	Forest Investigative Site 204	Brussel
Belgium	Forest Investigative Site 203	Bruxelles
Colombia	Forest Investigative Site 228	Bello
Colombia	Forest Investigative Site 226	Bogotá
Estonia	Forest Investigative Site 276	Tallinn
France	Forest Investigative Site 329	Bron Cedex
Hungary	Forest Investigative Site 376	Budapest
Hungary	Forest Investigative Site 378	Budapest
Hungary	Forest Investigative Site 381	Budapest
Iceland	Forest Investigative Site 401	Kopavogur
Italy	Forest Investigative Site 453	Roma
Italy	Forest Investigative Site 452	Siena
Korea, Republic of	Forest Investigative Site 701	Seoul
Korea, Republic of	Forest Investigative Site 702	Seoul
Korea, Republic of	Forest Investigative Site 703	Seoul
Korea, Republic of	Forest Investigative Site 704	Yangsan-si	Gyeongsangnam-do
New Zealand	Forest Investigative Site 526	Wellington
Poland	Forest Investigative Site 578	Gdansk
Poland	Forest Investigative Site 579	Gdansk
Poland	Forest Investigative Site 576	Kobierzyce
Poland	Forest Investigative Site 577	Warszawa
Serbia	Forest Investigative Site 626	Belgrade
Serbia	Forest Investigative Site 627	Belgrade
Serbia	Forest Investigative Site 629	Nis
Serbia	Forest Investigative Site 628	Novi Sad
South Africa	Forest Investigative Site 676	Cape Town	Western Cape
Spain	Forest Investigative Site 728	Sabadell	Barcelona
Ukraine	Forest Investigative Site 807	Kharkiv
Ukraine	Forest Investigative Site 802	Kherson,Vil. Stepanivka
Ukraine	Forest Investigative Site 804	Kyiv
United States	Forest Investigative Site 081	Albuquerque	New Mexico
United States	Forest Investigative Site 107	Albuquerque	New Mexico
United States	Forest Investigative Site 069	Avon Lake	Ohio
United States	Forest Investigative Site 071	Bothell	Washington
United States	Forest Investigative Site 078	Boulder	Colorado
United States	Forest Investigative Site 075	Bradenton	Florida
United States	Forest Investigative Site 073	Centennial	Colorado
United States	Forest Investigative Site 072	Chapel Hill	North Carolina
United States	Forest Investigative Site 105	Charleston	South Carolina
United States	Forest Investigative Site 119	Charleston	West Virginia
United States	Forest Investigative Site 064	Charlottesville	Virginia
United States	Forest Investigative Site 028	Clinton	Utah
United States	Forest Investigative Site 001	Columbus	Ohio
United States	Forest Investigative Site 068	Dothan	Alabama
United States	Forest Investigative Site 082	Evansville	Indiana
United States	Forest Investigative Site 080	Gainesville	Florida
United States	Forest Investigative Site 054	Glendale	California
United States	Forest Investigative Site 053	Gresham	Oregon
United States	Forest Investigative Site 130	Henderson	Nevada
United States	Forest Investigative Site 051	Houston	Texas
United States	Forest Investigative Site 109	Imperial	California
United States	Forest Investigative Site 056	Indianapolis	Indiana
United States	Forest Investigative Site 117	Jacksonville	Florida
United States	Forest Investigative Site 132	Johnstown	Pennsylvania
United States	Forest Investigative Site 095	Lake Charles	Louisiana
United States	Forest Investigative Site 104	Las Vegas	Nevada
United States	Forest Investigative Site 102	Libertyville	Illinois
United States	Forest Investigative Site 097	Lincoln	Nebraska
United States	Forest Investigative Site 116	Lincoln	Nebraska
United States	Forest Investigative Site 077	Little Rock	Arkansas
United States	Forest Investigative Site 096	Los Angeles	California
United States	Forest Investigative Site 061	Louisville	Kentucky
United States	Forest Investigative Site 065	Maitland	Florida
United States	Forest Investigative Site 131	McMurray	Pennsylvania
United States	Forest Investigative Site 100	Media	Pennsylvania
United States	Forest Investigative Site 090	Memphis	Tennessee
United States	Forest Investigative Site 118	Miami	Florida
United States	Forest Investigative Site 063	Middleton	Wisconsin
United States	Forest Investigative Site 023	Naperville	Illinois
United States	Forest Investigative Site 057	Nashville	Tennessee
United States	Forest Investigative Site 136	Neptune	New Jersey
United States	Forest Investigative Site 059	Newton	Massachusetts
United States	Forest Investigative Site 113	Norfolk	Virginia
United States	Forest Investigative Site 085	Oakland Park	Florida
United States	Forest Investigative Site 141	Ogden	Utah
United States	Forest Investigative Site 019	Oklahoma City	Oklahoma
United States	Forest Investigative Site 115	Orange City	Florida
United States	Forest Investigative Site 062	Orlando	Florida
United States	Forest Investigative Site 125	Orlando	Florida
United States	Forest Investigative Site 005	Phoenix	Arizona
United States	Forest Investigative Site 086	Rockville	Maryland
United States	Forest Investigative Site 029	Salt Lake City	Utah
United States	Forest Investigative Site 021	San Francisco	California
United States	Forest Investigative Site 026	Santa Ana	California
United States	Forest Investigative Site 108	Springfield	Massachusetts
United States	Forest Investigative Site 002	Stanford	California
United States	Forest Investigative Site 067	Tampa	Florida
United States	Forest Investigative Site 070	The Woodlands	Texas
United States	Forest Investigative Site 127	Toms River	New Jersey
United States	Forest Investigative Site 055	Tucson	Arizona
United States	Forest Investigative Site 092	Tulsa	Oklahoma
United States	Forest Investigative Site 052	Washington	District of Columbia
United States	Forest Investigative Site 101	Wellington	Florida
United States	Forest Investigative Site 106	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Forest Laboratories

Countries where clinical trial is conducted

United States,  Belgium,  Colombia,  Estonia,  France,  Hungary,  Iceland,  Italy,  Korea, Republic of,  New Zealand,  Poland,  Serbia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline (Visit 1) to week 12
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.	Baseline to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12
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).	Baseline (Visit 1) to week 12