Low-Dose Ketamine in Children With ADNP Syndrome

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose Ketamine in Children With ADNP Syndrome

Conditions
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ADNP Syndrome

Intervention / Treatment
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* Drug: Ketamine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>Total dose administration or 0.5 mg/kg of ketamine | Drug: Ketamine<br>* A single 40-minute intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Week 1 | 
| 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. | Baseline and Week 1 | 
| 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. | Baseline, Week 1 | 
| 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. | Baseline, Week 2, and Week 4 | 
| 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. | Baseline, Week 1 | 
| 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. | Baseline, Week 1, Week 2, and Week 4 | 
| 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. | Baseline, Day 1, Week 1 | 
| 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 | Baseline, Day 1, Week 1 | 
| 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. | Baseline, Day 1, Week 1 | 
| 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. | Baseline, Week 1, Week 2, and Week 4 | 
| 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). | Baseline and Week 4 | 
| 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. | Baseline and Week 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Activity-Dependent Neuroprotector Protein, Chromosome Disorders, Chromosome Aberrations, Ketamine, ADNP