Conditions: Angelman Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
The purpose of the study is to assess the safety and tolerability of oral OV101 (gaboxadol) in adult and adolescent subjects with Angelman syndrome. In addition, several exploratory efficacy outcome measures will be investigated.

Detailed description:
Two dosing schedules of OV101 (gaboxadol) giving as once daily or twice daily dose will be assessed against placebo.

Arms:
arm 1: OV101 once daily arm 2: OV101 twice daily arm 3: Twice daily

Interventions: intervention 1: OV101 Regimen 1 intervention 2: OV101 regimen 2 intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
1.
TITLE PAGE
PROTOCOL 
A Phase 2 Angelman Syndrome Clinical Trial: A Randomized, Double-blind, Safety 
and Efficacy Study of Gaboxadol (Short Name: STARS) 
Protocol No:  
OV101-15-001 
Investigational Product: 
Gaboxadol (OV101) 
Indication: 
Angelman syndrome (AS) 
Sponsor: 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
USA 
Sponsor Signatory and Medical 
Lead: 
 
 
Ovid Therapeutics Inc. 
Steering 
Committee 
Meeting 
Chair: 
 
 
 
Development Phase: 
Phase 2 
Date of the Protocol: 
Version of the Protocol: 
4.0 (Amendment 3) 
The confidential information in this document is provided to you as an investigator, 
potential investigator or consultant for review by you, your staff and applicable 
Institutional Review Board (IRB). It is understood that the information will not be 
disclosed to others without written authorization from Ovid Therapeutics Inc. except to 
the extent necessary to obtain informed consent from those persons to whom the drug 
may be administered. 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
24 Oct 2017


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2.
TABLE OF CONTENTS
1.
TITLE PAGE ............................................................................................................. 1 
2.
TABLE OF CONTENTS .......................................................................................... 2 
3.
SPONSOR INFORMATION .................................................................................... 8 
4.
SIGNATURE PAGES ............................................................................................... 9 
5.
GENERAL INFORMATION ................................................................................. 10 
6.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 12 
7.
STUDY SYNOPSIS ................................................................................................. 14 
8.
INTRODUCTION ................................................................................................... 26 
8.1 
Background and Overview of Angelman Syndrome ......................................................26 
8.2 
Study Rationale ..............................................................................................................28 
9.
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 29 
9.1 
Primary Objectives .........................................................................................................29 
9.2 
Secondary Objective .......................................................................................................29 
9.3 
Exploratory Objective ....................................................................................................31 
10.
STUDY DESIGN .................................................................................................. 32 
10.1 
Overall Study Design and Plan .......................................................................................32 
10.1.1 
Description .................................................................................................. 32 
10.1.2 
Schedule of Assessments ............................................................................. 32 
10.1.3 
Study Assessments ....................................................................................... 35 
10.2 
Discussion of Study Design ............................................................................................40 
10.3 
Risk/Benefit Assessment ................................................................................................40 
11.
SELECTION OF SUBJECTS ............................................................................ 41 
11.1 
Diagnosis and Main Criteria for Inclusion: ....................................................................41 
11.2 
Inclusion Criteria ............................................................................................................41 
11.3 
Exclusion Criteria ...........................................................................................................42 
11.4 
Withdrawal of Subjects ..................................................................................................43 
12.
TREATMENT OF SUBJECTS .......................................................................... 44 
12.1 
Identity of Study Treatment(s) .......................................................................................44 
12.1.1 
OV101 ......................................................................................................... 44 
12.1.2 
Placebo ....................................................................................................... 44 
12.1.3 
Administration of Study Treatments ............................................................ 44 
12.2 
Study Treatment Packaging and Labeling ......................................................................46 


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12.2.1 
Packaging ................................................................................................... 46 
12.2.2 
Labeling ...................................................................................................... 47 
12.2.3 
Storage ........................................................................................................ 47 
12.3 
Blinding and Randomization to Study Treatments .........................................................47 
12.4 
Procedure for Breaking the Randomization Code ..........................................................47 
12.5 
Subject Compliance ........................................................................................................48 
12.6 
Study Drug Accountability .............................................................................................48 
12.7 
Concomitant Therapy .....................................................................................................49 
13.
DISCONTINUATION OF STUDY TREATMENT OR WITHDRAWAL OF
SUBJECTS FROM STUDY........................................................................................... 50 
13.1 
Withdrawal/Discontinuation of Individual Subjects ......................................................50 
13.1.1 
Withdrawal from the Study ......................................................................... 50 
13.1.2 
Discontinuation of Study Drug ................................................................... 50 
13.2 
Study Termination ..........................................................................................................50 
14.
EFFICACY ASSESSMENTS ............................................................................. 51 
14.1 
Efficacy Assessments .....................................................................................................51 
14.1.1 
Gross Motor Ability/Function ..................................................................... 51 
14.1.2 
Fine Motor Ability/Function ....................................................................... 52 
14.1.3 
Sleep ............................................................................................................ 53 
14.1.4 
(Mal)adaptive Behaviors: ........................................................................... 54 
14.1.5 
Clinical Change: ......................................................................................... 55 
14.1.6 
Health-Related Quality of Life of the Individual with AS ........................... 55 
14.1.7 
Health-Related Quality of Life – Impact on Caregiver: ............................. 55 
15.
SAFETY ASSESSMENTS .................................................................................. 56 
15.1 
Suicidality .......................................................................................................................56 
15.2 
Physical Examination .....................................................................................................56 
15.3 
Vital Signs ......................................................................................................................56 
15.4 
Laboratory Assessments .................................................................................................56 
15.5 
Electroencephalogram Assessments ...............................................................................57 
15.6 
Optional Biomarker Analysis .........................................................................................57 
16.
SAFETY
DEFINITIONS, 
RECORDING, 
REPORTING, 
AND  
RESPONSIBILITIES ..................................................................................................... 58 
16.1 
Adverse Events ...............................................................................................................58 
16.1.1 
Definitions ................................................................................................... 58 


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16.1.2 
Overdose ..................................................................................................... 63 
16.1.3 
Pregnancy ................................................................................................... 63 
16.1.4 
Medical Emergency .................................................................................... 63 
16.1.5 
Safety Responsibilities ................................................................................ 63 
17.
STATISTICAL EVALUATION ......................................................................... 65 
17.1 
Sample Size and Power ..................................................................................................65 
17.2 
Statistical Methods .........................................................................................................65 
17.2.1 
General Considerations .............................................................................. 65 
17.2.2 
Statistical Analysis Sets ............................................................................... 66 
17.2.3 
Baseline, Efficacy, and Safety Variables .................................................... 66 
17.2.4 
Methods of Statistical Analyses .................................................................. 68 
18.
DIRECT ACCESS TO SOURCE DATA/NOTES ............................................ 70 
19.
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 71 
19.1 
Conduct of the Study ......................................................................................................71 
19.2 
Study Monitoring............................................................................................................71 
20.
ETHICS ................................................................................................................ 72 
20.1 
Institutional Review Board .............................................................................................72 
20.2 
Written Informed Consent ..............................................................................................72 
21.
DATA PROTECTION ........................................................................................ 74 
22.
CONFLICT OF INTEREST ............................................................................... 75 
23.
CLINICAL TRIAL STEERING COMMITTEE ............................................. 76 
24.
CHANGES TO FINAL STUDY PROTOCOL ................................................. 77 
25.
DATA HANDLING AND RECORD KEEPING .............................................. 78 
25.1 
Electronic Case Report Forms/Source Data Handling ...................................................78 
25.2 
Retention of Essential Documents ..................................................................................78 
26.
FINANCING AND INSURANCE ...................................................................... 79 
27.
REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS ............. 80 
28.
SIGNATURE OF INVESTIGATOR ................................................................. 81 
REFERENCE LIST ........................................................................................................ 82 


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List of Tables 
Table 1 
Schedule of Assessments ................................................................................ 33 
Table 2 
Study Titration Schedule ................................................................................ 45 
Table 3 
Clinical Chemistry and Hematology Tests ..................................................... 57 


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List of Figures 
Figure 1: 
Study Design ............................................................................................... 32 


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List of Appendices 
Not applicable 
24 October 2017


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3.
SPONSOR INFORMATION
Ovid Therapeutics Inc. is the Sponsor of this study. 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
For urgent medical issues that require the study’s Medical Director be contacted, please 
refer to the contact list for complete contact information. 
Ovid Therapeutics Inc. may transfer any or all if its study-related responsibilities to 
contract research organization and other third parties; however, Ovid retains overall 
accountability for these activities. 


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4.
SIGNATURE PAGES
SPONSOR SIGNATURE PAGE 
PROTOCOL 
A Phase 2 Angelman Syndrome Clinical Trial: A Randomized, Double-blind, Safety 
and Efficacy Study of Gaboxadol (Short Name: STARS) 
Protocol No: OV101-15-001 
Date (day/month/year) 
10/25/2017


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5.
GENERAL INFORMATION
PROTOCOL 
A Phase 2 Angelman Syndrome Clinical Trial: A Randomized, Double-blind, Safety 
and Efficacy Study of Gaboxadol (Short Name: STARS) 
Protocol No: OV101-15-001 
Sponsor: 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
USA 
Clinical Research Organization: 
 
 
 
 
 
Sponsor Medical Lead and 
Signatory 
 
 
 
 
 
 
Steering Committee Meeting 
Chair: 
 
 
 
 
 
 
 


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The Medical Monitor must be contacted in the event of any urgent safety issues. 
Ovid Therapeutics Inc. is transferring responsibilities as outlined in the Transfer of 
Obligations document. 


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6. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABC-C 
Aberrant Behavior Checklist – Community  
 
 
AE 
Adverse event 
AS 
Angelman syndrome 
 
 
ß-hCG 
beta-Human chorionic gonadotrophin 
BID 
Twice daily 
 
 
 
 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
 
 
CI 
Confidence interval 
COA 
Clinical outcomes assessment 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
eCRF 
Electronic case report form 
EEG 
Electroencephalogram 
 
 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FXS 
Fragile X syndrome 
GABA 
Gamma-aminobutyric acid 
GCP 
Good clinical practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional review board 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary of Regulatory Activities 
MM 
 
Medical Monitor 
 
MMRM 
Mixed model repeated measures 
 
 
 


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PT 
Preferred term 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
 
 
 
 
SOC 
System organ class 
SOL 
Sleep onset latency 
SOP 
Standard operating procedure 
SS 
Safety analysis set 
TEAE 
Treatment-emergent adverse event 
TST 
Total sleep time 
UBE3A/Ube3a 
Ubiquitin protein ligase E3A 
ULN 
Upper limit of normal 
USA 
United States of America 
WASO 
Wake after sleep onset 
 
 


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7. 
STUDY SYNOPSIS  
Name of Sponsor/Company:  
Ovid Therapeutics Inc. 
 
Name of Investigational Product:  
OV101 (gaboxadol) 
 
Name of Active Ingredient:  
OV101 (gaboxadol)  
 
Protocol Number:  
OV101-15-001 
 
Title of Study:  
A Phase 2 Angelman Syndrome Clinical Trial: A Randomized, Double-Blind, Safety and Efficacy Study 
of Gaboxadol (Short Name: STARS) 
 
Version Number:  
Protocol Version 4.0 
 
Study Indication:  
Angelman syndrome (AS) 
 
Study Rationale 
OV101 (gaboxadol) is being evaluated in Phase 2 studies of subjects with AS. This rare neuro-genetic 
disorder occurs in approximately 1 in every 15,000 live births and manifests as several distinct 
characteristics. Consistent clinical findings range in severity and include developmental delay, movement 
and/or balance disorder, and tremulous movement of limbs. Perhaps the most unique behavioral 
characteristic is the combination of a happy demeanor, smiling, and frequent bouts of laughter. Moreover, 
these individuals possess an easily excitable personality exhibited by hand-flapping or waving 
movements. Finally, these individuals suffer from motor dysfunction related to gait and balance, severe 
disruptions in sleep, impairments in speech, and frequent seizures with characteristic abnormal 
electroencephalogram (EEG) patterns. Individuals with AS will require life-long care. 
OV101 is the first highly selective extrasynaptic gamma-aminobutyric acid (GABA) receptor agonist that 
binds to the α4 and δ-subunit containing extrasynaptic GABA receptors as an orthosteric agonist and may 
restore the deficit in tonic inhibition that has been associated with AS. This is unlike any other 
GABAergic agent, including benzodiazepines, zolpidem and other Z-drugs, neurosteroids and drugs that 
act on GABA metabolism or uptake. Further, in a mouse model of AS, gaboxadol was shown to restore 
tonic inhibition in UBE3A-deficient cerebellar neurons and correct motor abnormalities in 
UBE3A-deficient mice. 
These results suggest that OV101 may alleviate the motor dysfunction observed in individuals with AS. 
These potential effects on tonic inhibition may impact motor function in people with AS. 
Previous Phase 2 and 3 studies in subjects with primary insomnia suggest OV101 is effective in restoring 
classical sleep parameters and slow-wave sleep, resulting in an improvement in the quality and restorative 
effects of sleep. One study using a transient insomnia model involving 100 subjects showed that 
administration of OV101 resulted in statistically significant improvements on both sleep induction and 
sleep maintenance. More importantly, these effects were achieved without the risk of drug dependence. 
 
 
 
 


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Since the targeted study population may not be compliant with certain study assessments, the highest 
possible level of flexibility will be applied to the schedule of assessments at each study center visit, thus 
minimizing the risk of missing or confounded data, while data reliability is maintained. 
 
Phase of Development:  
Phase 2 
 
Study Design:  
Multicenter, randomized, parallel (3-arm), double-blind, placebo-controlled 
 
Study Location:  
Approximately 15 specialized centers across the United States of America and 1 specialized site in Israel 
 
Principal Investigator:  
 
 
Study Period (first subject first visit to database lock):  
1.5 year 
 
Estimated date of first subject first visit: 
1st Quarter 2017 
 
Estimated date last subject last visit: 
2nd Quarter 2018 
 
Study Objectives and Endpoints: 
The primary objective of the study is to evaluate the safety and tolerability of OV101 from Baseline to 
Week 6 and Week 12 in adolescent and adult subjects with AS across different dose levels and in 2 dosing 
schedules.  
The following dosing schedules will be assessed against placebo: 
• 
Once daily (QD): An evening dose titrated to the target dose of 15 mg unless not tolerated 
• 
Twice daily (BID): Evening and morning doses titrated to the target doses of 15 mg evening dose 
and 10 mg morning dose unless not tolerated 
The safety endpoints that relate to this objective are as follows: 
• 
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) 
• 
Vital signs (weight, blood pressure, heart rate, and temperature) 
• 
Laboratory parameters (electrolytes, lipids, glucose, hepatic, renal and pancreatic function tests, 
and hematology). It is in the discretion of the study center staff to apply local best practices to 
obtain a blood sample from the subject 
• 
Irritability will be assessed using the Aberrant Behavior Checklist – Community (ABC-C) in an 
attempt to assess suicidality 
• 
EEG 
• 
Caregivers will maintain an electronic seizure diary. Any clinically important changes, including 
changes in seizure medication, will be reported as a safety event 
• 
Physical Exam findings 


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▪ 
 
 
 
 
 
 
 
 
 
 
  
All safety and efficacy assessments will be performed as indicated in the schedule of assessments 
(Table S2). Assessments such as laboratory sampling and EEG should be done towards the end of a visit 
to minimize any confounding impact on subject performance. Options to perform these safety assessments 
away from the study center prior to the study center visit will be assessed in collaboration with study 
center staff and approved by the Medical Monitor case by case, if required. 
Additional biomarker samples will be acquired from all subjects for whom the caregiver provides a 
separate informed consent for purification of DNA and plasma, to allow for identification of secondary 
pathogenic variants and metabolic profiles. 
 
Number of subjects (planned): 
Approximately 75 subjects will be enrolled. At the completion of the study, there will be approximately 
25 subjects in each of the 3 treatment groups: 1) single evening dose 2) morning and evening dose, and 
3) placebo. 
Sample size calculations for this study are based on the objective of estimating AE rates within each 
active treatment group. The sample size of 25 subjects per group provides sufficient precision for 
estimation of incidence of common AEs. For example, a 2-sided 95% confidence interval (CI) for a true 
incidence of 25% will estimate that incidence with a 17% precision (half-width of the 95% CI). 
While the expected enrollment is 25 subjects per treatment group, if enrollment expectations are not 
realized, the sample size may be as low as 20 subjects per group.  A sample size of 20 subjects per group 
provides sufficient precision for estimation of incidence of common AEs.  For example, a 2-sided 95% CI 
for the true incidence of 25% will estimate that incidence with 19% precision. 
 
 
 
 
 
 
 
 
 
 
 
  
Methodology: 
All subjects will receive a morning dose (either OV101 or placebo) and an evening dose (either OV101 or 
placebo) during the entire duration of treatment. The 2 dosing schedules of OV101 will be assessed; a 
single evening dose (QD): based on what was previously clinically assessed in the treatment of sleep 
disorder; Schedule A) and a morning plus evening dose (Schedule B: BID) designed to provide a more 
sustained exposure. Schedule C is morning and evening placebo. All subjects will be up-titrated to the 




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• 
Day 1: Treatment can start on any day during the week. The next up-titration will occur on 
Day 3. If the defined interval occurs during the weekend, a + 2 day window for next titration step 
is acceptable, but the investigator should consider scheduling the start of treatment appropriately 
to limit titration steps occurring during the weekend. All subjects will start with 1 capsule 
(OV101 or placebo) in the evening 
Given the potential effects with food: 
• 
For the morning dose, it is recommended that the study drug be given with or shortly after the 
morning meal 
• 
For the evening dose, it is recommended that study drug be given within 30 minutes of scheduled 
bedtime 
Target up-titration 
• 
Day 3 (window + 2 days): If no AE related to the study drug is observed from the previous time 
point by caregiver and/or the investigator, another capsule (OV101 or placebo) is added in the 
evening 
• 
Day 7 (window + 2 days): If no AE related to the study drug is observed from the previous time 
point by caregiver and/or the investigator, another capsule (OV101 or placebo) is added in the 
evening 
• 
Day 10 (window + 2 days): If no AE related to the study drug is observed from the previous time 
point by caregiver and/or the investigator, another capsule (OV101 or placebo) is added in the 
morning 
• 
Day 14 (window + 2 days): If no AE related to the study drug is observed from the previous time 
point by caregiver and/or the investigator, another capsule (OV101 or placebo) is added in the 
morning 
Slowed up-titration 
If tolerability does NOT allow immediate further dose-escalation at any of the above detailed 
days (3, 7, 10, or 14), but if that is possible at subsequent visit (e.g. Day 10 instead of Day 7), 
also such delayed up-titration will be acceptable. In such a case, the investigator will record 
up-titration data during the additional phone titrations calls. Any intolerability will be 
documented as an AE. 
Down-titration 
Modifications may be made per investigator judgment on urgent need or medical necessity. If 
tolerability is not acceptable (e.g. somnolence, dizziness, vomiting, or change in behavior) after a 
previous up-titration step or during the 12 weeks of treatment, the Investigator should discuss 
with the Sponsor MM or his/her delegate if necessary. Any such intolerability must be 
documented as an AE. Once a tolerable dose has been reached, it shall remain constant for the 
duration of the treatment period. 
Ongoing treatment 
• 
Day 14: Earliest day the target dose can be reached (10 mg [2 capsules] in the morning and 
15 mg [3 capsules] in the evening): if so, dosing should be kept stable until the End of Treatment 
visit (Week 12) unless intolerability requires down-titration per the above described conventions 




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to attend scheduled study visits to participate in all assessments described in the protocol 
5. Able to attend scheduled study visits and be willing to perform the required clinical evaluations  
6. Able to ingest the study drug  
7. Caregivers must agree not to post any subject’s personal medical data related to the study or 
information related to the study on any website or social media site (e.g. Facebook, Twitter, etc.) 
until the study is completed 
Exclusion Criteria 
1. Non-ambulatory subjects (e.g. requiring a wheelchair) not able to perform the assessments of 
Motor Ability/Function 
2. Poorly controlled seizures defined as > 3 seizures lasting less than 3 minutes per week or 
> 1 seizure episode lasting more than 3 minutes per week or as per medical monitor judgment 
3. Concomitant cardiovascular or respiratory diseases of a degree that would limit participation in 
the study 
4. Concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine or cardiovascular system 
disease) or condition or any clinically significant finding at screening that could interfere with 
the conduct of the study, or that would pose an unacceptable risk to the subject in this study. 
5. Any of the following laboratory abnormalities: total bilirubin >1.5 x upper limit of normal (ULN) 
(unless isolated Gilbert’s syndrome), alanine aminotransferase or aspartate aminotransferase 
>2.5 x ULN; serum creatinine >1.2 x ULN; absolute neutrophil count <1.5 x 109/L, platelets 
< 80 x109/L, hemoglobin <80 g/L; TSH >1.25 x ULN or <0.8 x ULN. 
6. Pregnancy 
7. Women of child-bearing potential who are not using a double-barrier method of contraception 
(e.g. condoms plus oral contraceptives), with abstinence being an accepted method 
8. Concomitant use of minocycline, levodopa, zolpidem, zaleplon, eszopiclone, ramelteon or 
benzodiazepines for sleep, as well as, cannabinoid derivatives, and any other use of any 
investigational agent, device, and/or investigational procedure 4 weeks prior to Baseline and 
during the study 
9. Allergy to OV101 or any excipients 
10. At increased risk of harming self and/or others based on investigator assessment 
11. Any condition or reason that in the opinion of the investigator makes the subject unsuitable for 
enrollment 
12. Inability of subject or caregiver to comply with study requirements 
 
Study periods, duration of treatment and follow-up:  
1. Screening (up to 28 days) if a subject needs a repeat lab or additional lab to confirm eligibility 
the screening period may be extended. 
2. Baseline visit (Day 1); full day visit 
3. Titration period (2 weeks); at least 4 titration phone visits during that period 
4. Treatment until end of Week 12; at least 3 safety phone visits during that period 
5. Interim; full day visit at Week 6 
6. End of Treatment; full day visit at Week 12 
7. Follow-up period; the study center will have 1 phone visit (2 weeks after End of Treatment) to 
capture information on any AEs which occur after the End of Treatment visit 


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Statistical methods for analysis: 
Descriptive statistics will be used to summarize all primary and secondary endpoints as well as baseline 
variables, by treatment group. For continuous variables, n, number of missing values, mean, standard 
deviation, median, minimum, and maximum will be provided. For categorical variables, frequency and 
percentage will be presented for each category. The CIs will be provided where meaningful. All CIs will 
be 2-sided 95% CIs. All data collected during the study will be listed. 
The primary endpoint is the incidence of treatment emergent adverse events (TEAE). The Safety Analysis 
Set (all subjects that received at least one dose of study drug) will be used for the analysis of the TEAEs. 
All AEs will be coded using the latest released version of Medical Dictionary of Regulatory Activities 
(MedDRA) and will be classified by MedDRA system organ class (SOC), and preferred term (PT). The 
number and percentage of subjects who experience at least one TEAE as well as the number and 
percentage of subjects who experience at least one TEAE within each specific SOC and PT will be 
presented by treatment group. 
 
 
 






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8.
INTRODUCTION
8.1 
Background and Overview of Angelman Syndrome 
Angelman syndrome (AS) is a rare neurogenetic disorder associated with the deletion of 
or mutation in the Ubiquitin Protein Ligase E3A gene (UBE3A). While expressed 
ubiquitously in the cells of other tissues, in neurons the paternal allele is preferentially 
silenced through the epigenetic process known as imprinting. Therefore, any alteration in 
the maternal copy of UBE3A results in the expression of the AS phenotype. The 
syndrome occurs in approximately 1 in every 15,000 live births and has several distinct 
characteristics. Clinical findings range in severity and may include developmental delay, 
movement and/or balance disorder, and tremulous movement of limbs. The most unique 
behavioral characteristic is the combination of a happy demeanor, smiling, and easily 
provoked. Moreover, these individuals possess a short attention span and an easily 
excitable personality exhibited by hand-flapping or waving movements. Finally, 
individuals with AS suffer from motor dysfunction related to gait and balance, severe 
disruptions in sleep, impairments in speech, anxiety, and frequent seizures with 
characteristic abnormal electroencephalogram (EEG) patterns1.  
Current Therapies for Angelman Syndrome 
There are no current specific treatments for AS. Clinical management includes 
management of symptoms including anti-epileptic medications for seizure control and 
oftentimes medications for sleep or anxiety. Physical and occupational therapies, 
communication therapy, and behavioral therapies are important in allowing individuals 
with AS to reach their maximum developmental potential2. 
Pre-clinical Experience with OV101 
Research has shown that absence (or dysfunction) of UBE3A results in an aberrant 
increase in the uptake of gamma-aminobutyric acid (GABA), which the main inhibitory 
neurotransmitter in the brain. OV101 is the first highly selective GABA receptor agonist 
that binds to the α4 and δ-containing GABAA receptors. These receptors mediate tonic 
inhibition and contribute to sleep maintenance. Further, in a mouse model of AS, 
gaboxadol was shown to restore tonic inhibition in Ube3a-deficient cerebellar neurons 
and correct motor abnormalities in Ube3a-deficient mice3. 
These results suggest that OV101 may alleviate the motor dysfunction observed in 
individuals with AS. Importantly, OV101’s ability to potentiate tonic inhibition is unlike 
any other GABAergic agent, including benzodiazepines, zolpidem, other Z-drugs, 
neurosteroids, and drugs that act on GABA metabolism or uptake. 
In addition to the data on presynaptic dysfunction leading to reduced tonic inhibition, 
there are additional studies which speak to the potential of OV101 in AS, including 
modulation of sleep and cognition domains that are impaired in AS subjects4,5,6,7,8,9. 
 
 
 
 
 


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Pharmacokinetics 
The pharmacokinetic profile of OV101 was similar whether administered in the morning 
or evening in the fasting state 
11. There were also no differences between 
morning and evening pharmacokinetics when OV101 was given with food. A high-fat 
meal just prior to OV101 administration in the morning or evening delayed absorption by 
0.5 to 1 hours and decreased maximum concentration by approximately 30%, while 
exposure was practically unchanged compared with the fasting state. 
Prior Clinical Experience 
OV101 was generally safe and well tolerated in all Phase 2 and 3 studies in more than 
4300 subjects with insomnia, in non-elderly adult subjects (aged 18 to 64 years) at doses 
up to 15 mg (in 1 early Phase 2 study up to 20 mg). In non-elderly adult subjects, the 
most common adverse events (AEs) occurring more frequently in OV101-treated subjects 
than in subjects on placebo were dizziness, nausea, vomiting, somnolence, and headache. 
Most AEs were of mild to moderate intensity. Generally, tolerability was better in male 
than in female subjects. 
OV101 administration in the morning was safe at all doses 
12. In healthy 
young men, doses up to 20 mg were well tolerated when given alone as single morning 
doses for 5 days. In young women, a 15 mg morning dose was not well tolerated or 
tolerated with considerable discomfort from Day 2 and onwards. An evening dose of 
15 mg was well tolerated in young women and women above 55 years for 3 consecutive 
days. Therefore, a 10 mg morning dose was chosen for this study. The AEs with the 
highest incidences were dizziness, nausea, headache, and somnolence. The majority of 
AEs had a rapid onset (within 1 to 2 hours post-dose) and resolved after the drug was 
discontinued. 


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Approximately 500 subjects were exposed to OV101 in clinical studies in 
non-insomnia-related development. The safety and tolerability profile of OV101 in the 
non-insomnia-related studies was similar to that in sleep disorder studies. In general, the 
AEs seemed to be dose related, with no AEs reported for the 5 mg dose, and only mild 
AEs reported for the 10 mg dose of OV101. 
8.2 
Study Rationale 
OV101 acts with high potency and efficacy at extrasynaptic α4 and δ-containing GABAA 
receptors which are not activated by benzodiazepines, or agents acting at the 
benzodiazepine binding site (such as zolpidem, zaleplon, indiplon, and zopiclone). These 
extrasynaptic δ receptors are thought to be involved in mechanisms underlying tonic 
inhibition and sleep maintenance. In vivo and in vitro studies have shown that neither 
alcohol nor benzodiazepines potentiate the activity of OV101. In contrast to 
benzodiazepine receptor agonists, no withdrawal effects with OV101 are seen after 
chronic dosing. 
The possibility that OV101 may alleviate the motor dysfunction observed in individuals 
with AS and the ability of OV101 to potentiate tonic inhibition makes OV101 a candidate 
for potential treatment of people with AS. 
Based on previous clinical experience, in this study OV101 will be titrated across 
different dose levels (15 mg evening dose and 10 mg morning dose) and in 3 dosing 
schedules for 12 weeks. 
The morning dose was selected based on a Phase 1 study in healthy volunteers which 
determined that a 10 mg morning dose had a comparable safety profile compared to 
placebo. The evening dose was selected based on the safety and efficacy data obtained 
from all studies conducted by H. Lundbeck A/S and Merck in the indication of insomnia 
(reference to IND 64,567). 
This Phase 2 study will assess the safety and tolerability of oral OV101 in adolescent and 
adult subjects with AS. In addition, multiple endpoints will be explored to identify the 
most appropriate efficacy outcome measures for future Phase 3 studies. 
This includes all main AS symptom domains of gross and fine motor function, sleep, 
behavior, and health-related quality of life, with focus on motor ability and sleep. The 
impact on caregivers will also be assessed. Questionnaires, diaries,
 will be 
used, complemented by more innovative outcome measures (gait analysis). 
Testing may be extensive for some of the study subjects, so the highest possible level of 
flexibility will be applied to the schedule of assessments at each study center visit to 
minimize the risk of missing or confounded data, while maintaining data reliability. 
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP). More information 
can be found in the Investigator’s Brochure.10 


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9. 
STUDY OBJECTIVES AND ENDPOINTS 
9.1 
Primary Objectives 
The primary objective of the study is to evaluate the safety and tolerability of OV101 
from Baseline to Week 6 and Week 12 in adolescent and adult subjects with AS across 
different dose levels and in 2 dosing schedules. 
The following dosing schedules will be assessed against placebo: 
• Once daily (QD): An evening dose titrated to the target dose of 15 mg unless not 
tolerated 
• Twice daily (BID): Evening and morning doses titrated to the target doses of 
15 mg evening dose and 10 mg morning dose unless not tolerated 
The safety endpoints that relate to this objective are as follows: 
• Frequency and severity of AEs and serious adverse events (SAEs) 
• Vital signs (weight, blood pressure, heart rate, and temperature) 
• Laboratory parameters (electrolytes, lipids, glucose, renal, hepatic and pancreatic 
function tests, and hematology). It is in the discretion of the study center staff to 
apply the best local practices to obtain a blood sample from the subject. 
Laboratory sampling should be done towards the end of a visit to minimize any 
confounding impact on subject performance 
• Irritability will be assessed using the Aberrant Behavior Checklist – Community 
(ABC-C), Irritability subscale as a surrogate measure for suicidality 
• EEG 
• Caregivers will maintain an electronic seizure diary. Any clinically important 
changes, including changes in seizure medication, will be reported as a safety 
event 
• Physical Exam findings 
9.2 
Secondary Objective 
 
 
 
 
 
 
 
 
 
 
 


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9.3 
Exploratory Objective 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








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10.1.3 Study Assessments 
Section 14 details the individual assessments. 
10.1.3.1 
Screening Period (Day -28 to Day 0) 
After obtaining a signed informed consent form (ICF) from the parent or legally 
authorized caregiver and assent as appropriate from the potential subject, individuals with 
AS will begin the study screening procedures for eligibility including clinical and 
laboratory evaluation and all measurements used for efficacy assessment (sleep, motor 
function, and behavior). Assent will be obtained if the investigator believes that the 
subject can provide it depending on the subject’s intellectual ability, but assent may not 
be relevant for non-verbal subjects. 
Investigators will explain to caregivers the necessity to discontinue the intermittent use of 
sleep medication and not to introduce new medication during the study. 
 
 
 
 
Study centers will request a subject registration and treatment code centrally generated by 
an Interactive Web Response System (IWRS) (Section 12.3). No subject may begin 
treatment prior to assignment of a unique identification number (registration) and 
randomization. Any subject identification numbers that are assigned will not be reused, 
even if the subject does not receive treatment. 
Screening laboratory assessments will be performed. 
Caregivers will also be asked to sign a separate ICF for the subject to provide an 
additional blood sample (1 tube) at Baseline (and on Day 84 [Section 10.1.3.2]) to permit 
purification of DNA and plasma to enable identification of secondary pathogenic gene 
variants and allow for metabolic profiling. Those not consenting to this will still be 
eligible for the main study. 
All subjects will be screened for participation in the study up to 28 days prior to the first 
dose administration. Subjects who meet all criteria can be randomized at any time during 
the screening period. The screening assessments are listed in Table 1. 
The caregiver will be provided with an e-Diary for documenting sleep and subject’s 
seizures
 
 
 
 
. 
During the screening period, it will be determined by the Investigator whether or not the 
caregiver and subject are able to complete all questionnaires and assessments that require 
their contribution to assess their ability to comply with study procedures.  


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For those without documentation of a molecularly-confirmed diagnosis, blood samples 
will be obtained during the screening period and subjected to methylation sensitive 
polymerase chain reaction amplification of a portion of the small nuclear 
ribonucleoprotein polypeptide N gene and/or UBE3A gene sequencing to confirm the 
diagnosis of AS. 
 
 
 
 
  
Screening and Baseline assessments must be performed within the 28-day period. If the 
subject can perform the Screening and Baseline visit within 5 days, the following 
assessments do not need to be repeated at the Baseline visit (medical history, clinical 
assessment, physical examination, clinical laboratory tests, serum pregnancy test, and 
concomitant medications).  
Those not meeting the inclusion criteria or meeting an exclusion criterion will be 
considered a screen failure. It shall be discussed with Medical Monitor whether later 
rescreening is acceptable. Rescreening may be allowed under circumstances where the 
subject passed the screening but could not be randomized within the 28 day screening 
window due to logistical, personal or other unforeseeable reasons. Rescreening will only 
be allowed in cases where no safety risk is posed to the subject.  
If a screening test result (lab or any other tests) is considered uncertain or abnormal, the 
test may be repeated to confirm the result after approval from the Medical Monitor. If a 
subject needs a repeat lab or additional lab to confirm eligibility the screening period may 
be extended. 
 
10.1.3.2 
Treatment Period (12 Weeks) 
Baseline Visit (Day 1; Full Day Visit) 
Eligible subjects will return to the study center for the Baseline (Day 1) visit. Caregivers 
will bring the e-Diary and wearables. Prior to randomization, study center staff must 
confirm proper recording of the wearables, appropriate completion of the e-Diary, and 
fulfilment of all selection criteria. 
Subjects will be randomized on a 1:1:1 ratio according to the following dosing 
schedule: 
• 
Schedule A: a single evening dose of OV101 (QD) plus morning placebo 
• 
Schedule B: a morning plus evening dose of OV101 (BID) 
• 
Schedule C: morning and evening placebo 
• Subjects will receive the assigned package of blinded study treatment as per 
treatment code for the titration period and until the next scheduled visit at Week 6 
• Baseline safety and efficacy assessments will be conducted 


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• Baseline laboratory assessments will be performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The e-Diary will be kept by the caregiver throughout the study. It must be charged 
overnight each day by the caregiver. Study center staff shall remotely check data 
completeness at least once a week and contact caregiver if there is non-adherence, such as 
missing data. 
Titration (Day 1 to Day 14) 
Section 12.1.1 details the dosing schedule. 
During the titration period (Day 1 to Day 14), doses progressively increase in 5 mg 
increments according to the titration schedule, allowing slower up- or down-titration if 
the OV101 or placebo treatment is not tolerated (Table 2) up to a target evening dose of 
15 mg (3 capsules) in Schedules A and B, and up to a target morning dose of 10 mg 
(2 capsules) in Schedule B. Multiple phone visits are scheduled to confirm tolerability of 
study treatment. Each dose-escalation will be performed after adequate tolerability has 
been assessed by the caregiver and investigator during a phone visit. At any time, ad-hoc 
study center visits may occur to further assess drug safety. These should follow the script 
for phone visits. 
If the target dose is not achieved at Day 14 (due to slowed titration based on 
intolerability), the up-titration can continue until the target dose or the maximum 
tolerated dose is reached. Additional phone visits to agree on next titration level will be 
performed. As a general guidance for investigators, for subjects undergoing a slowed 
titration regimen, the maximal tolerated dose for the duration of the study should be 
reached by Day 21. 
Investigators will decide whether to up- or down-titrate based on subject 
symptomatology, which should be discussed with the Sponsor MM or his/her delegate as 
necessary. The study center will document each titration step in the electronic case report 
form (eCRF) and in source documents. The AEs triggering any slower- or down-titration 
will be recorded. Modifications may be made per investigator judgment based on urgent 


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need or medical necessity. If tolerability is not acceptable (e.g. somnolence, dizziness, 
vomiting, or change in behavior) after a previous up-titration step or during the course of 
the 12 weeks of treatment, the Investigator should discuss with the Sponsor MM or 
designee if necessary. Any such intolerability must be documented as an AE. Once a 
tolerable dose has been reached, it shall remain constant for the duration of the treatment 
period. The study center will provide the caregiver with written dosing instructions until 
the next titration step, by fax, e-mail, or during an unscheduled study center visit. 
Treatment (Day 15 to Day 84); Until End of Week 12 
If the target dose was not yet achieved at Day 14 (due to slowed titration based on 
intolerability), up-titration can continue until the target dose or the maximum tolerated 
dose is reached. Additional phone visits to agree on next titration level will be performed. 
As a general guidance for investigators, for subjects undergoing a slowed titration 
regimen, the maximal tolerated dose for the duration of the study should be reached by 
Day 21. 
At Days 30 and 60 (±2 days) the caregiver will courier the wearables back to the study 
center, because battery life will come to an end around that time. Study center staff will 
upload and check data for any compliance or user errors. If errors are detected, the 
caregiver will be contacted to receive further instructions how to properly use the 
wearable. Study center staff will courier a new set of wearables to the caregiver. 
Interim Visit (Week 6; Full Day Visit) 
During the Week 6 visit (Day 43, window ±3 days); subjects will make an interim full 
day study center visit to for the following procedures:  
• All scheduled safety and efficacy assessments will be conducted 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Additional phone visits are scheduled to confirm tolerability of study drug 
• If tolerability is not acceptable (e.g. somnolence, dizziness, vomiting, or change in 
behavior) after a previous up-titration step or during the course of the 12 weeks of 


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treatment, the Investigator should discuss with the Sponsor MM or designee if 
necessary. Any such non-tolerability must be reported as an AE.  
End of Treatment (Week 12; Full Day Visit) 
During the Week 12 visit (Day 84, window +3 days); subjects will make a final full day 
study center visit for the following procedures: 
• Safety and efficacy assessments 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Caregivers will bring the e-Diary to the study center. Any e-Diaries no longer 
required will be returned to the 
 at or before 
study center closure 
• Subjects will be asked to volunteer an additional tube of blood to permit 
purification of DNA and plasma to enable identification of secondary pathogenic 
gene variants and allow for metabolic profiling 
• The last dose of study drug should be taken the morning of the Day 84 visit if the 
subject is on the BID dosing regimen. After the last dose during the treatment 
period, downward titration of OV101 is not necessary given that in previous 
clinical studies with OV101, no withdrawal effects were observed after chronic 
dosing.  
10.1.3.3 
Follow-Up Period (Day 85 to 98) 
During the follow-up period, the study center will have 1 phone visit (2 weeks after End 
of Treatment) to capture information on any AEs which occur after the End of Treatment 
visit, using the phone visit script. 
10.1.3.4 
Early Termination 
The study may be terminated at an individual study center if it becomes apparent that 
subject enrollment is unsatisfactory with respect to quality and/or quantity. Study centers 
may also be closed if they prove to be unable to comply with the requirements of the 
protocol or GCP, or data recording is inaccurate and/or incomplete. If the study is 
terminated in an individual study center for any reason, the investigator must make every 
effort to follow-up all subjects as planned according to the protocol. Replacement of 
study centers is allowed and new study centers may be initiated. An initiative for study 
center closure or study termination can be taken at any time either by Ovid Therapeutics 


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Inc. or by the investigator, provided there is reasonable cause and sufficient notice is 
given in advance of the intended termination.  
See Section 13 for early withdrawal from study. For early withdrawal, subject should 
follow Week 12 study visit schedule of assessment for safety measure which include 
medical history, clinical assessment, ABC-C irritability subscale, physical examination, 
clinical lab test, serum pregnancy test, concomitant medications. Efficacy assessments do 
not need to be completed. 
10.2 
Discussion of Study Design 
Neither the investigators nor the subjects will be aware of the treatment assignments, to 
minimize any subjective or unrecognized bias in reporting. Placebo will be used as the 
comparator. 
Based on the potential reproductive effects observed in pre-clinical studies, 
pre-menopausal females who have a positive pregnancy test at the screening or baseline 
visits, or those who are not able to use an effective method of contraception (with 
abstinence being an accepted method), will be excluded from the study. 
Pre-clinical and clinical data suggest that the doses prescribed in this study will likely be 
therapeutically relevant and well-tolerated.  
A variety of scales will be employed for the exploratory assessment of safety and 
exploratory efficacy endpoints (Section 13).  
10.3 
Risk/Benefit Assessment 
In adult subjects, the most common AEs occurring more frequently in OV101-treated 
subjects than in subjects on placebo have been dizziness, nausea, vomiting, somnolence, 
and headache. Most AEs have been mild to moderate severity. OV101 is generally 
tolerated better by males than females and has been generally safe and well tolerated in 
Phase 2 and 3 insomnia studies in adult subjects at doses up to 15 mg and in the elderly at 
doses up to 10 mg. 
OV101 is rapidly absorbed and eliminated when given orally at doses of 10 to 40 mg. 
The maximum plasma concentration is reached after half to 1 hour, the elimination 
half-life is approximately 1.5 hours and there is no evidence of accumulation after 5 days 
of multiple dosing. Pharmacokinetic data from the adolescent PK study OV101-16-001 
with a single 5 mg oral administration to adolescent male and female subjects with FXS 
or AS suggest the exposure of OV101 is comparable to young adult subjects given the 
same dose. The dosing recommendation for adolescents in this study is therefore the 
same as for adults. 
Close monitoring of safety will be conducted throughout this study. 


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11. 
SELECTION OF SUBJECTS 
11.1 
Diagnosis and Main Criteria for Inclusion:  
Adolescents and adults with a molecularly-confirmed diagnosis of AS will be eligible for 
inclusion in the study. See Section 10.1.3.1 for testing of individuals who do not have 
documentation of diagnosis. 
After obtaining signed informed consent from the legally authorized representative (e.g. 
parent or caregiver) and assent as appropriate from the potential subject, an individual 
with AS will begin the study screening procedures to confirm eligibility. The screening 
procedures to confirm eligibility will include clinical and laboratory evaluation as well as 
all measurements to assess exploratory efficacy (sleep, motor function, and behavior).  
Those who do not consent to the gene biomarker sampling will still be eligible to 
participate in the STARS study.  
 
 
 
 
 
 
For those individuals not possessing documentation of a molecularly confirmed AS 
diagnosis, DNA samples will be obtained during the screening period to confirm the 
diagnosis of AS. 
If a subject needs a repeat lab or additional lab to confirm eligibility the screening period 
may be extended. 
11.2 
Inclusion Criteria 
A subject will be eligible for enrollment in the study if ALL of the following criteria 
apply: 
1. Age ≥ 13 years, ≤ 49 years at the time of informed consent 
2. Molecular confirmation of AS 
3. Receiving a stable dose of concomitant medications such as anti-epileptic 
medication, gabapentin, clonidine, melatonin, trazadone, supplements, special 
diets for at least 4 weeks prior to Baseline; and able to maintain these throughout 
the duration of the study 
4. Has a parent or caregiver capable of providing informed consent on behalf of the 
subject and able to attend scheduled study visits to participate in all assessments 
described in the protocol 
5. Able to attend scheduled study visits and be willing to perform the required 
clinical evaluations 
6. Able to ingest the study drug  


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7. Caregivers must agree not to post any subject’s personal medical data related to 
the study or information related to the study on any website or social media site 
(e.g. Facebook, Twitter, etc.) until the study is completed 
11.3 
Exclusion Criteria 
A subject will NOT be eligible for this study if any of the following criteria apply: 
1. Non-ambulatory subjects (e.g. requiring a wheelchair) not able to perform the 
assessments of Motor Ability/Function 
2. Poorly controlled seizures defined as > 3 seizures lasting less than 3 minutes per 
week or > 1 seizure episode lasting more than 3 minutes per week or as per 
medical monitor judgment 
3. Concomitant cardiovascular or respiratory diseases of a degree that would limit 
participation in the study 
4. Concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine or 
cardiovascular system disease) or condition or any clinically significant finding at 
screening that could interfere with the conduct of the study, or that would pose an 
unacceptable risk to the subject in this study 
5. Any of the following laboratory abnormalities: total bilirubin >1.5 x upper limit 
of normal (ULN) (unless isolated Gilbert’s syndrome), alanine aminotransferase 
or aspartate aminotransferase >2.5 x ULN; serum creatinine >1.2 x ULN; absolute 
neutrophil count <1.5 x 109/L, platelets < 80 x109/L, hemoglobin <80 g/L; 
TSH >1.25 x ULN or <0.8 x ULN 
6. Pregnancy 
7. Women of child-bearing potential who are not using a double-barrier method of 
contraception (e.g. condoms plus oral contraceptives), with abstinence being an 
accepted method 
8. Concomitant use of minocycline, levodopa, zolpidem, zaleplon, eszopiclone, 
ramelteon or benzodiazepines for sleep, as well as, cannabinoid derivatives, and 
any other use of any investigational agent, device, and/or investigational 
procedure 4 weeks prior to Baseline and during the study 
9. Allergy to OV101 or any excipients 
10. At increased risk of harming self and/or others based on investigator assessment 
11. Any condition or reason that in the opinion of the investigator, makes the subject 
unsuitable for enrollment 
12. Inability of subject or caregiver to comply with study requirements 


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11.4 
Withdrawal of Subjects 
A subject may voluntarily withdraw at any time and for any reason. If a subject 
withdraws, at his or her request or at the request of his or her caregiver or legal 
representative, the reason(s) must be recorded on the relevant page of the subject’s eCRF. 
Subjects who withdraw from the study prematurely should undergo all end-of-study 
assessments where possible. It is vital to obtain follow-up data on any subject withdrawn 
because of an AE. In any case, every effort must be made to undertake protocol-specified 
safety follow-up procedures. If a subject refuses to continue with study procedures, the 
reason for refusal should be fully documented in the subject’s source document and 
recorded in the study specific eCRF. Subjects who withdraw from the study prior to 
completing the final follow-up visit may be replaced at the discretion of Ovid 
Therapeutics Inc.  


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12. 
TREATMENT OF SUBJECTS 
12.1 
Identity of Study Treatment(s) 
12.1.1 OV101 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.1.2 Placebo 
Placebo will be provided as a visually matching capsule, without active ingredient. 
12.1.3 Administration of Study Treatments 
OV101 will be supplied as a 5 mg capsule, and matching placebo, in bottles. The 
caregiver will receive a sufficient number of capsules in 1 bottle “Morning” and 1 bottle 
“Evening” at the baseline visit and at the Week 6 interim visit. 
All subjects will receive a morning dose of OV101 or placebo and an evening dose of 
OV101 or placebo during the entire duration of treatment. Two dosing schedules of 
OV101 will be assessed; a single evening dose (Schedule A: QD) based on what was 
previously clinically assessed in the treatment of sleep disorder, and a morning plus 
evening dose (Schedule B: BID) designed to provide a more sustained exposure. 
Schedule C is morning and evening placebo (BID). All subjects will be up-titrated to the 
target dose unless this target dose is not tolerated (for titration conventions see below). 
All subjects will receive treatment for a maximum of 12 weeks at their highest tolerated 
dose. The last dose of study drug should be taken the morning of the Day 84 visit if the 
subject is on the BID dosing regimen. 
Given the potential effects with food previously described: 
• For the morning dose, it is recommended that the study drug be given with or 
shortly after the morning meal 
• For the evening dose, it is recommended that study drug be given within 
30 minutes of scheduled bedtime 
The capsules can be opened and content added to one spoon of semi-liquid food 
(applesauce, pudding etc.). CAPSULE CONTENT CANNOT BE PLACED IN LIQUID. 
It must be documented specifically how the capsules were taken e.g. swallowed whole or 
taken in one spoon of applesauce or other food. 




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12.1.3.4 
Target Up-Titration 
Day 3 (window + 2 days): If no AE related to study treatment is observed from the 
previous time point by caregiver and/or the investigator, another OV101 or placebo 
capsule is added in the evening. 
Day 7 (window + 2 days): If no AE related to the study treatment is observed from the 
previous time point by caregiver and/or the investigator, another OV101 or placebo 
capsule is added in the evening. 
Day 10 (window + 2 days): If no AE related to the study treatment is observed from the 
previous time point by caregiver and/or the investigator, another OV101 or placebo 
capsule is added in the morning. 
Day 14 (window + 2 days): If no AE related to the study treatment is observed from the 
previous time point by caregiver and/or the investigator, another OV101 or placebo 
capsule is added in the morning. 
12.1.3.5 
Slowed Up-Titration 
If tolerability does NOT allow immediate further dose-escalation at any of the above 
detailed days (3, 7, 10, or 14), but does at subsequent visit (e.g. Day 10 instead of Day 7), 
delayed up-titration will also be acceptable. In this case, the investigator will record 
up-titration data during the additional phone titrations calls. Any such intolerability must 
be documented as an AE. 
12.1.3.6 
Down-Titration 
Modifications may be made per investigator judgment on urgent need or medical 
necessity. If tolerability is not acceptable (e.g. somnolence, dizziness, vomiting, or 
change in behavior) after a previous up-titration step or during the course of the 12 weeks 
of treatment, the Investigator should discuss with the Sponsor MM or his/her delegate if 
necessary. Any such intolerability must be documented as an AE. Once a tolerable dose 
has been reached, it shall remain constant for the duration of the treatment period. 
12.1.3.7 
Ongoing Treatment 
Day 14: Earliest day the target dose can be reached (10 mg [2 capsules] in the morning 
and 15 mg [3 capsules] in the evening): if so, dosing should be kept stable until End of 
Treatment visit (Week 12) unless intolerability requires down-titration according to the 
above described conventions. 
12.2 
Study Treatment Packaging and Labeling  
12.2.1 Packaging 
OV101 will be supplied as a 5 mg capsule, and matching placebo, in 75 mL bottles 
containing 90 capsules for morning and 120 mL bottles containing 140 capsules for 
evening. The caregiver will receive a “Morning” bottle and an “Evening” bottle at 
Baseline and Week 6, respectively. Depending on the allocated treatment group, the 
“Morning” or “Evening” bottles will contain the following: 
• Group A (QD): Morning – Placebo/Evening – OV101 


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• Group B (BID): Morning – OV101/Evening – OV101 
• Group C (Placebo): Morning – Placebo/Evening – Placebo 
12.2.2 Labeling 
Bottles containing OV101 or matching placebo, will have color tinted labels marked 
“Morning” (yellow label) or “Evening” (blue label). Labels will include the Sponsor 
Name (Ovid Therapeutics Inc.), protocol number, bottle number (based on 
randomization), expiration date, number of capsules (each bottle), “Morning” or 
“Evening” and “Take as directed”, as well as storage specifications. Each bottle will be 
labeled with an English and Spanish label. Bottles and study treatment will be distributed 
by unique bottle number as designated by the IWRS and bottle quantities will be supplied 
to each study center in accordance with IWRS. 
12.2.3 Storage 
Study treatment must be received by a designated person at the study center, handled and 
stored safely and properly, and kept in a secured location to which only the investigator 
and designated staff have access. Study treatments are to be dispensed only in accordance 
with the protocol. The investigator is responsible for keeping accurate records of study 
treatment supplies received from Ovid Therapeutics Inc., the amount dispensed to and 
returned by the subjects, and the amount remaining at the conclusion of the study. Study 
treatment should be stored at ≤ 86°F. 
12.3 
Blinding and Randomization to Study Treatments 
This is a double-blind, placebo-controlled study. Investigators, study staff, and study 
subjects will be blinded to the randomized study treatment assignments. Both 
randomization and blinding techniques will be used in this study to minimize bias. A 
computer-generated randomization schema will be centrally available via IWRS to all 
clinical centers that meet the requirements for participation in the study. The IWRS 
system can be accessed by individuals who have been issued a user ID and password, 
such as individuals at the study center or individuals from
 
 
 
 Caregivers and investigators will also be asked at the 
End of Treatment visit whether they believe the subject was in an OV101 or placebo 
treatment arm. 
12.4 
Procedure for Breaking the Randomization Code 
In most cases, study drug unblinding will not be necessary. In a medical emergency 
where knowledge of the subject’s treatment assignment may influence the subject’s 
clinical care, the investigator, and if applicable, designated personnel at
 may 
access the subject’s treatment assignment. The study center investigator and appropriate 
 project team members will be authorized to access the emergency unblinding 
functionality within the IWRS. The system will require the user to enter an authorization 
key number to complete the emergency unblinding transaction. The exact description of 
the treatment assigned to the individual subject then will be accessible. Emergency 


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unblinding can thus be made for any subject without affecting the double-blind nature of 
the study. Subject treatment information may only be accessed in the event of an 
emergency and out of necessity to know the identity of the allocated study drug to 
institute appropriate therapeutic management. The investigator should make every effort 
to discuss the rationale for emergency unblinding with the
 Medical Monitor prior 
to unblinding the individual subject. Emergency unblinding should only be considered in 
situations where the knowledge of the treatment code has an impact on the planned 
treatment of the emergency. Once the randomization code is broken for a subject, he/she 
must be withdrawn from the study. 
Should a situation arise where unblinding is urgently required (i.e. knowledge of 
treatment code is required to adequately manage a life-threatening situation), the 
investigator at that study center may perform immediate unblinding through IWRS 
without the need for communication with the 
 Medical Monitor. 
In the event that emergency unblinding is performed, the investigator can view and must 
print the blinded confirmation document from IWRS. The investigator must record on the 
confirmation document printout the reason for the emergency unblinding, and sign the 
document. The confirmation document must then to be kept in a safe place until the end 
of the study. Once a randomization code has been broken, the investigator must inform 
the 
 Medical Monitor in writing within 24 hours. The investigator is strongly 
advised not to divulge the subject’s treatment assignment to any individual not directly 
involved in managing the medical emergency, nor to personnel involved with the analysis 
and conduct of the study. The investigator can contact Ovid Therapeutics Inc. or their 
designee to discuss such situations without divulging subject’s treatment assignment. 
12.5 
Subject Compliance 
Study drug compliance will be assessed by the investigator and/or study center staff by 
recording capsule counts of study treatments from the previously dispensed capsules, 
separately for “Morning” and “Evening” bottles. The investigator and/or study center 
staff will also assess whether the subject has been given the capsules in the prescribed 
order. The total number of doses administered to each subject will be derived from dosing 
information recorded in the eCRF. 
Caregivers must bring the bottles back at each study center visit. Any remaining capsules 
will be counted and recorded to assess compliance. Caregivers shall be questioned as to 
the reason why remaining capsules have not been administered (e.g. forgot because not 
part of routine, subject refused, subject had side effects so parent decided to give a drug 
holiday, couldn’t open the bottle, down-titration recommended by doctor, etc.) and the 
approximate time of any missed doses. 
12.6 
Study Drug Accountability 
Records shall be maintained of the delivery of study drugs to the study centers, the 
inventory at the study centers, the use by each subject and the return to Ovid Therapeutics 
Inc. 
These records shall include dates, quantities, batch numbers, expiry dates and the unique 
code numbers assigned to the study drug and to the study subjects. 


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The investigator shall be responsible for ensuring that the records adequately document 
that the subjects were provided the doses specified in the protocol and that all study drug 
received from Ovid Therapeutics Inc. is reconciled. All randomization codes must be 
returned to Ovid Therapeutics Inc. at the end of the study. 
After completion of the study, all unused study drug will be inventoried and returned to 
Ovid Therapeutics Inc. or as directed by them. 
12.7 
Concomitant Therapy 
Medication other than those listed in the Exclusion Criteria (Section 11.3) that are given 
at stable dose for at least 4 weeks prior to Baseline (e.g. constant use of sleep or 
anti-epileptic medication) are acceptable, and must be documented in the eCRF.  
Any changes in dose should be avoided during the study and, if felt necessary, be 
previously discussed with the Medical Monitor. 
Medications that are not prohibited and considered necessary for the subject’s safety and 
well-being may be given during the study at the discretion of the investigator and must be 
recorded in the appropriate sections of the eCRF. 
All prior medications taken within 30 days and ongoing concomitant medication must be 
documented in the eCRF. 
Subjects must be receiving a stable dose of concomitant medications, including 
anti-epileptic medication, gabapentin, clonidine, melatonin, trazadone, supplements, and 
special diets, for at least 4 weeks prior to Baseline, and be able to maintain these 
throughout the study. Modifications may be made per investigator judgment based on 
urgent need or medical necessity. Subjects with questions about allowed concomitant 
therapy should seek medical guidance from the investigator. 


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13. 
DISCONTINUATION OF STUDY TREATMENT OR WITHDRAWAL OF 
 
SUBJECTS FROM STUDY 
13.1 
Withdrawal/Discontinuation of Individual Subjects 
The reasons for study drug discontinuation and/or subject withdrawal from the study 
must be recorded in the subject’s eCRF. The investigator must notify Ovid Therapeutics 
Inc. and/or the Medical 
Monitor immediately when a subject 
has 
been 
discontinued/withdrawn due to an AE. 
13.1.1 Withdrawal from the Study 
Subjects or their caregiver may withdraw subjects from the study at any time for any 
reason without compromising the subject’s medical care. The investigator may also 
withdraw subjects from the study. 
Subjects who withdraw from the study prior to the End of Treatment visit should 
complete the procedures scheduled for that visit. The reason for subject withdrawal will 
be recorded in the eCRF.  
Withdrawal of subjects for any reason should be discussed with the Medical Monitor. 
13.1.2 Discontinuation of Study Drug 
If it is necessary to discontinue the study drug earlier than planned, subjects should 
continue to be followed per protocol to capture safety and efficacy assessments for the 
duration of the study period if feasible. 
The investigator may withdraw the subject from the study drug for the following reasons: 
• Upon subject’s or caregiver’s request 
• The subject or caregiver is unwilling or unable to adhere to the protocol-specified 
visits 
• The subject experiences an intolerable AE 
• During the study, the subject develops symptoms or conditions listed in the 
exclusion criteria 
• Other medical reason, at the discretion of the investigator and/or the Medical 
Monitor 
Subjects who discontinue the study due to an AE considered related to study drug should 
be followed until the event is resolved, considered stable, or the investigator determines 
the event is no longer clinically significant. Study drug discontinuation due to AEs 
considered not related to study drug will be followed until resolution. 
13.2 
Study Termination 
The study, or any portion of it, may be terminated at any time for safety reasons including 
the occurrence of AEs or other findings suggesting unacceptable risk to subjects, 
administrative, or operational reasons. Study centers must promptly notify their IRB and 
initiate withdrawal procedures for participating subjects. 


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14. 
 
 
  
 
 
 
 
 
 
 
 
 
 
14.1 
Efficacy Assessments 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.1.4 (Mal)adaptive Behaviors: 
• The Aberrant Behavior Checklist - Community (ABC-C) is a rating scale that 
measures the severity of a range of problem behaviors commonly observed in 
individuals with intellectual and developmental disabilities17. It is completed by 
the caregiver. It is an empirically developed scale designed to measure psychiatric 
symptoms and behavioral disturbance exhibited by individuals across 5 domains 
with 58 items: irritability, agitation, and crying (15 items), lethargy, social 
withdrawal 
(16 items), 
stereotypy 
(7 items), 
hyperactivity/noncompliance 
(16 items), and inappropriate speech (4 items). Most individuals with AS are not 
able to communicate thoughts of suicidality, so subject irritability reported by the 
caregiver is being used as a surrogate measure of suicidality.  
• 
The ABC–C Irritability subscale will be used as an indicator for 
suicidality. The investigator will review the scale items with the caregiver 
at each scheduled time point. If grading worsens, the investigator must 
decide whether that indicates a suicidal ideation of the subject, and if so, 
must document it as an AE and closely monitor it until resolution. The 
ABC-C Irritability subscale will be used to assess risks of suicidality 
(safety variable). The Aberrant Behavior Checklist was developed for use 
with individuals living in institutions and residential settings. Revisions to 
the measure have made it more applicable for home and school settings; 
the commonly used measure is now the ABC-C version. 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.1.5 Clinical Change: 
Clinical Global Impressions (Severity [CGI-S] and Improvement [CGI-I] scales). 
Both scales will assess all sub-domains of AS (gross and fine motor ability, sleep, 
and adaptive behavior) and will be filled out by the caregiver and investigator. For 
the CGI-S, the rating should be relative to all people, including typically 
developing individuals in the community. This rating is based upon observed and 
reported symptoms, behavior, and function. The CGI-I rates total improvement 
compared to the subject’s condition at baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15. 
SAFETY ASSESSMENTS 
Details for safety assessments are provided below. Details regarding the management of 
AEs are provided in Section 16. 
15.1 
Suicidality 
Most individuals with AS are not able to communicate thoughts of suicidality, so subject 
irritability reported by the caregiver is being used as a surrogate measure of suicidality. 
The ABC–C Irritability subscale will be used as an indicator for suicidality. The 
investigator will review the scale items with the caregiver at each scheduled time point. If 
grading worsens, the investigator must decide whether that indicates a suicidal ideation of 
the subject, and if so, must document it as an AE and closely monitor it until resolution. 
15.2 
Physical Examination 
A physical examination should be performed at each visit to evaluate the medical 
condition of the subject and detect any sign/symptom of AEs, and to perform all the 
procedures required per protocol. 
A full physical examination will include a relevant general assessment of: head, eyes, 
ears, nose and throat; neck; heart; chest (including lungs); abdomen; extremities; skin; 
lymph nodes; as well as neurological and cardiovascular systems. 
15.3 
Vital Signs 
The following vital signs will be recorded during this study (this must include but not be 
limited to the measurement of changes in heart rate and blood pressure): 
• Heart rate 
• Blood pressure 
• Body temperature 
• Weight 
15.4 
Laboratory Assessments 
Blood samples will be collected for routine clinical laboratory safety evaluations. Study 
center staff can apply the best local practices to obtain a blood sample in this population. 
Additional laboratory safety evaluations will be performed at other times, if judged to be 
clinically appropriate, or if the ongoing review of the data suggests a more detailed 
assessment of laboratory safety evaluations is required. Any changes to the scheduled 
times of laboratory safety tests will be agreed with 
 and Ovid Therapeutics Inc. and 
documented. The investigator will perform a clinical assessment of all laboratory safety 
data. 
Laboratory parameters include electrolytes, lipids, glucose, renal, hepatic and pancreatic 
function tests, and hematology. A serum pregnancy test will be done for female subjects 
at the times noted in Table 1. 
Table 3 lists the clinical chemistry and hematology tests planned for this study. 


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Table 3 
Clinical Chemistry and Hematology Tests 
Clinical Chemistry 
Hematology  
Albumin 
Basophils (absolute) 
Alkaline phosphatase 
Eosinophils (absolute) 
Alanine aminotransferase 
Lymphocytes (absolute) 
Aspartate aminotransferase 
Monocytes (absolute) 
Bicarbonate 
Neutrophils (absolute) 
Calcium 
Basophils 
Chloride 
Eosinophils 
Cholesterol 
Hematocrit 
Creatine kinase 
Hematology slide 
Creatine, enzymatic 
Hemoglobin 
Direct bilirubin 
Lymphocytes 
Glucose, random, serum 
Monocytes 
High density lipoprotein cholesterol 
Neutrophils 
Indirect bilirubin 
Platelets 
Lactate dehydrogenase 
Red blood cells 
Low density lipoprotein cholesterol, calculated 
White blood cells 
Phosphorous 
- 
Potassium 
- 
Sodium 
- 
Total bilirubin 
- 
Total protein 
- 
Triglyceride 
- 
Urea (blood urea nitrogen) 
- 
Uric acid 
- 
Total cholesterol 
- 
Magnesium 
- 
Thyroid stimulating hormone 
- 
15.5 
Electroencephalogram Assessments 
EEG will be assessed as changes in background rhythms and the frequency of 
epileptiform discharges. Study centers will perform a routine EEG with local equipment. 
EEG should be done towards the end of a visit to minimize any confounding impact on 
subject performance. Standard protocol and montage will be followed as outlined in the 
separate EEG manual, including but not limited to resting and evoked stimuli. Placing of 
electrodes (if possible according to the international 10/20 system) must be documented. 
Recording should last about 10 minutes in the wake state, and if possible, recording 
should end with a nap period. Data will be collected in electronic format in European 
Data Format for centralized reading. An EEG manual will be provided. 
15.6 
Optional Biomarker Analysis 
Additional biomarker samples will be acquired from all subjects for whom the caregiver 
provides separate informed consent for purification of DNA, and plasma, to allow for 
identification of secondary pathogenic variants and metabolic profiles. 
Two tubes of blood will be collected at baseline for biomarker plasma and biomarker 
DNA and one tube of blood will be collected at End of Treatment (Day 84) for isolation 
biomarker plasma. DNA will be used to identify secondary pathogenic variants that may 
be present (e.g. microdeletions encompassing 2q21.3)18 and plasma for quantification of 
metabolites (e.g. glutamic acid)19. This data will not be captured in the CSR. 


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16. 
SAFETY 
DEFINITIONS, 
RECORDING, 
REPORTING, 
AND 
 
RESPONSIBILITIES  
The timing and frequency of safety assessments are described in Table 1 and Section 15. 
16.1 
Adverse Events 
16.1.1 Definitions 
The definitions for TEAEs, AEs, and SAEs are given below. The Principal Investigator is 
responsible for ensuring that all study center staff are familiar with the content of this 
section. Any AE experienced by the subject between the screening visit (Day -28) and up 
to completion of the follow-up period after the last administration of study drug (Day 98 
follow-up phone visit) must be recorded on the eCRF, regardless of the severity of the 
event or its relationship to study treatment. 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a clinical investigation subject, 
administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
Determination of whether an abnormal laboratory value meets the definition of an AE 
will be made by the investigator. Although abnormal laboratory values are typically not 
considered AEs, the following considerations may result in an abnormal laboratory value 
being considered an AE: 
• A laboratory test result meets the criteria for an SAE 
• A laboratory test result requires the subjects to receive specific corrective therapy 
• A laboratory abnormality that the investigator considers to be clinically 
significant 
Any intolerance that triggers a dose reduction during the titration period must be 
documented as an AE. 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that 
occurs after receiving study drug (AE start date ≥ first dose date) and within 30 days after 
receiving the last dose of study drug (AE start date minus last dose date ≤ 30), or an AE 
that occurs pre-treatment but worsens post treatment. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 


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• In the view of the investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it 
occurred in a more severe form, might have caused death 
• Requires inpatient hospitalization or prolongs existing hospitalization. Planned 
hospitalizations will NOT be reported as an SAE unless categorized as otherwise 
medically important 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is otherwise medically important: Important medical events that may not result in 
death, be life-threatening or require hospitalization may be considered a serious 
adverse drug experience, when based on appropriate medical judgment, they may 
jeopardize the subject or the subject may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition 
16.1.1.1 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment, including 
hospitalization that is part of the study design will not be considered an SAE, even if the 
subject is hospitalized. The study center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled prior to obtaining the informed consent to participate in the study 
• The condition requiring the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the 
opinion of the investigator between the informed consent and time of procedure or 
treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the 
sole reason for the intervention or hospital admission 
16.1.1.2 
Recording of Adverse Events 
For the purposes of this study, any detrimental change in the subject’s condition, from the 
screening visit (Day -28) and up to completion of the follow-up period after the last 
administration of study drug (Day 98 follow-up phone visit) should be considered an AE 
and must be recorded on the eCRF. 
All SAEs and AEs will be recorded starting from the screening visit (Day -28). 
All ongoing AEs should be followed up for 30 days after the last administration of study 
drug, with the exception of any ongoing study drug-related AEs, which should be 
followed until resolution, unless in the investigator’s opinion, the AE is unlikely to 
resolve due to the subject’s underlying disease. Any new SAEs occurring up to 28 days 
after the last administration of study drug (Day 98 follow-up phone visit) should be 
reported according to Section 16.1.1.6. 
At any time after the follow-up visit, if an investigator learns of an SAE that can be 
reasonably related to study drug, he/she should promptly notify Ovid Therapeutics Inc. 


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The severity of AEs and SAEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE, Version 4). Any AE not 
listed in the CTCAE will be graded as follows: 
 
Severity Grade 
Definition 
1 
Mild AE 
2 
Moderate AE 
3 
Severe or medically significant AE 
4 
Life-threatening AE 
5 
Death related to AE 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 16.1.1. 
An AE of severe intensity need not necessarily be considered serious. For example, 
nausea that persists for several hours may be considered severe nausea, but not an SAE. 
On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be an SAE. 
16.1.1.3 
Abnormal Laboratory Values/Vital Signs 
Laboratory/vital sign abnormalities should be reported as AEs if any one of the following 
criteria is met: 
• Any criterion for an SAE is fulfilled 
• The laboratory/vital signs abnormality causes the subject to discontinue from the 
study treatment 
• The laboratory/vital signs abnormality causes the subject to interrupt the study 
treatment 
• The laboratory/vital signs abnormality causes the subject to modify the dose of 
study treatment 
• The investigator believes that the abnormality should be reported as an AE 
• If an abnormal laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom should be reported as an AE and the associated 
laboratory result or vital sign should be considered additional information that 
must be collected on the relevant eCRF 
16.1.1.4 
Deaths 
Should a death occur within the study period or within 60 days after the last 
administration of study drug an AE form and an SAE form should be completed, 
detailing the AE that resulted in the death (death is an outcome, not an event). The SAE 
must be reported to the 
 Medical Monitor within 24 hours. The report should 
contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death. 


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16.1.1.5 
Relationship to Study Treatment 
The investigator will assess the causality/relationship between the study drug and the AE 
and record that assessment in the eCRF. The investigator should use medical judgment to 
determine whether there is a “reasonable causal relationship”, including all relevant 
factors such as temporal course and latency, results from de-challenge or re-challenge, 
pattern of the reaction, known pharmacological properties of the product, and alternative 
explanations, such as other drugs, medical history, and concomitant diseases. 
The expression “reasonable causal relationship” means to convey in general that there are 
facts (evidence) or arguments to suggest a causal relationship. Assessment will be 
documented on the AE and SAE form.  
The relationship should be assessed according to the following criteria: 
• No Reasonable Possibility: The relationship of the clinical event to the study drug 
makes a causal relationship unlikely, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the observed event. 
• 
None (intercurrent event): An event that is not and cannot be related to the 
study drug, such as subject is a passenger in a road traffic accident 
• 
Unlikely (remote): Relationship is not likely, such as a clinical event 
including laboratory test abnormality with temporal relationship to drug 
administration which makes a causal relationship improbable and in which 
other drugs, chemicals or underlying disease provide plausible 
explanations 
• Reasonable Possibility: The relationship of the clinical event to the study drug 
makes a causal relationship possible, and other drugs, therapeutic interventions, or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
• 
Possible: Relationship may exist, but event could have been produced by 
the subject’s condition or treatment or other cause 
• 
Probable: Relationship is likely, the AE abates upon discontinuation of 
study drug and cannot be due to the subject’s condition 
• 
Definite: Strong relationship, the event abates upon discontinuation of 
study drug and, if applicable, re-appears upon repeat exposure 
For the purposes of AE and SAE assessment, the causality criteria of Possible, Probable, 
and Definite are considered to represent a “reasonable causal relationship”. Conversely, 
the causality criteria of None or Unlikely are not considered to meet this threshold.  
For an AE to be a suspected study drug-related event there should be at least a reasonable 
possibility of a causal relationship between the study drug and the AE.  
16.1.1.6 
Reporting of Serious Adverse Events 
Investigators and other study center staff must inform appropriate
 representatives 
of any SAE that occurs (whether or not attributable to the study drug) in the study within 
24 hours (i.e. immediately but no later than the end of the next business day) or when he 


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or she becomes aware of it. It is the investigator’s responsibility to ensure that SAE 
reporting procedures are followed appropriately. 
All SAE reports must be faxed to the following number within 24 hours: 
 
 
 
 
 
 
 
 
 
 
 
In a study-related medical emergency situation, when assigned Medical Monitors for a 
study cannot be reached by a caller, an on-call Physician can be reached 24 hours per 
day, 7 days per week via the 
 
 
(chargeable telephone number allowing a global reach from both landlines and mobile 
phones) 
 
On this internet page, a list of country-specific toll-free telephone numbers is provided. It 
should be noted that not all countries globally have access to toll-free numbers 
as indicated on the “24/7 Medical Help Desk” index. Countries without toll-free 
numbers need to dial the chargeable number as indicated above. Furthermore, toll-free 
numbers are not available from mobile phones. 
The
 will work with the investigator to compile all the necessary 
information 
and 
ensure 
that 
the 
appropriate 
Ovid 
Therapeutics 
Inc. 
representative receives a report within one day (24 hours) for all fatal and life-
threatening cases and within 5 days for all other SAEs. 
Follow-up information on SAEs must also be reported by the investigator within the same 
time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided to
 within one day as described above. For a non-serious AE that 
become serious but which is not fatal or life-threatening a report should be 
received within 5 days. 
The following variables will be recorded for each AE: verbatim/AE description, time and 
date for AE start and stop, maximum intensity, seriousness, causality rating, whether 
or not the AE caused the subject to discontinue, and the outcome. 


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All SAEs have to be reported, whether or not considered causally related to the 
investigational product or to the study procedures. All SAEs will be recorded in the 
eCRF. The investigator is responsible for informing the Ethics Committee of the SAE as 
per local requirements. The investigator should report to 
, who will forward the 
report to the appropriate Ovid Therapeutics Inc. representative. 
16.1.2 Overdose 
An overdose is any dose of study treatment administered to a subject or taken by a 
subject that exceeds the dose assigned to the subject according to the protocol. Overdoses 
are not considered AEs and should not be recorded as an AE on the eCRF; however, all 
overdoses must be recorded on the overdose form and faxed to the 
 Safety Group 
within 24 hours of the study center becoming aware of the overdose. An overdose must 
be reported to the 
 Safety Group even if the overdose does not result in an AE. If an 
overdose results in an AE, the AE must be recorded. If an overdose results in an SAE, 
both the SAE and overdose forms must be faxed to the 
 Safety Group. If no AE is 
observed, this should be clearly stated in the report. 
16.1.3 Pregnancy 
Females of child-bearing potential (not surgically sterile) will undergo serum beta-human 
chorionic gonadotrophin (ß-hCG) pregnancy test at the times shown in Table 1. Any 
female subject with a positive pregnancy test result at Screening or Baseline must be 
excluded from the study. A serum ß-hCG pregnancy test must be performed if any 
woman is suspected of becoming pregnant during the study. 
If pregnancy occurs, study drug must be discontinued immediately. Pregnancy itself is 
not regarded as an AE unless there is a suspicion that the study drug may have interfered 
with the effectiveness of a contraceptive medication. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented even after the subject has been 
withdrawn from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages 
should also be reported and handled as SAEs. Elective abortions without complications 
should not be handled as AEs. All outcomes of pregnancy must be reported to Ovid 
Therapeutics Inc. on a pregnancy outcomes report form. 
16.1.4 Medical Emergency 
In a medical emergency requiring immediate attention, study center staff will apply 
appropriate medical intervention, according to standards of care. The investigator should 
contact the study Medical Director.  
16.1.5 Safety Responsibilities 
16.1.5.1 
Investigator 
The investigator responsibilities include: 
• Monitor and record all AEs and SAEs, regardless of severity or relationship to 
study treatment 


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• Determine the seriousness, relationship, and severity of each event 
• Determine the onset and resolution dates of each event 
• Complete an SAE form for each SAE and fax it to
 Safety within 24 hours 
of the study center becoming aware of the event 
• Pursue SAE follow-up information actively and persistently 
• Ensure all AE and SAE reports are supported by documentation in the subject’s 
medical records 
• Pursue AE follow-up information, if possible, until the event has resolved or 
become stable 
• Report SAEs to local ethics committees as required by local law 
16.1.5.2 
Ovid Therapeutics Inc. 
Ovid Therapeutics Inc. responsibilities include: 
• Before study center activation and subject enrollment, ensure the study center 
staff reviewed the definitions of AE and SAE and the instructions for monitoring, 
recording, and reporting them 
• Notify all appropriate regulatory authorities, ethics committees, and investigators 
of SAEs as required by local laws within required timeframes 


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17. 
STATISTICAL EVALUATION 
17.1 
Sample Size and Power 
Sample size calculations for this study are based on the objective of estimating AE rates 
within each active treatment group. The sample size of 25 subjects per group provides 
sufficient precision for estimation of incidence of common AEs. For example, a 2-sided 
95% confidence interval (CI) for a true incidence of 25% will estimate that incidence 
with a 17% precision (half-width of the 95% CI). 
While the expected enrollment is 25 subjects per treatment group, if enrollment 
expectations are not realized, the sample size may be as low as 20 subjects per group.  A 
sample size of 20 subjects per group provides sufficient precision for estimation of 
incidence of common AEs.  For example, a 2-sided 95% CI for the true incidence of 25% 
will estimate that incidence with 19% precision. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
17.2 
Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a separate Statistical Analysis Plan (SAP), which will be 
maintained by 
 This document may modify the plans outlined in 
the protocol; however, any major modifications of the endpoint definition and/or its 
analysis will also be reflected in a protocol amendment. Adverse events and efficacy 
variables may be further described by additional subgroups, such as age group, and 
details of this analysis will be provided in the SAP. Additional unplanned analyses may 
be required after all planned analyses have been completed. Any unplanned analyses will 
be clearly identified in the SAP. 
17.2.1 General Considerations 
All statistical analyses will be performed using Version 9.4 of Statistical Analysis 
Software (SAS®). 
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, and 
frequency and percentage for categorical and ordinal variables. If there are missing 


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values, the number missing will be presented, but without a percentage. All data collected 
will be included in by-subject data listings. 
Unless otherwise specified, all tests will be 2-tailed using a 0.05 level of significance. All 
CIs will be 2-sided 95% CIs. 
17.2.2 Statistical Analysis Sets 
The following 4 analysis sets will be included: 
Safety Analysis Set 
The Safety Analysis Set (SS) will consist of all subjects who receive at least one dose of 
study drug. Subjects will be analyzed according to the treatment they actually receive. 
The SS will be the primary analysis set for safety analyses. 
Intent-to-Treat Set 
The Intent-to-Treat set will consist of all subjects who are randomized, whether or not 
study drug is received. Subjects will be analyzed according to their randomized group. 
Full Analysis Set  
The Full Analysis Set (FAS) will consist of all randomized subjects who receive at least 1 
dose of study drug, and have at least 1 efficacy evaluation after receiving study drug. 
Subjects will be analyzed according to their randomized group. The FAS will be the 
primary analysis set for efficacy analyses. 
Per Protocol Set  
The Per Protocol Set is a subset of the FAS that includes all subjects who complete the 
Week 12 visit, and have no significant protocol violations that are deemed to impact 
efficacy. These violations include but are not limited to violations of inclusion/exclusion 
criteria, less than 80% study drug compliance, and usage of prohibited concomitant 
medications. Further details will be provided in the SAP. Subjects will be analyzed 
according to their randomized group. 
17.2.3 Baseline, Efficacy, and Safety Variables 
All baseline efficacy and safety variables will be presented using descriptive statistics by 
treatment group. The 2-sided 95% CIs will be provided where meaningful.  
More details of subgroup analysis will be provided in the SAP. 
17.2.3.1 
Baseline Variables 
Baseline variables include: 
• Demographic characteristics: age, age group (adolescents aged 13 to 17 versus 
adults aged 18 to 49 years), gender, race, and ethnicity 
• Enrollment by Study center/geographic region 
• Presence of baseline comorbidities  
• Baseline psychometric measures/scales 


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• Prior and concomitant medications 
• Medical and surgical history 
17.2.3.2 
Safety Variables 
The following safety variables will be evaluated: 
• SAEs, and TEAEs throughout the study, TEAEs leading to study discontinuation, 
treatment-related TEAEs, and TEAEs of special interest 
• Clinical safety laboratory values at Weeks 6 and 12 
• Suicidality (using the ABC–C Irritability subscale) at Weeks 6 and 12 
• Vital signs at Weeks 6 and 12 
• EEG and seizure diary assessments from baseline to end-of-study 
• Physical Exam at weeks 6 and 12 
17.2.3.3 
Efficacy Variables  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


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17.2.4 Methods of Statistical Analyses 
The SS and FAS will be used for safety and efficacy data analysis, respectively. Subjects 
in the FAS will be analyzed according to their randomized treatment arm. 
17.2.4.1 
Safety Analysis 
All AEs will be coded using MedDRA Dictionary Version 19.1 and will be classified by 
MedDRA system organ class (SOC) and preferred term (PT). 
The number and percentage of subjects who experience at least one TEAE and the 
number and percentage of subjects who experience at least one TEAE within each 
specific SOC and PT will be presented by treatment group. The 95% CIs will be 
displayed for the frequency of TEAEs. Treatment-related AEs will be considered those at 
least possibly related to investigational product based on the investigator’s assessment. 
The number and percentage of subjects reporting serious AEs, treatment-related AEs, and 
AEs leading to treatment discontinuation will also be summarized for each treatment 
group by MedDRA SOC and PT. 
Descriptive statistics for laboratory values and vital signs at each time point will be 
summarized by treatment group. Clinically significant laboratory values may be tabulated 
by treatment group. 
Shift tables for laboratory parameters will be presented to show the change of normality 
from Baseline to each post baseline visit. For each continuous laboratory parameter, 
results will be categorized as low, normal, or high based on the laboratory normal ranges. 
Frequencies and percentages will be presented by treatment arm for the shifts in these 
categories (i.e., low to normal, low to high, high to low, etc.) from baseline to each 
post-treatment assessment time point.  
Tables and graphical displays (such as scatter plots of baseline versus worst post-baseline 
values) of key safety parameters may be generated to better understand the study drug 
safety profile. 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. A table summarizing concomitant medications and by-subject listing of 
concomitant medications will include all medications taken during the study regardless of 
the timing for the start of the medication. 
17.2.4.2 
 
 
 
 


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17.2.4.3 
 
 
 
 
 


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18. 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, IRB review and regulatory inspection. 
 


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19. 
QUALITY CONTROL AND QUALITY ASSURANCE 
19.1 
Conduct of the Study 
Ovid Therapeutics Inc. or 
 shall implement and maintain quality control and quality 
assurance procedures with written standard operating procedures (SOPs) to ensure that 
the study is conducted and data are generated, documented and reported in compliance 
with the protocol, GCP and applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 1996) and all revisions thereof, and in accordance with Food and Drug 
Administration (FDA) regulations (Code of Federal Regulations, Sections 312.50 and 
312.56) and with ICH Guidelines on GCP (CPMP 135/95). 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change(s) involve(s) only 
logistical or administrative aspects of the study. Deviations must be reported to
 
and the IRB per local guidelines.  
19.2 
Study Monitoring 
The investigator shall permit the Study Center Monitor to review study data as frequently 
as deemed necessary to ensure that data are being recorded in an adequate manner and 
that protocol adherence is satisfactory. 
The investigator shall access medical records for the Study Center Monitor so that entries 
in the eCRFs may be verified. The investigator, as part of his/her responsibilities, is 
expected to co-operate with 
 in ensuring that the study adheres to GCP 
requirements. 
The investigator may not recruit subjects into the study until such time that a site visit, or 
with the agreement of Ovid Therapeutics Inc., attendance at the investigator meeting, has 
been made by an Ovid Therapeutics Inc. or
 monitor to conduct a detailed review of 
the protocol and eCRF. 


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20. 
ETHICS 
20.1 
Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol 
and ICF have been reviewed and approved by a relevant IRB. The IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH/GCP, 
and local requirements as applicable. 
The IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written ICFs and documents updates, subject recruitment procedures 
(e.g. advertisements), 
written 
information 
to 
be 
provided 
to 
the 
subjects, 
Investigator’s Brochure, available safety information, information about payment and 
compensation available to subjects, the investigators curriculum vitae and/or other 
evidence of qualifications and any other documents requested by the IRB and Regulatory 
Authority (Competent Authority) as applicable. 
When required, the IRB and Regulatory Authority must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with 
necessary timelines. 
20.2 
Written Informed Consent 
Prior to performing any study-related activities under this protocol, including screening 
tests and assessments, written informed consent from the parent/caregiver (or legally 
authorized representative) and assent, as appropriate, from the potential subject must be 
provided separately for each subject and their legally authorized caregiver in accordance 
with local practice and regulations.
 
 Should a subject gain the ability to sufficiently 
comprehend the situation and consent during the course of the study, written informed 
consent or verbal assent will be documented as required or recommended by the 
institution’s IRB.  
The background of the proposed study, the procedures, the benefits and risks of the study, 
and that the study participation is voluntary for the subject must be explained to the 
subject (or the subject’s legally authorized representative). The subject’s caregiver must 
be given sufficient time to consider whether to participate in the study. 
The form of consent to be obtained will depend on the condition of the subject as 
determined by the Principal Investigator. The ICF, as specified by the clinical site’s IRB, 
must follow the Protection of Human Subjects regulations listed in the Code of Federal 
Regulations, Title 21, Part 50. 
A copy of the signed and dated ICF (and assent as applicable) must be given to the 
subject’s caregiver or legally authorized representative. The signed and dated ICF will be 
retained with the study records. Local regulations must be followed with respect to the 
final disposition of the original (wet signature) and copies of the signed and dated ICFs.  
The ICF for subject participation must also be available as part of the subject’s medical 
record for review by the site’s dedicated study monitor or any authorized auditor of Ovid 
Therapeutics Inc. or regulatory authorities. 


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All ICFs must be approved by the appropriate IRB and by Ovid Therapeutics Inc. The 
ICF must not be altered without the prior agreement of the relevant IRB and Ovid 
Therapeutics Inc. 


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21. 
DATA PROTECTION 
Prior to any testing under this protocol, including screening test and assessments, subjects 
must also provide all authorizations required by local law (e.g. Protected Heath 
Authorization in North America). 
The subject will not be identified by name in the eCRF or in any study reports, and these 
reports will be used for research purposes only. Ovid Therapeutics Inc., its partners and 
designees, IRBs, and various government health agencies may inspect the records of this 
study. Every effort will be made to keep the subject’s personal medical information 
confidential. 


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22. 
CONFLICT OF INTEREST 
The investigators should address potential conflicts of interest (e.g. financial interest in 
Ovid or partnering companies) with the caregivers before the caregiver makes a decision 
to participate in the study. 


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23. 
CLINICAL TRIAL STEERING COMMITTEE 
A Clinical Trial Steering Committee will oversee all aspects of study design and 
execution and provide oversight and overall direction for the study. The committee 
members will contribute to the study design, protocol, protocol amendments, and ensure 
ethical conduct of study. The committee members will champion the study for 
investigators and study centers and ensure the well-being, rights, and safety of study 
participants, and will be responsible for communication of study results. 


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24. 
CHANGES TO FINAL STUDY PROTOCOL 
All protocol amendments must be submitted to the IRB and regulatory authorities as 
required by local law. Protocol modifications that affect subject safety, the scope of the 
study, or the scientific quality of study must be approved by the IRB before 
implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior 
to implementation. However, Ovid Therapeutics Inc. may at any time amend the protocol 
to eliminate an apparent immediate hazard to a subject. In this case, appropriate 
regulatory authorities will be notified subsequent to the modification. In the event of a 
protocol modification, the ICF may require similar modifications. 


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25. 
DATA HANDLING AND RECORD KEEPING 
25.1 
Electronic Case Report Forms/Source Data Handling 
The investigator shall be provided with standardized eCRFs and shall ensure that all data 
from subject visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The investigator must sign each eCRF to verify the integrity of the 
data recorded. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. If a central laboratory has been selected 
to conduct any or all tests, it is essential that all samples be analyzed at that laboratory. 
The investigator must maintain source documents, such as laboratory reports, EEGs, 
consultation reports, and complete medical history and physical examination reports. 
Data to be recorded directly on the eCRFs (i.e. no prior written or electronic record of 
data) and considered to be source data must be identified in the protocol. 
25.2 
Retention of Essential Documents 
The minimum retention time for study records will meet the strictest standard applicable 
to that study center, as dictated by institutional requirements or local laws or regulations. 
Prior to proceeding with destruction of records, the investigator must notify Ovid 
Therapeutics Inc. in writing and receive written authorization from them to destroy study 
records. The investigator must also notify Ovid Therapeutics Inc. of any changes in 
archival arrangements, including but not limited to, archival at an offsite facility or 
transfer of ownership if the investigator leaves the study center. 
The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents. 
Essential documents should be retained until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 5 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with Ovid Therapeutics Inc. It is the 
responsibility of Ovid Therapeutics Inc. to inform the investigator/institution as to when 
these documents no longer need to be retained. 


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26. 
FINANCING AND INSURANCE 
Ovid Therapeutics Inc. shall carry an insurance policy to cover compensation of subjects’ 
health injuries arising from the study. Subjects who incur a study-related injury may be 
treated (and other necessary measures taken) at the study center and/or another medical 
institution. If it is necessary to compensate for the treatment, Ovid Therapeutics Inc. will 
cover the cost and shall not impose on the subject the burden of proving the causal 
relation between the study and the injury. 
If any of the following is confirmed, Ovid Therapeutics Inc. may refuse or restrict the 
payment of the compensation: 
• A serious GCP or protocol deviation by the investigator or sub-investigator 
(except deviation medically necessary to avoid an immediate hazard to study 
subjects) 
• Intentional act or negligence on the part of the investigator or sub-investigator or 
malpractice thereby 
• Injury caused by unlawful act or delinquency of a third party 
• Injury caused by intentional act or negligence of the subject 
If compensation becomes necessary for a study-related injury, the study center will 
promptly notify Ovid Therapeutics Inc. and will co-operate with Ovid Therapeutics Inc. 
and its insurer (or their legal representatives) in their handling thereof. 


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27. 
REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS 
Ovid Therapeutics Inc. will register the study and post study results regardless of 
outcome on a publicly accessible website in accordance with the applicable laws and 
regulations. Ovid Therapeutics Inc. shall retain the ownership of all data. When the study 
is complete Ovid Therapeutics Inc. shall arrange the analysis and tabulation of data. A 
clinical study report shall then be prepared, which may be used for publication, 
presentation at scientific meetings or submission to regulatory authorities. All proposed 
publications based on this study must be subject to Ovid Therapeutics Inc.’ approval 
requirements. 
 
 


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28. 
SIGNATURE OF INVESTIGATOR 
I agree to conduct the study outlined above in accordance with the terms and conditions 
of the protocol, ICH guidelines for GCP and with applicable regulatory requirements. All 
information pertaining to the study shall be treated in a confidential manner.  
 
 
 
 
 
 
Investigator Signature 
 
 
 
 
Date (day/month/year) 
 
 
 
Print Name 
 
 
 
 
 
 


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REFERENCE LIST                 
 
1 
Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, et 
al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med 
Genet. 2006;140(5):413-8. 
2 
National 
Institute 
of 
Neurological 
Disorders 
and 
Stroke. 
http://www.ninds.nih.gov/disorders/angelman/angelman.htm 
3 
Egawa K, Kitagawa K, Inoue, K. Takayama M, Takayama C, Saitoh S, et al. 
Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a 
mouse model of Angelman syndrome. Sci Transl Med. 2012;4(163):163. 
4 
Dissel S, Angadi V, Kirszenblat L, Suzuki Y, Donlea J, Klose M, et al. Sleep 
restores 
behavioral 
plasticity 
to 
Drosophila 
mutants. 
Curr 
Biol. 
2015;25(10):1270-81. 
5 
Berry JA, Cervantes-Sandoval I, Chakraborty M, and Davis RL. Sleep Facilitates 
Memory 
by 
Blocking 
Dopamine 
Neuron-Mediated 
Forgetting. 
Cell. 
2015;161(7):1656-67. 
6 
Brickley SG and Mody I. Extrasynaptic GABA(A) receptors: their function in the 
CNS and implications for disease. Neuron. 2012;73(1):23-34. 
7 
Ramamoorthi K, and Lin Y. The contribution of GABAergic dysfunction to 
neurodevelopmental disorders. Trends Mol Med. 2011;17(8):452-62. 
8 
Egawa K, and Fukuda A. Pathophysiological power of improper tonic GABA(A) 
conductances in mature and immature models. Front Neural Circuits. 2013;7:170. 
9 
Deidda G, Bozarth IF, and Cancedda L. Modulation of GABAergic transmission in 
development and neurodevelopmental disorders: investigating physiology and 
pathology to gain therapeutic perspectives. Front Cell Neurosci. 2014;8:119. 
10 
Gaboxadol (OV101) Investigator’s Brochure. Edition 01. 14 June 2016. 
11 
Study 10218. Chronopharmacokinetics and Food Interaction (Merck 026) – open 
label, single dose, 4-way cross-over. Dose level 15 mg with two morning doses and 
2 evening doses with and without food. Complete Clinical Study Report. 
12 
H. Lundbeck A/S. Determination of gaboxadol (Lu 02-030) and metabolites 
(glucuronide and sulphate of gaboxadol) in urine from human volunteers. 
Study 99096. Report No: 263/823. 2003. 
13 
Phillips et al (Bone Abstracts [2015] 4 P136). 
14 
Grieco JC, Ciarlone SL, Gieron-Korthals M, Schoenberg MR, Smith AG, Philpot 
RM, et al. An open-label pilot trial of minocycline in children as a treatment for 
Angelman- syndrome. BMC Neurol. 2014;14:232. 
 


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15 
Wondra VC, Pitetti KH, and Beets MW. Gait parameters in children with motor 
disabilities using an electronic walkway system: assessment of reliability. Pediatr 
Phys Ther. 2007;19(4):326-31. 
16 
Prosser LA, Lauer RT, VanSant AF, Barbe MF, and Lee SC. Variability and 
symmetry of gait in early walkers with and without bilateral cerebral palsy. Gait 
Posture. 2010;31(4):522-6. 
17 
Aman MG, Singh NN, Stewart AW, and Field CJ. The aberrant behavior checklist: 
a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 
1985;89(5):485-91. 
18 
Neubert G, von Au K, Drossel K, Tzschach A, Horn D, Nickel R, et al. Angelman 
syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion 
and maternally inherited 2q21.3 microdeletion. Gene. 2013 Jan 10;512(2):453-5. 
PMID 23124039. 
19 
West PR, Amaral DG, Bais P, Smith AM, Egnash LA, Ross ME, et al. 
Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in 
the blood plasma of children. PLoS One. 2014;9(11):e112445. PMID 25380056. 

SAP_001.pdf: 
 
 
 
 
 
OVID THERAPEUTICS, INC. 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2 Angelman Syndrome Clinical Trial:  A Randomized, Double-blind, Safety 
and Efficacy Study of Gaboxadol (Short Name: STARS) 
 
OV101-15-001 
 
 
 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
 
 
Version 2.0 
 
27Jun2018 
 
 
 




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Table of Contents 
1 
INTRODUCTION .............................................................................................. 12 
2 
STUDY SUMMARY.......................................................................................... 12 
2.1 
STUDY OBJECTIVES ................................................................................ 12 
2.2 
STUDY DESIGN ......................................................................................... 13 
2.2.1 
Number of Subjects............................................................................... 14 
2.2.2 
Randomization and Blinding Procedures.............................................. 14 
2.2.3 
Exploratory Efficacy Assessments ....................................................... 14 
2.2.4 
Safety Assessments ............................................................................... 17 
2.2.5 
Other Assessments ................................................................................ 17 
3 
STATISTICAL METHODS ............................................................................... 21 
3.1 
General Methods .......................................................................................... 21 
3.1.1 
Baseline Value and Change from Baseline (if applicable) ................... 21 
3.1.2 
Handling of Missing/Incomplete Values .............................................. 21 
3.2 
Analysis Populations and Subgroups ........................................................... 22 
3.2.1 
Definition of Analysis Populations ....................................................... 22 
3.2.2 
Definition of Subgroups ........................................................................ 23 
3.3 
Analysis Variables........................................................................................ 23 
3.3.1 
Key Efficacy Endpoints ........................................................................ 23 
3.3.2 
Exploratory Efficacy Endpoints ............................................................ 24 
3.3.3 
Safety Endpoints ................................................................................... 27 
3.3.4 
Other Variables ..................................................................................... 27 


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3.4 
Subjects Disposition and Evaluability ......................................................... 27 
3.4.1 
Subject Disposition ............................................................................... 27 
3.4.2 
Protocol Deviations ............................................................................... 28 
3.5 
Demographics and Baseline Characteristics ................................................ 28 
3.5.1 
Demographics ....................................................................................... 28 
3.5.2 
Medical and Surgical History ............................................................... 28 
3.6 
Prior and Concomitant Medications ............................................................. 28 
3.7 
Treatment Compliance and Exposure .......................................................... 29 
3.7.1 
Compliance to Study Treatment ........................................................... 29 
3.8 
Efficacy Analyses ......................................................................................... 30 
3.8.1 
Treatment Comparisons ........................................................................ 30 
3.8.2 
Key Efficacy Endpoints – Testing hierarchy for Control of Type I Error
32 
3.8.3 
Analyses of the Exploratory Efficacy Endpoints .................................. 34 
3.8.4 
Subgroup Analyses ............................................................................... 36 
3.9 
Safety Analysis ............................................................................................. 36 
3.9.1 
Adverse Events ..................................................................................... 36 
3.9.2 
Clinical Laboratory Evaluation ............................................................. 37 
3.9.3 
Vital Signs and Other Physical Findings .............................................. 39 
3.9.4 
EEG ....................................................................................................... 39 
3.9.5 
Physical Examination............................................................................ 39 
3.9.6 
Biomarkers ............................................................................................ 39 
3.9.7 
Suicidality ............................................................................................. 40 


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3.10 
Interim Analysis ....................................................................................... 40 
3.11 
Changes from Protocol ............................................................................. 40 
4 
DATA HANDLING ........................................................................................... 42 
4.1 
Derived Endpoints and Data Handling......................................................... 42 
4.1.1 
Handing of Repeated Assessments ....................................................... 42 
4.1.2 
Aberrant Behavior Checklist-Community (ABC-C) ............................ 43 
4.1.3 
 
 
 
 
 
 
 
 
 
4.1.8 
EEG ....................................................................................................... 51 
4.2 
Computation of Derived Data ...................................................................... 51 
4.2.1 
Time Points and Duration ..................................................................... 51 
4.2.2 
Other Data Derivations ......................................................................... 52 
5 
Programming Specifications ............................................................................... 52 
6 
List of Tables ...................................................................................................... 54 
7 
List of Figures ..................................................................................................... 58 
8 
List of Listings .................................................................................................... 58 
 




Ovid Therapeutics, Inc. 
 
 
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CI 
Confidence Interval 
cm 
centimeter 
COA 
Clinical Outcome Assessments 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
EEG 
Electroencephalogram 
EQ-5D-5L 
EuroQOL-5L 
FAS 
Full Analysis Set 
GH 
General health 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
kg 
Kilograms 
MCS 
mental component scores  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mmHG 
Millimeter of mercury 
MH 
Mental health 
MMRM 
Mixed Model Repeated Measures 






















 
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OV101-15-001                                                                                                                                                                            Statistical Analysis Plan 
 
 
SAP Version 2.0: 27Jun2018 
 
 
 
                                                                                             
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Abbreviations: ABC-C = Aberrant Behavior Checklist – Community; ABC-C-Irritability Subscale = Aberrant Behavior Checklist – Community – Irritability Subscale; 
 
 CGI-I = Clinical Global Impression – Improvement; CGI-S = Clinical Global Impression – 
Severity; 
 EEG = Electroencephalogram; 
 ICF = Informed Consent Form; 
 
* Safety follow-up phone visit 2 weeks after End of Treatment. 
† Signs and symptoms of the syndrome. 
‡ Only if separate ICF was signed. 
§ Only if no written evidence for molecular diagnosis in subject records available. 
# Ongoing up-titration if target dose could not be reached until Day 14. Down-titration for non-tolerability should be discussed with the Sponsor MM or his/her delegates if necessary. 
** For women of child-bearing potential. 
†† Continuous use and documentation; 
electronic subject reported outcomes data will be downloaded by study center staff at baseline, interim, and End of Treatment visits. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3 STATISTICAL METHODS  
3.1 General Methods 
All statistical analyses will be performed using SAS Version 9.4 or higher for 
Windows. 
All clinical study data will be presented in subject data listings. In by-treatment group 
descriptive presentations, the 3 randomized treatment groups (15 mg evening dose 
only [QD], 15 mg evening dose plus 10 mg morning dose [BID], placebo) will be 
presented separately as well as a combined treatment group for OV101 QD and BID 
dosing. 
Descriptive statistics (n, mean, standard deviation, Q1, median, Q3, minimum, and 
maximum) will be calculated by treatment group for continuous variables.  
Confidence intervals will be provided where appropriate.  
Frequencies and percentages will be presented by treatment group for categorical 
variables.  If there are missing values, the number missing will be presented, but 
without a percentage.  
Means, medians, and confidence intervals will be reported to one decimal place more 
than the data reported on the Case Report Form (CRF) or by the laboratory/vendor. 
Standard deviations will be reported to two decimal places more than the data 
reported. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the laboratory/vendor. P-values will be reported to 
4 decimal places. 
Unless otherwise specified, all tests will be 2-tailed using a 0.05 level of significance. 
All confidence intervals (CIs) will be 2-sided 95% CIs. 
3.1.1 Baseline Value and Change from Baseline (if applicable) 
A Baseline value is defined as the most recent non-missing value obtained 
immediately prior to administration of first dose. Change from baseline will be 
calculated by subtracting the baseline value from the post-dose assessment for each 
subject (i.e., post-dose – baseline). 
3.1.2 Handling of Missing/Incomplete Values 
Selected efficacy analyses of Week12 endpoints will include missing value 
adjustments, if possible, by using the corresponding Week 6 observations either 
implicitly (in MMRM analyses) or by simple imputation (for binary endpoints).  


 
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These selected analyses are detailed below.  For all other analyses, observed case data 
will be used and no imputations for missing data will be performed.   
3.2 Analysis Populations and Subgroups 
3.2.1 Definition of Analysis Populations 
Safety Analysis Set 
The Safety Analysis Set consists of all subjects who received at least one dose of 
study drug. Subjects will be analyzed according to the treatment they actually 
received.  The Safety Analysis Set will be the analysis set used for all safety analyses. 
 
Intent-to-Treat Set 
The Intent-to-Treat set (ITT) consists of all subjects who are randomized, whether or 
not study drug is received. Subjects will be analyzed according to their randomized 
group.  
 
Full Analysis Set (also considered the modified Intent-to-Treat set) 
The Full Analysis Set (FAS) or modified Intent-to-Treat set (mITT) consists of all 
randomized subjects who receive at least 1 dose of study drug, and have at least 1 
efficacy evaluation after receiving study drug.  Subjects will be analyzed according to 
their randomized group. The FAS will be the primary analysis set for efficacy 
analyses. 
 
Per Protocol Set 
The Per Protocol Set (PP) is a subset of the FAS that includes all subjects who 
complete the Week 12 visit and have no major protocol deviations that are deemed to 
impact efficacy. These violations include but are not limited to violations of 
inclusion/exclusion criteria deemed to impact efficacy, inadequate study drug 
compliance over the dosing period as determined from the dosing information in the 
eCRF, usage of prohibited concomitant medications, and incorrect randomization. 
Subjects will be analyzed according to their randomized treatment group.  The PP set 
will be used for the analysis of the key efficacy endpoints only. 
 
Prior to database lock and unblinding, there will be a meeting to review protocol 
deviations.  The threshold for percent compliance that would be considered 
inadequate and would result in exclusion from the per protocol set will be determined 
in this meeting following review of the relevant compliance information.  In addition 
to the deviations listed above, other relevant protocol deviations, like early 
termination of treatment, may be identified for review. 












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3.4.2 Protocol Deviations 
For subjects excluded from the Per Protocol Set, all deviations will be shown in a 
subject listing by treatment group. 
3.5 Demographics and Baseline Characteristics 
3.5.1 Demographics 
Subject demographics and baseline characteristics will be summarized by treatment 
group and overall for all subject populations. 
Descriptive statistics will be displayed for age, height, weight, and body mass index 
(BMI).   
Age is calculated as (date of informed consent - date of birth + 1) / 365.25 and is 
truncated to complete years.  Height, weight and BMI will be summarized with the 
data collected at the baseline visit. 
Frequencies and percentages will be tabulated for sex, race, ethnicity, age group, 
childbearing potential, enrollment by study center, and country.  To assess potential 
baseline imbalances, the randomized treatment groups will be compared with respect 
to demographics at baseline using an analysis of variance model (ANOVA) with 
treatment group as the only independent variable and using a chi square test of 
independence for the categorical variables.  
3.5.2 Medical and Surgical History 
Medical and surgical history will be summarized by body system for each treatment 
group as well as overall for all subject populations.  Body system will be presented in 
descending order for all subjects. 
3.6 Prior and Concomitant Medications 
Therapies started and stopped prior to the start of study treatment are referred to as 
prior therapies. Therapies that started prior to treatment and continued on treatment as 
well as those that started during treatment are referred to as concomitant therapies. In 
order to define whether a medication with missing start or stop dates is a concomitant 
medication, refer to the following additional criteria. 


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OV101-15-001  
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•
if both the start and stop dates of a particular medication are missing, that
medication will be considered concomitant;
•
if the start date of a medication is missing and the stop date of that medication
falls on or after the dose date, that medication will be considered concomitant;
•
if the start date of a medication is missing and the stop date of the medication
is prior to the dose date, that medication is considered not concomitant;
•
If the start date of a medication is prior to the dose date and the stop date of
the medication is missing, that medication is considered concomitant.
Prior and concomitant medications will be coded using WHO Drug Dictionary 
Enhanced version June 2016 and will be classified by Anatomical Therapeutic Class 
(ATC) level 4 and preferred term (PT) for the Safety Analysis Set.  For the 
presentation of concomitant medications, the ATC level 4 terms will be sorted 
alphabetically, and within ATC level 4 term, the PT will be used and presented by 
decreasing total frequency overall. 
Frequencies and percentages of subjects using each concomitant medication will be 
presented for the Safety Analysis Set overall, and by treatment group.   
All medication use will be listed regardless of the timing of the start of the 
medication. 
3.7 Treatment Compliance and Exposure 
Subjects will receive 1 kit at Baseline and 1 kit at Day 43 (Interim visit).  Each kit 
will contain a bottle for morning doses and a bottle for evening doses. Each morning 
bottle will contain 90 capsules and each evening bottle will contain 140 capsules.    
3.7.1 Compliance to Study Treatment 
Compliance, days on treatment, and total capsules taken will be summarized 
descriptively by treatment group and presented by subject in a listing.   
Total capsules taken will be derived as the total number of capsules dispensed minus 
the total number of capsules returned minus the total number of capsules not taken 
and not returned.   
Expected days capsules taken will be based on the first and last expected days for 
taking study medication, using all available dosing information on the eCRF.  The 
calculation formula is (last dose date - first dose date + 1). 
















 
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SAP Version 2.0: 27Jun2018 
                                  
 
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• 
Missing AE start day:  
o If the partial date contains a different month from the date of first study dose, 
then impute it as the first day of the month.  
o If it contains the same month as the date of first dose, then impute it as date of 
first dose.  
• 
Missing AE start day and month:  
o If the partial date contains a different year from the date of first dose, then 
impute the missing day and month as Dec 31.  
o If it contains the same year as the date of first dose, then impute the missing 
day and month as day and month of first dose.  
• 
Completely missing AE date:  
o Impute the missing date as the date of first dose.  
 
The TEAE incidence will be presented by treatment group for all subjects in the 
Safety Analysis Set.  The number and percentage of subjects who experience at least 
one TEAE and the number and percentage of subjects who experience at least one 
TEAE within each specific SOC and PT will be presented by treatment group 
(placebo, combined OV101 and separate dose groups). Additionally, the incidence of 
TEAE within each specific SOC, HLGT, and PT and specific SOC, HLT, and PT will 
be presented.  The 95% CIs will be displayed for the frequency of TEAEs. Treatment-
related AEs will be considered those at least possibly related to investigational 
product based on the investigator’s assessment. The number and percentage of 
subjects reporting serious AEs, treatment-related AEs, and AEs leading to treatment 
discontinuation will also be summarized for each treatment group by MedDRA SOC 
and PT. 
The AEs of Special Interest include Dizziness, Somnolence, Nausea, Vomiting PTs, 
and will be reported separately.   
All adverse event data including baseline adverse events will be displayed in subject 
data listings. 
3.9.2 Clinical Laboratory Evaluation 
Blood samples will be collected for routine clinical laboratory safety evaluations at 
Screening, Baseline, Day 43 (week 6) and Day 84 (week 12).  Additional laboratory 
safety evaluations will be performed at other times, if judged to be clinically 


 
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appropriate, or if the ongoing review of the data suggests a more detailed assessment 
of laboratory safety evaluations is required.  
Laboratory parameters include electrolytes, lipids, glucose, renal, hepatic and 
pancreatic function tests, and hematology.  
Clinical chemistry and hematology tests are presented below: 
Clinical Chemistry and Hematology Tests 
Clinical Chemistry  
 
 
 
 
 
Hematology 
Albumin  
 
 
 
 
 
 
Basophils (absolute) 
Alkaline phosphatase   
 
 
 
 
Eosinophils (absolute) 
Alanine aminotransferase  
 
 
 
 
Lymphocytes (absolute) 
Aspartate aminotransferase   
 
 
 
Monocytes (absolute) 
Bicarbonate   
 
 
 
 
 
Neutrophils (absolute) 
Calcium  
 
 
 
 
 
 
Basophils 
Chloride  
 
 
 
 
 
 
Eosinophils 
Cholesterol  
 
 
 
 
 
 
Hematocrit 
Creatine kinase  
 
 
 
 
 
Hematology slide 
Creatine, enzymatic   
 
 
 
 
Hemoglobin 
Direct bilirubin  
 
 
 
 
 
Lymphocytes 
Glucose, random, serum  
 
 
 
 
Monocytes 
High density lipoprotein cholesterol   
 
 
Neutrophils 
Indirect bilirubin  
 
 
 
 
 
Platelets 
Lactate dehydrogenase  
 
 
 
 
Red blood cells 
Low density lipoprotein cholesterol, calculated  
 
White blood cells 
Phosphorous  
Potassium  
Sodium  
Total bilirubin  
Total protein  
Triglyceride  
Urea (blood urea nitrogen)  
Uric acid  
Total cholesterol  
Magnesium  
Thyroid stimulating hormone 
Continuous laboratory data will be examined for trends using descriptive statistics of 
actual values and changes from baseline over time. These data will also be 
categorized as low, normal or high based on the reference ranges of the central 


 
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OV101-15-001                                                                                   Statistical Analysis Plan 
 
 
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laboratory.  Shift tables from baseline to each post baseline time point will be 
presented.  
3.9.3 Vital Signs and Other Physical Findings 
The following vital signs will be collected at Screening, Baseline, Day 43 (week 6) 
and Day 84 (week 12): 
• Systolic and Diastolic blood pressure (mmHg)  
• heart rate (bpm)  
• body temperature (◦F) 
• weight (kg)  
Summary statistics will be presented for actual values and change from Baseline 
values by treatment group. 
3.9.4 EEG 
EEG is collected at Baseline and Day 84 (week 12).  Occipital rhythm, rhythmic 
theta, rhythmic delta, epileptiform abnormalities, and sleep will be analyzed 
descriptively.  For occipital rhythm, the categories are normal, slow, or absent, with 
undeterminable as a response option.  For rhythmic theta, the categories are <50% or 
>50%, with undeterminable as a response option.  For these discrete variables, 
frequencies and percentages will be presented by treatment group for each visit.  The 
sleep-related variables, total time of sleep recording in minutes, time asleep in 
minutes and percent time asleep will be summarized using descriptive statistics for 
each visit by treatment group.   
3.9.5 Physical Examination 
Physical exams will be evaluated by body system. Physical exam data are collected at 
Screening, Baseline, Day 43 (week 6) and Day 84 (week 12).  The number and 
percentage of subjects in each treatment group with normal and abnormal physical 
examination results for each body system by visit will be presented.  For each body 
system, shifts from baseline to final visit (no change, normal to abnormal or abnormal 
to normal) will also be presented.   
3.9.6 Biomarkers 
Blood will be drawn at Baseline and Day 84 (week 12) for Biomarker analysis.  
Analyses will not be performed at this time. 


























 
Ovid Therapeutics 
 
OV101-15-001                                                                                   Statistical Analysis Plan 
 
 
SAP Version 2.0: 27Jun2018 
                                  
 
                     Page 52 of 59 
 
4.2.2 
Other Data Derivations 
Body Mass Index BMI = Weight in Kg / (Height in meter)2 
Age is calculated as (date of informed consent - date of birth + 1) / 365.25 and is 
truncated to complete years. 
5 Programming Specifications 
It is suggested that computer-generated table output adhere to the following 
specifications. 
1. Unless otherwise specified, all computer-generated tables and listings should be 
produced in landscape mode using SAS ODS to create RTF output which can be 
imported by Microsoft Word in table format. All output should have the 
following two-line header at the upper left margin: 
Sponsor Company Name 
Study Protocol Name 
and the following header at the upper right margin: 
Page x of y 
 
2.  Each table should be identified by in a sequential numeric order, and the table 
designation should be centered above the title. A decimal system within the 
numeric numbering (i.e., x.y and x.y.z) should be used to identify tables and 
listings with related contents. The title is centered in initial capital characters and 
should include the population type analyzed (e.g. Safety Population). The title and 
table designation are single-spaced, but are separated from the table by at least a 
double space. 
Table No. 
 
First Line of Title 
Second Line of Title (if needed) 
Population Type Analyzed 
 
3.  Column headings should be in initial upper-case characters. 
4.  For variables with numeric values, include “unit” in column heading when 
appropriate. 
5.  Footnotes should be single spaced, but separated by at least a double space from 
the bottom line of the table. The notes are aligned vertically by the left vertical 
border of the table. All output should have at least the footnote about the program 
name and date of the program run.   
[1] Footnote 1 


 
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OV101-15-001                                                                                   Statistical Analysis Plan 
 
 
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[2] Footnote 2 
[3] Footnote 3 
PROGRAM: program file name                             DDMMMYYYY HH:MM 
6.  Unless specified otherwise, all data listings should be sorted by subject number 
with the investigation site, and by visit date within subject where appropriate. 
7.  For tables that summarize categorical (discrete) data, an Unknown or Missing 
category should be added to any parameters for which information is not available 
for any subject. 
 
8.  Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to one more decimal place than the raw (observed) data and 
rounded appropriately. Standard errors (or standard deviations) should be printed 
out to two additional decimal places than the raw (observed) data and rounded 
appropriately. For example, for age (with raw data in whole years): 
 
n 
 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
 
Median  
xx.x 
 
Min, Max 
xx,xx 
 
9.  The p-values will be printed in the tables rounded appropriately to 4 decimal 
places and formatted as '0.xxxx'. P-values less than 0.0001 will be formatted in 
the tables as '<0.0001'. 
10. All fractional numeric values should be printed with a zero to the left of the 
decimal point (e.g., 0.12, 0.3). 
11. Unless otherwise specified, percentage values should be printed with one digit to 
the right of the decimal point (e.g., 12.8%, 5.4%).  
12. Missing data should be represented on subject listings as either a hyphen (“-“). 
13. Dates printed as a result in the table, listing, or graph should be printed in SAS 
DATE9. format (“DDMONYYYY”: 01 JUL 2002). Missing portions of dates 
should be represented on subject listings as dashes (-- JUL 99). Dates that are 
missing because they are not applicable for the subject should be listed as “N/A”, 
unless otherwise specified.