A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose Ketamine in Children With ADNP Syndrome
Phase: PHASE1
Conditions: ADNP Syndrome
Sponsor: Alexander Kolevzon

A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-
Dose Ketamine in Children with ADNP Syndrome
PI: Alex Kolevzon, MD
NCT04388774
Document Date: 8-23-2021

1 
 
A Phase 2A Open-Label Study Evaluating the Safety and Efficacy of Low-Dose 
Ketamine in Children with ADNP Syndrome 
 
 
 
 
 
 
 
 
 
 
 
Seaver Autism Center for Research and Treatment at Mount Sinai 
Principal Investigator: Alex Kolevzon, MD 
One Gustave L. Levy Place, Box 1230 
New York, NY 10029 
Tel: 212-659-9134 
Email: alexander.kolevzon@mssm.edu 
 
 
 
 
 
Members of the DSMB  
James Murrough, MD 
 Robert Jaffe, MD 
Ethan Bryson, MD 
 
 
 
[DATE OF MEETING] 
 
[TIME], EST 
 

 
The goal of the proposed research is to conduct a Phase 2A, single dose, open-label study to evaluate 
the safety and tolerability of low-dose ketamine in children with ADNP syndrome. Ketamine is 
commercially available and FDA approved as an anesthetic for children in the proposed age range.  At 
the conclusion of this study, we expect to demonstrate the safety and tolerability of low-dose ketamine 
in children with ADNP syndrome and anticipate identifying meaningful signals of efficacy in clinical 
outcome measures to inform future phase 3 studies.  
 
Research design. The proposed study utilizes a single-dose (0.5 mg/kg), open-label design to 
investigate the safety, tolerability, and efficacy of treatment with low-dose ketamine in children with 
ADNP syndrome, ages 5 to 12. The study will comprise a: (1) Screening period which will take place 
within the 4 weeks preceding a Baseline visit; (2) Baseline visit on day 0 for baseline assessments 
and administration of study drug; (3) Clinic visits for safety and efficacy assessments at weeks Day 1, 
week 1, 2, and 4.  
 
 
Inclusion criteria: The proposed study will recruit 10 children between 5 and 12 years-old with 
ADNP syndrome, many of whom will have already been previously evaluated as part of ongoing 
studies at the Seaver Center. All subjects will have a Clinical Global Impression-Severity score of 4 
(moderately ill) or greater at screening (see Outcome Measures section). Subjects will also be on 
stable medication, including anti-epileptic and/or behavioral medications, supplements, and special 
diets, must be at a stable dose for at least 4 weeks prior to enrollment. Participants must also meet 
age-specific blood pressure criteria based on recommended guidelines.  
 
Exclusion criteria: Cases will be excluded if any of the following are applicable: 1) 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, 2) 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, 3) Hypertension that is not well controlled (systolic BP 
>130-140 mm Hg or diastolic BP >85-95 mm Hg depending on age), 4) have caretakers who are unable 
to speak English, be consistently present at visits to report on symptoms, or are otherwise judged unable 
to comply with the protocol by the study team; 5) A blood pressure reading over 160/90 or two separate 
readings over 140/90 at screening or baseline visits, 6) Thyroid impairment, as reflected by a TSH > 
4.2 mU/L, 7) Cardiac disease, as reflected by an EKG that is abnormal and of concern for cardiac 
disease, 8) Has had changes in his/her medication regimen within the previous month, 9) Has a history 
of uncontrollable seizure disorder or seizure episodes within 1 month of screening, 10) Has a history 
of suicidal behavior or considered by the investigator to be at high risk of suicide, 11) Has a current or 
past history of psychotic symptoms, 11) 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. 
 
Drug Administration: The proposed dose is a single daytime infusion. Dosing is based on data derived 
from previous pre-clinical and clinical studies in children and adults and will follow a pre-fixed dosing 
paradigm according to patients’ weight. Intravenous dosage will be 0.5 mg/kg over 40 minutes. The 
pharmacist will prepare the IV medication (ketamine) in a normal saline (NS) bag, and a nurse from 
the General Clinical Research Center (GCRC) at Mount Sinai or the Clinical Research Coordinator 
comes to retrieve it the morning of infusion, such that a fixed dose is administered. Each participant 
will receive an infusion of 0.5 mg/kg of racemic ketamine hydrochloride, which is dissolved in 0.9% 
saline in a total volume of 50 mL and administered with an infusion pump (Baxter, Deerfield, Ill) at a 
constant rate over 40 minutes. The ketamine will be stored and dispensed by Ivy Cohen and the research 
pharmacy at Mount Sinai.  

 
 
Active monitoring throughout the infusion and for one hour thereafter will ensure safety and 
tolerability. Tolerability will then be assessed by the research physician throughout the study. Vital 
signs and EKG will be monitored continuously during the infusion with a non-invasive blood pressure 
reading taken every 5 minutes and with continuous EKG and pulse oximetry. Following the infusion, 
the patient will have continuous EKG and pulse oximetry with blood pressure cycled every 15 minutes 
for at least one hour once it is within 20% of baseline. The patient will continue to be monitored 
clinically for one hour post-infusion. In addition to the pediatric anesthesiologist, clinical monitoring 
will also be done by the principal investigator (PI) who is a board certified child and adolescent 
psychiatrist with expertise in ADNP syndrome. The PI will be present throughout the entire infusion 
and for one hour thereafter in order to closely monitor and assess emergency phenomena (e.g., 
agitation, hallucinations, dissociation, bizarre behavior). Because individuals with ADNP syndrome 
are intellectually disabled and mainly nonverbal, close clinical observation is the best method to 
monitor these types of emergency phenomena. Should any agitation or bizarre behavior occur during 
the infusion, the infusion will be discontinued. Should these phenomena occur after the infusion, they 
will be recorded on the side effects log (i.e., SLAES).  To meet criteria for discharge, patients will be 
fully awake and alert with mental status returning to pre-infusion baseline and have at least two 
consecutive vital signs that are within 20% of baseline. 
 
Adverse Events (AEs): All subjects will be evaluated for study drug safety and tolerability using 
physical examination, laboratory assessments, and the Systematic Longitudinal Adverse Events Scale 
(SLAES). All patients will have a physical examination and specific laboratory tests as including: 
physical exam, electrocardiogram (ECG), vital signs, complete blood cell counts, electrolytes, thyroid 
functioning test, liver function tests, and urinalysis.  A urine pregnancy test will be performed in post-
pubertal girls. Results of these tests will identify patients who should be excluded because of active 
medical problems that might make study participation unsafe.  
 
An AE will be defined as any untoward medical occurrence in a study subject, temporally associated 
with the use of the experimental medication, whether or not considered related to the medication. An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study 
drug. A serious adverse event (SAE) will be defined as an AE that meets any of the following criteria: 
 is life threatening;  
 requires inpatient hospitalization;  
 results in a persistent or significant disability/incapacity;  
 any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the outcomes listed above 
 
Monitoring for AEs will be conducted during scheduled and unscheduled visits, if clinical concerns 
arise.  Safety and tolerability aspects of the data will be tabulated.  Assessments will include the 
frequency and severity of treatment-emergent adverse events (TEAEs) and SAEs, medication diary, 
concomitant psychosocial and medication treatment log, clinical evaluations including a physical exam 
and vital sign measurements, height and weight.  All safety and laboratory assessments will be 
completed at Screening and all Clinic Visits.   
 
The goals of this DSMB meeting are to review the research protocol and safety data to date. The 
session will include review of administrative reports that describe participants screened, enrolled, and 
completed, as well as baseline characteristics of the study population. All of the 10 screened 
participants have been enrolled and administered the study drug; no participants have withdrawn 
from the study to date. The study is closed to enrollment as recruitment goals were met. All study 
visits and data collection has been completed. The study remains open for data analysis.