An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome
Phase: PHASE3
Conditions: Angelman Syndrome
Sponsor: Healx AI

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 1 
CLINICAL
 STUDY PROTOCOL 
 
 
 
An Open-Label Study to Evaluate the Long-Term Safety, T
olerability, and 
Efficacy of OV101 in Individuals with Angelman Syndrome (ELARA) 
PROTOCOL
 NUMBER OV101-18-002 
Sponsor: 
Ovid Therapeutics Inc. 
 
 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
 
Current Protocol:  
Protocol Amendment 03 (Version 04) 
Date of Protocol:  
13 October 2020 
Previous Protocol Version 
and Date 
Protocol Amendment 02 (Version 03): 18 November 2019 
Protocol Amendment 01 (Version 02): 30 September 2019 
Original Protocol (Version 01): 18 September 2018 
 
 
CONFIDENTIAL
  
All financial and nonfinancial support for this study will be provided by Ovid Therapeutics 
Inc. The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of Ovid Therapeutics Inc. 
The study will be conducted according to the International Council for Harmonisation 
tripartite guideline E6 (R2): Good Clinical Practice.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 5 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “An Open-Label Study to 
Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals with 
Angelman Syndrome (ELARA)” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 4.0, the International Council for Harmonisation 
tripartite guideline E6 (R2): Good Clinical Practice and all applicable government regulations. I 
will not make changes to the protocol before consulting with Ovid Therapeutics Inc. or 
implement protocol changes without independent ethics committee approval except to eliminate 
an immediate risk to study participants. I agree to administer study treatment only to study 
participants under my personal supervision or the supervision of a sub-investigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Study participant identity will not be disclosed to third parties 
or appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Ovid Therapeutics Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
 
 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 6 
Table of Contents 
Table of Contents ....................................................................................................................... 6
 
List of Tables 
.............................................................................................................................. 9
 
List of Figures 
.......................................................................................................................... 10 
Protocol Synopsis..................................................................................................................... 11 
List
 of
 Abbreviations................................................................................................................ 21
 
1 Introduction 
...................................................................................................................... 23 
2 Study Objectives and Assessments Related to Endpoints 
................................................ 26
 
2.1 Primary Objective 
................................................................................................... 26
 
2.2 Secondary Objectives.............................................................................................. 26
 
2.3 Exploratory Objectives 
........................................................................................... 26
 
3 Investigational Plan 
.......................................................................................................... 27
 
3.1 Study Design 
........................................................................................................... 27
 
 
 
4 Study participant Selection and Withdrawal Criteria 
....................................................... 33
 
4.1 Selection of Study Population 
................................................................................. 33 
4.1.1 
Inclusion Criteria 
..................................................................................... 33
 
4.1.2 
Exclusion Criteria 
.................................................................................... 35
 
4.2 Withdrawal of Study participants from Study Treatment and/or the Study 
............ 36
 
4.2.1 
Reasons for Withdrawal/Discontinuation 
................................................ 36
 
4.2.2 
Handling of Withdrawals 
......................................................................... 37
 
4.2.3 
Replacements and Rescreening ............................................................... 37
 
5 Study Treatments 
.............................................................................................................. 38
 
5.1 Study participant Number Assignment 
................................................................... 38 
5.2 Treatments
 Administered 
........................................................................................ 38
 
5.2.1 
Dose Titration .......................................................................................... 39
 
5.2.1.1 Study participants 2 Years and older (≥2 yrs. of age) 
.............................. 39
 
5.2.1.2 Down-Titration for All Study participants 
............................................... 40
 
5.3 Description of Study Drug 
...................................................................................... 41 
5.4 Management of Clinical Supplies 
........................................................................... 41
 
5.4.1 
Study Drug Packaging and Storage 
......................................................... 41 
5.4.2 
Study
 Drug
 Accountability 
...................................................................... 42
 
5.4.3 
Other Supplies ......................................................................................... 42 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 7 
5.5 Overdose Reporting 
................................................................................................ 42 
5.5.1 
Treatment of Overdose ............................................................................ 42
 
5.6 Medication Errors 
................................................................................................... 42
 
5.6.1 
Treatment of Medication Errors 
............................................................... 43
 
5.7 Blinding .................................................................................................................. 43 
5.8 Treatment Compliance 
............................................................................................ 43
 
5.9 Prior and Concomitant Therapy 
.............................................................................. 43 
5.9.1 
Prohibited Medications and Therapies .................................................... 44
 
5.9.2 
Restrictions 
.............................................................................................. 44
 
6 Study Assessments and Procedures 
.................................................................................. 45
 
6.1 Study Visits 
............................................................................................................. 50
 
6.1.1 
Screening Period 
...................................................................................... 50
 
6.1.2 
Baseline Visit 
........................................................................................... 51
 
6.1.3 
Phone Visits for Dose Titration 
................................................................ 51
 
6.1.4 
Telehealth/Virtual Visits at Weeks 24, 48, 80, 112, and 144 
.................... 52 
6.1.5 
Clinic Visits at Weeks 12, 36, 64, 96, and 128 ........................................ 52 
6.1.6 
Week 160 or End-of-Treatment Clinic Visit 
............................................ 52
 
6.1.7 
End-of-Study Phone Visit 
........................................................................ 52
 
6.2 Safety
 and
 Tolerability
 Assessments 
....................................................................... 53
 
6.2.1 
Adverse Events 
........................................................................................ 53 
6.2.1.1 Definitions of Adverse Events 
................................................................. 53
 
6.2.1.2 Serious
 Adverse
 Events ........................................................................... 54
 
6.2.1.3 Eliciting and Documenting Adverse Events 
............................................ 55 
6.2.1.4 Reporting
 Adverse
 Events ....................................................................... 55
 
6.2.1.5 Reporting Serious Adverse Events .......................................................... 56 
6.2.1.6 Suspected Unexpected Serious Adverse Reactions and Nonserious Adverse 
Events of Special Interest ........................................................................ 57
 
6.2.1.7 Assessment of Severity 
............................................................................ 58
 
6.2.1.8 Assessment of Causality 
.......................................................................... 58
 
6.2.1.9 Follow-Up of Study participants Reporting Adverse Events .................. 59 
6.2.2 
Other
 Safety
 Assessments 
........................................................................ 59
 
6.2.2.1 Clinical Assessment of Suicidality .......................................................... 59
 
6.2.2.2 Vital Sign Measurements 
......................................................................... 59
 
6.2.2.3 Physical Examinations 
............................................................................. 60
 
6.2.2.4 Seizure Diary 
........................................................................................... 60
 
6.3 Exposure During Pregnancy and/or Lactation 
........................................................ 60 
6.4 Pregnancy 
................................................................................................................ 61 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 8 
6.5 Contraception and Pregnancy Avoidance Procedures 
............................................. 63 
6.6 Safety Monitoring Committee 
................................................................................ 63
 
6.7 Laboratory
 Analyses 
............................................................................................... 64
 
6.7.1 
Sample Collections 
.................................................................................. 64
 
6.8 Efficacy
 Assessments 
.............................................................................................. 64
 
6.8.1 
Caregiver
 Assessments ............................................................................ 65
 
6.8.1.1 Children’s Sleep Habits Questionnaire 
.................................................... 65 
6.8.1.2 Sleep Diary .............................................................................................. 65
 
6.8.1.3 Pediatric Quality of Life Inventory 
.......................................................... 66
 
6.8.2 
Clinician
 Assessments ............................................................................. 66
 
6.8.2.1 Vineland Adaptive Behavior Scale 
.......................................................... 66 
6.8.2.2 Clinical Global Impressions - Angelman Syndrome Scales 
.................... 67 
7 Statistical and Analytical Plan 
.......................................................................................... 68
 
7.1 Safety Endpoints 
..................................................................................................... 68 
7.2 Secondary Efficacy Endpoints 
................................................................................ 68 
7.2.1 
LAR/Caregiver-Completed Endpoints (for Study participants at Least 
4 Years Old) 
............................................................................................. 68
 
7.2.2 
Clinician-Completed Endpoints (for Study participants at Least 4 Years Old)
 ................................................................................................................. 68
 
7.3 Exploratory Endpoints 
............................................................................................ 69
 
7.3.1 
LAR/Caregiver-Completed Endpoints (for Study participants at Least 
4 Years Old) 
............................................................................................. 69
 
7.3.2 
Clinician-Completed Endpoints (for Study participants at Least 4 Years Old)
 ................................................................................................................. 69
 
7.3.3 
Endpoints for Relationship Exploration .................................................. 69 
7.4 Sample Size Calculations 
........................................................................................ 69
 
7.5 Analysis Sets 
........................................................................................................... 69
 
7.6 Subgroup
 Analysis 
.................................................................................................. 70
 
7.7 Statistical
 Analysis
 Methodology ........................................................................... 70
 
7.7.1 
Analysis of Primary Endpoints - Safety .................................................. 70
 
7.7.2 
Analysis of Secondary Efficacy Endpoints ............................................. 72 
7.7.3 
Analyses of Exploratory Efficacy Endpoints 
........................................... 72
 
7.7.4 
Other
 Analyses 
......................................................................................... 72
 
7.7.4.1 Demographics and Other Baseline Characteristics 
.................................. 72
 
7.7.4.2 Drug Treatments ...................................................................................... 72
 
7.7.5 
Interim
 Analyses 
...................................................................................... 73
 
8 Data
 Quality
 Assurance 
.................................................................................................... 74
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 9 
8.1 On-Site
 Audits 
......................................................................................................... 74
 
8.2 Data Management 
................................................................................................... 74
 
9 Ethics 
................................................................................................
................................ 76 
9.1 Independent Ethics Committee or Institutional Review Board 
.............................. 76
 
9.2 Ethical Conduct of the Study 
.................................................................................. 76 
9.3 Study participant Information and Consent 
............................................................ 76 
10 Investigator’s Obligations ................................................................................................ 78 
10.1 Confidentiality 
........................................................................................................ 78
 
10.2 Financial Disclosure and Obligations 
..................................................................... 78 
10.3 Investigator Documentation 
.................................................................................... 78
 
10.4 Study Conduct 
......................................................................................................... 79 
10.5 Adherence to Protocol ............................................................................................ 79 
10.6 Adverse Events and Study Report Requirements 
................................................... 79 
10.7 Investigator’s Final Report ..................................................................................... 80 
10.8 Records Retention 
................................................................................................... 80
 
10.9 Publications 
............................................................................................................. 80 
11 Study Management 
........................................................................................................... 81 
11.1 Monitoring 
.............................................................................................................. 81 
11.1.1 External Safety Monitoring Committee 
................................................... 81 
11.1.2 Monitoring the Study 
............................................................................... 81 
11.1.3 Inspection of Records 
.............................................................................. 81 
11.2 Management of Protocol Amendments and Deviations.......................................... 82 
11.2.1 Modification of the Protocol 
.................................................................... 82 
11.2.2 Protocol Deviations ................................................................................. 82 
11.3 Study Termination 
................................................................................................... 82
 
11.4 Final Report ............................................................................................................ 83 
12 Reference List................................................................................................................... 84 
13 Pandemic
 Addendum 
........................................................................................................ 86
 
 
List of Tables 
 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 10 
 
 
 
 
 
Table 6-1
 
Schedule of Activities by Study Visit ................................................................... 46 
Table 6-2
 
Efficacy Assessments by Domain and Participant Source 
.................................... 65
 
 
List of Figures 
Figure 3-1 
Study Design Schematic 
....................................................................................... 28 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 11 
Protocol Synopsis 
Protocol Number:  
OV101-18-002 
Title:  
An Open-Label Study to Evaluate the Long-Term Safety, Tolerability
, and Efficacy of 
OV101 in Individuals with Angelman Syndrome (ELARA) 
Sponsor:  
Ovid Therapeutics Inc.  
1460 Broadway 
New York, NY 10036 
Study Phase:  
3  
Study Sites:  
Approximately 15 sites (total) in the United States,
 Australia,
 Europe,
 and Israel  
Estimated Study Duration:  
The planned duration of study participation for a study participant is approximately 
3 years (from start of screening to the end-of-study visit), or until the study drug is 
commercially available. There are 8 scheduled clinic visits, 2 scheduled phone visits, and 
5 telehealth/virtual visits.  
Indication:  
Angelman syndrome (AS) 
Rationale:  
Ovid Therapeutics Inc. (Ovid) is developing OV101 (gaboxadol) for the treatment of rare 
genetic disorders that are associated with severe developmental and behavioral challenges 
that have no approved therapies, such as AS and Fragile X syndrome. Gaboxadol was 
initially developed for the treatment of insomnia by H. Lundbeck A/S and Merck, but its 
development was discontinued in 2007 for commercial reasons. Extensive nonclinical 
and clinical data were generated during the initial stages of development, including data 
from exposure to gaboxadol in more than 4000 adult study participants (950 study 
participant years) with insomnia and approximately 500 adult study participants in non–
insomnia-related studies.  
Angelman syndrome is a severe, complex, and rare neurogenetic disorder with the 
prevalence of approximately 1 in every 10,000 to 24,000 live births. The condition is 
associated with impaired expression of the ubiquitin protein ligase E3A
 gene (UBE3A). 
While ubiquitin protein ligase E3A
 (UBE3A) is expressed bi-allelically 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 AS. Clinical findings range in severity and include developmental 
delay/intellectual disability
, movement and/or balance disorder, and tremulous movement 
of limbs. Unique behavioral characteristics include the combination of a happy
, smiling 
demeanor with easily provoked laughter and excitability (exhibited by hand-flapping and 
stereotypic movements). Individuals with AS frequently have motor dysfunction related 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 12 
to gait and balance, severe disruptions in sleep, little to no speech, short attention span, 
anxiety
, and seizures with characteristic abnormal electroencephalogram patterns.  
Current treatments are aimed at managing symptoms and include antiepileptic 
medications for seizure control and medications for sleep and behavioral problems (e.g., 
anxiety). Other therapies include speech therapy
, physical therapy
, occupational therapy
, 
and educational resources. Notably
, current treatments do not target the underlying brain 
deficits.  
OV101 is the first highly selective, extrasynaptic gamma-aminobutyric acid (GABA) 
receptor agonist that binds orthosterically to the δ-subunit of extrasynaptic GABA
 
receptors. The mechanism of action of OV101 is unique among GABAergic agents, 
including benzodiazepines, zolpidem and other zolpidem-like drugs, neurosteroids, and 
drugs that act on GABA
 metabolism or uptake. Research has shown that absence (or 
dysfunction) of UBE3A
 results in an aberrant increase in the uptake of GABA, which is 
the main inhibitory neurotransmitter in the brain. OV101 is the first highly selective 
GABA
 receptor agonist that acts on α4δ-containing
 GABA
 A-receptors. These receptors 
mediate tonic inhibition and sleep maintenance. In a mouse model of AS, OV101 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. Importantly
, OV101’s 
ability to potentiate tonic inhibition is unlike any other GABAergic agent, including 
benzodiazepines, zolpidem, zaleplon, zopiclone, barbiturates, 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 study participants
 with
 AS.
  
Phase 2 and Phase 3 studies in adult study participants with primary insomnia 
demonstrated that OV101 is effective in restoring classical sleep parameters (sleep 
induction and sleep maintenance) and slow wave sleep, resulting in an improvement in 
the quality and restorative effects of sleep.  
A
 randomized, double-blind, placebo-controlled Phase 2 study (OV101-15-001, STARS; 
NCT02996305) evaluated the safety
, tolerability
, and efficacy of OV101 in adolescents 
and adults with AS over 12 weeks of treatment. Eighty-eight participants with AS (13 to 
49 years old) were randomly assigned to 1 of 3 groups: once-daily (QD) dose of OV101 
nightly (15 mg), twice-daily (BID) dose of OV101 (10 mg morning and 15 mg night), 
and placebo. The safety and tolerability of OV101 from Baseline to Week 12 was 
evaluated by comparing the frequency and severity of adverse events (AEs) and serious 
AEs (SAEs) in the OV101 treatment groups to those in the placebo group. OV101 was 
generally safe and well tolerated, with a similar incidence of AEs across all treatment 
groups: most AEs were mild. Treatment discontinuations due to AEs were low (placebo, 
1; OV101 QD, 0; OV101 BID, 3). The most frequent AEs across all treatment groups 
were vomiting, somnolence, irritability
, aggression, pyrexia, and upper respiratory 
infection. The AEs occurring in the OV101 treatment groups with greater frequency than 
placebo were pyrexia, rash, seizure, enuresis, myoclonic epilepsy
, otitis media, and viral 
infection. Two study participants had an SAE of seizure: 1 study participant in the BID 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 13 
group deemed “Possibly Related” and 1 study participant in the QD group deemed “Not 
Related.” 
 
 
 
 
 
 
 
 
 
 
This open-label study (OV101-18-002) will evaluate the long-term (160-week) safety and 
efficacy of OV101 in study participants with AS who either have completed previous 
Ovid studies (OV101-15-001, OV101-16-001, or OV101-19-001) or are siblings (with 
AS) of study participants with AS who have completed previous Ovid studies of OV101.  
Objectives:  
The primary objective of this study is to evaluate the long-term safety and tolerability of 
OV101 in individuals with AS assessed by the incidence and severity of AEs and SAEs in 
study participants who are at least 2 years old at the time of enrollment into this study. 
The secondary objectives of this study are the following:  
• To evaluate the long-term efficacy of OV101 treatment assessed by changes in 
behavior and sleep in study participants with AS who are at least 4 years old at the 
time of enrollment into this study 
• To evaluate long term efficacy as assessed by clinical global impression of severity 
and improvement scales, VABS, CHSQ, PedsQL, and Sleep Diary in study 
participants with AS who are at least 4 years old at the time of enrollment into this 
study  
• To evaluate the long-term safety and tolerability of OV101 treatment assessed by 
changes in suicidality assessments, vital sign measurements, laboratory assessments, 
physical examinations, and seizure frequency in study participants with AS who are 
at least 2 years old at the time of enrollment into this study
. 
The exploratory objective of this study is to explore the relationships among study 
endpoints (e.g., behavior and sleep), where appropriate. 
Study Population:  
Inclusion Criteria: 
Each study participant must meet all the following criteria to be enrolled in this study: 
1. Ovid study enrollment criteria:  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 14 
• Has completed the OV101-15-001 or OV101-16-001 study up to the end of study 
(EOS), or 
• Has completed the OV101-19-001 study up to the end of treatment (EOT), or 
• Is a sibling of a study participant with AS who has completed OV101-15-001, 
OV10116001, or OV101-19-001 
2. Has a previous diagnosis of AS with molecular confirmation. 
3. Is at least 2 years old and has a body weight of at least 9 kg. 
4. Has a legally acceptable representative (LAR)/caregiver capable of providing 
informed consent and able to attend all scheduled study visits, oversee the 
administration of study drug, and provide reliable, consistent feedback regarding the 
study participant’s symptoms and performance as described in the protocol. 
5. Provides assent to the protocol (to the extent possible and in accordance with local 
institutional review board and regulatory requirements) and has a LAR/caregiver who 
will provide written informed consent. Study participants providing assent must do so 
at the same visit as LAR/caregiver written informed consent is provided. 
6. Can swallow study drug capsules with water or ingest the contents of study drug 
capsules after sprinkling the capsule contents onto up to 1 teaspoon of low-fat 
semiliquid food. 
7. If a study participant is currently receiving a regimen of concomitant medications 
such as antiepileptic medication, gabapentin, clonidine, trazodone, melatonin, and/or 
a special dietary regimen, that study participant’s regimen is stable for at least 4 
weeks before Day 1 (first day of study drug administration) and will be maintained 
throughout the duration of the study (in the judgment of the investigator). 
8. Has a LAR/caregiver(s) who agree not to post any of the study participant’s personal 
medical data/condition or information related to the study on any website, message 
board, online support group, or social media site (e.g., Facebook, Instagram, Twitter) 
until notified that the study is completed.  
9. Female study participants who are of childbearing potential (defined as having 
experienced their first menarche) must agree to use either a highly effective or 
acceptable form of birth control during the study and for 30 days following the last 
dose of the study drug. Highly effective contraceptive methods are as follows: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation:  
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• Intrauterine device 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 15 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
• Male or female condom with or without spermicide* 
• Cap, diaphragm, or sponge with spermicide* 
*A
 combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 16 
Exclusion Criteria:  
Study participants meeting any of the following criteria will be excluded from the study: 
1. Discontinued from the OV101-15-001, OV101-16-001, or OV101-19-001 study due 
to safety reasons causally related to OV101. 
2. Has a circumstance, condition, concomitant disease (e.g., gastrointestinal, renal, 
hepatic, endocrine, respiratory
, or cardiovascular system disease), or any clinically 
significant finding that could interfere with the conduct of the study or that would 
pose an unacceptable risk to the study participant in this study
. 
3. Has poorly controlled seizures defined as any of the following: 
• Weekly seizures of any frequency with a duration of more than 3 minutes each  
• Weekly seizures occurring more than 3 times per week, each with a duration of 
less than 3 minutes 
• Investigator assessment 
4. Has any of the following laboratory abnormalities: total bilirubin >1.5 × upper limit 
of normal (ULN), unless known Gilbert’s syndrome; alanine aminotransferase or 
aspartate aminotransferase >2.5 × ULN; serum creatinine >1.2 × ULN; absolute 
neutrophil count <1.5 × 109/L; platelets <80 × 10
9/L; hemoglobin <80 g/L; or 
thyroid-stimulating hormone >1.25 × ULN or <0.8 × lower limit of normal. Retesting 
of clinical laboratory parameters may be allowed after consultation with the medical 
monitor or designee. 
5. Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, or 
ramelteon for sleep, or minocycline or levodopa within the 4 weeks prior to Day 1 or 
during the study
. Benzodiazepines administered as needed or regularly scheduled for 
indications other than insomnia and benzodiazepines for seizure control are 
permitted. 
6. Is at risk of harming self and/or others (based on investigator assessment). 
7. With the exception of an Ovid study of OV101, has enrolled in any clinical or used 
any investigational agent or device, or has participated in any investigational 
procedure, within the 30 days before screening or does so concurrently with this 
study
. Observational study participation is allowed. 
8. Is allergic to OV101 or any excipients of study drug. 
9. The study participant or LAR/caregiver is unable to comply with study requirements 
(based on investigator assessment). 
Study Design:  
This will be an open-label, long-term safety study for evaluation of treatment with 
OV101 in approximately 170 study participants with AS who either have completed 
previous Ovid studies (OV101-15-001, OV101-16-001, or OV101-19-001) or are siblings 
(with
 AS) of study participants with AS who have completed previous Ovid studies of 
OV101 There will be no placebo treatment. As this study will enroll study participants 
who may have completed previous studies for different periods of time before entering 
this study (as well as study participants with AS who have not been themselves enrolled 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 17 
in an Ovid study), study participants may be required to complete screening and baseline 
visits before receiving OV101 under this protocol. 
 
The study will comprise a screening period of up to 30 days; a baseline visit on Day 1 for 
baseline assessments (at which the first dose of study drug will be taken at the site unless 
a patient is unable to attend a clinic visit in person due to COVID-19 restrictions, in 
which case the first dose of study drug to be taken at bedtime in the evening of Day 1); 
and clinic visits for safety and efficacy assessments over a 3-year treatment period. 
Baseline visits must be conducted on site and not remotely for patients who did not 
complete an OV101 antecedent study (eg, siblings [with
 AS] of study participants with 
AS who have completed previous Ovid studies of OV101). 
After the baseline visit, the 
clinic visits will occur at Weeks 12, 36, 64, 96, 128, and 160 (end of treatment [EOT]).  If 
a patient cannot attend an in-person visit, a home visit may be conducted by 
a trained mobile healthcare professional to perform study assessments e.g. vital signs, 
body system assessment, clinical labs draws, review/collection of study materials. 
 
Telehealth/virtual visits will occur at Weeks 24, 48, 80, 112, and 144. A
 follow-up phone 
safety visit at the EOS will occur approximately 14 days after the last dose of study drug 
(EOT) to assess safety and tolerability associated with discontinuation of treatment. 
A 
home nurse/healthcare professional visit will replace a virtual visit if the latter is not 
feasible.   
A study participant will be considered to have completed the study after 
completing the EOS phone visit. 
The following study participants will be required to complete screening and baseline 
visits (and assessments) to determine eligibility before receiving OV101 under this 
protocol: 
• Study participants who completed OV101-15-001 or OV101-16-001 
• Study participants who are siblings of study participants who have completed 
OV101-15-001, OV101-16-001, or OV101-19-001 
• Study participants who completed treatment in OV101-19-001 more than 2 weeks 
before completing the baseline visit under this protocol (OV101-18-002)  
For study participants required to complete the screening and baseline visits, the planned 
duration of study participation is approximately 3 years (from the start of screening to the 
EOS visit), or until the study drug is commercially available.  
 
For study participants completing the EOT visit for OV101-19-001 two weeks or less 
before enrolling in this OV101-18-002 protocol, the OV101-19-001 EOT visit may serve 
as the baseline visit for OV101-18-002. Clinical laboratory results assessed at EOT in 
OV101-19-001 will serve as baseline clinical laboratory results in OV101-18-002.   
Study participants who meet all eligibility criteria will be enrolled on Day 1 (baseline 
visit) and start the study drug that evening at bedtime (not in the clinic). Each study 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 18 
participant’s LAR/caregiver will receive a package of study drug at the baseline visit, 
sufficient to last until the Week 12 visit.  
 
Each study participant’s dose of OV101 will be titrated to a maintenance dose, as 
tolerated by the study participant. The maximum tolerated dose (up to 15 mg at bedtime) 
will be maintained to the EOT
.
 
 
 
Phone calls to manage titration will occur on Days 6 and 11 for all study participants. 
 
 
 
At the Week 12, 36, 64, 96, and 128 visits, each study participant’s LAR/caregiver will 
receive a package of study drug sufficient to last until the next scheduled visit (e.g., every 
3 to 4 months) at the maximum possible dose. Unused study drug should be returned to 
the site at each visit.  
The LAR/caregivers will complete sleep diaries on behalf of study participants over the 
7-day periods immediately preceding Baseline and should be returned to the site at each 
visit.  
The LAR/caregivers will complete seizure diaries each day during the treatment period 
and should be returned to the site at each visit. 
Safety information will be collected during phone calls and during clinic visits. If a study 
participant experiences any AEs or is unable to take the study drug as prescribed, the 
caregiver/LAR is instructed to contact the study center
. Dose adjustments are permitted 
for study participants who are unable to tolerate the specified dosing regimen.  
At the investigator’s discretion throughout the study
, study participants may be evaluated 
at unscheduled clinic visits for reasons related to study participant safety
.
 At
 unscheduled
 
visits, study participants will be queried about AEs, changes in concomitant medications, 
and suicidality
, and safety laboratory assessments may be conducted. Periodic interim 
review of safety data will be performed as part of routine pharmacovigilance activities 
and to support regulatory submission. 
Assessments:  
Safety assessments related to the study objectives of evaluating safety and tolerability of 
OV101 will include frequency
, severity
, and causality of AEs (including SAEs and 
AEs 
leading to study discontinuation), vital sign measurements, laboratory assessments, 
physical examinations, suicidality assessments, and seizure diary
. 
Efficacy assessments will include the Children’s Sleep Habits Questionnaire; 7-day sleep 
diaries; the Pediatric Quality of Life Inventory; the
 Vineland
 Adaptive
 Behavior Scale, 
3rd Edition; and Clinical Global Impressions (Severity and Improvement) scales. Note 
that efficacy assessments are only to be conducted in study participants who are at least 4 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 19 
years old at study entry
. If a study participant is 2 to 3 years old at study entry and turns 4 
years old during the course of the study
, only safety assessments are to be continued. 
 
Study Drug, Dosage, and Route of Administration: 
OV101 will be supplied as capsules containing 5-mg, 2-mg, or 0.5-mg of study drug. 
Each study participant will be titrated to his/her maximum tolerated daily dose, up to a 
maximum daily dose of 15 mg (see Study Design, above).  
Study participants will take all doses orally (assisted by a LAR/caregiver, if necessary), in 
the evening at bedtime. Capsules may be opened, with the contents sprinkled onto up to 
1 teaspoon of low-fat semiliquid food (e.g., applesauce, yogurt, pudding) for ingestion, 
but this approach must be followed consistently throughout the study
.  
Sample Size:  
Approximately 170 study participants will be enrolled. 
Statistical Methods:  
Analysis sets include the enrolled analysis set (study participants enrolled in the 
extension study), the safety analysis set (all study participants who receive at least 1 dose 
of study drug), and the full-analysis set (all study participants who receive at least 1 dose 
of study drug and have at least 1 post baseline efficacy assessment).  
Descriptive statistics (number of study participants, mean, SD, median, minimum, and 
maximum) will be presented for continuous variables and frequency and percentage will 
be presented for categorical and ordinal variables. If there are missing values, the number 
missing will be presented, but without a percentage. All data collected will be included in 
by-study participant data listings. Two-sided 95% CIs will be provided where 
appropriate. Graphical displays will be utilized to investigate trends over time overall and 
by relevant subgroups as needed.  
Separate analyses of selected endpoints, including but not limited to Clinical Global 
Impressions-Improvement-Angelman syndrome, Clinical Global Impressions-Severity-
Angelman syndrome, and seizure diary data, will be performed for the study participants 
who have participated in STARS and the study participants who have participated in the 
NEPTUNE study (Study OV101-19-001).  
All safety analyses will be performed on the safety analysis set. Treatment-emergent 
adverse events (TEAEs) are defined as AEs that start or increase in severity after the first 
dose of study drug in this open-label study
. The number and percentage of study 
participants who experience at least 1 TEAE as well as the 95% exact CI for the 
incidence of TEAEs overall and within each specific Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class (SOC) and preferred term (PT) will be 
presented.  
Treatment-related AEs will be identified as those that are at least possibly related to study 
drug based on the investigator’s assessment. The number and percentage of study 
participants with treatment-related
 AEs,
 SAEs, TEAEs leading to study discontinuation, 
and TEAEs leading to death will also be summarized by SOC and PT
. For each SOC and 
each PT
, a study participant will be counted only once for study participant-incidence 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 20 
tabulations. For summaries by severity or relationship, for a given study participant, the 
highest severity and relationship for a specific PT will be considered. 
Descriptive statistics for laboratory values and vital sign measurements at each timepoint 
will be summarized. Clinically significant laboratory values may be tabulated. 
Shift tables for laboratory parameters will be presented.  
Shift tables for Clinical Assessments of Suicidality will also be presented to show the 
change in answers (yes/no) from baseline to post baseline visits. 
Abnormal findings in physical examinations will be listed. 
The 28-day seizure frequencies as captured in the seizure diary will be calculated for 
baseline and post baseline study periods for all seizure types and for subtypes of drop and 
nondrop. Percent change in 28-day seizure frequency from baseline to all post baseline 
study visits will also be summarized descriptively for all seizure types and for subtypes of 
drop and nondrop.  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary
. A
 table summarizing concomitant medications and a by-study participant 
listing of concomitant medications will include all medications taken during the study 
regardless of the timing for the start of medication. 
Descriptive statistics and 95% CIs for efficacy variables at each timepoint will be 
displayed. Line graphs of time course of change (or percent change) from baseline will be 
presented for the secondary efficacy endpoints and for the average dose.  
 
Version and Date of Protocol: Version 4.0; 17 September 2020 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 21 
List
 of
 Abbreviations 
Abbreviation 
Definition 
ABC 
Aberrant Behavior Checklist 
ABC-I 
Aberrant Behavior Checklist-Irritability subscale 
 
 
AE 
adverse event 
AS 
Angelman syndrome 
AUC0-∞ 
area under the concentration-time curve from 0 to infinite hours 
ß-hCG 
beta-human chorionic gonadotrophin 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impressions-Improvement 
CGI-I-AS 
Clinical Global Impressions-Improvement-Angelman syndrome 
CGI-S-AS 
Clinical Global Impressions-Severity-Angelman syndrome 
Cmax 
maximum plasma concentration 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
clinical study report 
DRF 
diagnostic review form 
EAS 
enrolled analysis set 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment 
FAS 
full-analysis set 
FDA 
US Food and Drug Administration 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
LAR 
legally acceptable representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
PedQoLI 
Pediatric Quality of Life Inventory 
PBPK 
physiologically based pharmacokinetic 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 22 
Abbreviation 
Definition 
PT 
preferred term 
QD 
once daily 
SAE 
serious adverse event 
SIF 
seizure identification form 
SOC 
system organ class 
SS 
safety analysis set 
TEAE 
treatment-emergent adverse event 
UBE3A 
ubiquitin protein ligase E3A
  
UBE3A 
ubiquitin protein ligase E3A gene 
ULN 
upper limit of normal 
VABS-3 
Vineland Adaptive Behavior Scale, 3rd Edition 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 23 
1 Introduction 
Ovid Therapeutics Inc. (Ovid) is developing OV101 (gaboxadol) for the treatment of rare genetic 
disorders that are associated with severe developmental and behavioral challenges that have no 
approved therapies, such as Angelman syndrome (AS) and Fragile X syndrome. Gaboxadol was 
initially developed for the treatment of insomnia by H. Lundbeck A/S and Merck, but its 
development was discontinued in 2007 for commercial reasons. Extensive nonclinical and 
clinical data were generated during the initial stages of development, including data from 
exposure to gaboxadol in more than 4000 adult study participants (950 study participant-years) 
with insomnia and approximately 500 adult study participants in non–insomnia-related studies.  
Angelman syndrome is a severe, complex, and rare neurogenetic disorder with the prevalence of 
approximately 1 in every 10,000 to 24,000 live births (Petersen et al 1995; Steffenburg et al 
1996; Mertz et al 2013). The condition is associated with impaired expression of the ubiquitin 
protein ligase E3A
 gene (UBE3A). While ubiquitin protein ligase E3A
 (UBE3A) is expressed bi-
allelically 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 AS. Clinical findings range in severity and include developmental 
delay/intellectual disability, movement and/or balance disorder, and tremulous movement of 
limbs. Unique behavioral characteristics include the combination of a happy, smiling demeanor 
with easily provoked laughter and excitability (exhibited by hand-flapping and stereotypic 
movements). Individuals
 with
 AS
 frequently have motor dysfunction related to gait and balance, 
severe disruptions in sleep, little to no speech, short attention span, anxiety
, and seizures with 
characteristic abnormal electroencephalogram patterns (Williams et al 2006).  
Current treatments are aimed at managing symptoms and include antiepileptic medications for 
seizure control and medications for sleep and behavioral problems (e.g., anxiety). Other therapies 
include speech therapy
, physical therapy
, occupational therapy
, and educational resources. 
Notably
, current treatments do not target the underlying brain deficits.  
OV101 is the first highly selective, extrasynaptic gamma-aminobutyric acid (GABA) receptor 
agonist that binds orthosterically to the δ-subunit of extrasynaptic GABA
 receptors. The 
mechanism of action of OV101 is unique among GABAergic agents, including benzodiazepines, 
zolpidem and other zolpidem-like drugs, neurosteroids, and drugs that act on GABA
 metabolism 
or uptake. Research has shown that absence (or dysfunction) of UBE3A results in an aberrant 
increase in the uptake of GABA, which is the main inhibitory neurotransmitter in the brain. 
OV101 is the first highly selective GABA
 receptor agonist that acts on α4δ-containing GABA
 A-
receptors. These receptors mediate tonic inhibition and sleep maintenance. In a mouse model of 
AS, OV101 was shown to restore tonic inhibition in UBE3A-deficient cerebellar neurons and 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 24 
correct motor abnormalities in UBE3A-deficient mice (Egawa et al 2012). 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, zaleplon, zopiclone, barbiturates, 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 study participants 
with AS (Ramamoorthi and Lin 2011; Brickley and Mody 2012; Egawa and Fukuda 2013; 
Deidda et al 2014; Berry et al 2015; Dissel et al 2015).  
Phase 2 and Phase 3 studies in adult study participants with primary insomnia demonstrated that 
OV101 is effective in restoring classical sleep parameters (sleep induction and sleep 
maintenance) and slow wave sleep, resulting in an improvement in the quality and restorative 
effects of sleep.  
A randomized, double-blind, placebo-controlled Phase 2 study (OV101-15-001, STARS; 
NCT02996305) evaluated the safety
, tolerability
, and efficacy of OV101 in adolescents and 
adults with AS over 12 weeks of treatment (Bird et al 2019). Eighty-eight participants with AS 
(13 to 49 years old) were randomly assigned to 1 of 3 groups: once-daily (QD) dose of OV101 
nightly (15 mg), twice-daily (BID) dose of OV101 (10 mg morning and 15 mg night), and 
placebo. The safety and tolerability of OV101 from Baseline to Week 12 was evaluated by 
comparing the frequency and severity of adverse events (AEs) and serious AEs (SAEs) in the 
OV101 treatment groups to those in the placebo group. OV101 was generally safe and well 
tolerated, with a similar incidence of AEs across all treatment groups: most 
AEs were mild. 
Treatment discontinuations due to AEs were low (placebo, 1; OV101 QD, 0; OV101 BID, 3). 
The most frequent AEs across all treatment groups were vomiting, somnolence, irritability
, 
aggression, pyrexia, and upper respiratory infection. The AEs occurring in the OV101 treatment 
groups with greater frequency than placebo were pyrexia, rash, seizure, enuresis, myoclonic 
epilepsy
, otitis media, and viral infection. Two study participants had an SAE of seizure: 1 study 
participant in the BID group deemed “Possibly Related” and 1 study participant in the QD group 
deemed “Not Related.” 
 
 
 
 
 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 25 
 
 
 
 
 
This open-label study (OV101-18-002) will evaluate the long-term (160-week) safety and 
efficacy of OV101 in study participants
 with
 AS
 who either have completed previous Ovid 
studies (OV101-15-001, OV101-16-001, or OV101-19-001) or are siblings (with AS) of study 
participants with AS who have completed previous Ovid studies of OV101. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 26 
2 Study Objectives and
 Assessments
 Related to Endpoints 
2.1 Primary Objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of OV101 
in individuals with AS assessed by the incidence and severity of AEs and SAEs in study 
participants who are at least 2 years old at the time of enrollment into this study.  
2.2 Secondary Objectives 
The secondary objectives of this study are the following:  
• To evaluate the long-term efficacy of OV101 treatment assessed by changes in behavior 
and sleep in study participants with
 AS who are at least 4 years old at the time of 
enrollment into this study 
• To evaluate long term efficacy as assessed by clinical global impressions of severity and 
improvement scales, VABS, CHSQ, PedsQL, and Sleep Diary in study participants with 
AS who are at least 4 years old at the time of enrollment into this study. 
• To evaluate the long-term safety and tolerability of OV101 treatment assessed by 
changes in suicidality assessments, vital sign measurements, laboratory assessments, 
physical examinations, and seizure frequency in study participants
 with
 AS
 who are at 
least 2 years old at the time of enrollment into this study
. 
2.3 Exploratory Objectives 
The exploratory objective of this study is the following:  
• To explore the relationships among study endpoints (e.g., behavior and sleep), where 
appropriate 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 27 
3 Investigational Plan 
3.1 Study Design 
This will be an open-label, long-term safety study for evaluation of treatment with OV101 in 
approximately 170 study participants with AS who either have completed previous Ovid studies 
(OV101-15-001, OV101-16-001, or OV101-19-001) or are siblings (with
 AS) of study 
participants with
 AS
 who have completed previous Ovid studies of OV101 There will be no 
placebo treatment. The study will be conducted at approximately 20 sites (total) in the United 
States, Australia, Europe, and Israel. As this study will enroll study participants who may have 
completed previous studies for different periods of time before entering this study (as well as 
study participants with AS who have not been themselves enrolled in an Ovid study), study 
participants may be required to complete screening and baseline visits before receiving OV101 
under this protocol. 
The study will comprise a screening period of up to 30 days; a baseline visit on Day 1 for 
baseline assessments; it is recommended that first dose of study drug be taken at the site unless a 
patient is unable to attend a clinic visit in person (e.g. due to COVID-19 restrictions) in which 
case the first dose of study drug to be taken in the evening of Day 1 (at bedtime), and clinic visits 
for safety and efficacy assessments over a 3-year treatment period (Figure 3-1). After the 
baseline visit, the clinic visits will occur at Weeks 12, 36, 64, 96, 128, and 160 (end of treatment 
[EOT]).  If a patient cannot attend an in-person visit, a home visit may be conducted by 
a trained mobile healthcare professional to perform study assessments e.g. vital signs, body 
system assessment, clinical lab draws, review/collection of study materials. 
Telehealth/virtual visits will occur at Weeks 24, 48, 80, 112, and 144. A
 follow-up phone safety 
visit at the end of study (EOS) will occur approximately 14 days after the last dose of study drug 
(EOT) to assess safety and tolerability associated with discontinuation of treatment. A
 home 
nurse visit will replace a virtual visit if the latter is not feasible. A study participant will be 
considered to have completed the study after completing the EOS phone visit. The schedule of 
activities for this study is fully presented in Table 6-1.  

Ovid Therapeutics Inc. 
      
   
   
 
OV101 
Protocol OV101-18-002 Version 4.0 
      
   
 
13 October 2020 
Page 28 
Figure 3-1 
Study Design Schematic 
 
*All study participants will be titrated in accordance with the titration schedule. 
*Neptune study participants EOT visit may serve as a baseline visit for ELARA. 
 
*Telehealth/Virtual visits for dose adjustments may be made throughout the treatment phase at the discretion of the investigator 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 29 
The following study participants will be required to complete screening and baseline visits (and 
assessments) to determine eligibility before receiving OV101 under this protocol: 
• Study participants who completed OV101-15-001 or OV101-16-001 
• Study participants who are siblings of study participants who have completed 
OV101-15-001, OV101-16-001, or OV101-19-001 
• Study participants who completed treatment in OV101-19-001 more than 2 weeks 
before completing the baseline visit under this protocol (OV101-18-002) 
 
For study participants required to complete the screening and baseline visits, the planned 
duration of study participation is approximately 166 weeks from the start of screening to the 
EOS visit, including 160 weeks of treatment with OV101.  
For study participants completing the EOT visit for OV101-19-001 two weeks or less before 
enrolling in this OV101-18-002 protocol, the OV101-19-001 EOT visit may serve as the baseline 
visit for OV101-18-002. Clinical laboratory results assessed at EOT in OV101-19-001 will serve 
as baseline clinical laboratory results in OV101-18-002. For such study participants, the 
maximum planned duration of study participation would be approximately 162 weeks or until 
commercially available.  
Study participants who meet all eligibility criteria will be enrolled on Day 1 (baseline visit) and 
start the study drug that evening at bedtime (not in the clinic). Each study participant’s legally 
acceptable representative (LAR)/caregiver will receive a package of study drug at the baseline 
visit, sufficient to last until the Week 12 visit.  
As presented in Figure 3-1, each study participant’s dose of OV101 will be titrated to a 
maintenance dose, as tolerated by the study participant 
 
. The maximum tolerated dose (up to 15 mg at bedtime) will be maintained to the EOT
. 
 
 
  
Phone calls to manage titration will occur on Days 6 and 11 for all study participants. 
 
 
 Phone calls to 
manage dose titration, 
 will occur 5 days later to assess tolerability. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 30 
At the Week 12, 36, 64, 96, and 128 visits, each study participant’s LAR/caregiver will receive a 
package of study drug sufficient to last until the next scheduled visit at the maximum possible 
dose. Unused study drug will be returned to the site following each scheduled visit. 
The sleep diary is to be completed over the 7-day periods immediately preceding the clinic visits 
when sleep diaries are scheduled to be reviewed; a calendar will be issued to ensure that the 
diary information collection starts on the appropriate days. Phone calls to remind 
LAR/caregivers to start recording diaries will be made 14 days before each study participant’s 
expected next visit date. The LAR/caregivers will complete seizure diaries each day during the 
treatment period and should be returned to the site at each visit. 
Safety information will be collected during phone calls and during clinic visits. If a study 
participant experiences any AEs or is unable to take the study drug as prescribed, the 
caregiver/LAR is instructed to contact the study center
. Dose adjustments are permitted for study 
participants who are unable to tolerate the specified dosing regimen (Section 5.2.1).  
At the investigator’s discretion throughout the study
, study participants may be evaluated at 
unscheduled clinic visits for reasons related to study participant safety
.
 At
 unscheduled
 visits,
 
study participants will be queried about AEs, changes in concomitant medications, and 
suicidality
, and safety laboratory assessments may be conducted. Periodic interim review of 
safety data will be performed as part of routine pharmacovigilance activities and to support 
regulatory submission. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 31 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 33 
4 Study participant Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 170 study participants will be enrolled at approximately 15 sites (total) in the 
United
 States,
 Australia,
  Germany
, Netherlands, and Israel. Study participants will be assigned 
to study treatment only if they meet all the inclusion criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed.  
Study participants will be individuals with AS who either have completed previous Ovid studies 
(OV101-15-001, OV101-16-001, or OV101-19-001) or are siblings (with
 AS) of study 
participants with AS who have completed previous Ovid studies of OV101. 
4.1.1 Inclusion Criteria 
Each study participant must meet all the following criteria to be enrolled in this study: 
1. Ovid study enrollment criteria:  
• Has completed the OV101-15-001 or OV101-16-001 study up to the EOS, or 
• Has completed the OV101-19-001 study up to the EOT
, or 
• Is a sibling of a study participant with AS who has completed OV101-15-001, 
OV10116001, or OV101-19-001.  
2. Has a previous diagnosis of AS with molecular confirmation. 
3. Is at least 2 years old and has a body weight of at least 9 kg. 
4. Has an LAR/caregiver capable of providing informed consent and able to attend all 
scheduled study visits, oversee the administration of study drug, and provide feedback 
regarding the study participant’s symptoms and performance as described in the protocol. 
5. Provides assent to the protocol (to the extent possible and in accordance with local 
institutional review board [IRB] and regulatory requirements) and has a LAR/caregiver 
who will provide written informed consent. Study participants providing assent must do 
so at the same visit as LAR/caregiver written informed consent is provided. 
6. Can swallow study drug capsules with water or ingest the contents of study drug capsules 
after sprinkling the capsule contents onto up to 1 teaspoon of low-fat semiliquid food. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 34 
7. If a study participant is currently receiving a regimen of concomitant medications such as 
antiepileptic medication, gabapentin, clonidine, trazodone, melatonin, and/or a special 
dietary regimen, that study participant’s regimen is stable for at least 4 weeks before 
Day 1 (first day of study drug administration) and will be maintained throughout the 
duration of the study (in the judgment of the investigator). 
8. Has LAR/caregiver(s) who agree not to post any of the study participant’s personal 
medical data or information related to the study on any website, message board, online 
support group, or social media site (e.g., Facebook, Instagram, Twitter) until notified that 
the study is completed. 
9. Female study participants who are of childbearing potential (defined as having 
experienced their first menarche) must agree to use either a highly effective or acceptable 
form of birth control during the study and for 30 days following the last dose of the study 
drug. Highly effective contraceptive methods are as follows: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o 
Oral 
o 
Injectable 
o 
Implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 35 
• Male or female condom with or without spermicide* 
• Cap, diaphragm, or sponge with spermicide* 
*A
 combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not highly 
effective, birth control methods. 
4.1.2 Exclusion Criteria 
Study participants meeting any of the following criteria will be excluded from the study: 
10. Discontinued from the OV101-15-001, OV101-16-001, or OV101-19-001 study due to 
safety reasons causally related to OV101. 
11. Has a circumstance, condition, concomitant disease (e.g., gastrointestinal, renal, hepatic, 
endocrine, respiratory
, or cardiovascular system disease), or any clinically significant 
finding that could interfere with the conduct of the study or that would pose an 
unacceptable risk to the study participant in this study
. 
12. Has poorly controlled seizures defined as any of the following:  
• Weekly seizures of any frequency with a duration of more than 3 minutes each 
• Weekly seizures occurring more than 3 times per week, each with a duration of 
less than 3 minutes 
• Investigator assessment 
13. Has any of the following laboratory abnormalities: total bilirubin >1.5 × upper limit of 
normal (ULN), unless known Gilbert’s syndrome; alanine aminotransferase or aspartate 
aminotransferase >2.5 × ULN; serum creatinine >1.2 × ULN; absolute neutrophil count 
<1.5 × 109/L; platelets <80 × 10
9/L; hemoglobin <80 g/L; or thyroid stimulating 
hormone >1.25 × ULN or <0.8 × lower limit of normal. Retesting of clinical laboratory 
parameters may be allowed after consultation with the medical monitor or designee. 
14. Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, or 
ramelteon for sleep, or minocycline or levodopa within the 4 weeks prior to Day 1 or 
during the study
. Benzodiazepines administered as needed or regularly scheduled for 
indications other than insomnia and benzodiazepines for seizure control are permitted.  
15. Is at risk of harming self and/or others (based on investigator assessment).  
16. With the exception of an Ovid study of OV101, has enrolled in any clinical or used any 
investigational agent or device, or has participated in any investigational procedure, within 
the 30 days before screening or does so concurrently with this study
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 36 
17. Is allergic to OV101 or any excipients of study drug. 
18. The study participant or LAR/caregiver is unable to comply with study requirements 
(based on investigator assessment). 
4.2 Withdrawal of Study participants from Study Treatment and/or the 
Study 
Study participants who discontinue treatment during the study will be encouraged by 
investigators to continue to participate in all scheduled clinic visits and assessments, and study 
data will be collected for these study participants per protocol.  
Discontinuation of a study participant from treatment early (before Week 160) for any reason 
will initiate procedures for discontinuation of the study participant from the study
, including 
EOT and EOS visits (Section 3.1). For study participants who stopped study treatment early 
(before Week 160), an EOT visit should be conducted within 2 weeks after the last day of study 
drug. After completing the EOT visit, an EOS visit should be completed within 2 weeks after 
completing the EOT visit. The duration of the study is defined for each study participant as the 
date signed written informed consent is provided through the EOS visit. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Study participants may withdraw from the study at any time and for any reason without prejudice 
to their future medical care by the investigator or at the study site. Study drug administration 
may be stopped early at the discretion of the investigator (or designee) if a study participant does 
not tolerate the dosing regimen. Every effort should be made to keep study participants in the 
study
. The reasons for study participants not continuing in the study will be recorded. A
 study 
participant may be withdrawn from the study for any of the following reasons: 
1. The study participant does not continue to meet the protocol inclusion or exclusion 
criteria. 
2. The study participant has a serious or intolerable AE that, in the investigator’s opinion, 
requires withdrawal from the study
.  
3. The study participant has laboratory safety results that reveal clinically significant changes 
from baseline in hematological or biochemical assessments.  
4. The study participant has symptoms (or an intercurrent illness) that are not consistent with 
the protocol requirements or that justify withdrawal. 
5. The study participant is lost to follow-up. 
6. Other reasons (e.g., development of contraindications to use of study drug). 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 37 
7. The study participant (or his/her LAR/caregiver) withdraws assent (consent), or the 
investigator or sponsor decides to discontinue the study participant’s participation in the 
study
. 
The investigator will also withdraw a study participant if Ovid terminates the study
. Upon 
occurrence of a serious or intolerable AE, the investigator will confer with the medical monitor 
and/or sponsor
. If a study participant is discontinued because of an AE, the event will be 
followed until it is resolved. Any study participant may withdraw his/her consent at any time. 
4.2.2 Handling of Withdrawals 
Study participants are free to withdraw from the study or study treatment at any time upon 
request. Study participant participation in the study may be stopped at any time at the discretion 
of the investigator or at the request of the sponsor
. 
Study participants who stop study treatment or active participation in the study will no longer 
receive study drug. When a study participant withdraws from the study treatment or active 
participation in the study
, the reason(s) for withdrawal shall be recorded by the investigator on 
the relevant page of the electronic case report form (eCRF) using the electronic data capture 
(EDC) system. Whenever possible, all study participants who stop study treatment or withdraw 
from the study prematurely will complete the EOT and EOS assessments. Study participants who 
fail to return for final assessments will be contacted by the site (2 documented phone calls 
followed by 1 registered letter, as applicable) in an attempt to have them comply with the 
protocol. 
It is vital to obtain follow-up data on any study participant withdrawn or who withdraws because 
of an AE or SAE. In every case, efforts must be made to undertake protocol-specified safety 
follow-up procedures. 
4.2.3 Replacements and Rescreening 
Enrollment in this extension study is open to all study participants meeting the eligibility criteria. 
Study participants who fail to satisfy all inclusion and exclusion criteria at Screening may be 
rescreened 1 additional time at the discretion of the medical monitor or his/her designee 
(Section 6.1.1). Study participants identified for rescreening should be discussed with the 
medical monitor
. There are no plans to replace study participants. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 38 
5 Study Treatments 
All study participants will receive OV101. No study participant will receive placebo treatment in 
this open-label extension study
. The planned doses of OV101 represent the intended therapeutic 
doses of OV101. See Section 5.2.1 for details of dosing. 
5.1 Study participant Number
 Assignment 
Study participant numbers for this study will be assigned at Screening.  
5.2 Treatments
 Administered 
OV101 will be supplied as capsules containing 5-mg, 2-mg, or 0.5-mg of study drug. 
At clinic 
visits at Baseline and at Weeks 12, 36, 64, 96, and 128, each study participant’s primary 
LAR/caregiver will receive enough capsules to cover OV101 administration until the next visit. 
Study participants will take all doses orally (assisted by a LAR/caregiver, if necessary), in the 
evening at bedtime. Capsules may be opened, with the contents sprinkled onto up to 1 teaspoon 
of low-fat semiliquid food (e.g., applesauce, yogurt, pudding) for ingestion, but this approach 
must be followed consistently throughout the study
. The capsule contents must not be placed 
directly in liquid. The LAR/caregiver must document in the medication diary (Section 5.6) 
specifically how the capsules were taken (e.g., swallowed whole or taken in up to 1 teaspoon of 
food). 
On Day 1, study participants will take their first dose of study drug at the study site during the 
daytime, taking all subsequent doses at bedtime, starting with the evening of Day 2. The 
LAR/caregiver should make every effort to administer the drug at approximately the same time 
each night.  
If a study participant misses a dose of study drug for any reason, unless within a 3-hour window 
of the usual administration time, the study participant should not make up the missed dose. The 
study participant should wait to take the next dose as scheduled and take a single dose at that 
time. It is important that the dosing regimen be documented in the medication diary by the 
LAR/caregiver and monitored by the study site to ensure that appropriate dosing is being 
followed. Study participants experiencing dose interruptions should be evaluated by the 
investigator in conjunction with the medical monitor
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 39 
5.2.1 Dose Titration 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 40 
 
 
 
 
 
 
 
 
  
5.2.1.2 Down-Titration
 for
 All
 Study participants 
The investigator may initiate down-titration by 1 capsule based on the investigator assessments 
of tolerability and AEs, or medical necessity
. If down-titration is initiated, then the investigator 
should reassess tolerability with the modified dose regimen within 3 days of the dosing change.  
If tolerability is not acceptable (e.g., excessive somnolence, dizziness, vomiting, or change in 
behavior) at any time during the study
, the investigator should discuss the situation with the 
medical monitor
. Unscheduled clinic visits are optional at any time to confirm tolerability
. Any 
event of poor tolerability must be documented as an AE. The study site will document any dose 
adjustments or changes in dosing in the eCRF and the supporting rationale must be documented 
in the medical record or other appropriate source document. Adverse events triggering any down-
titration must be reported. 
For study participants enrolled in this study, the daily dose 
 may not be 
lower than the reduced maintenance dose indicated in Table 5-2. If at any point in the study a 
down titration is considered due to significant loss of weight, this should be discussed and agreed 
to in consultation with the medical monitor prior to any change. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 41 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3 Description of Study Drug 
 
 
 
 
 
 
 
 
 
All capsules are imprinted with a dark blue band on the cap and body
. Each capsule contains 
white to off-white powder
. Excipients will be 
 
Note that the original white capsule currently in use will be used till completion. 
5.4 Management of Clinical Supplies 
Bulk capsules of OV101 will be shipped to the vendor, who will package, label, and deliver the 
kits to each study site. 
5.4.1 Study Drug Packaging and Storage 
Study drug will be packaged as capsules of OV101 in bottles or cards. 
A
 clinical label will be 
affixed to the outside of each bottle/card. The label will specify the sponsor name (Ovid 
Therapeutics Inc.); study participant number; protocol number; bottle/card number; number of 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 42 
capsules (each bottle/card); “Evening,” and “Take as directed.” The recommended storage 
conditions and expiry date (where required) will be stated on the product label. At the study site, 
study drug must be stored in a secure area (e.g., a locked cabinet), protected from moisture, and 
kept at a controlled room temperature, 59°F to 77°F (15°C to 25°C). Study participants and 
LARs/caregivers must keep all study drug in the original bottles/cards and maintain it at room 
temperature. 
5.4.2 Study Drug 
Accountability 
The investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study drug is 
dispensed and used by each study participant in the study
. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study
, to satisfy 
regulatory requirements regarding drug accountability
, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 
5.4.3 Other Supplies 
No other clinical supplies will be provided to study sites.  
5.5 Overdose Reporting 
An overdose is any dose of study treatment given to a study participant or taken by a study 
participant that exceeds the dose described in the protocol. Any overdose, with or without 
associated AEs, must be recorded in the eCRF. 
Any AEs associated with an overdose should be 
reported in the relevant AE/SAE sections in the eCRF
. Any associated SAEs must be promptly 
reported to Ovid using SAE reporting procedures (Section 6.2.1.5). Overdoses without signs or 
symptoms do not need to be recorded as AEs. 
5.5.1 Treatment of Overdose 
In the event of a suspected overdose, the appropriate supportive clinical care should be provided 
as dictated by the study participant’s clinical status. 
5.6 Medication Errors 
A
 medication diary will be maintained by the LAR/caregiver on behalf of the study participant 
for the duration of the treatment period to confirm dosing dates and times and to permit 
monitoring for medication compliance and medication errors. The medication diary will be 
reviewed at each clinic/home health visit by either the site investigator, study coordinator or 
home health nurse if the study participant is unable to come to clinic due to Covid-19. If a dose is 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 43 
missed (beyond the 3-hour dosing window), this should be noted, and the study participant 
should resume prescribed dosing the following evening (without doubling the dose). 
5.6.1 Treatment of Medication Errors 
An example of a medication error is overdose; treatment of overdose is described in 
Section 5.5.1. 
5.7 Blinding 
This is an open-label study: there will be no blinding.  
5.8 Treatment Compliance 
Study participant compliance will be determined by comparing the capsule counts of returned 
study drug to the capsule count of study drug dispensed at the previous visit (Table 6-1). An 
investigator may suspend a study participant’s administration of study drug for up to 2 weeks; 
suspension for longer than 2 weeks should be discussed with the medical monitor
. Re-titration 
may not be necessary
. The number of capsules remaining will be tracked and recorded. The 
LAR/caregiver will be questioned as to the reason(s) why unexpected remaining capsules have 
not been administered (e.g., forgot, study participant refused, study participant experienced
 AE
 
or LAR/caregiver decided to reduce dose); the reason(s) and the approximate date and time of 
any missed doses will be recorded in the eCRF
. The study participant’s medication diary will be 
reviewed for supporting information. 
The medication diary (Section 5.6) will serve as a strategy that may improve compliance in 
addition to serving as a method for monitoring adherence. 
5.9 Prior and Concomitant Therapy  
Study participants should be on stable regular or as-needed doses of prescribed medications and 
on stable nonmedication interventions (e.g., speech therapy
, physical therapy
, occupational 
therapy) for 4 weeks before Baseline (Day 1). Study participants should remain on the stable 
regimens until after the EOS visit. Additionally
, unless required to treat AEs, there should be no 
new medications or changes to concomitant medications (e.g., products containing cannabidiol), 
approved dietary and herbal supplements, and nonmedication interventions during the study until 
after the EOS visit. 
Use of all concomitant medications will be recorded in the study participant’s eCRF
. The 
minimum requirement is that drug name and the dates of administration are recorded. 
Concomitant medications include all prescription drugs, herbal products, vitamins, minerals, and 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 44 
over-the-counter medications. Any changes in concomitant medications or significant nondrug 
therapies will also be recorded in the study participant’s eCRF
.  
Any concomitant medication deemed necessary for the welfare of the study participant during 
the study may be given at the discretion of the investigator
. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the eCRF
. 
5.9.1 Prohibited Medications and Therapies 
Use of any GABAergic agents (e.g., acamprosate, baclofen, vigabatrin, tiagabine and riluzole) on 
a regular schedule is prohibited from the time informed consent is obtained to the end of a study 
participant’s participation in the study
. Sodium oxybate is also prohibited. Study participants who 
entered the study on a stable dose of gabapentin (i.e., stable dose for at least 4 weeks prior to 
randomization), may continue on the treatment as long as no dose modifications are expected 
during the study
. Any change in gabapentin dose during the study must be captured and 
documented as a protocol deviation. 
Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, or ramelteon 
for sleep is prohibited within the 4 weeks prior to Day 1 or during the study
. Benzodiazepines 
administered as needed or as a regularly scheduled dose for indications other than insomnia (e.g., 
seizures, anxiety) are permitted. Minocycline and levodopa are prohibited from 4 weeks prior to 
Day 1 to the end of a study participant’s participation in the study
. 
Use of other investigational agents (e.g., products without market authorization [approved label]) 
is prohibited during the study
.  
5.9.2 Restrictions 
Any prior or concomitant medication, including antiepileptic and/or behavioral medications, 
supplements, or special diets, must be at a stable dose for at least 4 weeks before Day 1, and 
must be maintained throughout the study
.  
Benzodiazepines prescribed on an as-needed basis for situational anxiety (e.g., for occasional 
procedures or events) or scheduled for indications that are not related to sleep (e.g., seizures, 
anxiety) are permitted.  
Study participants should not consume alcohol during the study
.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 45 
6 Study Assessments and Procedures 
Before submitting to any study procedures, all potential study participants and/or 
LAR/caregivers will sign an informed consent form (ICF). Study participants and 
LAR/caregivers will have the opportunity to have any questions answered before signing the 
ICF
. The investigator must address all questions raised by the study participants and 
LAR/caregivers. The investigator or designee will also sign the ICF
.  
The schedule of activities by clinic visit for this study is presented in Table 6-1. 
Telehealth/virtual visits should be consistent with local and individual institutions’
 policies and 
standard practices. Detailed instructions for virtual/phone visits will be provided in the 
investigators’
 virtual/phone visit study manual. A
 home nurse visit will replace a virtual visit if 
the latter is not feasible. 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 46 
Table 6-1 
Schedule of Activities by Study Visit 
Visit Namec 
Screeninga Baselineb 
Phone 
Titration 
Week 
12 
Week  
24 
Telehe
alth/Vi
rtual 
Visitp 
Week 
36 
Week 
48 
Telehe
alth/Vi
rtual 
Visitp 
 
Week 
64 
Week 
80 
Telehe
alth/Vi
rtual 
Visitp 
Week 
96 
Week 
112 
Telehe
alth/Vi
rtual 
Visitp 
Week 
128 
Week 
144 
Telehe
alth/Vi
rtual 
Visitp 
EOT 
EOSd 
(Phone) 
Window (days)  
–e 
+1 
+3 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
Dayf  
–30 to -1  
1 
6, 11, 15 
84 
168 
252 
336 
448 
560 
672 
784 
896 1008 1120 
1134 
Week  
– 
0 
1-3 
12 
24 
36 
48 
64 
80 
96 
112 
128 
144 
160  
162 
Obtain informed 
consent and 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify inclusion/ 
exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain medical 
history and 
demographic 
information 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct clinical 
assessment for 
ASg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm prior 
molecular AS 
diagnosish 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
Vital sign 
measurements 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Clinical 
laboratory tests 
X 
Xi 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy testj 
Xj 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 
Xj 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 47 
Visit Namec 
Screeninga Baselineb 
Phone 
Titration 
Week 
12 
Week  
24 
Telehe
alth/Vi
rtual 
Visitp 
Week 
36 
Week 
48 
Telehe
alth/Vi
rtual 
Visitp 
 
Week 
64 
Week 
80 
Telehe
alth/Vi
rtual 
Visitp 
Week 
96 
Week 
112 
Telehe
alth/Vi
rtual 
Visitp 
Week 
128 
Week 
144 
Telehe
alth/Vi
rtual 
Visitp 
EOT 
EOSd 
(Phone) 
Window (days)  
–e 
+1 
+3 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
Dayf  
–30 to -1
  
1 
6, 11, 15 
84 
168 
252 
336 
448 
560 
672 
784 
896 1008 1120 
1134 
Week  
– 
0 
1-3 
12 
24 
36 
48 
64 
80 
96 
112 
128 
144 
160  
162 
Adverse event 
inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
suicidality: ABC-
I
n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure diary 
issued 
SIF/DRF forms 
completed/submi
tted
o 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Seizure diary 
review/collection  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Dispense 
medication diary  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review/collect 
medication diary, 
assess 
compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study 
drug 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect unused 
study drug 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 48 
Visit Namec 
Screeninga Baselineb 
Phone 
Titration 
Week 
12 
Week  
24 
Telehe
alth/Vi
rtual 
Visitp 
Week 
36 
Week 
48 
Telehe
alth/Vi
rtual 
Visitp 
 
Week 
64 
Week 
80 
Telehe
alth/Vi
rtual 
Visitp 
Week 
96 
Week 
112 
Telehe
alth/Vi
rtual 
Visitp 
Week 
128 
Week 
144 
Telehe
alth/Vi
rtual 
Visitp 
EOT 
EOSd 
(Phone) 
Window (days)  
–e 
+1 
+3 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
±7 
±5 
Dayf  
–30 to -1
  
1 
6, 11, 15 
84 
168 
252 
336 
448 
560 
672 
784 
896 1008 1120 
1134 
Week  
– 
0 
1-3 
12 
24 
36 
48 
64 
80 
96 
112 
128 
144 
160  
162 
Clinician-Completed Measures 
VABS-3
k 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CGI-S-AS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CGI-I-ASl 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Caregiver-Completed Measures 
CSHQ 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PedQoLI 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Sleep diary 
issued
m 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Sleep Diary 
collected/ 
reviewed 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Abbreviations:
 ABC-I, Aberrant Behavior Checklist-Irritability subscale; AS, Angelman syndrome; CGI-I-AS, Clinical Global Impressions-Improvement-
Angelman syndrome; CGI-S-AS, Clinical Global Impressions-Severity-Angelman syndrome; CSHQ, Children’s Sleep Habits Questionnaire; EOS, end of 
study; EOT
, end of treatment; PedQoLI, Pediatric Quality of Life Inventory; VABS-3, Vineland Adaptive Behavior Scale, 3rd Edition. 
Notes: At the investigator’s discretion, study participants may be evaluated at unscheduled clinic visits for reasons related to study participant safety
.
 At
 
unscheduled visits, study participants will be queried about adverse events, changes in concomitant medications, and suicidality; and safety laboratory 
assessments may be conducted. Efficacy assessments will be only for study participants who are at least 4 years old. If study drug is dispensed at 
unscheduled visit, dosage should be maintained at the same level as at the previous scheduled visit. If a down-titration is required for a clinical indication, 
this must be discussed with the medical monitor prior to making the change or at the earliest opportunity
. Up-titration should not be performed at an 
unscheduled visit.  
a For study participants entering this study within 2 weeks of completing the EOT visit of OV101-19-001, the screening activities can be verified or conducted at 
the baseline (Day 1) visit. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 49 
b If the screening and baseline visits can be completed within 14 days, the following assessments do not need to be repeated at the baseline visit: medical history
, 
clinical assessment, physical examination, clinical laboratory tests, and determination of concomitant medications. For study participants entering this study 
within 2 weeks of completing the EOT visit of OV101-19-001, the EOT visit activities need not be repeated. 
c If a study participant could not attend an in person visit, a telehealth/virtual or home visits, may be conducted by a trained mobile healthcare professional to 
perform study assessments e.g. vital signs, body system assessment, clinical labs draws, review/collection of study materials  Baseline visits must be 
conducted on site and not remotely for patients who did not complete an OV101 antecedent study (eg, siblings [with
 AS] of study participants
 with
 AS
 who
 
have completed previous Ovid studies of OV101). 
d 
An ET study participant should complete both EOS and EOT visit assessments.  
e Screening is to be conducted for up to 30 days (inclusive) before Day 1; study participants who meet all entry criteria can start treatment at any time during the 
screening period. 
f There is no Day 0.  
g Signs and symptoms of AS. 
h Review documentation of previous molecular AS testing from the OV101-15-001, OV101-16-001 study
, or OV101-19-001. 
i If the baseline visit occurs within 14 days of the clinical laboratory tests during screening or during the study participant’s EOT visit in OV101-19-001, clinical 
laboratory testing does not need to be performed at the baseline visit.  
j Serum pregnancy testing is to be completed at screening and baseline visits. At subsequent visits, urine pregnancy testing is performed. 
k T h 
e 
 VA B S-3 will be assessed by a trained qualified rater based on an interview of the study participant’s caregiver
. For each study site, the same rater is to be 
used throughout the study
. As an exception, another sponsor-trained qualified rater in VABS-3 may be used 
l Within 24 hours prior to the study participant’s visit at Week 12 (the first CGI-I-AS assessment), the investigator must review the study participant’s baseline 
CGI-S-AS score and investigator notes. Within 24 hours prior to the study participant’s visit at Week 36 (and all subsequent visits with assessments of CGI-
I-AS), the investigator must review the study participant’s baseline CGI-S-AS score and investigator notes and the prior clinic visit’s CGIIAS score and 
investigator notes. The same clinician rater, trained in CGI-S-AS and CGI-I-AS rating by the sponsor, must be used throughout the study to assess a given 
study participant. It is recommended that the same rater be used at a given site. As an exception, a clinician sub-investigator, trained in CGISAS and CGI-I-
AS rating by the sponsor, may be used.  
m The sleep diary is to be completed over the 7-day periods immediately preceding the clinic visits when sleep diaries are scheduled to be reviewed; a calendar 
will be issued to ensure that the diary information collection starts on the appropriate days. Phone calls to remind legally acceptable representative/caregivers 
to start recording diaries will be made 14 days before each study participant’s expected next visit date. 
n The entire Aberrant Behavior Checklist – Community (ABC-C) will be administered. Only
 ABC-I will be used to evaluate the potential for self-harm 
o Seizure Identification Form and Diagnostic Review Form (SIF/DRF) will be completed by site personnel for every eligible study participant. This information 
will be faxed or emailed to The Epilepsy Study Consortium (TESC) for review and approval. The SIF/DRF will be used to ensure that the seizures are classified 
accurately
. SIF and DRF forms will be collected for patients who have enrolled/completed the study if feasible. 
p A
 home nurse visit will replace a virtual visit if the latter is not feasible. 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 50 
6.1 Study Visits  
6.1.1 Screening Period 
Study participants entering this study within 2 weeks of completing the EOT visit of 
OV101-19-001 do not need to have a screening period; the screening activities can be verified or 
conducted at the baseline (Day 1) visit. All other study participants will be screened for 
participation in the study up to 30 days before Baseline (Day 1), when the first dose will be 
administered. Study participants who meet all entry criteria can have their baseline clinic visit at 
any time during the screening period. 
Written informed consent (from the study participant’s LAR/caregiver) and assent (from the 
study participant) will be obtained before the study participant participates in any study 
procedure and begins the study screening procedures for eligibility
. Assent will be obtained if the 
investigator believes that the study participant has the intellectual capacity to provide it, but 
assent may not be relevant based on the study participant’s intellectual disability and/or age 
(Section 9.3).  
Molecular confirmation of the diagnosis of AS was an inclusion criterion for OV101-15-001, 
OV101-16-001, and OV101-19-001. Blood tests for molecular confirmation of AS will not be 
performed unless the study participant is a sibling of a previous participant and does not have 
prior documented molecular confirmation.  
During the screening period, the investigator will determine whether the LAR/caregiver and 
study participant are able to complete all questionnaires and assessments that require their 
contributions and will also assess their ability to comply with study procedures.  
In preparation for participation in this trial, LAR/caregivers will be educated on the clinical 
safety data for OV101 obtained thus far and will be trained to report assessments and to identify
, 
manage, and report any potential AEs.  
The LAR/caregiver will be provided with a sleep diary for documenting the study participant’s 
sleep and a seizure diary for documenting the study participant’s seizures. The LAR/caregiver 
will record data in the sleep diary for at least 7 days before each clinic visit. A
 calendar reminder 
will also be provided for recording data in the sleep diary
.  
A study participant who does not meet the inclusion criteria or who meets an exclusion criterion 
will be considered a screen failure. Whether rescreening is acceptable will be discussed with the 
medical monitor
. Rescreening will only be allowed once and only in cases where no safety risk is 
posed to the study participant (Section 4.2.3).  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 51 
If a screening test result (laboratory or any other test) is considered uncertain or abnormal, the 
test may be repeated to confirm the result after approval from the medical monitor or designee.  
6.1.2 Baseline Visit 
For study participants entering this study within 2 weeks of completing the EOT visit of 
OV101-19-001, the EOT visit activities need not be repeated at the baseline visit. The EOT visit 
of OV101-19-001 can serve as the baseline visit for the present study
. Screened study 
participants will return to the study site for the baseline (Day 1) visit, and the LAR/caregiver will 
bring the study participant’s completed sleep and seizure diaries for review by study staff. Study 
staff will collect the sleep diary (for recording in the eCRF) and will review it for completeness. 
If quality issues are detected, study staff will again instruct the LAR/caregiver in the proper use 
of the sleep diary
. A
 new sleep diary will be issued to the LAR/caregiver for use in the 7-day 
period preceding the Week 2 clinic visit. A
 calendar reminder will also be provided for the start 
of sleep diary assessments.  
Before dispensing study drug, study site staff must confirm appropriate completion of the sleep 
and seizure diaries and fulfilment of all eligibility criteria (Section 4.1). Study participants who 
meet all eligibility criteria will receive study drug at Baseline as described in Section 5.2.  
Screening and baseline assessments must be performed within a 30-day period. If the screening 
and baseline visits are separated by no more than 14 days, the following assessments do not need 
to be repeated at the baseline visit: medical history
, clinical assessment, physical examination, 
clinical laboratory tests, and determination of concomitant medications.  
6.1.3 Phone Visits for Dose Titration  
Phone visits are scheduled to assess each study participant’s tolerance for OV101 and to 
determine how to continue the dose titration. The investigator may initiate additional phone visits 
for managing dose titration or adjustment at his/her discretion. Phone visits for dose titration of 
all study participants   will be scheduled for Days 6 and 11.  
The LAR/caregivers will be queried about AEs, concomitant medications, and study participant 
suicidality (Table 6-1). Detailed instructions for the phone visits are presented in the 
investigators’
 phone visit study manual. Results of inquiries about AEs and changes in 
concomitant medications and assessment of suicidality must be documented and recorded in the 
eCRF
.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 52 
6.1.4 Telehealth/Virtual Visits at Weeks 24, 48, 80, 112, and 144 
Phone visits by a nurse, nurse practitioner, or similarly qualified person are scheduled during 
Weeks 24, 48, 80, 112, and 144 to conduct assessments as detailed in Table 6-1. Detailed 
instructions for the phone visits are presented in the investigators’
 virtual/ phone visit study 
manual. A
 home nurse visit will replace a virtual visit if the latter is not feasible. 
6.1.5 Clinic Visits at Weeks 12, 36, 64, 96, and 128  
Study participants will return to the study site for the Week 12, 36, 64, 96, and 128 visits. The 
LAR/caregiver will bring the study participant’s completed sleep diary
, seizure diary
, medication 
diary
, and study drug in original containers for review by study staff. Study staff will collect the 
sleep diary (for recording in the eCRF) and will review it for completeness. If quality issues are 
detected, study staff will again instruct the LAR/caregiver in the proper use of the sleep diary
. 
New sleep and seizure diaries will be issued to the LAR/caregiver for use in the 7-day period 
preceding the next clinic visit. A
 calendar reminder will also be provided for the start of sleep 
diary assessments.  
Review of the seizure diary will occur as described in Section 6.2.2.4. 
Before dispensing study drug, study site staff must confirm appropriate completion of the sleep 
and seizure diaries and continued fulfilment of all eligibility criteria (Section 4.1). Study 
participants who continue to meet all eligibility criteria will receive study drug at Weeks 12, 36, 
64, 96, and 128.  
6.1.6 Week 160 or End-of-Treatment Clinic Visit 
Study participants will return to the study site for the Week 160 visit. An EOT visit, with the 
same assessments as the Week 160 visit, should be scheduled for a study participant who 
discontinues study treatment before Week 160.  
The LAR/caregiver will bring the study participant’s completed sleep diary
, seizure diary
, 
medication diary
, and study drug bottles/cards for review by study staff. Study staff will collect 
the sleep diary (for recording in the eCRF) and will review it for completeness.  
6.1.7 End-of-Study Phone Visit 
The EOS phone visit is scheduled to occur 2 weeks after the EOT visit to assess each study 
participant’s response to discontinuation of treatment with OV101.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 53 
The LAR/caregivers will be queried about AEs, concomitant medications, and study participant 
suicidality (Table 6-1), and the investigator (or designee) will conduct the Clinical Global 
Impressions-Severity-Angelman syndrome (CGI-S-AS) and Clinical Global 
Impressions-Improvement-Angelman syndrome (CGI-I-AS) assessments. Detailed instructions 
for the phone visits are presented in the investigators’
 phone visit study manual. Results of 
inquiries about AEs and changes in concomitant medications and assessment of suicidality must 
be documented and recorded in the eCRF
.  
6.2 Safety and Tolerability 
Assessments  
Safety and tolerability will be assessed by the frequency
, severity, and causality of
 AEs
 and
 
SAEs, vital sign measurements, laboratory assessments, physical examinations, suicidality 
assessments, and seizure diary. Safety and tolerability assessments will be conducted according 
to the schedule presented in Table 6-1. 
6.2.1 Adverse Events 
6.2.1.1 Definitions of
 Adverse
 Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study
, regardless of their relationship to study drug or severity. Each study participant’s 
LAR/caregiver will be instructed to contact the study center if the study participant experiences 
any AEs, including whether there was any change in the study drug administration (e.g., dose 
withheld, dose reduced, or dose missed). 
An AE is defined as any untoward medical occurrence in a study participant enrolled into this 
study regardless of its causal relationship to study drug. Each study participant’s LAR/caregiver 
will be instructed to contact the investigator at any time after enrollment if any new or worsening 
symptoms develop.  
Treatment-emergent AEs (TEAEs) are defined as AEs that start or increase in severity after the 
first dose of study drug in this open-label study. All AEs occurring after the study participant 
receives the first dose of study drug must be reported to Ovid or its designee via the eCRF
. 
Anticipated day-to-day fluctuations of preexisting disease(s), condition(s), or behavior(s) present 
or detected at the start of the study that do not worsen are not AEs. Lack of drug effect is not an 
AE. Social and/or convenience situations and/or admissions to the hospital, where an untoward 
medical occurrence did not occur, are not AEs. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 54 
Cases of pregnancy that occur during maternal or paternal exposures to study drug are to be 
reported. Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug 
safety evaluation. 
Study staff will record the occurrence and nature of each study participant’s preexisting 
conditions (e.g., prior to enrollment in ELARA), including clinically significant signs and 
symptoms of the disease under treatment in the study (e.g., seizures, motor dysfunction, sleep 
disruption, anxiety), as part of the medical history
. 
As seizures are often a baseline condition in study participants with AS, seizures should be 
reported as an AE in any of the following circumstances:  
• There is a clear increase in the frequency of seizures compared to the study participant’s 
baseline.  
• There is an emergence of a new seizure type.  
• The study participant experiences status epilepticus.  
• The investigator believes the seizure should be captured as an AE (in which case the 
investigator should document their reasoning).  
Seizures in this study participant population will be detected and assessed using the seizure diary 
(Section 6.2.2.4). Diaries will be collected at the study site during the study and will be analyzed by 
the sponsor along with the reportable SAEs in evaluating risks and benefits.  
After the ICF is signed, study staff will record any change in the condition(s) and the occurrence 
and nature of any AEs. If a study participant experiences an AE after the ICF has been signed but 
before receiving study drug, the event will be reported and will be included in the study 
participant’s medical history unless the event is serious, or the investigator feels the event may 
have been caused by a protocol procedure.  
6.2.1.2 Serious
 Adverse
 Events 
An SAE is defined as any event that: 
• Results in death 
• Is immediately life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 55 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the study participant or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
6.2.1.3 Eliciting and Documenting
 Adverse
 Events 
Adverse events will be assessed beginning at enrollment (date of signed informed consent) and 
up to 30 days after the last dose of study drug. Adverse events must be followed until resolution 
or for 30 days after the study participant’s last study drug dose, whichever comes first. 
After informed consent is obtained, at every clinic, phone and/or home health visit, study 
participants and their LAR/caregivers will be asked a standard nonleading question to elicit any 
medically related changes in their wellbeing. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
regimens (both prescription and over the counter medications). 
In addition to study participant observations, AEs identified from any study data (e.g., laboratory 
values, physical examination findings) or identified from the review of other documents (e.g., 
study participant diaries) that are relevant to study participant safety or considered to be 
clinically significant, in the medical and scientific judgment of the investigator, will be 
documented on the AE page in the eCRF
. 
6.2.1.4 Reporting
 Adverse
 Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF
. 
Information to be collected includes the following: 
• Drug treatment 
• Dose 
• Event term 
• Time of onset 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 56 
• Investigator-specified assessment of severity and relationship to study drug 
• Time of resolution of the event 
• Seriousness 
• Any required treatment or evaluations 
• Outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs will be 
followed to adequate resolution. The Medical Dictionary for Regulatory
 Activities
 (MedDRA)
 
will be used to code all AEs. 
Any medical condition that is present at the time that the study participant is screened and 
remains stable should not be reported as an AE. However, if the condition worsens at any time 
during the study
, it should be recorded as an AE. In general, an elective procedure is not 
considered an AE unless it is required to address worsening of an underlying condition. In this 
case, the underlying AE should be reported and not the procedure. 
Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (e.g., vital sign measurements), including those that worsen from baseline, that are 
felt to be clinically significant in the medical and scientific judgment of the investigator are to be 
recorded
 as
 AEs.
  
6.2.1.5 Reporting
 Serious
 Adverse
 Events 
All AEs must be recorded in the eCRF upon awareness.  
Any AE that meets SAE criteria (Section 6.2.1.2) must immediately (i.e., within 1 business day) 
inform Ovid Drug Safety upon learning of any SAE that occurs (whether or not attributable to 
the study drug). It is the investigator’s responsibility to ensure that SAE reporting procedures are 
followed appropriately
. All SAE reports and any revisions to an SAE report must be sent to the 
email address provided below. All supporting source information concerning the SAE (e.g., 
hospital records) should also be provided by email. 
 
If there is a question concerning an SAE, the site needs guidance regarding the reporting of an 
SAE, the site is returning a call from an Ovid Drug Safety specialist, the site urgently needs to 
report an SAE or make Ovid Drug Safety aware of an SAE, the safety hotline should be used 
(country-specific hotline numbers provided in a separate document). 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 57 
If an SAE is reported via the hotline, the site should first submit the SAE paper form and then 
enter the SAE in the eCRF
. Any AE that meets SAE criteria (Section 6.2.1.2) must be entered 
into the EDC system immediately (i.e., within 1 business day) after study staff first learn about 
the event, in addition to emailing the SAE Report form. Once the qualifying SAE data are 
entered into the EDC system, Ovid will be notified by an email alert that will contain high-level 
safety information.  
All SAEs must be reported starting from the time that informed consent for study participation is 
provided. If the investigator becomes aware of an SAE within 30 days after the study 
participant’s last dose of study drug or within 30 days after the last study visit, the SAE must be 
reported. Serious AEs must be followed until the event resolves, the event or sequelae stabilize, 
or it is unlikely that additional information can be obtained after demonstration of due diligence 
with follow-up efforts (i.e., the study participant or health care practitioner is unable to provide 
additional information, or the study participant is lost to follow-up). Serious AEs that occur more 
than 30 days after the last dose of study drug should be submitted to the sponsor if the 
investigator becomes aware, however, these do not need to be reported to the IRB/IEC or 
regulators unless the investigator or sponsor considers them related to study drug. 
6.2.1.6 Suspected Unexpected Serious Adverse Reactions and Nonserious 
Adverse Events of Special Interest 
The sponsor will promptly evaluate all suspected unexpected serious adverse reactions and 
nonserious AEs of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs and independent 
ethics committees (IECs), and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the current OV101 investigator’s brochure. (Ovid 
Therapeutics Inc. 2018).  
The sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use the appropriate section 
of the current investigator’s brochure as the Reference Safety Document. The expectedness and 
reporting criteria of an SAE will be determined by the sponsor from the Reference Safety 
Document. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 58 
6.2.1.7 Assessment of Severity 
The severity
, or intensity
, of an AE refers to the extent to which an AE affects the study 
participant’s daily activities. The intensity of the AE will be rated as mild, moderate, or severe 
using the following criteria: 
Mild: 
An AE that is transient in nature and generally does not interfere with the study 
participant’s normal activities. 
Moderate: An AE that is sufficiently discomforting to interfere with the study participant’s 
normal activities. 
Severe: 
An AE that is incapacitating and prevents normal activities. 
 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of the onset and duration of each episode. 
6.2.1.8 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study
. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
The relationship or association of the test article in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: This relationship suggests that there is no association between the study drug 
and the reported event. 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed
 to
 the
 AE,
 i.e., the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study drug but could also have been produced by other factors. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 59 
Probable: This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study drug seems likely
. The event 
disappears or decreases on cessation or reduction of the dose of study drug. 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
drug is re-administered. 
6.2.1.9 Follow-Up of Study participants Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant or until the study participant is considered to be stable.  
6.2.2 Other Safety
 Assessments 
Safety assessments other than AEs (Section 6.2.1) include assessment of suicidality
, vital sign 
measurements, laboratory assessments (Section 6.7), physical examinations, and seizure diary.  
6.2.2.1 Clinical Assessment of Suicidality 
The
 full
 ABC-Irritability subscale (ABC-I) will be administered. The
 ABC-I will be used to 
assess suicidality instead of the Columbia-Suicide Severity Rating Scale, since cognitive 
impairment in patients
 with
 AS interferes with the understanding of the concept of suicide. Most 
individuals with AS are not able to communicate thoughts of suicidality
, so the study 
participant’s irritability reported by the LAR/caregiver is being used as a surrogate measure of 
suicidality
. The investigator will review the scale items with the LAR/caregiver at each 
scheduled timepoint. If grading worsens, the investigator must decide whether that indicates a 
potential for self-harm by the study participant, and if so, must document it as an AE and closely 
monitor it until resolution. The entire Aberrant Behavior Checklist – Community (ABC-C) will 
be administered, although only the ABC-I will be used to assess the potential for self-harm. 
6.2.2.2 Vital Sign Measurements 
Vital sign measurements will include height, weight, blood pressure, heart rate, and temperature. 
Measurements of blood pressure, heart rate, and temperature should be attempted after the study 
participant has been resting in a supine or sitting position for at least 10 minutes. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 60 
6.2.2.3 Physical Examinations 
A
 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. 
6.2.2.4 Seizure Diary 
The seizure diary is a caregiver-reported clinical outcome assessment measure that captures the 
total number and duration of seizures. Caregivers will record the number, duration, and type of 
seizures each day using the paper seizure diary
. Please also see Section 6.2.1.1 for
 AE
 reporting
 
criteria for these seizure events. 
The caregiver will be trained by the site with specific instructions beginning with the screening 
visit to ensure compliance in recording seizures. The seizure diary will be completed each day 
during the study
, beginning at Screening (Baseline for study participants entering this study 
within 2 weeks of completing the EOT visit of OV101-19-001) and continuing through the EOT
. 
Seizure diaries will be collected and reviewed by the investigator with the study participant’s 
caregiver for proper recording at specified timepoints (Table 6-1). Seizure Identification Form 
and Diagnostic Review Forms (SIF/DRF) will be completed by site personnel for every eligible 
study participant. This information will be faxed or emailed to The Epilepsy Study Consortium 
(TESC) for review and approval. The SIF/DRF will be used to ensure that the seizures are 
classified accurately
. SIF and DRF forms will be collected for patients who have 
enrolled/completed the study if feasible. 
For the prospective baseline period, the seizure frequency (expressed as a 28-day frequency) will 
be calculated as 
(number of seizures) / (number of days seizures were assessed) × 28 
Seizure frequency calculated through this method will be used to confirm the eligibility.  
6.3 Exposure During Pregnancy and/or Lactation 
OV101 should not be administered to pregnant or lactating females because the potential for 
adverse reactions to OV101 in pregnant females, fetuses, and nursing infants is unknown. 
Pregnancy data will be collected during this study for all study participants. Exposure during 
pregnancy (also referred to as exposure in-utero) can be the result of either maternal exposure or 
transmission of drug product via semen following paternal exposure. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 61 
Exposure during pregnancy must be recorded and the study participant followed until the 
outcome of the pregnancy is known (spontaneous miscarriage, elective termination, normal birth, 
or congenital abnormality), even if the study participant discontinues study drug or discontinues 
from the study
. 
If a study participant within this study or a study participant’s partner becomes pregnant while 
treated or exposed to study drug, the investigator must submit a pregnancy form to Ovid via the 
same method as SAE reporting (Section 6.2.1.5). Pharmacovigilance will supply the investigator 
with a copy of a “Pregnancy Reporting and Outcome Form/Breastfeeding.” When the outcome 
of the pregnancy becomes known, the form should be completed and returned to Ovid or Ovid 
Pharmacovigilance delegate. If additional follow-up is required, the investigator will be 
requested to provide the information. 
Exposure of an infant to an Ovid product during breastfeeding must also be reported and any 
AEs experienced by the infant must be reported to Ovid Pharmacovigilance or designee via 
email (Section 6.2.1.5). 
Pregnancy is an outcome of an event and should not be reported as an AE unless there is a 
suspicion that study drug may have interfered with the effectiveness of a contraceptive 
medication. However, complications of pregnancy and abnormal outcomes of pregnancy are AEs 
and may meet criteria for an SAE (such as ectopic pregnancy
, spontaneous abortion, intrauterine 
fetal demise, neonatal death, or congenital anomaly). Elective abortions without complications 
should not be reported as AEs 
6.4 Pregnancy 
Female study participants who are of childbearing potential (defined as having experienced their 
first menarche) must agree to use either a highly effective or acceptable form of birth control 
during the study and for 30 days following the last dose of the study drug. Highly effective 
contraceptive methods are as follows: 
a. Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
• Oral 
• Intravaginal 
• Transdermal 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 62 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
• Oral 
• Injectable 
• Implantable 
c. Intrauterine device 
d. Intrauterine hormone-releasing system  
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action. 
b. Male or female condom with or without spermicide. 
c. Cap, diaphragm, or sponge with spermicide. 
d. A
 combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods. 
For male study participants with women of childbearing potential partners, there are no 
restrictions. Female study participants who have experienced menarche and are not surgically 
sterile will undergo serum (or urine) beta-human chorionic gonadotrophin (ß-hCG) pregnancy 
testing at clinic visits shown in Table 6-1. 
After the screening and baseline visits, if serum is not 
obtainable, urine pregnancy testing is allowed. Any study participant 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 female study participant is suspected of becoming pregnant during 
the study
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 63 
If pregnancy occurs at any time during the study
, study drug must be discontinued immediately 
(or not started). Pregnancy is not regarded as an AE unless there is a suspicion that a study drug 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported using the same procedures as an SAE 
(Section 6.2.1.5) but using a clinical study pregnancy form. The pregnancy must be followed-up 
to determine outcome (including spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) and status of mother and child, even if the study participant is 
discontinued from the study
. Pregnancy complications and elective terminations for medical 
reasons should not be reported as an AE or SAE. Spontaneous miscarriages must be reported as 
an SAE. 
Any SAE occurring in association with a pregnancy
, brought to the investigator’s attention after 
the study participant has completed the study and considered by the investigator as possibly 
related to the study treatment, must be promptly reported to Ovid Drug Safety
. 
6.5 Contraception and Pregnancy Avoidance Procedures  
Please refer to Section 6.4 for detailed contraception requirements. 
Study participants will be provided with information on acceptable methods of contraception as 
part of the study participant informed consent process and will be asked to sign a consent form 
stating that they understand the requirements for avoidance of pregnancy during the study and 
for 30 days after the last dose of study drug and avoidance of donation of ova or sperm during 
the course of the study and for 90 days after the last dose of study drug. This may be signed by 
the LAR/caregiver of the study participant. 
Female study participants who have experienced menarche must have a negative serum ß-hCG 
pregnancy test at Screening (Visit 1) and a negative serum ß-hCG pregnancy test on Day 1 
(Visit 2), before receiving any dose of study drug. If pregnancy results cannot be collected at 
Visit 2, the reason should be documented in the source document, the results of the serum 
pregnancy test obtained at Visit 1 must be confirmed to be negative by the investigator prior to 
randomization, and results of a serum pregnancy test at Visit 2 must be confirmed to be negative 
before the study participant can receive the first dose of study drug. During the study
, study 
participants will receive continued guidance with respect to the avoidance of pregnancy and ova 
or sperm donation as part of the study procedures. An additional serum ß-hCG pregnancy test 
will be performed at the EOT visit. 
6.6 Safety Monitoring Committee 
The Safety Monitoring Committee is described in Section 11.1.1. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 64 
6.7 Laboratory
 Analyses 
The following clinical analytes will be assessed:  
Hematology (safety assessment): hematocrit; hemoglobin; red blood cell count with indices 
(mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration); reticulocytes; white blood cell count and differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) reported as percentages and absolute values; and platelets 
(platelet count, prothrombin time and partial thromboplastin time, international normalization 
ratio).  
Clinical chemistry (safety assessment): albumin; alkaline phosphatase; blood urea nitrogen; 
gamma-glutamyl transferase; calcium; creatinine; glucose; cholesterol (high-density lipoprotein 
and low-density lipoprotein [calculated] and homogenous low-density lipoprotein); triglycerides; 
phosphate; potassium; alanine aminotransferase; aspartate aminotransferase; lactate 
dehydrogenase; sodium; chloride; bilirubin (total, direct); total protein; uric acid; and creatine 
phosphokinase.  
6.7.1 Sample Collections 
Blood samples collected from study participants will be forwarded to a central laboratory for 
analysis. Further details regarding sample collections and processing and specific testing can be 
found in the central laboratory manual (provided to study sites as a separate document). 
All samples for clinical laboratory analysis will be collected as described in the central 
laboratory manual, according to the schedule of activities (Table 6-1). Samples for hematology
, 
clinical chemistry
, or urinalysis (pregnancy testing only) will be used only for the evaluation of 
safety and tolerability
.  
Blood samples will be collected only for clinical laboratory safety assessments. The maximum 
volume of blood to be collected per study participant over the course of the study is estimated to 
be less than 175 mL.  
6.8 Efficacy
 Assessments 
Efficacy assessments will be conducted according to the schedule presented in Table 6-1. The 
efficacy assessments, grouped by efficacy domain and participant source, are presented in 
Table 6-2. Every effort should be made to have the same LAR/caregiver complete the 
LAR/caregiver-reported assessments. Additionally
, every effort should be made to have the same 
investigator and raters complete the clinician assessments.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 65 
Efficacy assessments are only to be conducted in study participants who are at least 4 years old at 
study entry
. If a study participant is 2 to 3 years old at study entry and turns 4 years old during 
the course of the study
, only safety assessments are to be continued. 
Table 6-2 
Efficacy Assessments by Domain and Participant Source 
Domain 
LAR/Caregiver
 Assessment 
Clinician
 Assessment 
Sleep 
• Children’s Sleep Habits Questionnaire  
• Sleep diary 
– 
Motor 
– 
• Vineland Adaptive Behavior Scale 
(Motor domain) 
Global 
functioning and 
quality of life 
• Pediatric Quality of Life Inventory  
 
• Vineland Adaptive Behavior Scale 
(Socialization, Communication, Daily 
Living Skills, and Maladaptive 
Behavior domains) 
• CGI-AS scales 
Abbreviations: CGI-AS, Clinical Global Impressions-Angelman syndrome; LAR, legally acceptable representative.  
 
6.8.1 Caregiver
 Assessments 
6.8.1.1 Children’s Sleep Habits Questionnaire 
The Children’s Sleep Habits Questionnaire (CSHQ) is a retrospective, 33-item caregiver 
questionnaire that has been used in studies to examine sleep behavior in young children (Owens 
et al 2000). The CSHQ includes items relating to sleep domains that encompass the major 
presenting sleep complaints in this age group, evaluating the child’s sleep based on sleep 
behaviors within 8 different subscales: bedtime resistance, sleep-onset delay
, sleep duration, 
anxiety around sleep, behavior occurring around night waking, parasomnias, sleep-disordered 
breathing, and morning waking/daytime sleepiness. Caregivers will be asked to recall sleep 
behaviors occurring over the 7 days immediately preceding specified timepoints outlined in 
Table 6-1. Items are rated on a 3-point scale: “usually” if the sleep behavior occurred 5 to 7 
times/week; “sometimes” for 2 to 4 times/week; and “rarely” for 0 to 1 time/week. The scoring 
of some items can be reversed to consistently make a higher score indicative of more disturbed 
sleep.  
6.8.1.2 Sleep Diary 
A
 sleep diary will be completed by each study participant’s LAR/caregiver, on behalf of the 
study participant. Endpoints assessed by the sleep diary are presented in Section 7.2.1. The sleep 
diary will be completed each day during the 7 days immediately preceding each clinic visit after 
screening.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 66 
At each clinic visit when a sleep diary is issued (Table 6-1), a calendar will be issued to remind 
the LAR/caregiver when next to start recording data in the sleep diary
. In addition, 14 days 
before the study participant’s expected next visit date, study staff will phone the LAR/caregiver 
as a reminder to start recording data in the sleep diary
.  
Sleep diaries will be collected at each clinic visit, starting with the baseline visit (Table 6-1) and 
continuing through the EOT visit.  
6.8.1.3 Pediatric Quality of Life Inventory 
The Peds QL® Cerebral Palsy
, Multidimensional Fatigue, and Family Impact modules will be 
administered in this study (Varni et al 2004; Varni et al 2005). The 22-item Cerebral Palsy 
module assesses daily activities, school activities, movement and balance, pain and hurt, fatigue, 
eating activities, and speech and communication. The 18-item Multidimensional Fatigue module 
assesses general fatigue, sleep/rest fatigue, and cognitive fatigue. The 36-item Family Impact 
module assesses the impact of pediatric chronic health conditions on caregivers and family
, 
including caregiver-reported assessments of physical, emotional, social, and cognitive 
functioning, communication, and worry
. It also assesses caregiver-reported family daily activities 
and family relationships. 
For this study
, the Peds QL
® Cerebral Palsy
, Multidimensional Fatigue, and Family Impact 
should be performed for all study participants, including those over the age of 25.  
6.8.2 Clinician
 Assessments 
6.8.2.1 Vineland Adaptive Behavior Scale 
The
 Vineland
 Adaptive
 Behavior Scale, 3rd Edition (VABS-3) is a standardized psychometric 
instrument designed to measure personal and social skills needed for everyday living (Sparrow et 
al 2005; Sparrow et al 2016). The VABS-3 is administered via a caregiver using a semi-
structured interview format and assesses 4 main adaptive domains: communication (receptive, 
expressive, and written), socialization (interpersonal relationships, play and leisure, coping 
skills), daily living skills (personal, domestic, community), and motor skills (fine and gross). It 
also includes a maladaptive behavior scale for identifying behavior problems in children through 
18 years of age. The scale has been found to have good internal consistency
, test-retest reliability, 
and validity (Sparrow et al 2016). The VABS-3 interview form will be used to evaluate study 
participants on the communication, socialization, daily living skills, motor skills, and 
maladaptive behavior domains to assess their overall functioning. This assessment is an 
interview of the caregiver by a trained qualified rater, and for each study site, the same rater is to 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 67 
be used throughout the study
. As an exception, another sponsor-trained qualified rater may be 
used. 
6.8.2.2 Clinical Global Impressions - Angelman Syndrome Scales 
The CGI-S-AS scale
 with
 AS-specific anchors will be used by the investigator to assess the 
severity of symptoms, and the CGI-I-AS scale will be used by investigators to assess 
improvement from Baseline. The CGI-S-AS captures specific characteristics commonly present 
in the AS population; the CGI-I-AS captures clinical impression that reflects the rater’s estimate 
of change from the initiation (Baseline) of treatment. Both the CGI-S-AS and the CGI-I-AS 
assessments will be conducted by a rater with experience in AS and trained in CGI-S-AS and 
CGI-I-AS rating by the sponsor
. It is highly preferable that each site uses the same rater
. 
Whenever possible, the same rater (the principal investigator) at each site must evaluate a given 
study participant throughout the study
. As an exception, a clinician sub-investigator, trained in 
CGI-S-AS and CGI-I-AS rating by the sponsor, may be used.  
The baseline CGI-S-AS will be accompanied by detailed investigator notes. Each CGI-I-AS 
rating will also be accompanied by detailed investigator notes 
 
 
 
 To reduce recall bias, within 24 hours prior to the study participant’s 
clinic visit at Week 12 (the first CGI-I-AS assessment), the investigator must review the study 
participant’s baseline CGI-S-AS score and investigator notes. Within 24 hours prior to the study 
participant’s visit at Week 36 (and all subsequent visits with assessments of CGI-I-AS), the 
investigator must review the study participant’s baseline CGI-S-AS score and investigator notes 
and the prior clinic visit’s CGI-I-AS score and investigator notes. If the CGI-I-AS assessment is 
missing at a study visit, the reason for the absence will be noted in the eCRF
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 68 
7 Statistical and
 Analytical
 Plan  
7.1 Safety Endpoints 
The following safety endpoints will be evaluated for study participants who are at least 2 years 
old at study entry: 
• Incidence of SAEs, TEAEs, treatment-related TEAEs, and TEAEs leading to study 
discontinuation 
• Vital sign measurements 
• Clinical safety laboratory values 
• Physical examination 
• Assessment of suicidality (ABC-I; Section 6.2.2.1)  
• The 28-day seizure frequency (Section 6.2.2.4)  
7.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints below are not listed in order of importance. Efficacy 
assessments are only to be conducted in study participants who are at least 4 years old at study 
entry
. If a study participant is 2 to 3 years old at study entry and turns 4 years old during the 
course of the study
, only safety assessments are to be continued. 
7.2.1 LAR/Caregiver-Completed Endpoints (for Study participants at 
Least 4 Years Old) 
• Change from baseline in the CSHQ total and subscale scores 
• Change from baseline in sleep diary parameters:  
o Latency of sleep onset (LSO), defined as time from beginning of rest period to 
start of sleep onset 
o Sleep efficiency
, defined as the percentage of total sleep time out of duration of 
the rest period  
o Total daytime sleep, defined as duration of sleep time in the active interval 
7.2.2 Clinician-Completed Endpoints (for Study participants at Least 
4 Years Old) 
• CGI-I-AS scores 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 69 
• Change from baseline in CGI-S-AS scores:  
o The CGI-S-AS symptoms overall score 
o The CGI-S-AS domain scores 
• Change from baseline in the VABS-3 overall composite and subscale scores:  
o Communication domain and its subdomains  
o Socialization domain and its subdomains  
o Daily Living Skills domain and its subdomains  
o Maladaptive Behavior domain and its subdomains  
7.3 Exploratory Endpoints 
The exploratory efficacy endpoints below are not listed in order of importance. 
7.3.1 LAR/Caregiver-Completed Endpoints (for Study participants at 
Least 4 Years Old) 
• Change from baseline in PedQoLI total and subscale scores 
7.3.2 Clinician-Completed Endpoints (for Study participants at Least 
4 Years Old) 
• Change from baseline in the VABS-3 Motor Skills domain and its subdomains 
7.3.3 Endpoints for Relationship Exploration 
• Endpoints of interest may be identified to explore the relationships among them.  
7.4 Sample Size Calculations 
This is an open-label extension study from 3 prior protocols, and siblings of study participants 
completing those studies are eligible to enroll; thus, sample size calculation is not based on 
power calculations. The number of study participants enrolled in the study will be dependent on 
the number of study participants who are eligible and consent to participate in the extension 
study
. Approximately 170 study participants will be enrolled in the study
. 
7.5 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Enrolled
 Analysis
 Set (EAS): The EAS will consist of all study participants enrolled in the 
extension study
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 70 
Safety
 Analysis
 Set
 (SS): The SS will consist of all study participants who receive at least 1 dose 
of study drug.  
Full-Analysis Set (FAS): The FAS will consist of all study participants who receive at least 
1 dose of study drug and have at least 1 post baseline efficacy assessment.  
The EAS will be used for summaries of study participant disposition, demographics and other 
baseline characteristics. All safety evaluations will be carried out on the SS. All efficacy 
evaluations will be carried out on the FAS.  
7.6 Subgroup Analysis 
Subgroup statistical analyses may be performed and will be detailed in a  statistical analysis plan. 
7.7 Statistical
 Analysis Methodology 
The detailed methodology for the summary and statistical analyses of the data collected in this 
study will be documented in a separate statistical analysis plan.  
All statistical analysis will be performed using SAS® software (SAS Institute Inc., Cary
, NC) 
Version 9.4 or higher
. 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation prior to or 
on the date that the first dose of treatment is taken in this study. 
Descriptive statistics (number of study participants, mean, SD, median, minimum, and 
maximum) will be presented for continuous variables and frequency and percentage will be 
presented for categorical and ordinal variables. If there are missing values, the number missing 
will be presented, but without a percentage. All data collected will be included in by -study 
participant data listings. Two--sided 95% CIs will be provided where appropriate. Graphical 
displays will be utilized to investigate trends over time overall and by relevant subgroups as 
needed.  
Separate analyses of selected endpoints, including but not limited to CGI-I-AS, CGI-S-AS, and 
seizure diary data, will be performed for the study participants who have participated in STARS 
and the study participants who have participated in the NEPTUNE study (Study OV101-19-001). 
7.7.1 Analysis of Primary Endpoints - Safety 
All safety analyses will be performed on the SS. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 71 
All AEs will be coded using latest version of MedDRA
 and will be classified by MedDRA
 
system organ class (SOC) and preferred term (PT). 
The number and percentage of study participants who experience at least 1 TEAE as well as the 
95% exact CI for the incidence of TEAEs overall and within each specific SOC and PT will be 
presented. 
Treatment emergent adverse event is defined as newly or worsening AEs start from the first dose 
of study medication till 30 days after the last dose of study medication. 
Treatment-related AEs will be identified as those that are at least possibly related to study drug 
based on the investigator’s assessment. The number and percentage of study participants with 
treatment-related
 AEs,
 SAEs, TEAEs leading to study discontinuation, and TEAEs leading to 
death will also be summarized by SOC and PT
. 
For each SOC and each PT
, a study participant will be counted only once for study participant-
incidence tabulations. For summaries by severity or relationship, for a given study participant, 
the highest severity and relationship for a specific PT will be considered.  
Descriptive statistics for the observed values and changes from baseline to each post baseline 
visit with respect to clinical laboratory and vital sign measurements will be summarized. 
Clinically significant laboratory values may be tabulated. 
Shift tables for laboratory parameters will be presented. For each continuous laboratory 
parameter, results will be categorized as low
, normal, and high based on the laboratory normal 
ranges. Frequencies and percentages will be presented for the shifts in these categories from 
baseline to each posttreatment assessment timepoint. 
Suicidality
 assessed
 by
 ABC-I will be summarized descriptively at baseline and all post baseline 
study visits. Change from baseline to all post baseline study visits also will be summarized 
descriptively
. 
Abnormal findings in physical examinations will be listed. 
The 28-day seizure frequencies as captured in the seizure diary will be calculated for baseline 
and post baseline study periods for all seizure types and for subtypes of drop and nondrop. 
Percent change in 28-day seizure frequency from baseline to all post baseline study visits will 
also be summarized descriptively for all seizure types and for subtypes of drop and nondrop.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 72 
Concomitant medications will be coded using the World Health Organization Drug Dictionary
. A
 
table summarizing concomitant medications and a by-study participant listing of concomitant 
medications will include all medications taken during the study regardless of the timing for the 
start of medication. 
7.7.2 Analysis of Secondary Efficacy Endpoints 
Descriptive statistics and 95% CIs for efficacy variables at each timepoint will be displayed. Line 
graphs of time course of change (or percent change) from baseline will be presented for the 
secondary efficacy endpoints and for the average dose.  
For CGI-I-AS and CGI-S-AS endpoints, analyses will be conducted for the subset of study 
participants that had valid CGI-S-AS measurements at baseline. The long-term durability will be 
assessed on the improvement from the baseline at previous study
. 
7.7.3 Analyses of Exploratory Efficacy Endpoints 
Exploratory endpoints will be analyzed using the same methods as used for the secondary 
efficacy endpoints. For the endpoints of interest for their relationships, suitable analysis methods 
will be specified in the statistical analysis plan. 
7.7.4 Other
 Analyses 
7.7.4.1 Demographics and Other Baseline Characteristics 
Demographic and background information variables and study participant disposition will be 
listed by study participant and summarized using frequency distributions for categorical 
variables and descriptive statistics for continuous variables. Relevant medical history/current 
medical conditions will be summarized by MedDRA
 SOC and PT
. 
Background information will consist of data collected in the molecular AS testing, and clinical 
assessment
 of
 AS. 
The above analyses will be performed using the EAS. 
7.7.4.2 Drug Treatments 
7.7.4.2.1 
Study Drug 
Using the SS, duration (days) of exposure to study drug and treatment compliance will be listed 
by study participant and summarized descriptively by dose. Frequency and percentages for study 
participant disposition and reasons for discontinuation of study drug will be presented. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 73 
7.7.4.2.2 
Prior and Concomitant Medications 
Using the EAS, prior and concomitant medications will be listed by study participant and 
summarized descriptively
. 
7.7.5 Interim
 Analyses 
Periodic data review will be performed to support regulatory submissions as needed. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 74 
8 Data
 Quality
 Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) E6 
(R2) risk and quality processes described in the applicable procedural documents. The quality 
management approach to be implemented in this study will be documented and will comply with 
the current ICH guidance on quality and risk management.  
Standard operating procedures are available for all activities relevant to the quality of this study
. 
Designated staff will be responsible for implementing and maintaining quality assurance and 
quality control systems to ensure that the study is conducted and that data are generated, 
documented, and reported in compliance with the study protocol, Good Clinical Practice (GCP), 
and Good Laboratory Practice requirements as well as applicable regulatory requirements and 
local laws, rules, and regulations relating to the conduct of the clinical trial. 
An authorized quality assurance auditor will audit the study data and procedures at periodic 
intervals as indicated. Domestic or foreign regulatory authorities, the IRB or IEC, and a sponsor-
authorized auditor may request access to all study documentation for an on-site inspection or 
audit. The investigator must notify the sponsor of any regulatory authority inspections and 
forward copies of the inspection report to the sponsor
. 
Electronic data systems will be in accordance with applicable aspects of US Title 21 Code of 
Federal Regulations (CFR) Part 11, ICH guidelines, GCP
, local laws and legislation, and the 
Health Insurance Portability and Accountability Act. 
8.1 On-Site
 Audits 
At any time, quality assurance representatives of the sponsor and/or regulatory bodies may visit 
the unit to carry out an audit of the study in compliance with regulatory guidelines and company 
policy
. Such audits will require access to study records, documentation, and regulatory files. At 
all times, study participant privacy will be of utmost importance and respected. Typically
, 
sufficient notice will be given to the investigator to prepare for the visit. 
8.2 Data Management 
As part of the responsibilities assumed by participating in the study
, the investigator agrees to 
maintain adequate case histories for the study participants treated as part of the research under 
this protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include such documents as questionnaire 
results, sleep diaries, and computerized or otherwise automated assessments.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 75 
Investigative site staff will enter study participant data into 
 (the eCRF 
program). The analysis data sets will be a combination of these data and data from other sources 
(e.g., laboratory data). 
Clinical data management will be performed in accordance with applicable sponsor standards 
and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data. Adverse event terms will be coded using MedDRA, an internal 
validated medical dictionary
, and concomitant medications will be coded using the World Health 
Organization Drug Dictionary
. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary
. 
After database lock, each study site will receive a CDROM containing all its site specific eCRF 
data as entered into the EDC system for the study
, including full discrepancy and audit history
. 
Additionally
, a CDROM copy of all the site’s data from the study will be created and sent to the 
sponsor for storage. 
 maintain a duplicate CDROM copy for their records. In all cases, 
study participant initials will not be collected or transmitted to the sponsor
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 76 
9 Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human study participants in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study participants, 
and any other written information regarding this study to be provided to the study participant or 
the study participant’s legal guardian must be approved by the IRB/IEC. Documentation of all 
IRB/IEC approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline E6 
(R2): GCP will be maintained by the site and will be available for review by the sponsor or its 
designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator 
must promptly supply the sponsor or its designee, the IRB/IEC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to study participants. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 Study participant Information and Consent 
A
 written informed consent in compliance with applicable regulatory authority regulations shall 
be obtained from each adult competent study participant (or from the LAR/caregiver of a minor 
or adult of diminished mental capacity
, as applicable) before the study participant enters the 
study or any unusual or non-routine procedure that involves risk to the study participant is 
performed. For minors or adults of diminished mental capacity
, an assent document will be 
presented and assent obtained before the study participant participates in any study procedure. 
Informed consent and assent template documents may be provided by the sponsor to 
investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent and assent should be reviewed by the sponsor or its 
designee or both before IRB submission. Once reviewed, the consent and assent will be 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 77 
submitted by the investigator to his/her IRB for review and approval before the start of the study
. 
If the ICF is revised during the study
, all active participating study participants and 
LAR/caregivers (as applicable) must sign the revised forms. 
Before recruitment and enrollment, each prospective study participant’s LAR/caregiver and 
study participant (as applicable) will be given a full explanation of the study and will be allowed 
to read the approved ICF/assent. Once the investigator is assured that the LAR/caregiver and 
study participant understand the implications of participating in the study
, the LAR/caregiver and 
study participant will be asked to give consent/assent to participate in the study by 
signing/approving the ICF/assent. 
The investigator shall retain the signed original ICFs/assents and give copies of the signed 
original forms to the LAR/caregivers and study participants, as applicable.  

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 78 
10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be study participant to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain study participant confidentiality
. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the study participant (or the study participant’s legal guardian or LAR/caregiver), 
except as necessary for monitoring and auditing by the sponsor, its designee, the US Food and 
Drug
 Administration (FDA) or other applicable regulatory agency
, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study
. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 21 CFR 
54. In addition, the investigator must provide to the sponsor a commitment to promptly update 
this information if any relevant changes occur during the study and for 1 year following the 
completion of the study
. 
Neither 
 is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither 
 is financially responsible for further 
treatment of the study participant’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study
, the investigator will be asked to comply with ICH E6 (R2) 8.2 and 
Title 21 of the CFR by providing essential documents, including but not limited to the following: 
• IRB/IEC approval. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 79 
• Original investigator-signed investigator agreement page of the protocol. 
• Form FDA
 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
for sites in the United States, Clinical Investigator Form for sites outside of the United 
States. 
• Curriculum vitae for the investigator and each sub-investigator listed on Form FDA 1572 
or Clinical Investigator Form. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study
. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment for 
this study
, and any other written information regarding this study that is to be provided to 
the study participant or legal guardian. 
• Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with 42 CFR 493. 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH E6 
(R2). The investigator will conduct all aspects of this study in accordance with all national, state, 
and local laws or regulations. Study information from this protocol will be posted on publicly 
available clinical trial registers before the enrollment of study participants begins. 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6 (R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study
, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 80 
10.7 Investigator’s Final Report 
Upon completion of the study
, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the sponsor and regulatory authority(ies) with any reports required. 
10.8 Records Retention 
Essential documents should be retained until at least 2 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 at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
sponsor
. It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
10.9 Publications 
After completion of the study
, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the sponsor will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
The data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 
 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 81 
11 Study Management 
The administrative structure will include a scientific steering committee, an external safety 
monitoring committee, an event adjudication committee, and an independent statistician. 
11.1 Monitoring 
11.1.1 External Safety Monitoring Committee 
The Safety Monitoring Committee will consist of at least 3 external, independent, non-Ovid 
experts responsible for monitoring the safety data to ensure that the study does not pose 
unacceptable risks to the study participants. 
11.1.2 Monitoring the Study 
The medical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely
.  
The study medical monitor may visit the investigator and study site at periodic intervals, in 
addition to maintaining necessary telephone and letter contact. The study medical monitor will 
maintain current personal knowledge of the study through observation, review of study records 
and source documentation, and discussion of the conduct of the study with the investigator and 
staff. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review
, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow the sponsor, representatives of the sponsor, or a 
regulatory agency access to all study records. 
The investigator should promptly notify the sponsor 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor
. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 82 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity
, except those necessary to remove an apparent, immediate 
hazard to the study participant, must be reviewed and approved by the sponsor or its designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB/IEC for 
approval before study participants can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the study participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
participants without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, and 
to the regulatory authorities, if required. 
A
 deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the sponsor and the IRB/IEC and agreed to by the investigator
. A
 
significant deviation occurs when there is nonadherence to the protocol by the study participant 
or investigator that results in a significant, additional risk to the study participant. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, or nonadherence to FDA
 
regulations or ICH GCP guidelines, and will lead to the study participant being withdrawn from 
the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of deviations. 
The IRB/IEC should be notified of all protocol deviations in a timely manner
. 
11.3 Study Termination 
Although Ovid has every intention of completing the study
, Ovid reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last study participant completes the last 
visit (includes the phone EOS visit). 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 83 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports (CSRs) are prepared and provided to the regulatory agency(ies) as required 
by the applicable regulatory requirement(s). The sponsor will also ensure that the CSRs in 
marketing applications meet the standards of the ICH harmonised tripartite guideline E3: 
Structure and content of CSRs.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, the sponsor will provide the investigator with the full summary of 
the study results. The investigator is encouraged to share the summary results with the study 
participants, as appropriate. The study results will be posted on publicly available clinical trial 
registers. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 84 
12 Reference List 
Berry JA, Cervantes-Sandoval I, Chakraborty M, et al. Sleep facilitates memory by blocking 
dopamine neuron-mediated forgetting. Cell. 2015;161(7):1656-67. 
Bird LM, Ocha-Lubinoff C, Tan WH, et al. STARS: results from a safety and efficacy study of 
OV101 (gaboxadol) in adults and adolescents with Angelman syndrome. Poster session 
presented at: 71st American Academy of Neurology Annual Meeting; 2019 May 4-10; 
Philadelphia, PA. 
Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and 
implications for disease. Neuron. 2012;73(1):23-34. 
Deidda G, Bozarth IF
, 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. 
Dissel S, Angadi V
, Kirszenblat L, et al. Sleep restores behavioral plasticity to Drosophila 
mutants. Curr Biol. 2015;25(10):1270-81. 
Egawa K, Fukuda A. Pathophysiological power of improper tonic GABA(A) conductances in 
mature and immature models. Front Neural Circuits. 2013;7:170. 
Egawa K, Kitagawa K, Inoue, K, 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. 
Merck. Study # 027: A
 placebo-controlled, double-blind, multiple dose safety
, tolerability and 
pharmacokinetic study of Lu 02-030 following sequentially escalating doses in healthy young 
men and at one dose level in healthy young women and healthy elderly
. 2001 
Merck. Study # P031: A
 2-part study to assess the tolerability of gaboxadol (MK-0928) 
administered intravenously (Part 1) and a 6-period crossover to examine the dose proportionality 
of 5 single oral doses of MK-0928 in the range of 2.5 to 20 mg administered over periods 1 
through 5 followed by a fixed sequence, open IV arm (period 6) in healthy young adult male and 
female study participants (Part 2). 2006. 
Mertz LG, Christensen R, Vogel I, et al. Angelman syndrome in Denmark. Birth incidence, 
genetic findings, and age at diagnosis. Am J Med Genet A. 2013;161A(9): 2197-203. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 85 
Ovid Therapeutics Inc. Gaboxadol (OV101). Investigator’s Brochure, 3rd ed. New York (NY); 
2018. 87 p.  
Owens J, Spirito A, McGuinn M. The Children
's Sleep Habits Questionnaire (CSHQ): 
psychometric properties of a survey instrument for school-aged children. Sleep. 
2000;23(8):1043-51.  
Petersen MB, Brøndum-Nielsen K, Hansen LK, et al. Clinical, cytogenetic, and molecular 
diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county
. Am J Med 
Genet. 1995;60(3):261-2. 
Ramamoorthi K, Lin Y
. The contribution of GABAergic dysfunction to neurodevelopmental 
disorders. Trends Mol Med. 2011;17(8):452-62. 
Sparrow SS, Cicchetti DV
, Balla DA. Vineland II: Vineland Adaptive Behavior Scales. Circle 
Pines, MN, American Guidance Service 2005. 
Sparrow SS, Cicchetti DV
, Saulnier CA. Vineland Adaptive Behavior Scales, Third edition 
(Vineland-3). Toronto (Canada): Pearson; 2016. 
Steffenburg S, Gillberg CL, Steffenburg U, et al. Autism in Angelman syndrome: a population-
based study
. Pediatr Neurol. 1996;14(2):131-6. 
Varni JW
, Burwinkle TM, Sherman SA, et al. Health-related quality of life of children and 
adolescents with cerebral palsy: hearing the voices of the children. Dev Med Child Neurol. 
2005;47(9):592-7. 
Varni JW
, Sherman SA, Burwinkle TM, et al. The PedQoLI™ Family Impact Module: 
preliminary reliability and validity
. Health Qual Life Outcomes. 2004;2:55. 
Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus 
for diagnostic criteria. Am J Med Genet. 2006;140(5):413-8. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 86 
13 Pandemic
 Addendum 
The purpose of this addendum is to safeguard the safety of study participants, ensure 
continuation of study conduct, and preserve the integrity of the study, in case of a general public 
health crisis such as the COVID-19 pandemic. This addendum addresses situations in which 
scheduled in-person clinic visits are not feasible due to local, regional or national restrictions. If 
a patient cannot attend an in-person visit, a home visit may be conducted by a mobile healthcare 
professional trained to perform study assessments e.g. vital signs, body system assessment, 
clinical labs draws, review/collection of study materials. 
Specifically, the addendum aims to ensure: 
• Continued safe study conduct and participation of existing patients  
• Uninterrupted supply of study drug  
• Integrity of data capture and minimization of missing data  
 Written communication from sponsor Medical Advisor or Clinical Operations Lead is required 
before any portion of this addendum is put into effect. The communication shall be documented 
and captured in the Trial Master File.  
The Principal Investigator holds the ultimate responsibility for the safety and well-being of study 
participants and as always, shall maintain compliance with the current local and health authority 
guidelines and recommendations pertaining to the pandemic.  
This guidance is categorized below by the different stages of study participant participation in 
the ELARA study:  
Guidance for study participants scheduled to undergo study screening 
Guidance for Screening visits occurring within 2 Weeks of Completing NEPTUNE study  
• Study Participants who are scheduled to roll over to ELARA within 2 weeks of 
completing NEPTUNE are NOT required to complete a separate screening visit for 
ELARA. Per protocol their data for the last visit in NEPTUNE will be used for the 
ELARA baseline visit. Therefore, please skip the Guidance for Screening below and go 
to Guidance for Baseline. 
Guidance for Screening Visits beyond 2 Weeks of Completing NEPTUNE  
• 2-3-year-old study Participants MUST be scheduled for ONSITE screening 
• Consider remote screening via telehealth/virtual and/or telephone for Participants >4 
years old 
o Telehealth/virtual platform selection is at investigator discretion and should be 
consistent with local and individual institution’s policies and standard practice. A 
home nurse visit will replace a virtual visit if the latter is not feasible. 
• Informed consent/assent should be sent to the study participant and LAR/caregiver either 
electronically (PDF format) or by mail prior to the scheduled screening visit  
o Informed consent/assent can be performed via Telehealth/virtual and/or 
Telephone during the Screening Visit and documented in the source document 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 87 
with the date and time of the verbal consent/assent. A home nurse visit will 
replace a virtual visit if the latter is not feasible 
o Documentation of the consent/assent must be captured in the Study Participant’s 
source documents.  Please ensure the following is documented: 
 The date and time of the consent/assent. 
 Method of consent/assent (Telehealth/virtual or Telephone). A home nurse 
visit will replace a virtual visit if the latter is not feasible. 
 Individuals who signed consent/assent (site personnel and participant’s 
LAR/caregiver). 
 Method by which the signed consent/assent will be provided to the site.   
Study participant/LAR/caregiver can provide proof of wet ink signature via fax, scan or picture.   
Site should advise LAR/caregiver to bring in the original ICF/assent along with the addendum 
with wet ink signature at next possible on-site visit or via courier envelope provided by the site at 
their earliest convenience. 
• 
 
 
• Screening visit clinical labs, vital sign testing, and weight measurement may be 
performed at a local lab or by the home health nurse.  
• Copies of seizure and sleep diary forms should be sent to LAR/caregivers.  
o Electronic copies may be provided if LAR/caregivers can print physical copies.  
o Instructions for completion of diary forms should be provided verbally/in writing. 
o Pre-paid envelopes should be provided to support the return shipping of the 
diaries. The study title and/or protocol number should NOT be noted on the 
envelope. 
• Update EDC as soon as possible to allow planning of Investigational Product (IP) 
shipment. 
• Notify 
 plan support for IP shipment arrangement 
 
Guidance for Baseline Visits for Participants scheduled within 2 Weeks of 
completing NEPTUNE 
 
• Whenever possible, the Baseline Visit should be completed onsite. 
• If an onsite visit is not possible, a remote visit including assessment of the CGI-S-AS, 
VABS3, and other Reported Outcomes required per protocol may be performed via each 
site’s institution-approved Telehealth/virtual system and/or Telephone. A home nurse 
visit will replace a virtual visit if the latter is not feasible. 
• Notify 
 advance of the visit to define IP shipment arrangements. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 88 
• Informed consent/addendum/assent should be sent to the study participant and 
LAR/caregiver either electronically (pdf format) or by mail prior to the scheduled 
Baseline visit.   
o Informed consent/addendum/assent can be performed via Telehealth/virtual 
and/or Telephone during the Baseline Visit and documented in the source 
document with the date and time of the verbal consent/assent. A home nurse visit 
will replace a virtual visit if the latter is not feasible. 
o Documentation of the consent/assent must be captured in the study participant’s 
source documents.  Please ensure the following is documented: 
 The date and time of the consent/assent. 
 Method of consent/assent (Telehealth/virtual or Telephone). 
 Individuals who signed consent/assent (Site personnel and Participant’s 
LAR/caregiver). 
 Method by which the signed consent/assent will be provided to the Site.   
Study Participant can provide proof of wet ink signature via fax, scan or picture.   Site should 
advise Caregiver to bring in the original ICF/assent with wet ink signature at next possible on-
site visit or via courier envelope provided by the Site at their earliest convenience. 
• For remote screening, ensure that the Study Participant has access to 
 
 Baseline Visit clinical labs, vital sign testing, 
and weight measurement may be performed at a local lab or by the home health nurse.  
• Copies of seizure and sleep diary forms should be sent to LAR/caregivers.  
o Electronic copies may be provided if LAR/caregivers can make physical copies.  
o Instructions for completion of diary forms should be provided verbally/in writing 
to the LAR/caregivers. 
o Pre-paid envelopes should be provided by the site to the LAR/caregivers by the 
site to support the shipping of the diaries. 
• ALL scale administrations should capture the CGI-S-AS/CGI-I-AS, PedsQL, and CSHQ 
data on the paper source even when administered by phone. Please still use 
 to 
score the Vineland-3. 
• Update EDC accordingly. 
 
Guidance for Baseline Visits for study participants scheduled beyond 2 Weeks of 
completing NEPTUNE 
• For these study participants a Screening Visit must have been performed prior to 
Baseline. 
• Baseline visits can ONLY occur when study participants can appear ON-SITE.  
• If the baseline visit cannot be conducted within 28 days of the Screening Visit, this 
should be captured as a Protocol Deviation due to COVID-19 restrictions, but not a 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 89 
screen fail of the Study Participant. IWRS and EDC will not automatically screen fail 
study participants  
• Every attempt should be made to follow Baseline Visit procedures per the Schedule of 
Activities (SOA).  
o Any deviation should be appropriately documented. 
• IP will be provided to the study participant at the site. 
• Please collect and review seizure and sleep diaries per protocol and epilepsy consortium 
instructions.  
o Provide physical/electronic PDF copies of diaries (seizure, sleep, medication). 
o Pre-paid envelopes should be provided to the LAR/caregivers by the site to 
support the shipping of the diaries. 
• Update EDC when diaries are received. 
  
Guidance for Week s 12, 36, 64, 96, and 124 Clinic Visits  
• Schedule the visit as close as possible to planned visit date to allow adequate time to ship 
IP. 
• If an onsite visit is not possible, a remote visit including AE/SAE collection,  assessment 
of the CGI-AS, CGI-S,-AS, VABS3, and other PROs required per protocol may be 
performed via your institution-approved (HIPAA compliant) home visit, 
Telehealth/virtual system and/or Telephone software, which also should be compliant and 
consistent with local and individual institution’s policies and standard practice. 
• ALL scale administrations should capture the CGI-S-AS/CGI-I-AS, PedsQL, and CSHQ 
data on the paper source even when administered by phone.  
 should be used to 
score the VABS-3. 
• Clinical labs and vital signs required per SOA may be performed at a local lab or by the 
home health nurse.  
• IP with kit number to be assigned to the study participant.  
• Please organize the courier to pick up and deliver the IP to the study participant. 
• Alternatively, your site can inform vendor (via email) to pick up the IP and ship to 
the study participant directly by providing the shipment orders by email. Delivery 
addresses, including contact information and consignee details will be provided to 
the vendor. Unused study drug should be returned to the site at each visit.   
• Copies of seizure and sleep diary forms should be sent to LAR/caregivers.  
• Electronic copies may be provided if LAR/caregivers can print physical copies.  
• Pre-paid envelopes should be provided to support the shipping of the diaries. The 
study title and/or protocol number should NOT be noted on the envelope. 
• Update EDC when diaries are received. 
  
***The guidance below is only for sites still operating under Protocol Version 1.0.  
Sites utilizing Protocol Version 3.0 (which allows rollover from Neptune) may disregard this 
section              
                                                           
Protocol Version 1.0 - Guidance for Week 24, 48, 80, 112 and 144  
• Schedule the visit as close as possible to planned visit date to allow adequate time to ship 
IP. 

Ovid Therapeutics Inc. 
OV101 
Protocol OV101-18-002 Version 4.0 
13 October 2020 
Page 90 
• A remote visit should be completed to monitor the study participant and collect AE/SAE 
assessments via telehealth/virtual and/or telephone. 
• Telehealth/virtual platform selection is at investigator discretion and should be 
consistent with local and individual institution’s policies and standard practice. 
• Clinical labs and vital signs required per SOA may be performed at a local lab.  
  
Guidance pertaining to the EOT Visit 
• Whenever possible, the EOT Visit should be completed onsite. 
• If an onsite visit is not possible, a remote visit to monitor the study participant and collect 
AEs and assessment of the CGI-I-AS, CGI-S,-AS, VABS3, and other PROs required per 
protocol may be performed via a home visit, institution-approved Telehealth/virtual 
system and/or Telephone 
• ALL scale administrations should capture the CGI-S-AS/CGI-I-AS, PedsQL, and CSHQ 
data on the paper source even when administered by phone. 
 should be used to 
score the VABS-3. 
• Clinical labs and vital signs required per SOA may be performed at a local lab.  
• Unused IP to be shipped back to site for reconciliation. 
• Ensure study participant diaries are collected and reviewed appropriately. 
 
Please ensure that all protocol deviations resulting from the COVID-19 pandemic are 
communicated 
 appropriately documented.  If at any time during the conduct of the 
ELARA study /a study participant contracts COVID-19 infection or any reportable infectious 
disease, the local health authority requirements regarding treatment/reporting/quarantine should 
be followed. The event should be reported as an AE/SAE and the investigator should determine 
if study treatment should be continued, temporarily interrupted, or discontinued.