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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 479
- 试验地点
- 94
- 主要终点
- Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases)
研究概览
简要总结
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).
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Years 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo
Dosing will be once daily for up to 12 weeks.
干预措施: Placebo capsules (Drug)
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.
干预措施: Memantine Hydrochloride (HCl) (Drug)
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.
干预措施: Memantine Hydrochloride (HCl) (Drug)
结局指标
主要结局
Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases)
时间窗: 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.
次要结局
- Time to First Loss of Therapeutic (LTR) Response(Baseline to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12(Baseline (Visit 1) to week 12)
- Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12(Baseline (Visit 1) to week 12)