Clinical trial NCT03633058
Conditions: Rett Syndrome
Keywords: MECP2 RTT Retts ketamine
Sponsor: Rett Syndrome Research Trust
Start date: 2019-03-12; Completion date: 2021-11-22
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This 2 cohort, sequential, ascending dose study will assess the safety, tolerability and efficacy of oral ketamine dosed in a single 5-day BID regimen in addition to placebo, in a 4-week cross-over design in patients with Rett Syndrome. Approximately 12 patients per cohort are anticipated to participate for approximately 8-10 weeks at approximately 7 US study centers.

Detailed description:
This study is designed to assess oral ketamine for the treatment of Rett Syndrome and consists of up to 4 ascending dose cohorts, each assessing 1 dose level of ketamine vs placebo. Patients will receive in either order, a 5-day BID regimen of both placebo and the cohort-specified dose level of oral ketamine. Patients may only participate in 1 cohort. Safety and tolerability will be assessed via patient disposition, vital signs, physical examination, adverse events and concomitant medication use. Efficacy will be assessed via physician and caregiver questionnaires and assessments, and continuous, wearable, at-home biosensor data collection. An independent safety committee will review safety data from each cohort to determine if the subsequent ascending dose cohort is warranted. A total of 12 patients per cohort is anticipated at approximately 7 sites. The screening period will last between 2 and 4 weeks, the cross-over treatment period will last 4 weeks, and the safety follow-up period will last 2 weeks. Total patient participation is approximately 8-10 weeks.

Arms: arm 1: ketamine will be dosed orally twice daily for 5 days at 0.75 mg/kg, in addition to 5 days of placebo arm 2: ketamine will be dosed orally twice daily for 5 days at 0.75 mg/kg, in addition to 5 days of placebo
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: oral ketamine dosed twice daily for 5 days

Protocol documents:
Prot_SAP_000.pdf: 
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A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSS-OVER STUDY TO 
ASSESS THE SAFETY, TOLERABILITY, AND EFFICACY OF ORAL KETAMINE IN 
PATIENTS WITH RETT SYNDROME 
 
INVESTIGATIONAL PRODUCT: 
 
Ketamine 
PROTOCOL NUMBER: 
 
Ket-101-RSRT 
IND NUMBER: 
NCT NUMBER: 
 
AMENDMENT 2: 
 
 
 
140628 
NCT03633058 
 
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SPONSOR-INVESTIGATOR: 
 
 
COLLABORATOR NAME / ADDRESS: 
 
Jeffrey L. Neul, MD, PhD 
Vanderbilt University Kennedy Center 
 
Rett Syndrome Research Trust 
67 Under Cliff Rd,  
Trumbull, CT 06611 
 
 


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1. 
SYNOPSIS 
Sponsor - 
Investigator 
Jeffrey L. Neul, MD, PhD 
Title of Study: 
A double-blind, randomized, placebo-controlled, cross-over study to assess 
the safety, tolerability, and efficacy of oral ketamine in patients with Rett 
Syndrome 
Study Phase: 
IIa 
Name of 
Investigational 
Drug; Route: 
Ketamine; oral dosing 
Study Centers: 
multicenter study; approximately 7 sites 
Study Duration: 
Estimated first patient enrolled: October 2018 
Estimated last patient completed: August 2021 
Study Design: 
Double-blind, randomized, placebo-controlled, cross-over study  
Patient Population:  Female patients with Rett Syndrome aged 6 – 12 years, inclusive, who 
have not achieved menarche  
Total Sample Size:  Approximately 48 patients are planned to be enrolled. For each of the 4 
cohorts, approximately 12 patients will be enrolled. 
Objectives: 
To explore the safety, tolerability and efficacy of a 5-day regimen of 
ketamine administered to individuals with Rett syndrome. 
The primary objective is: 
• 
To assess the safety and tolerability of administration of oral 
ketamine  
The exploratory objectives are: 
• 
To assess the effect of oral ketamine on treating symptoms of Rett 
syndrome as measured by the change from baseline in: 
o Continuous biosensor data (activity, movement, heart rate, 
gait, sleep, posture, breathing regularity)  
o Rett syndrome severity as measured by the clinician Motor 
Behavioral Assessment (MBA) 
o Rett syndrome severity as measured by the parent Rett 
Syndrome Behavior Questionnaire (RSBQ) 
o Rett syndrome severity and improvement as measured by 
the clinician Clinical Global Impression Severity (CGI-S) and 
Improvement (CGI-I) Scales 
o Symptom severity as measured by the clinician Domain 
Likert Scale  
o Symptom severity as measured by the parent Domain Likert 
Scale 
o Sleep as measured by the parent Child Sleep Habits 
Questionnaire (CHSQ) 
o Rett Caregiver Inventory Assessment (RTT CIA) 


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o EEG signature compared to placebo 
Methodology: 
Overview 
This is a double-blind, randomized, placebo-controlled, multi-center, cross-
over study to evaluate the safety, tolerability and efficacy of oral ketamine 
in patients 6 – 12 years of age, inclusive, who have not achieved 
menarche, diagnosed with Rett Syndrome with a confirmed MECP2 
mutation.  
The study consists of up to 4 cohorts initiated sequentially in ascending 
dose order (0.75 mg/kg BID, 1.5 mg/kg BID, 3 mg/kg BID, and 4.5 mg/kg 
BID). Each cohort will assess 1 dose of ketamine compared to placebo. 
After each cohort, an independent safety monitoring committee will 
determine if there are adequate safety data to support initiation of the 
subsequent dosing cohort. Patients may only participate in one cohort. 
A cohort within the study is divided into 3 periods: Screening, Cross-over 
Treatment, and Safety Follow-up. The Screening Period may last between 
14 and 28 days prior to the initiation of study drug. The Cross-over 
Treatment period is a 4-week, double-blind, placebo-controlled, cross-over 
period to define safety and explore efficacy for the study. The Safety 
Follow-up Period is the final 2 weeks of the study to assess safety following 
Treatment Period completion.  
Study Design Figure  
 
 
 
 
 
 


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Screening and Baseline 
Parents, legally authorized representatives (LARs), or authorized 
caregivers will provide appropriately obtained informed consent, and where 
appropriate, patients will provide assent, prior to the completion of any 
screening procedures.  
At the Screening visit, patients will be assessed for initial eligibility and will 
take home biosensors for collection of daily in-home data prior to the Day 1 
Randomization Visit. Eligible patients will return for the Randomization Visit 
on Day 1 for review of eligibility and additional baseline safety and efficacy 
assessments including a baseline EEG at select centers, physical 
examination, vital signs, ECG, as well as physician CGI-S, RSBQ, MBA, 
and an exploratory Clinician Rated Domain Likert Scale consisting of 8 
domains (hand function, walking, verbal and non-verbal communication, 
comprehension, attention, behavior problems, mood). Caregiver rated 
scales including the CSHQ, RTT CIA, and an exploratory Parent Rated 
Domain Likert Scale of the same 8 clinician domains with the addition of a 
seizures domain, will also be completed.   
Cross-Over Treatment Period 
For each cohort, the double-blind, placebo-controlled, cross-over 
Treatment Period will last a total of 4 weeks starting with the first treatment 
on Day 1 and initiation of the alternate treatment 2 weeks later on Day 15.  
Each ordered cross-over dosing regimen comprises 5 days of BID dosing 
(treatment 1: Day 1-5, treatment 2: Day 15-19) and patient safety and 
efficacy evaluation for 14 days after dose initiation (Period 1: Day 15, 
Period 2: Day 29).  
After dosing completion and conclusion of the 4-week Treatment Period, 
patients will return on Day 29 for final efficacy assessments, safety 
assessments, and turn in the biosensors.  
Safety Follow-up 
A final Safety Follow-up phone call will occur on Day 43, 2 weeks after the 
Day 29 Visit and conclusion of the Treatment Period. 
In-Clinic Assessments 
At the clinic visits, safety and efficacy assessments will be performed by 
the clinician and the caregiver. Physical examination, EEG at select sites, 
vital signs, physician CGI-S or CGI-I, RSBQ, MBA, Clinician Rated Domain 
Likert Scale, CSHQ, RTT CIA, and Parent Rated Domain Likert Scale will 
be completed.  
Dosing 
Patients will receive the first oral dose of each 5-day dosing regimen in-
clinic under observation. Tolerability of the in-clinic oral dose will be 
evaluated for two hours through assessment of vital signs and oxygen 
saturation at 15-minute intervals for the first hour, as well as monitoring of 
patient disposition. If well tolerated, subsequent doses will be administered 
in the home.  The site will contact the caregiver each day of active dosing 
to confirm continued tolerability and to assess for emergent side effects.  


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The patient and the clinical team will be blinded to treatment group 
assignments throughout the study. The pharmacist will be unblinded to 
ensure appropriate treatment assignment. 
At-home Assessments 
Over the following 2-week period after each of the observed in-clinic doses, 
caregivers will continuously capture biosensor data to assess patient 
activity, movement, heart rate, gait, sleep, posture, and breathing 
regularity. On Days 8 and 22, caregivers will report a Parent Domain 
Report Likert Scale and complete the CSHQ. The Parent Domain Likert 
Scale and the RTT CIA will also be completed on Day 43. 
Safety Monitoring 
Patient safety will be monitored throughout the study. Investigators will 
monitor safety and tolerability through a 2-hour observation and monitoring 
of in-clinic dosing of the first dose of each treatment, and through daily 
communication with the caregiver on at-home dosing days. In addition, 
study Investigators will form a medical monitoring committee and convene 
on a regular basis to discuss adverse events (AEs) and overall 
interpretation of tolerability. 
An independent safety monitoring committee will perform a safety 
assessment of each cohort with a subsequent ascending dose to assess if 
initiation of the subsequent cohort is supported.  
In the case of intolerability during the 5-day dosing period the patient will 
stop dosing at the assigned blinded dose and discontinue the study, and 
any adverse events will be followed until an acceptable clinical resolution is 
achieved.  Patients who discontinue study drug due to an AE during the 
Treatment Period will return for the Day 29/Early Termination Visit 2 to 4 
weeks after the last dose and receive a final Safety Follow-up phone call.   
Duration of Study 
Participation: 
Patients who complete the study will participate for approximately 8 to 10 
weeks including Screening (2-4 weeks), Treatment (4 weeks), and Safety 
Follow-up (2 weeks).  
Duration of 
Treatment 
Patients will receive one 5-day treatment with ketamine 
Reference 
Therapy, dosage 
and mode of 
administration 
Matched placebo consisting of sterile water and masking flavor 
Diagnosis and 
main criteria for 
inclusion 
 
Patients eligible for enrollment must meet all of following inclusion criteria 
and none of the exclusion criteria. 
Inclusion 
1. Prior to the conduct of any study-specific procedures, the patient must 
provide verbal assent to participate in the study (if developmentally 
appropriate), and the parent/caregiver/LAR must provide written 
informed consent.  If the caregiver attending the clinic visits is not the 
parent or LAR, written consent must be obtained from the parent or 
LAR for the caregiver’s participation in the study.  


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2. Female patients 6 to 12 years of age, inclusive, at the time of consent, 
who have not achieved menarche.  
3. Diagnosis of typical or atypical Rett Syndrome according to the revised 
Clinical Diagnostic Criteria5 and presence of a disease causing MECP2 
genetic mutation 
4. Ability to take oral liquid medications orally or through a feeding tube. 
5. The patient’s parent/caregiver/LAR must be able to understand the 
nature of the study and to allow for the completion of all study 
assessments. The same parent/caregiver/LAR must be capable of 
providing reliable information about the patient’s condition, agree to 
oversee the administration of study drug, and accompany the patient to 
all clinic visits. 
Exclusion 
1. Uncontrolled epilepsy, defined as caregiver report of unusual variability 
in seizure frequency that may warrant regimen change during the study 
to either untreated patients or patients on stable anti-seizure medication 
regimens. 
2. Plans to initiate or change pharmacologic interventions during the 
course of the study or have not been on stable interventions for at least 
4 weeks prior to Screening, or stable anti-seizure medication regimens 
(if applicable) for 12 weeks prior to the Randomization Visit. 
3. Plans to initiate or change non-pharmacologic interventions (behavioral, 
educational or dietary) during the course of the study or have not been 
on stable interventions for at least 4 weeks prior to Screening. Typical 
school vacations are not considered modifications of stable 
interventions. 
4. Patients who achieve menarche during study participation and prior to 
conclusion of the second dosing period of the cohort. 
5. A history of prolonged QT syndrome or a Screening QTc interval with 
Fridericia’s correction (QTcF) >460 for females less than 15 years or 
>470 for females over 15 years. 
6. Have taken another investigational drug within the greater of 4 weeks of 
5 half-lives prior to Screening or during the study.  
7. Concurrent treatment with other NMDA receptor antagonists, 
treatments with known ketamine interactions, sedatives, barbiturates, 
benzodiazepines, narcotics, or opioids. 
8. Concurrent treatment with strong CYP3A4 or CYP2B6 inhibitors dosed 
for systemic exposure, or for 4 weeks prior to initiating study drug. 
9. Concurrent treatment with strong CYP3A4 or CYP2B6 inducers dosed 
for systemic exposure, or for 4 weeks prior to initiating study drug. 
10. A history of hypersensitivity to ketamine. 
11. A history of any condition that may be worsened by increased blood 
pressure or heart rate, bronchodilation, intraocular or intracranial 
pressure, or a history of porphyria. 


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12. Patients with any condition that, in the opinion of the principal 
investigator, might interfere with the conduct of the study, confound 
interpretation of the study results, endanger their own well-being, or 
who may otherwise not be suitable for the study.  
Primary Outcome 
Measure: 
• 
Safety and Tolerability 
Safety Outcome 
Measures: 
• 
Adverse Events 
• 
Concomitant medications 
• 
Physical examination 
• 
Vital signs and oxygen saturation 
Exploratory 
Efficacy Outcome 
Measures 
• 
Biosensor data (activity, movement, heart rate, gait, sleep, breathing 
regularity and posture) 
• 
CGI-S and CGI-I  
• 
MBA 
• 
RSBQ 
• 
Clinician Rated Domain Likert Scale 
• 
Parent Rated Domain Likert Scale 
• 
CSHQ 
• 
RTT CIA 
• 
EEG 


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Statistical 
Methodology: 
Sample Size 
Sample size determinations for this study are based on the primary 
outcome of safety and tolerability. For a dose-limiting adverse event with a 
10% incidence rate, a sample size of 10 patients/dose level (10 
patients/cohort) provides a 65% probability of observing at least 1 event at 
each dose level, and an 88% probability of observing at least 1 event by 
completion of Cohort 2.  
For measures of efficacy, there are no studies in the literature to provide 
reliable estimates of treatment effects of ketamine or the estimate of 
variance in symptom management for Rett Syndrome patients. Each dose 
level provides 80% power to detect a 1.00 standard deviation treatment 
difference with the 2-sided paired t-test with 0.05 Type I error. Assuming a 
discontinuation rate between 15 and 20%, approximately 12 patients will be 
enrolled in each cohort to provide 10 patients who complete the treatment 
period. 
The Safety Population will comprise all patients who take at least one dose 
of study medication.  Safety data will be tabulated and summarized by 
treatment. Adverse events will be coded by MedDRA and concomitant 
medications will be summarized by WHODrug by ATCC classification and 
preferred term. By patient listings will be provided for serious adverse 
events, AEs leading to discontinuation, and deaths.  
Data collected in this study will be documented using summary tables, 
figures, and patient data listings. Data will be summarized by treatment and 
cross-over period. Continuous measures will be summarized descriptively 
(mean, standard deviation, median, minimum and maximum value) and 
categorical measures will be presented as number and percentage. 
 
 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ..................................................................................................................2 
 
TABLE OF CONTENTS ............................................................................................9 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................15 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Overview of Rett Syndrome ...................................................................................17 
2.2. 
Scientific Rationale for the Study ..........................................................................17 
2.3. 
Preclinical Information for Ketamine .....................................................................19 
2.4. 
Clinical Information ..................................................................................................19 
2.4.1. 
Clinical Safety of IV Ketamine in Anesthesia.......................................................20 
2.4.1.1. 
Adverse Events with IV Ketamine in Anesthesia ................................................20 
2.4.1.2. 
Emergence Reactions with IV Ketamine in Anesthesia .....................................20 
2.4.2. 
Clinical Studies of Ketamine in Adults with Neuropsychiatric 
Conditions .................................................................................................................21 
2.4.3. 
Clinical Studies of Ketamine Dosed Orally in Adults ..........................................22 
2.4.4. 
Clinical Studies of Ketamine Dosed Orally in Children ......................................23 
2.4.5. 
Clinical Studies of Ketamine Dosed Orally in Children with Rett 
Syndrome ..................................................................................................................23 
3. 
ETHICS ......................................................................................................................25 
3.1. 
Institutional Review Board ......................................................................................25 
3.2. 
Written Informed Consent .......................................................................................25 
4. 
STUDY OBJECTIVES .............................................................................................26 
4.1. 
Primary Objectives ...................................................................................................26 
4.2. 
Exploratory Objectives ............................................................................................26 
5. 
OVERALL STUDY DESIGN ...................................................................................27 
5.1. 
Study Design.............................................................................................................27 
5.1.1. 
Screening and Baseline ..........................................................................................28 
5.1.2. 
Treatment Period and Safety Follow-Up Period .................................................28 
5.1.3. 
In-Clinic Assessments .............................................................................................29 
5.1.4. 
Dosing ........................................................................................................................29 
5.1.5. 
At-home Assessments ............................................................................................29 
5.1.6. 
Safety Monitoring .....................................................................................................29 
5.2. 
Number of Patients and Sites ................................................................................30 
5.3. 
Method of Treatment Assignment and Blinding ..................................................30 


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5.4. 
Rationale for Study Design .....................................................................................30 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ............................................31 
6.1. 
Patient Inclusion Criteria .........................................................................................31 
6.2. 
Patient Exclusion Criteria ........................................................................................31 
6.3. 
Patient Withdrawal Criteria .....................................................................................32 
6.3.1. 
Withdrawal Safety Criteria ......................................................................................32 
6.3.2. 
Patient Withdrawal Procedures .............................................................................32 
6.4. 
Criteria for Study Termination ................................................................................33 
7. 
DESCRIPTION OF STUDY TREATMENTS .......................................................34 
7.1. 
Description of Treatments.......................................................................................34 
7.2. 
Treatment Compliance ............................................................................................34 
7.3. 
Study Drug Treatment Descriptions and Management ......................................34 
7.3.1. 
Physical Description of Treatments ......................................................................34 
7.3.2. 
Treatment Supplies, Labeling, and Storage ........................................................35 
7.3.3. 
Study Drug Preparation...........................................................................................35 
7.3.4. 
Study Drug Administration ......................................................................................35 
7.3.5. 
Study Drug Return and Disposal ...........................................................................36 
7.3.6. 
Study Drug Accountability.......................................................................................36 
7.4. 
Concomitant Medications and Procedures ..........................................................36 
8. 
STUDY ASSESSMENTS AND PROCEDURES .................................................37 
8.1. 
Demographic Characteristics and Medical History .............................................37 
8.2. 
Actigraph ...................................................................................................................37 
8.3. 
Hexoskin Smart Garment .......................................................................................37 
8.4. 
Clinical Global Impression Scales .........................................................................37 
8.5. 
Rett Syndrome Behaviour Questionnaire ............................................................37 
8.6. 
Motor Behavioral Assessment ...............................................................................38 
8.7. 
Parent and Clinician Rated Domain Likert Scales ..............................................38 
8.8. 
Children’s Sleep Habits Questionnaire .................................................................38 
8.9. 
Rett Caregiver Burden Inventory Assessment ....................................................38 
8.10. 
Physical Examination ..............................................................................................38 
8.11. 
Vital Signs, Weight, and Height .............................................................................38 
8.12. 
Electrocardiogram ....................................................................................................39 
8.13. 
Electroencephalogram ............................................................................................39 
9. 
ADVERSE EVENTS ................................................................................................40 


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9.1.1. 
Definition of Adverse Event ....................................................................................40 
9.1.2. 
Evaluation of Adverse Events ................................................................................40 
9.1.2.1. 
Serious Adverse Event ............................................................................................40 
9.1.2.2. 
Severity/Intensity ......................................................................................................41 
9.1.2.3. 
Relationship to Study Drug .....................................................................................41 
9.1.2.4. 
Duration .....................................................................................................................41 
9.1.2.5. 
Action Taken .............................................................................................................41 
9.1.2.6. 
Outcome ....................................................................................................................42 
9.1.3. 
Follow-Up ..................................................................................................................42 
9.1.4. 
Recording Adverse Events .....................................................................................42 
9.1.5. 
Reporting Adverse Events ......................................................................................42 
9.1.5.1. 
Reporting Serious Adverse Events .......................................................................42 
9.1.5.2. 
Reporting Urgent Safety Issues .............................................................................42 
10. 
STATISTICAL METHODS ......................................................................................43 
10.1. 
Sample Size Rationale ............................................................................................43 
10.2. 
Endpoints...................................................................................................................43 
10.2.1. 
Safety .........................................................................................................................43 
10.2.2. 
Efficacy ......................................................................................................................43 
10.3. 
Analysis Populations ...............................................................................................43 
10.3.1. 
Treatment Period .....................................................................................................43 
10.4. 
Analyses ....................................................................................................................43 
10.4.1. 
Disposition and Baseline Characteristics .............................................................44 
10.4.2. 
Efficacy ......................................................................................................................44 
10.4.3. 
Study Drug Exposure ..............................................................................................44 
10.4.4. 
Safety .........................................................................................................................44 
11. 
REGULATORY CONSIDERATIONS ....................................................................46 
11.1. 
Good Clinical Practice .............................................................................................46 
11.2. 
Protocol Amendments .............................................................................................46 
11.3. 
Audits and Inspections ............................................................................................46 
12. 
DATA HANDLING AND RECORDKEEPING ......................................................47 
12.1. 
Confidentiality ...........................................................................................................47 
12.2. 
Patient Data Protection ...........................................................................................47 
12.3. 
Data Collection .........................................................................................................47 
12.4. 
Case Report Form Completion ..............................................................................47 


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12.5. 
Database Management, Data Clarification, and Quality Assurance ................47 
12.6. 
Inspection of Records ..............................................................................................47 
12.7. 
Retention of Records ...............................................................................................47 
13. 
PUBLICATION POLICY ..........................................................................................49 
14. 
LIST OF REFERENCES .........................................................................................50 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ......................................................................15 
Table 2:  Ketamine Bioavailability by Route of Administration ..........................................18 
Table 3: 
Treatments ................................................................................................................35 
 


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LIST OF FIGURES 
Figure 1: Ketamine reduces apneic breathing in Mecp2-/- mice .................................. 19 
Figure 2: Study Design ................................................................................................ 29 
 
  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1: Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Definition 
AE 
Adverse Event 
ATCC 
Anatomical-Therapeutic-Chemical classification 
BDNF 
Brain-derived Neurotrophic Factor 
BID 
Twice daily dosing 
BPM 
Beats per minute 
CFR 
Code of Federal Regulations 
CRO 
Contract Research Organization 
CSHQ 
Children’s Sleep Habits Questionnaire 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CTCAE 
Common terminology criteria for adverse events 
CYP2B6 
Cytochrome P450 2B6 
CYP3A4 
Cytochrome P450 3A4 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LAR 
Legally authorized representative 
LLN 
Lower limit of normal 
MDD 
Major depressive disorder 
MBA 
Motor Behavior Assessment 
MeCP2 / MECP2 
Methyl-CpG-binding protein 2 
MedDRA 
Medical Dictionary for Regulatory Activities 
mTOR 
Mammalian Target of Rapamycin 
NMDA 
N-methyl-D-aspartate  
OCD 
Obsessive compulsive disorder 
QT 
QT interval 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate (Fridericia’s method) 
RSBQ 
Rett Syndrome Behavior Questionnaire 
RSRT 
Rett Syndrome Research Trust 
RTT 
Rett Syndrome 
RTT CIA 
Rett Caregiver Burden Inventory Assessment 


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Abbreviation or Specialist Term 
Definition 
SOP 
Standard Operating Practices 
TEAE 
Treatment-emergent adverse events 
TID 
Three times daily dosing 
TPN 
Total parenteral nutrition 
TRD 
Treatment-refractory depression 
ULN 
Upper limit of normal 
WHODrug 
World Health Organization Drug dictionary 


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2. 
INTRODUCTION 
2.1. 
Overview of Rett Syndrome 
Rett Syndrome is a severe and complex neurodevelopmental disorder resulting primarily from 
loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). As a 
transcriptional regulatory protein, loss of MeCP2 results in dysregulation of more than 100 
genes causing defects in synapse formation and neurotransmission. MECP2 is encoded on the 
X chromosome and as an X-linked dominant disorder, mutations are typically inherited from a 
random spontaneous mutation in sperm thereby affecting females at an incidence of 
approximately 1 in 10,000 live female births.  
A heterozygous mutation in MECP2 disrupts MeCP2-dependent functions in half of the patient’s 
cells due to X inactivation and the resulting expression of either the normal or mutant MECP2 
gene. The phenotype of the disorder can be further complicated by skewed X inactivation that 
may contribute to more mild or more severe phenotypes depending on the direction and 
percentage of skewed expression6,7. 
After a period of apparently normal development through 6 to 18 months of age, Rett patients 
develop a spectrum of symptoms that generally includes loss of acquired speech and 
purposeful hand movements, head growth deceleration, motor, respiratory and autonomic 
dysfunction, stereotypic hand movements and increased risk of seizures 8,9. Additional 
symptoms include gastrointestinal distress, sleep dysfunction, scoliosis, and orthopedic issues, 
and full-time care is required. Currently, no cure for Rett Syndrome exists and individual 
symptom management as well as physical and occupational therapies are the standard of care. 
2.2. 
Scientific Rationale for the Study 
In Rett Syndrome patients, cognitive and behavioral abnormalities are consistent with forebrain 
hypofunction seen in animal models coupled with brainstem hyperexcitability causing 
paroxysmal respiratory and autonomic events. NMDA receptor antagonists with the ability to 
differentially affect the excitatory/inhibitory imbalance across the brain due to regional 
differences in glutamatergic circuitry may provide a potential therapeutic intervention. The non-
selective NMDA receptor antagonist ketamine (2-O-chlorophenyl-2-methylamino 
cyclohexanone) has previously been shown to increase cortical network function10 and 
decrease synaptic excitability in brainstem networks important for respiratory and autonomic 
control11.  
The therapeutic potential of ketamine for treatment of Rett syndrome is supported by several 
studies in mice. Treatment of Mecp2 mutant mice with a sub-anesthetic dose of ketamine at 
8mg/kg demonstrates acute effects on circuit function and reverses several mutant phenotypes 
including hypoactivity in forebrain circuits, abnormal sensorimotor gating12, as well as apneic 
breathing (Figure 1).  
Sub-anesthetic ketamine has demonstrated effects against chronic and neuropathic pain, 
anxiety, depression and treatment-resistant depression syndromes, bipolar disorder, and has 
shown positive effects on cognition in children, as described later. Ketamine rapidly stimulates 
dendritic growth and translation and expression of key synaptic proteins regulated by brain-
derived neurotrophic factor (BDNF) and mTOR signaling13, shown to be deficient in Mecp2 
mutants14.  
 


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Figure 1: Ketamine reduces apneic  
breathing episodes in Mecp2-/- mice 
 
Table 2: Ketamine Bioavailability by Route 
of Administration 
Administration   
Route 
Relative  
Bioavailability 
Dose 
Equivalence 
Correction 
Factor 
Intravenous 
100% 
1 
Oral 
~20% 
5 
Intranasal 
~44% 
2.25 
Intramuscular 
~22% 
4.65 
Additionally, as shown in animal models of depression and stress,15,16,17 ketamine has the 
potential to effect long-term synaptic repair by enhancing structural and functional connectivity. 
Supporting long-term effects of ketamine, more recent studies demonstrate prolonged efficacy 
with repeated dosing. For example, mice given 3 mg/kg intraperitoneal ketamine, once every 3 
days for 4 weeks have reduced apneas even 24 hours after the last drug administration, 
indicating a durable treatment effect of repeated drug administration (Katz et al., unpublished). 
Clinical studies on the effects of sub-anesthetic ketamine in several neuropsychiatric indications 
also indicate that repeated dosing is likely to lead to more durable treatment effects than single 
doses. Together, these published and unpublished observations provide new insight into 
potential strategies for enhancing the efficacy of ketamine, including dosing regimen and route 
of administration. 
The bioavailability of ketamine administered in various routes has been summarized18 and 
shown in the table below. Due to extensive first-pass metabolism and approximately 20% oral 
bioavailability in humans, a starting oral dose of 0.75 mg/kg of ketamine is equivalent to an 
intravenous dose of approximately 0.15 mg/kg. The safety and efficacy of single oral doses up 
to 10 mg/kg19 as well as repeated oral doses up to 1.5 mg/kg TID20, has already been 
demonstrated for pediatric indications. The model of therapeutic intervention for this study is 
designed to assess an oral dosing regimen of ketamine within the sub-anesthetic range for 
tolerability and safety, and to explore potential efficacy of doses that theoretically should impact 
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In selecting the age range for this study, the ketamine label indicates that patients under the age 
of 3 years may be at an increased risk of neurotoxicity. Additionally, studies in rats indicate the 
sexually mature brain may be susceptible to excitotoxicity21 that is not observed in younger 
animals22. Therefore, to ensure that patients enrolled in the study are not at increased risk for 
neurotoxic events, only patients between the ages of 6 to 12 years, inclusive, who have not 
achieved menarche, will be included. 
2.3. 
Preclinical Information for Ketamine 
The ketamine prescribing information23 should be consulted for more detailed technical 
information, current discussion of nonclinical evaluations, and relevant information regarding the 
known safety profile of ketamine to date.  
2.4. 
Clinical Information 
Ketamine was initially developed for use as a general anesthetic and approved by the FDA in 
1970 almost 50 years ago. Ketamine is now available generically through Hospira, Inc; Mylan 
Institutional; Par Pharmaceutical; and West-Ward Pharmaceuticals. The ketamine prescribing 
information23 should be consulted for complete clinical information on ketamine to date. 
Ketamine hydrochloride injection is indicated as the sole anesthetic agent for diagnostic and 
surgical procedures that do not require skeletal muscle relaxation and is best suited for short 
procedures but it can be used, with additional doses, for longer procedures. Ketamine 
hydrochloride is also indicated for the induction of anesthesia prior to the administration of other 
general anesthetic agents, and to supplement low-potency agents such as nitrous oxide. Routes 
of administration are intravenous or intramuscular injection. 
Specific areas of application have included the following: 
1. Debridement, painful dressings, and skin grafting in burn patients, as well as other 
superficial surgical procedures. 
2. Neurodiagnostic procedures such as pneumonencephalograms, ventriculograms, 
myelograms, and lumbar punctures.  
3. Diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental 
extractions. 
4. Diagnostic and operative procedures of the pharynx, larynx, or bronchial tree.  
5. Sigmoidoscopy and minor surgery of the anus and rectum, and circumcision. 
6. Extraperitoneal procedures used in gynecology such as dilatation and curettage. 
7. Orthopedic procedures such as closed reductions, manipulations, femoral pinning, 
amputations, and biopsies. 
8. As an anesthetic in poor-risk patients with depression of vital functions. 
9. In procedures where the intramuscular route of administration is preferred. 
10. In cardiac catheterization procedures. 


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2.4.1. 
Clinical Safety of IV Ketamine in Anesthesia 
Ketamine has a wide margin of safety. Several instances of unintentional administration of 
overdoses of ketamine (up to ten times that usually required) have been followed by prolonged 
but complete recovery. 
Ketamine has been studied in over 12,000 operative and diagnostic procedures, involving over 
10,000 patients from 105 separate studies (ketamine prescribing information). During the course 
of these studies ketamine hydrochloride was administered as the sole agent, as induction for 
other general agents, or to supplement low-potency agents. Safety and effectiveness in 
pediatric patients below the age of 16 have not been established. 
2.4.1.1. 
Adverse Events with IV Ketamine in Anesthesia 
The following adverse reactions have been described when ketamine was used as indicated: 
Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration 
of ketamine alone. However, hypotension and bradycardia have been observed. Arrhythmia has 
also occurred. 
Respiration: Although respiration is frequently stimulated, severe depression of respiration or 
apnea may occur following rapid intravenous administration of high doses of ketamine. 
Laryngospasms and other forms of airway obstruction have occurred during ketamine 
anesthesia. 
Eye: Diplopia and nystagmus have been noted following ketamine administration. It also may 
cause a slight elevation in intraocular pressure measurement. 
Genitourinary: In individuals with history of chronic ketamine use or abuse, lower urinary tract 
and bladder symptoms including dysuria, increased urinary frequency, urgency, urge 
incontinence, and hematuria have been reported. In addition, diagnostic studies performed to 
assess the cause of these symptoms have reported cystitis (including cystitis non-infective, 
cystitis interstitial, cystitis ulcerative, cystitis erosive and cystitis hemorrhagic) as well as 
hydronephrosis and reduced bladder capacity. 
Neurological: In some patients, enhanced skeletal muscle tone may be manifested by tonic and 
clonic movements sometimes resembling seizures. 
Gastrointestinal: Anorexia, nausea and vomiting have been observed; however, this is not 
usually severe and allows the great majority of patients to take liquids by mouth shortly after 
regaining consciousness. 
General: Anaphylaxis. Local pain and exanthema at the injection site have infrequently been 
reported. Transient erythema and/or morbilliform rash have also been reported. 
2.4.1.2. 
Emergence Reactions with IV Ketamine in Anesthesia 
Emergence reactions have occurred in approximately 12% of patients when ketamine was used 
as indicated. The psychological manifestations vary in severity between pleasant dream-like 
states, vivid imagery, hallucinations, and emergence delirium, and in some cases accompanied 
by confusion, excitement, and irrational behavior which a few patients recall as an unpleasant 
experience. The duration ordinarily is no more than a few hours; in a few cases, however, 
recurrences have taken place up to 24 hours postoperatively. No residual psychological effects 
are known to have resulted from use of ketamine. Incidence of emergence phenomena is least 


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in the elderly (over 65 years of age) patient, are less frequent when the drug is given 
intramuscularly, and incidence is reduced as experience with the drug is gained. The literature 
suggests that pediatric patients are at lower risk for psychotomimetic side effects related to 
ketamine administration than adults24. 
The incidence of psychological manifestations during emergence, particularly dream-like 
observations and emergence delirium, may be reduced by using lower recommended dosages 
of ketamine in conjunction with intravenous diazepam during induction and maintenance of 
anesthesia. Also, these reactions may be reduced if verbal, tactile, and visual stimulation of the 
patient is minimized during the recovery period. This does not preclude the monitoring of vital 
signs. In order to terminate a severe emergence reaction, the use of a small hypnotic dose of a 
short-acting or ultra short-acting barbiturate may be required.  
When ketamine is used on an outpatient basis, the patient should not be released until recovery 
from anesthesia is complete and then should be accompanied by a responsible adult. 
2.4.2. 
Clinical Studies of Ketamine in Adults with Neuropsychiatric Conditions 
Several neuropsychiatric conditions including bipolar disorder, depression syndromes, and 
obsessive compulsive disorder (OCD) are hypothesized to be caused by dysfunctional NMDA 
receptor signaling and have shown evidence of symptom improvement in adults when treated 
with ketamine. Though not all studies assessing ketamine have shown efficacy in every case, 
route of administration and duration of dosing, the studies described below support the 
therapeutic dose range under study and demonstrate the possibility for short- and long-term 
effects to be achieved in Rett syndrome.   
Bipolar Disorder 
The pathophysiology of bipolar disorder may be due to dysfunctional NMDA signaling, and 
ketamine as a non-competitive NMDA receptor antagonist was investigated for utility as a rapid 
onset anti-depressant in treatment-resistance bi-polar depression in a randomized trial of 18 
patients25. The authors found that a single treatment with ketamine at a dose of 0.5 mg/kg over 
a 40-minute IV infusion time resulted in significant changes in depression and anxiety compared 
to placebo. Adverse events associated with ketamine included dissociation; feeling strange, 
weird or bizarre; dry mouth; tachycardia; and increased blood pressure. No serious adverse 
events and no significant changes in ECG, respiratory or laboratory values were reported25.  
Depression  
NMDA receptor antagonists have also been evaluated in treating treatment-refractory 
depression (TRD) and major depressive disorder (MDD). Ketamine has been reported to lead to 
sustained improvements for up to 12 months in TRD in a case-series of 2 patients, where each 
received a 5-day regimen of intravenous ketamine and were titrated to an individual maximum 
tolerated dose lacking psychotomimetic effects but where both patients reported feeling “a bit 
heady”. Each patient received a 1-hour infusion of 27.5 mg or 30 mg, respectively, on each day 
of the 5-day treatment period26.  
In a randomized controlled cross-over trial in 18 patients with MDD, 50 mg of ketamine given 
intranasally over the span of 20 minutes demonstrated significant improvements in depressive 
symptoms through 48 hours post-dose, was associated with improvement of anxiety at 24 
hours, and was well tolerated with small increases in psychotomimetic measures that typically 
resolved within 4 hours of dosing27. 


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In March 2019, Spravato (esketamine) CIII nasal spray by Janssen Pharmaceuticals was 
approved for the treatment of TRD in adults taking an oral antidepressant. Esketamine, the S-
enantiomer of racemic ketamine, was assessed intranasally in 1,709 adults in 6 clinical trials. 
The indicated treatment regimen includes a 2-hour in-clinic observation of dosing at 56 mg or 84 
mg twice weekly for up to 4 weeks, followed by in-clinic maintenance at once weekly or once bi-
weekly dosing. Side effects reported during clinical development at any dose at an incidence 
≥5% and at least twice that of placebo were dissociation, dizziness, nausea, sedation, vertigo, 
hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk28. 
Obsessive Compulsive Disorder 
In a randomized controlled crossover trial of 15 patients receiving either placebo or ketamine 
dosed at 0.5 mg/kg over a 40-minute IV infusion, symptom relief of OCD met responder criteria 
and was statistically significant up to a week post-infusion29, confirming shorter-term effects 
noted in a case report30. Additionally, in an open label trial of the same regimen in 10 patients 
with less severe OCD, acute relief of OCD symptoms was attained though no patients achieved 
responder status31. Of these, 59% of patients with comorbid depression demonstrated a 
significant and persistent improvement in depressive symptoms. In both studies, ketamine 
treatment was considered well tolerated. The most common adverse events reported were 
dissociative symptoms that resolved within 1-2 hours post-infusion and transient increases in 
blood pressure during infusion29,30,31. Two non-depressed patients in the open-label trial 
reported dysphoria, anxiety and passive suicidal ideation within the first 48 hours post-
infusion31. 
2.4.3. 
Clinical Studies of Ketamine Dosed Orally in Adults 
Oral ketamine has been assessed in adults in several neuropsychiatric conditions including 
palliative care settings for depression and anxiety, and analgesia. Chronic forms of pain have 
employed the highest doses and longest durations of oral ketamine in a clinical setting. Oral 
ketamine has been reported to have a more favorable side effect profile than parenteral 
ketamine, including reduced levels of psychotomimetic effects 32,33,34,35,36. 
Depression and Anxiety 
Oral ketamine was assessed in 14 adults in hospice as a once-daily treatment at 0.5 mg/kg for 
28 days for the treatment of depression and anxiety. Eight subjects completed the study. On 
days 14 and 28, anxiety and depression were found to be significantly improved. Adverse 
events reported were mild and included diarrhea, trouble sleeping and trouble sitting still. No 
changes in vital signs were reported and no serious adverse events occurred37. A case-series of 
2 patients suffering from treatment-resistant depression with suicidal ideation received an 
ascending dose oral ketamine regimen of 0.5 mg/kg to 3 mg/kg and demonstrated sustained 
efficacy in relieving symptoms38.  
Pain  
In a co-analgesic oncology palliative care setting, a study of 29 adults receiving an optimized 
sub-cutaneous infusion of ketamine for pain control demonstrated maintenance of efficacy upon 
switching to dose-equivalent oral administration TID for up to 9 days, at doses as high as 750 
mg/day. A symptom score evaluation revealed side effects of slight (83%) or moderate (17%) 
insobriety, slight (86%) or moderate (14%) somnolence, and 1 report of hallucinations during 
sub-cutaneous administration, and no occurrences reported during oral administration32. 


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A patient with complex regional pain syndrome type I was administered 30 mg TID that 
increased by 5 mg per week until achieving 60 mg 4 times a day and maintained the regimen for 
more than 2 years39. Another case-report documented a significant improvement in pain, 
allodynia and hyperalgesia in a patient with central post-stroke pain at a dose of 50 mg TID for 3 
months40. 
2.4.4. 
Clinical Studies of Ketamine Dosed Orally in Children 
Due to ketamine’s well characterized safety profile, single sub-anesthetic doses of oral ketamine 
have been explored to aid surgical procedures in children, and more recently, repeat dosing of 
oral ketamine up to 14 days has been explored to assess the impact on chronic pain and 
cognitive function in children.  
The effects of oral ketamine were evaluated in an open-label ascending dose cohort study in 12 
children, aged 11 to 19 years, for assessment of chronic pain management and short- and long-
term cognitive effects20,41. The oral doses evaluated were 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 
and 1.5 mg/kg dosed TID over 14 days. Five of 12 patients (42%) demonstrated an 
improvement in pain score over the 14-day treatment period, with 2 patients reporting pain 
resolution20. Eleven of 12 patients (92%) demonstrated a significant and persistent improvement 
in executive functioning at 14 days as well as 3 months post-ketamine treatment41. Adverse 
events reported were generally mild and included short-term fatigue or somnolence after the 
first dose of oral ketamine, which resolved within 1–2 hours and did not recur upon repeat 
administrations. Delayed dysphoria (e.g., confusion, dizziness) was experienced by 7 of 12 
participants and CTCAE v4.0 grade 2 dysuria without hematuria was experienced by 1 
participant in the 1.5 mg/kg cohort. Grade 2 (moderate) anorexia and depressed level of 
consciousness were considered dose-limiting toxicities of the 14-day 1.5 mg/kg TID cohort20.  
In another double-blind, randomized, controlled study in 45 children aged 1-7 years, patients 
received a single dose of placebo, 3 mg/kg, or 6mg/kg oral ketamine prior to induction of 
anesthesia for a surgical procedure to assess ease of anesthesia induction and potential overall 
improvement of the patient’s surgery experience42. Both 3 mg/kg and 6 mg/kg single doses of 
oral ketamine were considered well tolerated, with incidence of nystagmus statistically elevated 
from placebo. There were no reports of altered vital signs or surgery recovery, and no 
emergence phenomena were reported. Sedation occurred in 11 of 15 (73%) of patients who 
received 3 mg/kg and 100% of patients who received 6 mg/kg. 
Another open-label study assessed a single 10 mg/kg dose of oral ketamine in 35 pediatric 
oncology patients aged 14 months to 17 years and demonstrated less distress related to 
surgical procedures than historical controls. The dose of 10 mg/kg oral ketamine resulted in 
87% of patients attaining maximum levels of sedation at 45 minutes post dose with recovery 
within 2-4 hours. No cardiorespiratory adverse events related to ketamine were reported and no 
serious adverse events occurred. Emergence phenomena were experienced by 3 patients (9%) 
and included 2 patients (6%) that demonstrated mild confusion and disorientation, and 1 patient 
(3%) that demonstrated moderate agitation that resolved without intervention19.     
2.4.5. 
Clinical Studies of Ketamine Dosed Orally in Children with Rett 
Syndrome 
To date, one open-label pilot study and one case report have indicated positive effects from oral 
ketamine treatment in Rett syndrome patients and support a controlled study to assess its 
therapeutic potential. Consistent with mouse model data, a multiple ascending dose pilot study 
in 4 Rett syndrome patients conducted by Case Western Reserve University and the Cleveland 


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Clinic demonstrated evidence for efficacy of single doses of intravenous ketamine on breathing 
regularity over the dose range tested (0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg) with 
profound effects observed at 10 hours post-dose (Katz, unpublished). All 4 doses of intravenous 
ketamine were considered well-tolerated.  
In a case report called “The Scottish Patient” (Welham et al., Presented at the 2017 British 
Pediatric Neurology Association Annual Meeting), repeated oral dosing of ketamine in a 10-year 
old Rett syndrome patient was described. In this case, the patient was given oral ketamine at 
0.75 mg/kg BID for 5 days for refractory seizures that resulted in not only seizure resolution but 
also improvement in motor function, communication, and cognition lasting 8 weeks before 
seizures re-emerged. The patient was dosed with another 5-day regimen of ketamine at 0.75 
mg/kg BID conferring additional seizure control and sustained improvements in Rett symptoms. 
In a 12-month review of the patient’s hospital admissions for seizures, an 80% reduction in 
hospital admission time was recorded in the 6 months after ketamine treatment compared to the 
6 months prior to treatment. 


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3. 
ETHICS 
The procedures set out in this study protocol, pertaining to the conduct, evaluation and 
documentation of this study, are designed to ensure that the Investigators abide by Good 
Clinical Practice (GCP), including but not limited to Title 21 Code of Federal Regulations (CFR) 
Parts 50, 56, and 312, and the International Conference on Harmonisation (ICH) guidelines and 
directives.  Compliance with these regulations also constitutes compliance with the ethical 
principles described in the current revision of the Declaration of Helsinki and applicable local 
regulatory requirements and law.   
The Investigator is responsible for protecting the rights, safety, and welfare of patients under 
their care, and for the control of the medication under investigation.  All ethical, regulatory, and 
legal requirements must be met before the first patient is enrolled in the study. 
3.1. 
Institutional Review Board 
The Institutional Review Board (IRB) will meet all FDA requirements governing IRBs according 
to CFR, Title 21, Part 56. The Investigator (or designee) must submit this study protocol and any 
amendments, the approved informed consent form(s) (ICF), patient information sheets, patient 
recruitment materials, and other appropriate documents to the IRB for review and approval.  
3.2. 
Written Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the 
parent/legally authorized representative (hereafter referred to as caregiver) for the patient. 
Where possible, assent should be obtained from the patient.  
The ICF, as specified by the clinical site’s IRB, must follow the Protection of Human Patients 
regulations listed in the CFR, Title 21, Part 50.  
All ICFs used in this study must be approved by the appropriate IRB. Amendments to the ICF 
must be approved by the presiding IRB before use.  


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4. 
STUDY OBJECTIVES 
The overall objectives of the study are to assess the safety, tolerability, and efficacy of oral 
ketamine in patients with Rett syndrome. 
4.1. 
Primary Objectives 
The primary objective is: 
• 
To assess the safety and tolerability of administration of a 5-day dosing regimen of 
oral ketamine in Rett syndrome patients. 
4.2. 
Exploratory Objectives 
The exploratory objectives are: 
• 
To assess the change in continuous biosensor data (activity, movement, heart rate, 
gait, sleep, posture, breathing regularity) from baseline; 
• 
To assess the change in Rett syndrome severity as measured by the Motor Behavior 
Assessment (MBA) from baseline; 
• 
To assess the change in Rett syndrome severity as measured by the Rett Syndrome 
Behavior Questionnaire (RSBQ) from baseline; 
• 
To assess the change in Rett syndrome severity and improvement as measured by 
the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of 
Improvement (CGI-I) from baseline; 
• 
To assess the change in symptom severity as measured by the clinician Domain 
Likert Scale from baseline; 
• 
To assess the change in symptom severity as measured by the parent Domain Likert 
Scale from baseline;  
• 
To assess the change in sleep from baseline as measured by the Child Sleep Habits 
Questionnaire (CSHQ) 
• 
To assess the change in caregiver burden as measured by the Rett Caregiver 
Burden Inventory Assessment (RTT CIA) from baseline 
• 
To assess the change in EEG signature between placebo and ketamine dosing 


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5. 
OVERALL STUDY DESIGN 
5.1. 
Study Design 
This is a double-blind, randomized, placebo-controlled, multi-center, cross-over study to 
evaluate the safety, tolerability, and efficacy of oral ketamine in patients with Rett syndrome in 
an ascending dose, 4-cohort design.  The patient must have a documented MECP2 mutation 
considered causative for the disorder. Patients will have a clinical evaluation involving physical 
examination and medical history review and require a definitive diagnosis of Rett syndrome 
based on the Revised Diagnostic Criteria5. 
Patients will be female between the ages of 6 and 12, inclusive, who have not achieved 
menarche, and should not be treated concurrently with other NMDA receptor antagonists, or 
with other treatments with known ketamine interactions. 
The study consists of up to 4 cohorts initiated sequentially in ascending dose order. Each cohort 
will assess 1 dose level of ketamine (0.75 mg/kg, 1.5 mg/kg BID, 3 mg/kg, or 4.5 mg/kg BID). At 
the conclusion of each cohort, an independent safety monitoring committee will determine if 
there are adequate safety data to support initiation of the subsequent cohort.  
A cohort within the study is divided into 3 periods: Screening, Cross-over Treatment (comprising 
a regimented 2-treatment cross-over), and Post-Treatment Safety Follow-Up (Figure 2). The 
Screening Period will last between 14 and 28 days prior to the initiation of study drug.  The 4-
week Treatment Period is a double-blind, placebo-controlled period to define safety and explore 
efficacy for the study. The Post-Treatment Safety Follow-up Period is the final 2 weeks of each 
cohort to assess safety following treatment completion.  
Each cohort is designed to assess 1 dose of ketamine compared to placebo. In the 2-treatment 
cross-over period patients will receive either placebo or ketamine in the first cross-over regimen 
and the alternate treatment in the second, based on their blinded randomization assignment. 
Patients may only participate in one cohort. 


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Figure 1: Study Design 
 
5.1.1. 
Screening and Baseline 
Caregivers will provide appropriately obtained informed consent, and where possible, patients 
will provide assent, prior to completing any screening procedures.   
At the Screening visit, eligibility will be confirmed and patients will take home the biosensor 
systems for collection of daily in-home data prior to the Day 1 Randomization Visit. Eligible 
patients will return for the Randomization Visit on Day 1 for review of eligibility and additional 
baseline safety and efficacy assessments including an EEG at select centers, physical 
examination, vital signs, ECG, as well as physician CGI-S, MBA, and the Clinician Rated 
Domain Likert Scale consisting of 8 domains (hand function, walking, verbal and non-verbal 
communication, comprehension, attention, behavior problems, mood). Caregiver rated scales 
including the RSBQ, CSHQ, RTT CIA, and an exploratory Parent Rated Domain Likert Scale of 
the same 8 clinician domains with the addition of a seizures domain, will also be completed.   
Due to the COVID-19 pandemic, the Screening visit may be conducted remotely via telehealth 
per institutional SOPs. In this case, safety assessments including vital signs may be collected 
off-site by qualified study personnel and ECG may be collected at Visit 2 to confirm eligibility 
prior to dosing. 
5.1.2. 
Treatment Period and Safety Follow-Up Period 
The double-blind, placebo-controlled, cross-over Treatment Period will last a total of 4 weeks, 
starting with the first treatment on Day 1 and initiation of the alternate treatment 2 weeks later 
on Day 15.  Patients receiving ketamine in the first treatment will cross-over to receive placebo 


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in the second, and patients receiving placebo in the first treatment will cross-over to receive 
ketamine in the second.  
Each ordered cross-over dosing regimen comprises 5 days of BID dosing (treatment 1: Day 1-5, 
treatment 2: Day 15-19) and patient safety and efficacy evaluation for 14 days after dose 
initiation (Period 1: Day 15, Period 2: Day 29).  
After dosing completion and conclusion of the 4-week cross-over Treatment Period, patients will 
return on Day 29 for final safety and efficacy assessments. Due to the COVID-19 pandemic, 
Day 29 may be conducted remotely via telehealth per institutional SOPs. In this case, safety 
assessments including vital signs may be collected off-site by qualified study personnel. 
Patients will be assessed for safety for an additional two weeks and a final Safety Follow-up 
phone call will occur on Day 43. 
5.1.3. 
In-Clinic Assessments 
At the clinic visits, safety and efficacy assessments will be performed by the clinician and the 
caregiver. Exploratory efficacy assessments including physician CGI-S or CGI-I, MBA, and 
Clinician Rated Domain Likert Scale should be performed prior to dosing to establish baseline 
and thereafter, to assess effects from the preceding treatment. Caregiver assessments 
including the Parent Rated Domain Likert Scale, RSBQ, RTT CIA, and CSHQ should also be 
performed. 
Safety assessments including observation of patient disposition and vital signs should occur 
pre- and post-dose to assess tolerability of the in-clinic dose and inform continuation of the 
dosing regimen at home.  
5.1.4. 
Dosing 
Patients will receive the first oral dose of each 5-day dosing regimen in-clinic under observation. 
Tolerability of the first oral dose will be evaluated for two hours post dose in-clinic through 
monitoring of patient disposition and through assessment of vital signs at regular intervals. If 
well tolerated, subsequent doses of the 5-day dosing regimen will be administered in the home 
at approximately 12-hour intervals, with or without food. The site will contact the caregiver each 
day of active dosing to confirm continued tolerability and to assess for emergent side effects. 
5.1.5. 
At-home Assessments 
Over the following 2-week period after each of the observed in-clinic doses, caregivers will 
continuously capture biosensor data to assess patient activity, movement, heart rate, gait, 
sleep, posture, and breathing regularity. On Days 8 and 22, caregivers will report a Parent 
Domain Likert Scale and complete the CSHQ. The Parent Domain Likert Scale and the RTT 
CIA will also be completed on Day 43. 
5.1.6. 
Safety Monitoring 
Patient safety will be monitored throughout the study. Investigators will monitor safety and 
tolerability through observation and monitoring of in-clinic dosing of the first dose of each 
treatment, and through daily communication with the caregiver on at-home dosing days.  
An independent safety monitoring committee will perform a safety assessment of each cohort 
with a subsequent ascending dose after the last patient has completed the final efficacy and 
safety assessment of the Treatment Period (Day 29). The safety committee will review 
accumulated safety data to assess if initiation of dosing for the subsequent cohort is supported.  
In the case of treatment intolerability during the 5-day dosing period, the patient will stop 
treatment at the assigned blinded dose and discontinue the study, and any adverse events will 
be followed until an acceptable clinical resolution is achieved.  Patients who discontinue study 
drug due to an adverse event (AE) during the Treatment Period will return for the Day 29/Early 


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Termination Visit two to four weeks after the last dose and receive a final Safety Follow-up 
phone call.   
5.2. 
Number of Patients and Sites 
Approximately 48 patients are planned to be enrolled (12 per cohort) in the study at 
approximately 7 sites.  
5.3. 
Method of Treatment Assignment and Blinding 
For each cohort, patients meeting all eligibility criteria will be randomized in a 1:1 ratio to receive 
placebo and ketamine, in either order. Randomization will not be stratified.  
All study participants will be blinded to study drug assignment for the duration of the study. 
Packaging, administration, and flavor masking between placebo and ketamine will be identical. 
Pharmacists will remain unblinded and will keep confidential all treatment assignments. 
5.4. 
Rationale for Study Design 
Double-blind, randomized, placebo-controlled studies are considered optimal for obtaining 
unbiased estimates of the safety and efficacy of investigational treatments.  The cross-over 
design allows for each patient to serve as her own control, which increases the ability to detect 
treatment differences. Analysis for carry-over effects is planned. The 4-week duration of the 
Treatment Period is anticipated to allow assessment of the safety and tolerability profile 
associated with a 5-day regimen of ketamine, and to explore potential efficacy.   
 
 
 
 
 
 
 
 


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6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients eligible for enrollment in the study must meet all of the following inclusion criteria and 
none of the exclusion criteria. 
6.1. 
Patient Inclusion Criteria 
1. Prior to the conduct of any study-specific procedures, the patient must provide verbal 
assent to participate in the study (if developmentally appropriate), and the 
parent/caregiver/LAR must provide written informed consent.  If the caregiver attending 
the clinic visits is not the parent or LAR, written consent must be obtained from the 
parent or LAR for the caregiver’s participation in the study. 
2. Female patients 6 to 12 years of age, inclusive, at the time of informed consent, who 
have not achieved menarche. 
3. Diagnosis of typical or atypical Rett Syndrome according to the revised Clinical 
Diagnostic Criteria 20105 and presence of a disease-causing MECP2 genetic mutation. 
4. Ability to take liquid medications orally or through a feeding tube. 
5. The patient’s caregiver must be able to understand the nature of the study and to allow 
for the completion of all study assessments. The same caregiver must be capable of 
providing reliable information about the patient’s condition, agree to oversee the 
administration of study drug, and accompany the patient to all clinic visits. 
6.2. 
Patient Exclusion Criteria 
1. Uncontrolled epilepsy, defined as caregiver report of unusual variability in seizure 
frequency that may warrant regimen change during the study to either untreated patients 
or patients on stable anti-seizure medication regimens. 
2. Plans to initiate or change pharmacologic interventions during the course of the study or 
have not been on stable interventions for at least 4 weeks prior to Screening, or stable 
anti-seizure medication regimens (if applicable) for 12 weeks prior to the Randomization 
Visit. 
3. Plans to initiate or change non-pharmacologic interventions (behavioral, educational or 
dietary) during the course of the study or have not been on stable interventions for at 
least 4 weeks prior to Screening. Typical school vacations are not considered 
modifications of stable interventions. 
4. Patients who achieve menarche during study participation and prior to conclusion of the 
second dosing period of the cohort. 
5. A history of prolonged QT syndrome or a Screening QTc interval with Fridericia’s 
correction (QTcF) >460 for females less than 15 years or >470 for females over 15 
years. 
6. Have taken another investigational drug within the greater of 4 weeks of 5 half-lives prior 
to Screening or during the study.  
7. Concurrent treatment with other NMDA receptor antagonists, treatments with known 
ketamine interactions, sedatives, barbiturates, benzodiazepines, narcotics, or opioids. 


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8. Concurrent treatment with strong CYP3A4 or CYP2B6 inhibitors dosed for systemic 
exposure, or for 4 weeks prior to initiating study drug. 
9. Concurrent treatment with strong CYP3A4 or CYP2B6 inducers dosed for systemic 
exposure, or for 4 weeks prior to initiating study drug. 
10. A history of hypersensitivity to ketamine. 
11. A history of any condition that may be worsened by increased blood pressure or heart 
rate, bronchodilation, intraocular or intracranial pressure, or a history of porphyria. 
12. Patients with any condition that, in the opinion of the principal investigator, might 
interfere with the conduct of the study, confound interpretation of the study results, 
endanger their own well-being, or who may otherwise not be suitable for the study.  
6.3. 
Patient Withdrawal Criteria 
All caregivers and patients are free to withdraw from participation in the study at any time, for 
any reason, and without prejudice.  The Investigator may remove a patient from the study at any 
time and for any reason. Patients who withdraw or are withdrawn from the study will not be 
replaced. 
6.3.1. 
Withdrawal Safety Criteria  
At each in-clinic dosing, vital sign parameters will be assessed and patient disposition will also 
be monitored. Should intolerable adverse events emerge during the observation period, the 
patient should be withdrawn. Investigators will contact caregivers daily during dosing days to 
assess for adverse events and general patient tolerability. 
Patients who appear to experience intolerable adverse events, emergent adverse events, or 
other adverse events considered to be related to study drug that may reflect an unfavorable 
risk-benefit profile should be withdrawn from the study at the discretion of the Investigator.  
Patients who are withdrawn from the study should undergo an Early Termination Visit and 
subsequent Safety Follow-up Phone Call as appropriate per Section 8.3.2 Patient Withdrawal 
Procedures, and associated adverse events followed as described in Section 11 Adverse 
Events. 
Caregivers should receive instructions to monitor the patient after at-home dose administration 
to assess for emergent adverse events or other signs of intolerability. Patients who discontinue 
the study due to intolerable adverse events should continue to be monitored as appropriate 
through an acceptable clinical resolution of the event. 
6.3.2. 
Patient Withdrawal Procedures 
A patient who prematurely discontinues study treatment/study participation should have all Day 
29 assessments performed as an Early Termination Visit, as well as the Safety Follow-up 
Phone Call.  
If a patient discontinues early from the study, the Investigator will record the reason(s) for early 
termination on the relevant electronic case report form (eCRF).  The specific reason for the 
withdrawal should be documented on the eCRF.   
Patients who experience an intolerable adverse event should be discontinued from the study. 
Adverse events resulting in patient early termination will be followed to the satisfactory 


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resolution and determination of outcome, as ascertained by the Investigator; See 
Section 11.1.2: Adverse Events.  The data will be recorded on the appropriate eCRF. 
6.4. 
Criteria for Study Termination 
The study may be discontinued at any time for clinical or administrative reasons. If the 
Investigators or independent safety review committee determine that treatment with oral 
ketamine poses an unjustified risk to patients, the study may be terminated.   
The Investigator will promptly notify the IRB of study termination or dose modification. Any study 
termination must be implemented by the Investigator in a time frame that is compatible with the 
patient’s well-being. 


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7. 
DESCRIPTION OF STUDY TREATMENTS 
7.1. 
Description of Treatments 
For each cohort, patients will be randomized in a 1:1 ratio to 1 of 2 ordered cross-over treatment 
regimens as follows: 
• 
Cohort 1 
o 0.75 mg/kg BID  placebo 
o placebo  0.75 mg/kg BID 
 
• 
Cohort 2 
o 1.5 mg/kg BID  placebo 
o placebo  1.5 mg/kg BID 
 
• 
Cohort 3 
o 3 mg/kg BID  placebo 
o placebo  3 mg/kg BID 
 
• 
Cohort 4 
o 4.5 mg/kg BID  placebo 
o placebo  4.5 mg/kg BID 
If the safety committee review of safety parameters for patients in each cohort indicates no 
safety concerns, the subsequent ascending dose cohort will be initiated. 
7.2. 
Treatment Compliance 
At each scheduled study visit after Randomization, the Investigator or designee will interview 
the caregiver regarding treatment compliance and compare the volume of dispensed versus 
returned study drug. Caregivers should strive for 100% compliance with the 5-day BID dosing 
schedule. 
7.3. 
Study Drug Treatment Descriptions and Management 
Please consult the full ketamine Prescribing Information and the description of study drug 
treatment requirements below for storage, handling, compounding, dispensing, accountability, 
returns and destruction. 
7.3.1. 
Physical Description of Treatments 
Treatments will include ketamine and matching placebo.  Details regarding formulation and 
dosage are presented in Table 3. 
 
 


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Table 3: Treatments 
Product Name: 
Ketamine or 
placebo (sterile water) 
Dosage Form: 
Solution 
Intended Manufacturer 
Dosage Strength:  
50 mg/mL or 100 mg/mL ketamine concentrate 
Route of Administration: 
Oral 
Physical Description: 
Transparent or opaque liquid solution  
7.3.2. 
Treatment Supplies, Labeling, and Storage 
Each patient will receive a sufficient supply of ketamine solution or matching placebo solution 
based on patient weight in kilograms to complete the 5-day BID dosing regimen at the Day 1 
Randomization Visit (cross-over treatment 1) and at the Day 15 Visit (cross-over treatment 2).  
The pharmacy label for the ketamine or placebo treatments will minimally include Investigator 
name, address and telephone number, study treatment as “ketamine or placebo”, administration 
instructions (mLs per dose, frequency, and duration), and storage conditions.  Additional 
information may be included on the label per Institution requirements. 
Ketamine vials and stock solutions should be stored protected from light in the original package 
as stated on the ketamine label. Storage should occur in a secure, temperature-monitored, 
locked area, under the responsibility of the Investigator or other authorized individual until 
compounded and dispensed to the patient. Returned study drug should also be securely stored 
until full reconciliation is complete. 
Special Note: Ketamine is considered a drug of abuse and extra care should be taken to 
monitor supplies and limit access. 
Study drug bottles dispensed to patients should be stored at home in the original containers 
provided by the pharmacy protected from light according to the directions on the pharmacy 
label.  
7.3.3. 
Study Drug Preparation  
Treatment compounding by the pharmacist is required and may be performed according to the 
Institution’s standard operating procedures. Compounding materials include Ketamine stock 
concentrates, sterile water, and masking flavor. Treatment preparations should be based on the 
weight of the patient in kilograms on the day of the Visit. Placebo solutions should consist of 
sterile water and masking flavor and be indistinguishable from ketamine solutions. The same 
volume of placebo or ketamine solution should be prepared and administered when appropriate 
to maintain the blind.  
Refer to the pharmacy manual for general guidance on compounding.  
7.3.4. 
 Study Drug Administration 
Patients will take the first dose of each ketamine or placebo treatment in-clinic on Day 1 and 
Day 15 and caregivers will be instructed to administer subsequent doses approximately every 
12 hours for the duration of the remaining 5-day dosing regimen. 


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7.3.5. 
Study Drug Return and Disposal 
The Investigator and relevant site personnel will follow the Institutional standard operating 
procedure for study treatment disposal, and/or destruction.  
7.3.6. 
Study Drug Accountability 
To satisfy regulatory requirements regarding drug accountability, treatments will be reconciled in 
full. The unblinded pharmacist must maintain accurate records of the receipt of ketamine stock 
solutions, including the date and amount received, and disposition. Current dispensing records 
will also be maintained, including the date and amount of ketamine used to create patient 
solutions and the amount dispensed to each individual patient. Returned study drug records will 
be maintained and final study drug reconciliation will be recorded for each patient.  
7.4. 
Concomitant Medications and Procedures 
All medications, including over-the-counter therapies (e.g., vitamins, herbal, and nutritional 
supplements), taken at the time of the Screening Visit through the Follow-Up Visit will be 
recorded in the patient’s source documentation and documented in the eCRF. 
The following treatments are not permitted during the study: 
• 
Use of other NMDA receptor antagonists, treatments with known ketamine 
interactions, sedatives, barbiturates, benzodiazepines, narcotics, or opioids; 
• 
Use of strong CYP3A4 or CYP2B6 inhibitors dosed for systemic exposure, or for 4 
weeks prior to initiating study drug; 
• 
Use of strong CYP3A4 or CYP2B6 inducers dosed for systemic exposure, or for 4 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Demographic Characteristics and Medical History 
Demographic characteristics will be collected at the Screening Visit including documentation of 
a causative MECP2 genetic mutation, thorough medical history, and the patient’s typical Rett 
Syndrome diagnosis according to Revised Diagnostic Criteria5. 
8.2. 
Actigraph 
The ActiGraph wGT3X-BT is an FDA cleared Class II medical device intended to capture and 
record high resolution raw acceleration data that can be converted into activity and sleep 
measures.  
In this study, patients will wear the ActiGraph xGT3X-BT on the wrist for continuous data 
collection during the Screening and Treatment Periods. Collected data will be uploaded at the 
Visit. Raw datasets collected will be explored for Rett syndrome-specific signatures in addition 
to pre-defined algorithms. 
8.3. 
Hexoskin Smart Garment 
The Hexoskin Smart Kit developed by Carre Technologies, Inc (Hexoskin), uses non-invasive 
biometric sensors embedded within machine-washable, breathable, light-weight fabric clothing 
to continuously track activity, sleep, heart and lung function. Specifically, hexoskin monitors 
ECG and heartbeat, heart rate variability, breathing rate and volume (L/min), activity intensity, 
acceleration, cadence, energy expenditure (kCal), position, and sleep.  
In this study, patients will wear the Hexoskin Smart Garment for continuous data collection 
during the Screening and Treatment Periods. Since hexoskin Smart Garments are not indicated 
for children under the age of 13 or for patients with neurodevelopmental disorders, the raw 
datasets collected will be explored for Rett syndrome-specific signatures in addition to pre-
defined algorithms. 
8.4. 
Clinical Global Impression Scales 
The Global Impression Scales are measures commonly used in clinical trials to allow integration 
of several sources of information into a single rating of the patient’s condition43. The Clinical 
Global Impression Scales employ a 7-point Likert scale measuring either disease state severity 
or improvement after treatment.  
In this study, the Clinical Global Impression Scale of Severity and Improvement will be 
performed by the Investigator. Assessment of Rett syndrome severity should consider the 
condition of the patient at the time of the assessment, while assessment of Rett syndrome 
improvement should consider the condition of the patient at the time of the assessment 
compared to Baseline. To reduce variability, one rater should perform the global impression 
scales for the patient for the duration of the study. 
8.5. 
Rett Syndrome Behaviour Questionnaire 
The Rett Syndrome Behaviour Questionnaire (RSBQ) is a 45-item measure to evaluate the 
behavioral and emotional features of Rett syndrome and to discriminate between patients with 
Rett Syndrome and idiopathic severe to profound intellectual disability44.  


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8.6. 
Motor Behavioral Assessment 
The Rett Syndrome Motor Behavioral Assessment (MBA) is a 40-item scale used to assess 3 
subgroups in Rett syndrome patients: behavioral/social, orofacial/respiratory, and motor 
assessment/physical signs, in their current state and the worst ever state45. 
8.7. 
Parent and Clinician Rated Domain Likert Scales 
In addition to the Global Impression Scales that assess the patient overall, an evaluation of 
individual symptom domains will also be explored. To assess potential changes in specific 
symptoms of a patient’s condition, the Investigator will complete a 7-point Likert Scale for each 
of the following 8 domains: hand function, walking, verbal and non-verbal communication, 
comprehension, attention, behavior problems, mood. The caregiver will complete an exploratory 
Parent Rated Domain Likert Scale of the same 8 clinician domains (hand function, walking, 
verbal and non-verbal communication, comprehension, attention, behavior problems, mood) 
with the addition of a seizures domain.  
8.8. 
Children’s Sleep Habits Questionnaire 
The Children’s Sleep Habit’s Questionnaire (CSHQ) was designed for children aged 4 through 
12 years, to screen for the most common sleep problems in that age group, though it will be 
collected for all patients in this study46.  The 35-item questionnaire will be completed by the 
caregiver.  
8.9. 
Rett Caregiver Burden Inventory Assessment 
The Rett Caregiver Burden Inventory Assessment (Rett CIA) was adapted from the Caregiver 
Burden Inventory created for Alzheimer disease to assess caregiver burden specifically for 
individuals with Rett Syndrome47. The RTT CIA consists of 26 questions across 4 domains (time 
dependency, physical burden, emotional burden, social burden) appropriate for the Rett 
Syndrome patient population and utilizes a 5-point Likert scale for answering each item: (1) I 
never feel this way, (2) I rarely feel this way, (3) I sometimes feel this way, (4) I quite frequently 
feel this way, (5) I nearly always feel this way.  
8.10. 
Physical Examination 
A physical examination will include an examination of all major organ systems. Caregivers 
should be instructed to notify the clinic of any signs of changes in the patient’s physical or 
neurological state between visits for appropriate monitoring and follow-up. 
8.11. 
Vital Signs, Weight, and Height 
At each Visit, vital signs will be measured after the patient has been in a supine or semi-supine 
position for at least 5 minutes and will include body temperature, blood pressure, pulse rate, 
respiratory rate, and oxygen saturation.  
Weight and height will be measured per Institution standard of care. 


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8.12. 
Electrocardiogram 
A twelve-lead electrocardiogram will be performed at the Screening Visit or at Visit 2 to confirm 
eligibility prior to dosing after the patient has rested in a supine or semi-supine position for at 
least 5 minutes.  
8.13. 
Electroencephalogram 
For select sites performing an electroencephalogram (EEG), an electronic EEG recording will be 
collected for evaluation of NMDA receptor target engagement and subsequent changes in EEG 
signature expected with ketamine treatment.  


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9. 
ADVERSE EVENTS 
9.1.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence that may appear or worsen in a patient 
during the course of a study.  It may be a new intercurrent illness, a worsening concomitant 
illness, an injury, or any concomitant impairment of the patient’s health, including laboratory test 
values, regardless of etiology.  Any worsening (ie, any clinically significant adverse change in 
the frequency or intensity of a pre-existing condition) should be considered an adverse event.  A 
diagnosis or syndrome should be recorded on the adverse event page of the eCRF rather than 
the individual signs or symptoms of the diagnosis or syndrome.  
9.1.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to seriousness, severity/intensity, 
relationship to study drug, duration, action taken, and outcome.   
9.1.2.1. 
Serious Adverse Event  
A serious adverse event is an adverse event, as per Title 21 CFR 312.32 and ICH E2A.II.B that 
fulfills the following criteria: 
• 
Is fatal (results in death); 
• 
Is life-threatening (Note: the term "life-threatening" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that 
could hypothetically have caused death had it been more severe); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• 
Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient's ability to conduct normal life functions); 
• 
Is a congenital anomaly/birth defect; or 
• 
Constitutes an important medical event that may jeopardize the patient or may 
require medical or surgical intervention to prevent one of the other outcomes listed 
above. 
Important medical events are defined as those occurrences that may not be immediately 
life-threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization.   
Events not considered to be serious adverse events are hospitalizations for: 
• 
A procedure for protocol/disease-related investigations (e.g., sampling for laboratory, 
pharmacokinetic, and pharmacodynamic tests).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
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• 
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an adverse event. 
• 
A procedure that is planned (i.e., planned prior to the starting of treatment on study); 
must be documented in the source document and the eCRF.  Hospitalization or 
prolonged hospitalization for a complication remains a reportable serious adverse 
event. 
• 
An elective treatment of or an elective procedure for a pre-existing medical condition 
that does not worsen.  
• 
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
If an adverse event is considered serious, the adverse event eCRF must be completed. 
For each serious adverse event, the Investigator will provide information on severity, start and 
stop dates, relationship to investigational product, action taken regarding investigational 
product, and outcome. 
9.1.2.2. 
Severity/Intensity 
For both adverse events and serious adverse events, the Investigator must assess the 
severity/intensity of the event.  
The National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 should be used to grade the severity/intensity of all events. If a CTCAE criterion 
does not exist, the Investigator should grade the severity according to the following criteria:  
• 
Grade 1 (mild): does not interfere with the patient’s usual function 
• 
Grade 2 (moderate): interferes to some extent with patient's usual function 
• 
Grade 3 (severe): interferes significantly with patient's usual function 
• 
Grade 4 (life-threatening): results in a threat to life or in an incapacitating disability 
• 
Grade 5 (death): results in death 
9.1.2.3. 
Relationship to Study Drug 
Relationship should be assessed and provided for every adverse event/serious adverse event 
based on currently available information.  Relationship is to be reassessed and provided as 
additional information becomes available.  Adverse events will be classified by the Investigator 
as definitely related, probably related, possibly related, unlikely related, or not related. 
9.1.2.4. 
Duration 
For all adverse events whether or not considered serious, the Investigator will provide a record 
of the start and stop dates of the event. If an event is unresolved at the end of the study it will be 
recorded as ongoing.  
9.1.2.5. 
Action Taken 
The Investigator will record the action taken with investigational product as a result of an 
adverse event or serious adverse event on the eCRF, as applicable, and record if concomitant 
and/or additional treatments were given for the event. 


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9.1.2.6. 
Outcome 
The Investigator will record the outcome of adverse events on the eCRF, as applicable.   
9.1.3. 
Follow-Up 
Adverse events assessed as not related to study drug, including physical examination findings, 
must be followed until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the final study visit occurs, whichever comes first.     
Adverse events assessed as related to study drug and serious adverse events will be followed 
for as long as necessary to adequately evaluate the patient’s safety, or until the event stabilizes, 
is otherwise explained, death occurs, or the patient is lost to follow up.   
9.1.4. 
Recording Adverse Events 
All adverse events (regardless of seriousness or relationship to study drug) including those from 
the time informed consent is obtained through to the final study visit are to be recorded in the 
eCRF.  Each individual adverse event is to be listed as a separate entry.  The Investigator will 
provide information about dates of onset and resolution, seriousness, severity, action(s) taken, 
outcome, and relationship to the study drug. All adverse events should be documented in the 
patient’s source documents.  
9.1.5. 
Reporting Adverse Events 
The Investigator must report all adverse events that occur during the study from the time written 
informed consent is given until the final study visit/phone call or early termination, regardless of 
their relationship to the study drug.  
9.1.5.1. 
Reporting Serious Adverse Events 
Serious adverse events will be reported from the time written informed consent is given through 
30 days beyond the last dose of study drug. The Sponsor-Investigator will be responsible for 
reporting serious adverse events to the FDA, as required.  
9.1.5.2. 
Reporting Urgent Safety Issues 
The Sponsor-Investigator should be notified if the Investigator becomes aware of an actual or 
potential urgent safety issue.  
Urgent safety issues should be treated as medically appropriate. An urgent safety issue may 
include: (1) issues with an investigational drug or comparators; (2) study procedures; (3) inter-
current illness (including pandemic infections); (4) concomitant medications; (5) concurrent 
medical conditions; or (6) any other issues related to the safe conduct of the study or that pose 
a risk to study patients. 
   


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10. 
STATISTICAL METHODS 
For statistical methods, treatment refers to placebo, ketamine 0.75 mg/kg, ketamine 1.5 mg/kg, 
ketamine 3.0 mg/kg, and ketamine 4.5 mg/kg.  
10.1. 
Sample Size Rationale 
Sample size determinations for this study are based on the primary outcome of safety and 
tolerability. For a dose-limiting adverse event with a 10% incidence rate, a sample size of 10 
patients/dose level (10 patients/cohort) provides a 65% probability of observing at least 1 event 
at each dose level, and an 88% probability of observing at least 1 event by completion of Cohort 
2.  
For measures of efficacy, there are no studies in the literature to provide reliable estimates of 
treatment effects of ketamine or the estimate of variance in symptom management for Rett 
Syndrome patients. Each dose level provides 80% power to detect a 1.00 standard deviation 
treatment difference with the 2-sided paired t-test with 0.05 Type I error. Assuming a 
discontinuation rate between 15 and 20%, approximately 12 patients will be enrolled in each 
cohort to provide 10 patients who complete the treatment period. 
10.2. 
Endpoints 
10.2.1. 
Safety 
Safety and tolerability of oral ketamine will be assessed by evaluating adverse events, vital 
signs, concomitant medications and physical examinations. 
10.2.2. 
Efficacy 
Efficacy is exploratory in this study.  Endpoints will include the CGI-I score and published total 
and/or domain scores for the Clinical Domain Report, Parent Domain Report, RSBQ, MBA, RTT 
CIA, and CSHQ. Biosensor device algorithms and raw datasets will be explored.   
Additional exploratory statistical methods to further assess for treatment effect will be described 
in the clinical study report and/or resulting publications, as deemed appropriate. 
10.3. 
Analysis Populations 
10.3.1. 
Treatment Period 
The Safety Population will include all patients who receive study drug during the Treatment 
Period.   
The Efficacy Population will include all patients who receive both assigned study drugs and 
have at least 1 post-treatment efficacy assessment for both assigned study drugs.   
10.4. 
Analyses 
Statistical analyses will be summarized in a statistical analysis plan prior to database lock. All 
data captured in the electronic data capture system (EDC) will be listed by patient. 
Continuous measures will be summarized descriptively (mean, standard deviation, median, 
minimum value, and maximum value) and categorical measures will be presented as number 
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10.4.1. 
Disposition and Baseline Characteristics 
Disposition will be summarized by cohort and randomized sequence. The number and 
percentage of patients, who are randomized, treated, prematurely discontinued, and complete 
the study will be summarized.  
Baseline characteristics will be summarized by cohort and randomized sequence. 
The number of patients in each cohort will be summarized for each investigative site for the 
Treatment Period.  Medical history will be coded with the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. Concomitant medications will be summarized by World Health 
Organization Drug Dictionary Anatomical-Therapeutic-Chemical classification (ATCC) and 
preferred term.   
10.4.2. 
Efficacy 
Unless otherwise indicated, treatment differences will be assessed with an analysis of variance 
model that includes sequence (placebo-ketamine, ketamine-placebo), treatment, and treatment 
by sequence interaction as fixed effects and patient nested within sequence as a random effect.  
Sequence will be tested using patient nested within sequence as the error term.  
For daily biosensor data, change from the average value during Screening to the average value 
during treatment (Days 1 to 5 during first treatment and Days 15 to 19 during the second 
treatment) will be assessed for treatment differences. Additionally, change from the average 
value during Screening to the average value during the full treatment period (Days 1 to 14 
during first treatment and Days 15 to 28 during the second treatment) will be assessed for 
treatment differences.  
Change from pre-dose baseline (Day 1) to post-dose (Day 15 for first treatment and Day 29 for 
second treatment) will be assessed for treatment differences for total and domain scores of the 
Clinical Domain Report, Parent Domain Report, RSBQ, MBA, RTT CIA, and CSHQ. 
Additionally, change from pre-dose baseline (Day 1) to post-dose (Day 8 for first treatment and 
Day 22 for second treatment) will be assessed for treatment differences for total and domain 
scores of the Parent Domain Report and CSHQ, as well as Day 43 for the Parent Domain 
Report and the RTT CIA. As a secondary analysis, pre-dose baseline will be defined as day 1 of 
each treatment (Day 1 for first treatment and Day 15 for second treatment). 
For the CGI-I, scores on Day 15 and Day 29 will be assessed for treatment differences with the 
analysis of variance.  Additionally, each patient will be categorized as improved (at least minimal 
improvement per the CGI-I) or not improved. The McNemar test will be used to assess 
treatment differences in the proportion of patients who improve. 
EEG analysis will be described separately. 
10.4.3. 
Study Drug Exposure 
Study drug exposure will be summarized for each treatment. The number of days on which 
study drug was dosed will be summarized. 
10.4.4. 
Safety 
All safety summaries will be descriptive with no statistical hypothesis testing and based on the 
Safety Population. Patients will be summarized according to the study drug received. All safety 
endpoints will be listed in by-patient data listings. 


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Adverse events will be coded using MedDRA and summarized by system organ class and 
preferred term.  Clinically significant deteriorations in physical examination findings will be 
reported and summarized as adverse events. 
Adverse Events 
An adverse event reported after informed consent, but before the first dose of study drug (i.e., 
Day 1), will be considered a pre-treatment adverse event.  Treatment-emergent adverse events 
(TEAEs) will be defined as any adverse event that occurs after administration of the first dose of 
study drug.  The number and percentage of patients who report TEAEs will be summarized by 
treatment, system organ class, and preferred term.  
Treatment emergent adverse events will also be summarized by intensity as well as relationship 
to study drug.   
Patients who report the same preferred term on multiple occasions within a treatment will be 
counted once for the preferred term within the treatment: under the highest severity when 
summarized by severity and under the closest relationship to study drug when summarized by 
relationship.  If a patient reports multiple preferred terms for a system organ class within a 
treatment, the patient will be counted only once for that system organ class within the treatment. 
The number and percentage of patients who experience TEAEs will be summarized by 
treatment for the following: 
• 
By system organ class and preferred term 
• 
Severe TEAEs by system organ class, and preferred term 
• 
Drug-related TEAEs by system organ class, and preferred term 
• 
Serious adverse events by system organ class and preferred term 
• 
Serious adverse events related to study drug, system organ class, and preferred 
term 
• 
Adverse events resulting in discontinuation of study drug by system organ class and 
preferred term 
By-patient listings will be provided for any deaths, serious adverse events, and adverse events 
leading to discontinuation of treatment.  
Vital Signs 
The mean change from baseline to each scheduled assessment will be summarized 
descriptively by treatment group for each vital sign variable specified in this protocol. 
Baseline will be defined as the last vital sign value obtained before the first dose of study drug 
(Day 1 for first treatment and Day 15 for second treatment).  


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11. 
REGULATORY CONSIDERATIONS 
11.1. 
Good Clinical Practice 
The conduct, evaluation, and documentation of this study are designed to ensure that the study 
is conducted according to GCP, as described in ICH Guideline E6 and in accordance with the 
general ethical principles outlined in the Declaration of Helsinki.   
11.2. 
Protocol Amendments 
Any permanent change to the protocol, whether it is an overall change or a change for specific 
study center(s), must be handled as a protocol amendment.  The Investigator will not make any 
changes to this protocol without prior written consent from the Sponsor-Investigator and 
subsequent approval by the IRB.     
11.3. 
Audits and Inspections 
Regulatory authorities may audit the Investigator during or after the study. 


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12. 
DATA HANDLING AND RECORDKEEPING 
12.1. 
Confidentiality 
Submission of this protocol and any other necessary documentation to the IRB is expressly 
permitted. Authorized regulatory officials will be allowed full access to inspect and copy the 
records.  The copied and inspected records will remain at the site and will not be transmitted or 
removed from the site.     
12.2. 
Patient Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., protected health information 
authorization).  
The Investigator will protect individual patient information to the fullest extent possible during 
this study. Patients will be identified only by unique subject numbers in eCRFs and other 
datasets generated for this study.   
12.3. 
Data Collection 
Data obtained for analysis in this protocol will use an electronic data capture system for use by 
individuals who authorized to make or change entries. Data from the biosensor systems will be 
uploaded to the appropriate database and housed separately, according to the company’s data 
management practices and standard operating procedures. 
12.4. 
Case Report Form Completion 
Data within the eCRF will be monitored according to the study-specific Monitoring Plan. The 
completed eCRF for each patient must be signed and dated by the Investigator to signify that 
the eCRF has been certified to be complete and accurate. 
12.5. 
Database Management, Data Clarification, and Quality 
Assurance 
A designated Contract Research Organization (CRO) will be responsible for data management. 
Quality control procedures will be conducted prior to database lock according to the CRO’s 
standard operating procedures. When the database has been declared to be complete and 
accurate, it will be locked.   
12.6. 
Inspection of Records 
All data required for completion of the eCRF for this study should be captured in source notes or 
electronic records. All source documents should be correctly labeled, filed, and associated with 
a single, verifiable patient, maintained by the Investigator, and made available for inspection by 
authorized persons.   
12.7. 
Retention of Records 
For investigational studies, Investigators must retain study records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 


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is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until two years after the investigation is discontinued and FDA is notified. 


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13. 
PUBLICATION POLICY 
The results of this study may be published in a medical publication, journal, or another public 
dissemination, or may be presented at a medical conference or used for teaching purposes.  
This study and its results may be submitted for inclusion in health authority study registry 
websites as required by local health authority regulations.   


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14. 
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