Low-Dose Ketamine in Children With ADNP Syndrome

• ClinicalTrials.gov Identifier: NCT04388774
• Recruitment Status: Recruiting
• First Posted: May 14, 2020
• Last Update Posted: September 10, 2020
• Sponsor: Alexander Kolevzon
• Information provided by (Responsible Party): Alexander Kolevzon, Icahn School of Medicine at Mount Sinai

Tracking Information

• First Submitted Date: May 12, 2020
• First Posted Date: May 14, 2020
• Last Update Posted Date: September 10, 2020
• Actual Study Start Date: August 19, 2020
• Estimated Primary Completion Date: August 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 12, 2020)

The Systematic Longitudinal Assessment of Adverse Events (SLAES) [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]

Changes in scale at weeks 1, 2, and 4 compared to baseline. The Systematic Longitudinal Assessment of Adverse Events (SLAES) 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 12, 2020)

• Aberrant Behavior Checklist [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Changes in scale at weeks 1, 2, and 4 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), total scale from 0 to 48, with higher score indicating worse health outcomes.
• Vineland Adaptive Behavior Scales [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Changes in scale at week 4 compared to baseline. Vineland Adaptive Behavior Scales measures adaptive functioning. Full scale from 20 to 140, with higher score indicating better health outcomes.
• Repetitive Behavior Scale-Revised (RBS-R) [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Change in repetitive behaviors at weeks 1, 2, and 4 compared to baseline. RBS-R total scale from 0 to 126 with higher score indicating worse health outcomes.
• Clinical Global Impressions - Improvement Scale (CGI-I) [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Changes in scale at weeks 1, 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 [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Change in sleep habits at weeks 1, 2, and 4 compared to baseline. Full scale from 0 to 110, with higher score indicating worse health outcomes.
• Peabody Picture Vocabulary Test and Expressive Vocabulary Test [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Change in expressive and receptive language at weeks 1, 2, and 4 compared to baseline. Full scale from 40 to 160, with higher score indicating better health outcomes.
• Computerized Eye Tracking [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  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.
• Electrophysiology Recording [ Time Frame: Baseline, Week 1, Week 2, and Week 4 ]
  Change at week 1, week 2, and week 4 as compared to baseline using electroencephalographic recordings to measure Visual Evoked and Auditory Event Related Potentials

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: ADNP Syndrome

Intervention

Drug: Ketamine

A single 40-minute intravenous infusion

Study Arms

Experimental: Ketamine

Total dose administration or 0.5 mg/kg of ketamine

Intervention: Drug: Ketamine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 12, 2020): 10
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 2022
• Estimated Primary Completion Date: August 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 12 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Hannah Walker; 212-241-3692; hannah.walker@mssm.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04388774
• Other Study ID Numbers: GCO 20-1253
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Alexander Kolevzon, Icahn School of Medicine at Mount Sinai
• Study Sponsor: Alexander Kolevzon
• Collaborators: Not Provided

Investigators

• Principal Investigator: Alexander Kolevzon, MD; Icahn School of Medicine at Mount Sinai

• PRS Account: Icahn School of Medicine at Mount Sinai
• Verification Date: September 2020