Back to resultsLow-Dose Ketamine in Children With ADNP Syndrome
Primary Purpose
ADNP Syndrome
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ketamine
Sponsored by
About this trial
This is an interventional treatment trial for ADNP Syndrome focused on measuring Ketamine, ADNP, Activity-Dependent Neuroprotector Protein, Chromosome Disorders, Chromosome Aberrations
Eligibility Criteria
Inclusion Criteria:
- 5 to 12 years old (inclusive) at the time of informed consent;
- Has a diagnosis of ADNP syndrome, confirmed by genetic testing prior to subject randomization;
- Has a Clinical Global Impression-Severity score of 4 (moderately ill) or greater at screening;
- Any concomitant medication, including anti-epileptic and/or behavioral medications, supplements, and special diets, must be at a stable dose for at least 4 weeks before;
- Has an English-speaking caregiver capable of providing informed consent and able to attend all scheduled study visits, oversee the administration of study drug, and provide feedback regarding the subject's behavior and other symptoms as described in the protocol;
- Provide assent to the protocol (when applicable);
- Has a caregiver who will agree not to post any of the subject's personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook and Twitter) until they have been notified that the study is completed.
- Age-specific blood pressure parameters for inclusion in the study will be based on established guidelines.
Exclusion Criteria:
- Has a concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or any clinically significant finding at screening that could interfere with the conduct of the study or that would pose an unacceptable risk to the subject in this study;
- Has clinically significant lab abnormalities or vital signs at the time of screening (e.g., alanine aminotransferase or aspartate aminotransferase >2.5 × upper limit of normal; total bilirubin or creatinine >1.5 × upper limit of normal). Re-testing of safety labs is allowed;
- Hypertension that is not well controlled (systolic BP >130-140 mm Hg or diastolic BP >85-95 mm Hg depending on age);
- A blood pressure reading over 160/90 or two separate readings over 140/90 at screening or baseline visits;
- Thyroid impairment, as reflected by a TSH > 4.2 mU/L;
- Cardiac disease, as reflected by an EKG that is abnormal and of concern for cardiac disease;
- Has had changes in his/her medication regimen within the previous month;
- Has a history of uncontrollable seizure disorder or seizure episodes within 1 month of screening;
- Has a history of suicidal behavior or considered by the investigator to be at high risk of suicide;
- Has a current or past history of psychotic symptoms;
- Has enrolled in any clinical trial or used of any investigational agent, device, and/or investigational procedure within the 30 days before screening or does so concurrently with this study.
Sites / Locations
- Icahn School of Medicine at Mount Sinai
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ketamine
Arm Description
Total dose administration or 0.5 mg/kg of ketamine
Outcomes
Primary Outcome Measures
Number of Participants With an Adverse Event
Number of Participants with an adverse event as defined by the Systematic Longitudinal Assessment of Adverse Events (SLAES) which is a comprehensive form that assesses medical and behavioral conditions that were present at screening and/or baseline. Conditions are considered treatment emergent if their severity increased significantly after the participant had taken at least one dose of the study treatment. Treatment emergent adverse events will be tracked considered in the adverse event safety analysis. Severity of adverse events are categorized as mild, moderate, severe, life-threatening, or resulting in death and the treating physician indicates if the adverse event was related or unrelated to study drug.
Secondary Outcome Measures
Aberrant Behavior Checklist
Changes in scale at week 1 compared to baseline. Aberrant Behavior Checklist is a behavior rating scale for the assessment of treatment effects. Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). Subscales from 0-45 for Irritability; 0-48 for Social Withdrawal and Hyperactivity; from 0-21 for Stereotypy; and 0-12 for In Speech , with total scale from 0 to 48, with higher score indicating worse health outcomes.
Anxiety, Depression and Mood Scales (ADAMS)
The ADAMS is a parent/caregiver-completed measure and consists of 28 items, grouped into five subscales (Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, Obsessive Behavior), and scored on a four-point Likert scale that combines frequency and severity ratings from 0-3. Subscales range - Hyperactivity 0-15; Depressed 0-21; Social Avoidance 0-21; General anxiety 0-21; OCD 0-9. Scores are not summed. Higher score indicates poorer health outcomes.
Repetitive Behavior Scale-Revised (RBS-R)
Change in repetitive behaviors at weeks 1 compared to baseline. RBS-R subscales - Stereo 0-18; Self injury 0-24; Compulsive 0-24; Ritualistic 0-18; Sameness 0-33; Restricted 0-12. Total scale range from 0 to 126 with higher score indicating worse health outcomes.
Clinical Global Impressions - Improvement Scale (CGI-I)
Changes in scale at weeks 2, and 4 compared to baseline. Clinical Global impressions - Improvement Scale is anchored to symptoms of ADNP syndrome for the assessment of treatment effects. CGI-I total score from 1 to 7 point scale, with higher score indicating worse health outcomes.
Childrens Sleep Habits Questionnaire
Change in sleep habits at week 1 compared to baseline. Full scale from 0 to 110, with higher score indicating worse health outcomes.
Peabody Picture Vocabulary Test and Expressive Vocabulary Test
Expressive and receptive language assessed by Peabody Picture Vocabulary Test and Expressive Vocabulary Test at Day 1, Weeks 1, 2, and 4. Full scale from 40 to 160, with higher score indicating better health outcomes.
Proportion of Target-First Trials Saccades
Change at Day 1 and Week 1 as compared to baseline using computerized eye tracking to record where the subject is looking during an activity in which the subject will see a video of a person with two objects, turning her head towards one of the objects, the target.
Mean proportion of trials in which participants made saccades to the target before the distractor.
Latency to First Saccade
Change at week 1, week 2, and week 4 as compared to baseline using computerized eye tracking to record where the subject is looking during an activity in which the subject will see different social and non-social stimuli.
Latency to first saccade to the target
Proportion of Target-Dwelling
Change at Day 1 and Week 1 as compared to baseline using computerized eye tracking to record where the subject is looking during an activity in which the subject will see different social and non-social stimuli.
Proportion of time participants spent dwelling on the target versus distractor.
Electrophysiology Recording
Electroencephalographic recordings to measure Auditory Event Related Potentials at baseline, week 1, week 2, and week 4.
In separate blocks, participants heard a 500-ms click at either a stimulation rate of 40 or 20 Hz. Click trains were presented 150 times each, with an intertrial interval of 50 ms, at approximately 60 db.
Higher number indicates higher amplitude neural response to auditory stimuli.
Vineland Adaptive Behavior Scales
Changes in scale at week 4 compared to baseline. Vineland Adaptive Behavior Scales measures adaptive functioning. Higher score indicating better health outcomes. Domain scores are standard scores - population mean 100 standard deviation 15.
an overall composite score, it consists of three subscales: (a) communication (receptive, expressive, written), (b) socialization (interpersonal relationships, play and leisure, coping skills), and (c) daily living (person, domestic, community).
Caregiver Strain Questionnaire (CGSQ)
Caregiver Strain Questionnaire (CGSQ) is a 13 question tool, with a 5-point Likert scale ranging from Not at all (0) to Very much (4). Domains (Objective strain, Subjective externalized strain, Subjective internalized strain) are averaged scores, range from 0-4. Total score (Global score) is a sum of the three subdomains. Full scale range 0-12, higher score indicates more severe strain.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04388774
Brief Title
Low-Dose Ketamine in Children With ADNP Syndrome
Official Title
A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose Ketamine in Children With ADNP Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
August 19, 2020 (Actual)
Primary Completion Date
June 8, 2021 (Actual)
Study Completion Date
June 8, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Alexander Kolevzon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a Phase 2A, single dose, open-label study to evaluate the safety, tolerability, and efficacy of a low-dose, 40-minute infusion into the veins (intravenous infusion or "IV") of ketamine in children with ADNP syndrome (Activity-Dependent Neuroprotective Protein). The study team will enroll 10 participants, ages 5 to 12, at Mount Sinai. The study participation is expected to last 4 weeks and will include 5 scheduled clinic visits in order to complete safety monitoring, clinical assessments, and biomarker collection. At the conclusion of this study, the study team expects to demonstrate the safety and tolerability of low-dose ketamine in children with ADNP syndrome. Additionally, the study team anticipates identifying meaningful signals of efficacy in clinical outcome measures using RNA and DNA sequencing to analyze ADNP protein expression and DNA methylation profiles, a natural process by which methyl groups are added to the DNA to change its activity, in order to assess sensitivity to change with low-dose ketamine treatment and inform future phase 3 studies. Ketamine is not currently approved by the Food and Drug Administration to treat this syndrome, but it is approved for use in children in other situations, for example in anesthesia.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ADNP Syndrome
Keywords
Ketamine, ADNP, Activity-Dependent Neuroprotector Protein, Chromosome Disorders, Chromosome Aberrations
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ketamine
Arm Type
Experimental
Arm Description
Total dose administration or 0.5 mg/kg of ketamine
Intervention Type
Drug
Intervention Name(s)
Ketamine
Intervention Description
A single 40-minute intravenous infusion
Primary Outcome Measure Information:
Title
Number of Participants With an Adverse Event
Description
Number of Participants with an adverse event as defined by the Systematic Longitudinal Assessment of Adverse Events (SLAES) which is a comprehensive form that assesses medical and behavioral conditions that were present at screening and/or baseline. Conditions are considered treatment emergent if their severity increased significantly after the participant had taken at least one dose of the study treatment. Treatment emergent adverse events will be tracked considered in the adverse event safety analysis. Severity of adverse events are categorized as mild, moderate, severe, life-threatening, or resulting in death and the treating physician indicates if the adverse event was related or unrelated to study drug.
Time Frame
Week 4
Secondary Outcome Measure Information:
Title
Aberrant Behavior Checklist
Description
Changes in scale at week 1 compared to baseline. Aberrant Behavior Checklist is a behavior rating scale for the assessment of treatment effects. Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). Subscales from 0-45 for Irritability; 0-48 for Social Withdrawal and Hyperactivity; from 0-21 for Stereotypy; and 0-12 for In Speech , with total scale from 0 to 48, with higher score indicating worse health outcomes.
Time Frame
Baseline, Week 1
Title
Anxiety, Depression and Mood Scales (ADAMS)
Description
The ADAMS is a parent/caregiver-completed measure and consists of 28 items, grouped into five subscales (Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, Obsessive Behavior), and scored on a four-point Likert scale that combines frequency and severity ratings from 0-3. Subscales range - Hyperactivity 0-15; Depressed 0-21; Social Avoidance 0-21; General anxiety 0-21; OCD 0-9. Scores are not summed. Higher score indicates poorer health outcomes.
Time Frame
Baseline and Week 1
Title
Repetitive Behavior Scale-Revised (RBS-R)
Description
Change in repetitive behaviors at weeks 1 compared to baseline. RBS-R subscales - Stereo 0-18; Self injury 0-24; Compulsive 0-24; Ritualistic 0-18; Sameness 0-33; Restricted 0-12. Total scale range from 0 to 126 with higher score indicating worse health outcomes.
Time Frame
Baseline, Week 1
Title
Clinical Global Impressions - Improvement Scale (CGI-I)
Description
Changes in scale at weeks 2, and 4 compared to baseline. Clinical Global impressions - Improvement Scale is anchored to symptoms of ADNP syndrome for the assessment of treatment effects. CGI-I total score from 1 to 7 point scale, with higher score indicating worse health outcomes.
Time Frame
Baseline, Week 2, and Week 4
Title
Childrens Sleep Habits Questionnaire
Description
Change in sleep habits at week 1 compared to baseline. Full scale from 0 to 110, with higher score indicating worse health outcomes.
Time Frame
Baseline, Week 1
Title
Peabody Picture Vocabulary Test and Expressive Vocabulary Test
Description
Expressive and receptive language assessed by Peabody Picture Vocabulary Test and Expressive Vocabulary Test at Day 1, Weeks 1, 2, and 4. Full scale from 40 to 160, with higher score indicating better health outcomes.
Time Frame
Baseline, Week 1, Week 2, and Week 4
Title
Proportion of Target-First Trials Saccades
Description
Change at Day 1 and Week 1 as compared to baseline using computerized eye tracking to record where the subject is looking during an activity in which the subject will see a video of a person with two objects, turning her head towards one of the objects, the target.
Mean proportion of trials in which participants made saccades to the target before the distractor.
Time Frame
Baseline, Day 1, Week 1
Title
Latency to First Saccade
Description
Change at week 1, week 2, and week 4 as compared to baseline using computerized eye tracking to record where the subject is looking during an activity in which the subject will see different social and non-social stimuli.
Latency to first saccade to the target
Time Frame
Baseline, Day 1, Week 1
Title
Proportion of Target-Dwelling
Description
Change at Day 1 and Week 1 as compared to baseline using computerized eye tracking to record where the subject is looking during an activity in which the subject will see different social and non-social stimuli.
Proportion of time participants spent dwelling on the target versus distractor.
Time Frame
Baseline, Day 1, Week 1
Title
Electrophysiology Recording
Description
Electroencephalographic recordings to measure Auditory Event Related Potentials at baseline, week 1, week 2, and week 4.
In separate blocks, participants heard a 500-ms click at either a stimulation rate of 40 or 20 Hz. Click trains were presented 150 times each, with an intertrial interval of 50 ms, at approximately 60 db.
Higher number indicates higher amplitude neural response to auditory stimuli.
Time Frame
Baseline, Week 1, Week 2, and Week 4
Title
Vineland Adaptive Behavior Scales
Description
Changes in scale at week 4 compared to baseline. Vineland Adaptive Behavior Scales measures adaptive functioning. Higher score indicating better health outcomes. Domain scores are standard scores - population mean 100 standard deviation 15.
an overall composite score, it consists of three subscales: (a) communication (receptive, expressive, written), (b) socialization (interpersonal relationships, play and leisure, coping skills), and (c) daily living (person, domestic, community).
Time Frame
Baseline and Week 4
Title
Caregiver Strain Questionnaire (CGSQ)
Description
Caregiver Strain Questionnaire (CGSQ) is a 13 question tool, with a 5-point Likert scale ranging from Not at all (0) to Very much (4). Domains (Objective strain, Subjective externalized strain, Subjective internalized strain) are averaged scores, range from 0-4. Total score (Global score) is a sum of the three subdomains. Full scale range 0-12, higher score indicates more severe strain.
Time Frame
Baseline and Week 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
5 to 12 years old (inclusive) at the time of informed consent;
Has a diagnosis of ADNP syndrome, confirmed by genetic testing prior to subject randomization;
Has a Clinical Global Impression-Severity score of 4 (moderately ill) or greater at screening;
Any concomitant medication, including anti-epileptic and/or behavioral medications, supplements, and special diets, must be at a stable dose for at least 4 weeks before;
Has an English-speaking caregiver capable of providing informed consent and able to attend all scheduled study visits, oversee the administration of study drug, and provide feedback regarding the subject's behavior and other symptoms as described in the protocol;
Provide assent to the protocol (when applicable);
Has a caregiver who will agree not to post any of the subject's personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook and Twitter) until they have been notified that the study is completed.
Age-specific blood pressure parameters for inclusion in the study will be based on established guidelines.
Exclusion Criteria:
Has a concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or any clinically significant finding at screening that could interfere with the conduct of the study or that would pose an unacceptable risk to the subject in this study;
Has clinically significant lab abnormalities or vital signs at the time of screening (e.g., alanine aminotransferase or aspartate aminotransferase >2.5 × upper limit of normal; total bilirubin or creatinine >1.5 × upper limit of normal). Re-testing of safety labs is allowed;
Hypertension that is not well controlled (systolic BP >130-140 mm Hg or diastolic BP >85-95 mm Hg depending on age);
A blood pressure reading over 160/90 or two separate readings over 140/90 at screening or baseline visits;
Thyroid impairment, as reflected by a TSH > 4.2 mU/L;
Cardiac disease, as reflected by an EKG that is abnormal and of concern for cardiac disease;
Has had changes in his/her medication regimen within the previous month;
Has a history of uncontrollable seizure disorder or seizure episodes within 1 month of screening;
Has a history of suicidal behavior or considered by the investigator to be at high risk of suicide;
Has a current or past history of psychotic symptoms;
Has enrolled in any clinical trial or used of any investigational agent, device, and/or investigational procedure within the 30 days before screening or does so concurrently with this study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexander Kolevzon, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Principal Investigator
Facility Information:
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Low-Dose Ketamine in Children With ADNP Syndrome
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