Conditions: Epilepsy Dravet Syndrome Lennox-Gastaut Syndrome
Keywords: Drug Therapy Brain Diseases Central Nervous System Diseases Tuberous Sclerosis CDKL5 deficiency disorder Dup15Q syndrome Anoxic brain injury Infantile spams West syndrome Cortical dysplasia SCN1A OV-935 Cholesterol 24S-hydroxylase inhibitor Seizure Anti-epileptic drug Anticonvulsants Nervous System Diseases Drop seizure Atonic seizure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 141
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the effect on the frequency of all seizures (convulsive and drop) in participants treated with TAK-935 compared to placebo.

Detailed description:
The drug being tested in this study is called TAK-935 (OV935). This randomized, double-blind study will assess the effects of TAK-935 (OV935), compared to placebo, on efficacy, safety, and tolerability in pediatric participants with Dravet syndrome (DS) or Lennox Gastaut syndrome (LGS). This multi-center trial will be conducted worldwide and will enroll approximately 126 participants.

Participants will be randomized based on their diagnosis in 2 categories; DS or LGS. The study will consist of 2 periods: Screening Period and Treatment Period. The overall duration of Treatment Period is up to 20 weeks including 8-week Dose Optimization Period and 12-week Maintenance Period. The overall time to participants in this study is approximately 30 weeks.

Participants completing this study will have an option to enroll in the open-label extension study, under a separate protocol.

Arms:
arm 1: TAK-935 placebo-matching tablets, orally or via gastrostomy tube (G-tube)/percutaneous endoscopic gastrostomy (PEG), twice a day (BID) up to Week 20. arm 2: TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing \<60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.

Interventions: intervention 1: TAK-935 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-935 tablets or mini-tablets. intervention 2: TAK-935 placebo-matching tablets or mini-tablets.

Protocol document:
Prot_000.pdf: 



Title: A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF TAK-935 (OV935) AS AN ADJUNCTIVE THERAPY IN PEDIATRIC 
PATIENTS WITH DEVELOPMENTAL AND/OR EPILEPTIC ENCEPHALOPATHIES (ELEKTRA)
NCT Number: NCT03650452
Protocol Approve Date: 14 February 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company confidential 
information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 1 of 106
PROTOCOL TAK-935-2002 (OV935)
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF TAK-935 (OV935) AS AN ADJUNCTIVE THERAPY IN 
PEDIATRIC PATIENTS WITH DEVELOPMENTAL AND/OR EPILEPTIC 
ENCEPHALOPATHIES (ELEKTRA)
Sponsor:
Ovid Therapeutics, Inc.
1460 Broadway
New York, NY 10036
Telephone: +1 (646) 661-7661
Sponsor Contact:
Medical Monitor:
Date of Amendment 2:
14 February 2019
Date of Amendment 1:
23 April 2018
Date of Original Protocol:
16 February 2018
PPD
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SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE:  A Phase 2, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-935 
(OV935) as an Adjunctive Therapy in Pediatric Patients with Developmental and/or 
Epileptic Encephalopathies (ELEKTRA) 

PROTOCOL NUMBER:  TAK-935-2002 (OV935) Amendment 2 
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
'DWH
02/13/2019
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 3 of 106
PROTOCOL AMENDMENT 2 SUMMARY OF CHANGES
Rationale for Amendment 2
This document describes the changes in reference to the protocol incorporating Amendment
No. 2. The primary reasons for this amendment are to update the study design (adding 6 weeks to 
the treatment duration), change the primary endpoint, change the secondary and exploratory 
endpoints, revise the inclusion criteria to clarify the use of benzodiazepines as antiepileptic 
drugs, and clarify the criteria regarding the diagnosis of Dravet syndrome and Lennox-Gastaut 
syndrome. 
Changes Implemented by Amendment 2:
In addition to the changes described above, the following changes were also implemented:

Clarified that for all clinical studies across the TAK-935 program, the independent Data 
Monitoring Committee will review the AE profiles of 12 patients aged ≥9 years 
completing 4 weeks of treatment of TAK-935 in the TAK-935 program before opening 
enrollment to younger patients

Added history of confirmed cataract (untreated with surgery) as an exclusion criterion 

Added perampanel as a prohibited medication

Added 2 new forms of approved contraceptive methods

Clarified that only sexually active female patients of childbearing potential will have 
pregnancy tests performed

Clarified the duration for avoidance of pregnancy and donation of sperm and ova for 
male and female patients, respectively

Revised the PK sampling time points
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. A detailed description of and rationale for changes implemented by 
Amendment 2 are provided in Appendix 5.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 4 of 106
INVESTIGATOR’S AGREEMENT
I have received and read the Investigator’s Brochure for TAK-935. I have read the
TAK-935-2002 (OV935) Protocol Amendment 2, dated 11 February 2019, and agree to conduct 
the study in accordance with this protocol, all applicable government regulations, the principles 
of the ICH E6 Guidelines for Good Clinical Practice, and the principles of the World Medical 
Association Declaration of Helsinki. I also agree to maintain the confidentiality of all 
information received or developed in connection with this protocol.
Printed Name of Investigator
Signature of Investigator
Date
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 5 of 106
1.
SYNOPSIS
Name of Sponsor/Company:
Ovid Therapeutics, Inc.
Name of Study drug:
TAK-935
Title of Study:
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, 
Safety, and Tolerability of TAK-935 (OV935) as an Adjunctive Therapy in Pediatric Patients with 
Developmental and/or Epileptic Encephalopathies (ELEKTRA)
Study Number: TAK-935-2002 (OV935)
Phase: 2
Study Design:
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, study in 
pediatric patients (aged ≥2 and ≤17 years) with Dravet syndrome and Lennox Gastaut syndrome (LGS) 
demonstrating ≥3 convulsive or ≥4 drop seizures, respectively, per month during the 3 months 
immediately prior to Screening (based on historical information) and ≥3 convulsive or ≥4 drop seizures, 
respectively, during a minimum of 4 weeks during the prospective Baseline Period (based on the seizure 
diary records). Convulsive seizures include generalized tonic-clonic, focal to bilateral tonic-clonic with 
impaired awareness, hemi-clonic, and simultaneous bilateral clonic (generalized clonic) seizures. Drop 
seizures are defined as involving the entire body, trunk, or head that leads to a fall, injury, slumping in a 
chair, or head hitting a surface, or that could have led to a fall or injury, depending on the position of the 
patient at the time of the seizure or spell. Examples of seizures causing drop include, but are not limited 
to, atonic, clonic, and tonic seizures.
Approximately 126 patients will be randomized to ensure 112 evaluable patients. Randomization will be 
stratified by 2 categories: patients with Dravet syndrome with convulsive seizures and patients with LGS 
with drop seizures. Stratification will be performed to ensure balance of treatments within each stratum.
The study will begin with a phased enrollment based on age. Patients aged ≥9 years will be enrolled first, 
prior to open enrollment in the study, for assessment of safety. The independent Data Monitoring 
Committee (iDMC) will review the adverse event (AE) profiles of the first 12 patients aged ≥9 years 
completing 4 weeks of treatment across all ongoing pediatric TAK-935 studies, prior to recommending 
treatment for patients aged <9 years.
Study Periods:
This study consists of 2 main periods:

4- to 6-week Screening/Baseline Period

20-week Treatment Period

8-week Dose Optimization Period

12-week Maintenance Period
The Treatment Period consists of the Dose Optimization Period and Maintenance Period.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 6 of 106
Dravet syndrome patients who have had on average ≥3 convulsive or LGS patients who have had on 
average ≥4 drop seizures per month during the 3 months immediately prior to Screening (based on the 
historical information) and ≥3 convulsive or ≥4 drop seizures, respectively, during a minimum of 
4 weeks during the Baseline Period (based on the seizure diary records) will be eligible for entry into the
study.
At the end of the 4-week Baseline Period, patients will return to the clinic (Visit 2). Seizure diaries will 
be reviewed by the Medical Monitor or delegated staff and if a patient did not meet the eligibility criteria, 
including minimum number of seizures required for the study, the patient will be discontinued from the 
study and considered a screen failure. 
The patients who meet the entry criteria will be randomized in a 1:1 ratio to double-blind treatment with 
TAK-935 or matching placebo for the 20-week Treatment Period (8-week Dose Optimization Period and 
12-week Maintenance Period).
Dosing and Titration Schedule
All patients will receive TAK-935 twice a day (BID) orally or via gastrostomy tube (G-tube)/
percutaneous endoscopic gastrostomy (PEG) tube with or without food (patients enrolled in clinical sites 
in China are not to receive study drug via G-tube/PEG tube).
For patients weighing <60 kg, the total daily dose of study drug (either placebo or TAK-935) is 
calculated based on body weight at Visit 1 and will be given BID (Table 1). The selected doses for the 
different weight groups are listed in Table 1. For patients weighing ≥60 kg at Visit 1, dosing will be 200 
mg/day followed by 400 mg/day, then 600 mg/day (Table 1). Study drug can be taken with or without 
food. For patients aged ≥9 years at Visit 1, the total daily dose of study drug (either placebo or TAK-935) 
is calculated based on body weight at Visit 1 and will be given BID. Patients will receive the initial dose 
of study drug, Dose 1, for the first 7 days after randomization on Visit 2. In the subsequent phone call 
and visit (phone call 1 [Day 8] and Visit 3 [Day 15]), the study drug dose will be increased to Dose 2 and 
Dose 3. The maximum dose for any patient will be 600 mg/day (300 mg BID). Patients will be contacted 
by phone within the first 2 days following escalation to the maximum dose to assess safety and 
tolerability of the study drug. Study drug dose will be allowed to change in first 6 weeks of Dose 
Optimization Period, based on the judgment of the Investigator and with the approval of the Medical 
Monitor. The final dose level will be maintained until the end of the Maintenance Period; however, the 
dose may be decreased to the previous lower doses, for safety and tolerability issues. Patients who cannot 
tolerate Dose 1 will be withdrawn from the study (and will complete the early termination and safety 
follow-up visits).
Dosing Schedule by Weight:
Weight 
(kg)
Dose 1
Dose 2
Dose 3
(mg/day)a
No. Tablets/ 
Mini-tablets
(mg/day)a
No. Tablets/ 
Mini-tablets
(mg/day)a
No. Tablets/ 
Mini-tablets
10-14
80
0/4
160
0/8
220
0/11
15-19
120
0/6
200
0/10
260
0/13
20-24
120
0/6
240
0/12
320
0/16
25-29
120
0/6
240
0/12
360
0/18
30-34
160
0/8
280
0/14
400
0/20
35-39
160
0/8
280
0/14
440
0/22
40-44
160
0/8
320
0/16
480
0/24
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 7 of 106
45-49
200
0/10
360
0/18
480
0/24
50-54
200
0/10
360
0/18
520
0/26
55-59
200
0/10
360
0/18
560
0/28
≥60
200
2/0
400
4/0
600
6/0
a Total dose administered twice daily.
Pharmacokinetic Assessments:
Pharmacokinetic (PK) sample collection will start at Visit 2 (Day 1), and it is designed to investigate the 
PK in all patients. The first 12 randomized patients aged ≥9 years and the first 12 randomized patients 
aged <9 years will receive the first dose of TAK-935 or placebo in the clinic; PK blood draws will occur 
within 1 hour before the morning dose (pre-morning dose) and 30 min (±10 min) and 1, 2, and 4 hours 
(±10 min) post-morning dose. After Visit 2 (Day 1), additional PK samples will be collected within 
1 hour before the morning dose (pre-morning dose) and 30 min (±10 min) post-morning dose at Visits 3, 
4, 5, and 6 during the study.
The remaining randomized patients in the study will receive the first dose of TAK-935 or placebo in the 
clinic, with PK blood draws occurring within 1 hour before the morning dose (pre-morning dose) and 
30 min (±10 min) post-morning dose at Visits 2, 3, 4, 5, and 6 during the study.
Concomitant and Prohibited Medications:
Adjunctive antiepileptic drug (AED) treatment, (medical) marijuana, cannabidiol products, vagal nerve 
stimulator (VNS) settings, and ketogenic diet should not be altered during the study. Concurrent 
treatment regimen data will be collected throughout the study.
Use of strong inducers and inhibitors of cytochrome P450 (CYP) 3A4 (prescription medications, OTC 
medications, or dietary supplements) within 30 days before randomization through follow-up is 
prohibited, except for AEDs (e.g., carbamazepine, phenobarbital, phenytoin). Refer to Appendix 4 for a 
list of prohibited CYP3A4 inducers and inhibitors.
Use of perampanel from screening through follow-up is prohibited.
Use of traditional Chinese medicines should be approved by the Medical Monitor at screening.
Following completion of the study, patients will have the option to enroll in a long-term (24-month), 
open-label extension study (under a separate protocol, TAK-935-18-001 [OV935]) or to enter a 
double-blind taper period (maximum 14 days). During the taper period, the study drug dose will be de-
escalated to a lower dose (taper Dose 3 to Dose 2, taper Dose 2 to Dose 1) every 3 days or less frequently 
based on Investigator’s discretion until there is no de-escalation and study drug dose is discontinued. 
After tapering, the patients will complete a Safety Follow-up visit approximately 15 days after the last 
dose of study drug and exit the study. The total study duration from Screening to the last visit in this 
study will be approximately 30 weeks.
An iDMC will monitor the patients’ safety, in accordance with the iDMC charter.
Procedures:
Daily seizure diaries will be used to determine seizure frequency for the evaluation of efficacy.
Blood samples for clinical safety laboratory tests (5.7 mL at each sample time point), including 
hematology and chemistry, will be collected at Visit 1 (Screening), Visit 2 (Day 1), Visit 4 (Day 36), and 
at Visit 6 (Day 141). One blood sample will be collected (2 mL for PD assessment) at Visit 7 (Day 169), 
the follow-up visit. In addition, urinalysis will be performed at the specified visits.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 8 of 106
Blood samples for PK analysis of TAK-935 and M-I will be drawn within 1 hour of the morning dose 
(pre-morning dose) and 30 min (±10 min) and 1, 2, and 4 hours (±10 min) post-morning dose for the 
first 12 patients aged ≥9 years and the first 12 patients aged <9 years. After Visit 2 (Day 1), additional 
PK samples will be collected within 1 hour before the morning dose (pre-morning dose) and 30 min 
(±10 min) post-morning dose at Visits 3, 4, 5, and 6 during the study from those patients. The remaining 
randomized patients in the study will receive the first dose of TAK-935 or placebo in the clinic, with PK 
blood draws occurring within 1 hour before the morning dose (pre-morning dose) and 30 min (±10 min)
post-morning dose at Visits 2, 3, 4, 5, and 6 during the study.
The total blood volume collected during the study will be approximately 73.2 mL for patients. The 
maximum blood volume collected during a 30-day period will be 28.4 mL and maximum blood volume 
collected during a single visit will be 14.7 mL. The total blood volume limits are consistent with 
physiological minimal risk as specified by the WHO guidelines.1
Primary Objective:
To investigate the effect on the frequency of all seizures (convulsive and drop) in patients treated with 
TAK-935 as an adjunctive therapy compared to placebo in the Maintenance Period
Secondary Objectives:

To investigate the effect on the frequency of all seizures (convulsive and drop) in patients 
treated with TAK-935 as an adjunctive therapy compared to placebo throughout the Treatment 
Period

To investigate the effect on the frequency of convulsive seizure in patients with Dravet 
syndrome treated with TAK-935 as an adjunctive therapy compared to placebo in the 
Maintenance Period

To investigate the effect on the frequency of drop seizure in patients with LGS treated with 
TAK-935 as an adjunctive therapy compared to placebo in the Maintenance Period

To investigate the seizure frequency of LGS patients considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with:

Worsening of 25% or more in drop seizures from baseline

Worsening of 1% to 25% in drop seizures from baseline

No change in drop seizures from baseline (Worsening of 1% to Reduction of 1%)

Reduction of 25% or more in drop seizures from baseline

Reduction of 50% or more in drop seizures from baseline

Reduction of 75% or more in drop seizures from baseline

Reduction of 100% in drop seizures from baseline

To investigate the seizure frequency of Dravet patients considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with:

Worsening of 25% or more in convulsive seizures from baseline

Worsening of 1% to 25% in convulsive seizures from baseline

No change in convulsive seizures from baseline (Worsening of 1% to Reduction of 1%)
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 9 of 106
∀
Reduction of 25% or more in convulsive seizures from baseline
∀
Reduction of 50% or more in convulsive seizures from baseline
∀
Reduction of 75% or more in convulsive seizures from baseline
∀
Reduction of 100% in convulsive seizures from baseline
!
To investigate the change in Clinical Global Impression of Severity and Change assessment 
(CGI-S/C) responses of Investigator and Caregiver Clinical Global Impression of Change 
assessment (Care GI-C) in patients treated with TAK-935 as an adjunctive therapy compared to 
placebo
!
To characterize the relationship between plasma 24S-hydroxycholesterol (24HC) levels and 
seizure frequency
Safety Objectives:
!
To evaluate safety and tolerability of TAK-935 as adjunctive therapy as compared to placebo
!
To investigate the effect on behavior and adaptive function in patients treated with TAK-935 as 
adjunctive therapy compared to placebo using the Vineland Adaptive Behavioral scales (VABS) 
and Aberrant Behavior Checklist community questionnaire (ABC-C)
!
To evaluate the occurrence of myoclonic and atypical absence-free days to determine if there is 
worsening of these seizure types during treatment with TAK-935
Study Population:
Pediatric patients aged ≥2 and ≤17 years with Dravet syndrome or LGS who are on background AED 
therapy
CCI
Property of Takeda: For Non-Commercial U
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 10 of 106
Number of Patients:
Approximately 126 male and female patients will 
be randomized to ensure at least 112 eligible 
patients (a minimum of 46 in the Dravet stratum, 
and 80 in the LGS stratum).
Number of Sites:
Estimated total: approximately 45 sites globally
Study Drug:
Patients will be dosed with either TAK-935 or 
matching placebo
Route of Administration:
Oral or via gastrostomy tube (G-tube)/
percutaneous endoscopic gastrostomy (PEG) 
tube.
Note: Patients enrolled in clinical sites 
in China are not to receive study drug via 
G-tube/PEG tube.
Twice daily
Duration of Treatment:
20 weeks plus 2-week taper
Period of Evaluation:
~30 weeks (includes 4- to 6-week 
Screening/Baseline period, 20-week 
double-blind treatment period [8-week Dose 
Optimization Period and 12-week Maintenance
Period], 2-week taper, and 2-week safety follow-
up period)
Main Criteria for Inclusion:
1.
The patient and patient’s legal representative (i.e., parent or legal guardian) are willing and 
able to read, understand, and sign the informed consent form and assent, if applicable
2.
Male and female patients aged ≥2 and ≤17 years at the time of informed consent and the first 
dose of study drug
3.
Clinical diagnosis of LGS and a history of, on average, ≥4 drop seizures per month during the 
3 months immediately prior to Screening based on historical information, and the patient has 
≥4 drop seizures during a minimum of 4 weeks of seizure data collection during the 
prospective Baseline Period
- OR -
Clinical diagnosis of Dravet syndrome and a history of, on average, ≥3 convulsive seizures per 
month during the past 3 months based on the historical information, and the patient has ≥3 
convulsive seizures during a minimum of 4 weeks of seizure data collection during the 
prospective Baseline Period
4.
Weight of ≥10 kg at the Screening visit (Visit 1)
5.
Currently taking 1 to 4 AEDs at a stable dose for 4 weeks prior to the Screening visit (Visit 1); 
benzodiazepines used chronically (on daily frequency) to treat seizures are considered AEDs
6.
If using a VNS, must have VNS placed at least 3 months prior to the Screening visit with 
stable settings for >1 month; VNS parameters must remain constant throughout the study 
(VNS will not be counted as an AED)
7.
If on a ketogenic diet, must have started the ketogenic diet at least 3 months prior to the 
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 11 of 106
Screening visit (Visit 1), diet should be stable for 4 weeks before the Screening visit (Visit 1); 
and should continue through the duration of the study (ketogenic diet will not be counted as an 
AED)
8.
Failed to become and remain seizure free with trials of at least 2 AEDs
9.
The patient and patient’s legal representative (i.e., parent or legal guardian) are willing to keep 
the AED, VNS, and ketogenic diet regimen(s) stable throughout the study
10. The patient is able to carry out all appropriate assessment and take study drug in the opinion of 
the Investigator and parent/caregiver
11. The patient has a documented clinical diagnosis of Dravet syndrome or LGS: 
Diagnosis of Dravet syndrome supported by:

Onset of seizures around 6 months of age

Initial seizures
-
Fever-induced or fever-triggered seizures
-
Hemiclonic or generalized tonic seizures
-
Prolonged seizures (approximately 15 minutes or longer, some >30 min)

Between 1 and 5 years, other seizure types emerge:
-
Myoclonic seizures
-
Focal awareness altered
-
Absence
-
Non-convulsive status (absence or myoclonic)
-
Convulsive status epilepticus

Development normal within 1st year of life, then intellectual disability emerges
-
May regress with recurrent status epilepticus
Diagnosis of Lennox-Gastaut syndrome supported by:

History of abnormal EEG consistent with LGS 
-
EEG with slow and/or disorganized background AND one of the following:
o
EEG with bursts of generalized 2.5 Hz (or less) spike and wave activity, OR
o
Generalized paroxysmal fast activity (GPFA)

Greater than 1 type of generalized seizure for at least 6 months
-
At least 1 seizure type with drop seizures

Less than 11 years of age at the onset of LGS
-
Evidence of development delay or regression OR history of special education classed 
OR measured IQ <70
12. Sexually active female patients of childbearing potential (defined as first menarche) must agree 
to use a highly effective method of birth control during the study and for 30 days following the 
last dose of study drug
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 12 of 106
Main Criteria for Exclusion:
Patients will be excluded from study enrollment if they meet any of the following criteria:
1.
The patient has been admitted to a medical facility and intubated for treatment of status 
epilepticus 2 or more times in the 3 months immediately prior to the screening visit
2.
Non-epileptic events that cannot be reliably distinguished from epileptic seizures (e.g., 
gastroesophageal reflux, muscle cramps, etc.)
3.
Patients with history of confirmed cataract (untreated with surgery)
4.
Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, 
cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, 
urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive 
tumors, or other abnormality, which may impact the ability to participate in the study or that 
may potentially confound the study results. It is the responsibility of the Investigator to assess 
the clinical significance; however, consultation with the Medical Monitor may be warranted
5.
Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-V), within the 2 years immediately prior to 
the Screening visit (Visit 1)
6.
Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the 
Investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the Columbia-Suicide 
Severity Rating Scale [C-SSRS] at Screening) or appearing suicidal per Investigator judgment
7.
History of human immunodeficiency virus (HIV) infection (patient who has tested positive for 
human immunodeficiency virus antibodies (HIV)-1/2Ab), or history of active hepatitis B, or 
active hepatitis C infection. (Note that patients who have been vaccinated against hepatitis B 
[hepatitis B surface antibody {Ab}-positive] who are negative for other markers of prior 
hepatitis B infection [eg, negative for hepatitis B Core Ab] are eligible)
8.
Abnormal and clinically significant ECG abnormality at Screening
a.
QT interval with Fridericia’s correction method (QTcF) >450 ms (males) or >470 ms 
(females), confirmed with one repeat testing, at the Screening visit
9.
Abnormal clinical laboratory test results at the Screening visit that suggest a clinically 
significant underlying disease that would compromise the well-being of the patient (if the 
patient has alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] 
>2.5 × the upper limit of normal [ULN], the Medical Monitor should be consulted)
10. Participated in a clinical study involving another study drug in the previous month (or 5 half-
lives of the study drug, whichever is longer) or currently receiving another study drug
11. Received TAK-935 in a previous clinical study or as a therapeutic agent
12. Immediate family members, or in a dependent relationship with a study site employee who is 
involved in the conduct of this study (eg, child, sibling)
13. Known hypersensitivity to any component of the TAK-935 formulation
14. Currently pregnant or breastfeeding or is planning to become pregnant within 90 days of the 
last dose of study drug
Endpoints:
Primary Efficacy Endpoint
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 13 of 106
!
Percent change from Baseline in seizure frequency per 28 days (based only on convulsive 
seizures for the patients in the Dravet syndrome stratum and drop seizures for the patients in the 
LGS stratum) in patients receiving TAK-935 as compared to placebo during the Maintenance 
Period
Secondary Efficacy Endpoints
!
Percent change from Baseline in seizure frequency per 28 days (based only on convulsive 
seizures for the patients in the Dravet syndrome stratum and drop seizures for the patients in the 
LGS stratum) in patients receiving TAK-935 as compared to placebo during the Treatment 
Period
!
Percent change from Baseline in convulsive seizure frequency per 28 days in patients 
randomized to the Dravet syndrome stratum and receiving TAK-935 as compared to placebo 
during the Maintenance Period
!
Percent change from Baseline in drop seizure frequency per 28 days in patients randomized to 
the LGS stratum and receiving TAK-935 as compared to placebo during the Maintenance Period
!
Proportion of patients in the LGS stratum considered treatment responders throughout the 
Maintenance Period; treatment responders defined as those with: 
-
Worsening of 25% or more in drop seizures from baseline
-
Worsening of 1% to 25% in drop seizures from baseline
-
No change in drop seizures from baseline (Worsening of 1% to Reduction of 1%)
-
Reduction of 25% or more in drop seizures from baseline
-
Reduction of 50% or more in drop seizures from baseline
-
Reduction of 75% or more in drop seizures from baseline
-
Reduction of 100% in drop seizures from baseline
!
Proportion of patients in the Dravet syndrome stratum considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with:
-
Worsening of 25% or more in convulsive seizures from baseline
-
Worsening of 1% to 25% in convulsive seizures from baseline
-
No change in convulsive seizures from baseline (Worsening of 1% to Reduction of 1%)
-
Reduction of 25% or more in convulsive seizures from baseline
-
Reduction of 50% or more in convulsive seizures from baseline
-
Reduction of 75% or more in convulsive seizures from baseline
-
Reduction of 100% in convulsive seizures from baseline
!
Change in CGI-S/C responses of Investigator reported impression of efficacy and tolerability of 
study drug
!
Change in Care GI-C responses of parent/family reported impression of efficacy and tolerability 
of study drug
!
To characterize plasma 24HC levels and change in seizure frequency in patients treated with 
TAK-935 as an adjunctive therapy
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 14 of 106
Pharmacokinetic Endpoints
!
To determine the plasma concentrations of TAK-935 and the TAK-935 metabolite (M-I) at 
multiple time points
!
Estimate exposure parameters from sparse PK samples using population modelling
!
Determine any potential relationship with estimated TAK-935 exposure parameters with 
changes in seizure frequency
Safety Endpoints
!
Incidence of treatment-emergent adverse events (TEAEs)
!
Change in behavioral and adaptive functional measures using the VABS
!
Change in behavior measures using total scores and subscale scores of ABC-C for patients 
≥6 years of age
!
Incidence of abnormal values for clinical laboratory evaluations, vital signs, body weight and 
height, and electrocardiogram (ECG) parameters after TAK-935 treatment
!
Change from Baseline in clinical laboratory evaluations, vital signs, body weight, C-SSRS, and 
ECG parameter values after TAK-935 treatment
!
Mean percent of myoclonic- and atypical-absence free days in patients receiving TAK-935 as 
compared to placebo during the Maintenance Period
Safety:
An iDMC will monitor the patient safety in accordance with the iDMC charter.
Statistical Considerations:
All statistical analyses will be performed using SAS® Version 9.4 or higher. All clinical study data will 
be presented in patient data listings. Data summaries will be presented for all endpoints and will include 
descriptive statistics (number of patients [n], mean, standard deviation [SD], first quartile [Q1], median, 
third quartile [Q3], minimum and maximum) for continuous variables, and frequency and percentage for 
categorical and ordinal variables. If there are missing values, the number of missing will be presented, 
but without a percentage.
For all analyses, ‘Baseline’ refers to the prospective 4-week Baseline Period. 
Modified Intent-to-Treat Analysis Set
All randomized patients who have received at least 1 dose of study drug and have been assessed for at 
least 1 day in the Treatment Period will be included in the modified intent-to-treat (mITT) analysis set. 
All mITT analyses will be based on each patient’s randomized treatment assignment.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 15 of 106
Efficacy Analysis Set
All mITT patients whose efficacy assessments are compliant with Protocol Amendment 2 will be 
included in the efficacy analysis set. Efficacy analyses for primary and secondary efficacy endpoints will 
be based on the efficacy analysis set. 
 
Efficacy analyses will be based on each patient’s randomized treatment 
assignment.
Safety Analysis Set
All randomized patients who take at least 1 dose of study medication will be included in the Safety 
Analysis Set. Safety analyses will be based on the medication that was actually administered to each 
patient. 
Stratification by Seizure Type
At Visit 2, all eligible patients will be stratified by 2 categories: Dravet syndrome patients with 
convulsive seizures, and LGS patients with drop seizures to ensure balance of treatments within each 
stratum. Note that patients with the minimum number of convulsive or drop seizures will be assigned to 
a stratum following the stratification rules.
Patients with Dravet syndrome:
!
46 eligible patients diagnosed with Dravet syndrome with ≥3 convulsive seizures per 28 days 
during the prospective Baseline period will be randomized into the Dravet syndrome stratum.
Patients with LGS (Lennox Gastaut Syndrome):
!
80 eligible patients diagnosed with LGS with ≥4 drop seizures per 28 days during the 
prospective Baseline period will be randomized into the LGS stratum.
If a patient does not meet any of these criteria, the patient will be considered a screen failure.
Primary Efficacy Analyses
For the patients randomized to the Dravet syndrome stratum (≥3 convulsive seizures per 28 days), 
convulsive seizure frequencies per 28 days for the 4-week prospective Baseline Period and the
Maintenance Period will be calculated.
For the patients randomized to the LGS stratum (≥4 drop seizures per 28 days), drop seizure frequencies 
per 28 days for the 4-week prospective Baseline Period and the Maintenance Period will be calculated.
For each patient, percent change from Baseline to the frequency during Maintenance Period (per 
28 days) will be calculated for the seizure type corresponding to the assigned stratum of that patient 
(convulsive for the Dravet stratum and drop for the LGS stratum). Percent change from Baseline will be 
compared between TAK-935 and placebo using a Mann-Whitney (Wilcoxon) test adjusting for Baseline 
and randomization stratum.
The null hypothesis of no treatment difference will be tested at a two-sided 0.05 level of significance. 
The Mann-Whitney estimator and the corresponding 95% confidence interval (CI) comparing TAK-935 
with placebo will also be displayed.
Secondary Efficacy Analyses
For each patient, percent change from Baseline to the frequency during Treatment Period (per 28 days) 
will be calculated for the seizure type corresponding to the assigned stratum of that patient (convulsive 
for the Dravet stratum and drop for the LGS stratum). Percent change from Baseline will be compared 
between TAK-935 and placebo using a Mann-Whitney (Wilcoxon) test adjusting for Baseline and 
randomization stratum.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 16 of 106
For Dravet syndrome stratum, percent change in convulsive seizure frequency from Baseline to the 
frequency of convulsive seizures during the Maintenance Period will be compared between TAK-935 
and placebo using a Mann-Whitney test adjusting for Baseline convulsive seizure frequency and 
randomization stratum. For the drop seizures in LGS stratum, percent change in drop seizure frequency 
from Baseline to the frequency of drop seizures during the Maintenance Period will be compared 
between TAK-935 and placebo using a Mann-Whitney test adjusting for Baseline drop seizure 
frequency. For the 2 randomization strata, the null hypothesis of no treatment difference will be tested at 
a two-sided 0.1 level of significance. The Mann-Whitney estimator and the corresponding 95% 
confidence interval (CI) comparing TAK-935 with placebo will also be displayed.
The primary analysis will be repeated for the 20-week Treatment Period.
For the Dravet syndrome stratum, the proportion of treatment responders based on ≥25% worsening, 
<25% and >1% worsening, no change (Worsening of 1% to Reduction of 1%), ≥25% reduction, ≥50% 
reduction, ≥75% reduction, and 100% reduction from Baseline in convulsive seizure frequency for the 
Maintenance Period will be summarized for TAK-935 and placebo. The 95% CIs for the difference of 
proportions will be displayed for each responder category. For the LGS stratum, the proportion of 
treatment responders based on ≥25% worsening, <25% and >1% worsening, no change (Worsening of 
1% to Reduction of 1%), ≥25% reduction, ≥50% reduction, ≥75% reduction, and 100% reduction from 
Baseline in drop seizure frequency for the Maintenance Period will be summarized for TAK-935 and 
placebo; 95% CIs for the difference of proportions will be displayed for each responder category.
Change in CGI-S/C responses of Investigator reported impression of efficacy and tolerability of study 
drug and change in Care GI-C responses of parent/family reported impression of efficacy and tolerability 
of study drug will be analyzed descriptively.
Techniques for handling missing information with respect to reporting of seizures in the treatment period 
(Dose Optimization and Maintenance) will be specified in detail in the statistical analysis plan (SAP). 
Safety Analyses
Descriptive statistics will be used to summarize all safety endpoints, by treatment group. Two-sided 95% 
CIs will be presented where meaningful. Data summaries will be displayed for incidence of AEs, clinical 
laboratory variables, vital signs, body weight and height, ECG parameters, percent myoclonic and 
atypical absence-free days, as well as changes in behavioral and adaptive functioning measures using 
VABS and sub-scales of ABC-C, as appropriate. 
Pharmacokinetic Analyses
Plasma concentrations of TAK-935 and the metabolite of TAK-935 (M-I) will be summarized and 
displayed graphically per nominal time points. Mean plasma concentrations over time will be presented 
graphically.
The plasma concentration-time and PD (24HC) data obtained in this study will be used to estimate TAK-
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 17 of 106
935 exposure parameters, analyze target engagement in terms of 24HC reduction, and evaluate potential 
relationships between TAK-935 exposure or 24HC responses and clinical and safety endpoints. Full 
details of the relevant population PK/PD modeling work (including objectives, relevant endpoints, 
methodology, software, etc.) will be defined in a separate data analysis plan or the study SAP, and 
results will be reported separately. The actual elapsed time from dose will be used in the final PK 
modeling and parameter calculations.
Sample Size Justification:
The sample size calculations are based on unadjusted Mann-Whitney (Wilcoxon rank-sum) test.
The randomization will be stratified by 2 categories: Dravet syndrome stratum and LGS stratum. The 
primary endpoint is defined as percent change in convulsive seizures for the patients in the Dravet 
syndrome and percent change in drop seizures for those in the LGS stratum.
Assuming that the mean difference in percentage change from baseline between active and placebo arms 
is 29% for the 2 strata combined and the standard deviation is 42.3%, with 56 patients per treatment 
group, there will be 92% power to test the treatment difference at a two-sided 0.05 level of significance. 
Assuming a 10% drop-out rate, 63 patients per arm will be randomized.
Within the 2 randomization strata, hypothesis tests will be performed at levels of significance higher 
than 0.05 in this Phase 2 proof of concept trial and will have power of 80%. The following table shows 
the within stratum sample size calculations:
Dravet Syndrome Stratum
LGS Stratum
Alpha
0.1
0.1
1-sided or 2-sided
2
2
Treatment Difference
0.30
0.28
Standard Deviation
0.35
0.45
Power
80%
80%
N per group
20
36
N per group (after 10% adjustment)
23
40
Total N
46
80
Interim Analysis:
Plasma concentrations of TAK-935 in first 12 patients within each category of aged ≥9 years and 
<9 years will be used to estimate PK parameters using the current population PK model. If needed, 
adjustment to the dose will be made. The frequency of PK sample collection may be changed based on 
results of interim analysis.
Overall and by-stratum (LGS and Dravet strata) futility and interim analyses may be performed. 
Enrollment may be stopped for one of the strata if the treatment effect is not sufficiently strong. If one 
stratum is discontinued, enrollment will continue with the other stratum until the total sample size is 
achieved. Thresholds for stopping enrollment will be pre-specified in the interim analysis plan.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 18 of 106
TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ................................................................................................2
PROTOCOL AMENDMENT 2 SUMMARY OF CHANGES ....................................................3
INVESTIGATOR’S AGREEMENT ...........................................................................................4
1.
SYNOPSIS..........................................................................................................................5
TABLE OF CONTENTS..........................................................................................................18
LIST OF TABLES....................................................................................................................22
LIST OF FIGURES ..................................................................................................................22
2.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................23
3.
INTRODUCTION .............................................................................................................25
3.1.
Background.................................................................................................................25
3.2.
Study Rationale...........................................................................................................25
4.
STUDY OBJECTIVES AND ENDPOINTS......................................................................27
4.1.
Objectives...................................................................................................................27
4.1.1.
Primary Objective................................................................................................27
4.1.2.
Secondary Objectives...........................................................................................27
4.1.3.
Exploratory Objectives.........................................................................................28
4.1.4.
Safety Objectives.................................................................................................28
4.2.
Endpoints....................................................................................................................29
4.2.1.
Primary Endpoint.................................................................................................29
4.2.2.
Secondary Efficacy Endpoints..............................................................................29
4.2.3.
Exploratory Endpoints .........................................................................................30
4.2.4.
Pharmacokinetic Endpoints..................................................................................30
4.2.5.
Safety Endpoints..................................................................................................30
5.
INVESTIGATIONAL PLAN ............................................................................................31
5.1.
Summary of Study Design ..........................................................................................31
5.1.1.
End of Study Definition .......................................................................................32
5.1.2.
Study Extension...................................................................................................32
5.2.
Selection and Timing of Doses in the Study ................................................................33
5.2.1.
Modeling and Simulation of Clinical Data ...........................................................33
6.
STUDY POPULATION ....................................................................................................34
6.1.
Inclusion Criteria ........................................................................................................34
6.2.
Exclusion Criteria .......................................................................................................36
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Date: 11 February 2019 
Page 19 of 106
6.3.
Discontinuations .........................................................................................................37
6.3.1.
Discontinuation of Patients ..................................................................................37
6.3.2.
Discontinuation of Study Sites/Site Terminated by Sponsor.................................39
6.3.3.
Discontinuation of the Study/Study Terminated by Sponsor.................................39
7.
TREATMENT...................................................................................................................40
7.1.
Materials and Supplies ................................................................................................40
7.1.1.
Storage.................................................................................................................40
7.2.
Treatments Administered ............................................................................................40
7.3.
Method of Assignment to Treatment ...........................................................................42
7.4.
Continued Access to Study drug..................................................................................43
7.5.
Blinding......................................................................................................................43
7.6.
Concomitant Medications and Non-Pharmacologic Therapies and Procedures ............44
7.7.
Treatment Compliance ................................................................................................44
8.
STUDY ASSESSMENTS..................................................................................................45
8.1.
Study Procedures ........................................................................................................45
8.1.1.
Informed Consent Procedure................................................................................45
8.1.1.1.
Study Informed Consent Procedure...............................................................45
8.1.2.
Demographics, Medical History, and Medication History Procedure....................45
8.1.3.
Physical Examination Procedure..........................................................................45
8.1.4.
Neurological Examination Procedure...................................................................46
8.1.5.
Weight and Height ...............................................................................................46
8.1.6.
Vital Signs Procedure...........................................................................................46
8.1.7.
Seizure Diary Procedure.......................................................................................46
8.1.8.
Documentation of Study Drug..............................................................................47
8.1.9.
Documentation of Concomitant Medications........................................................47
8.1.10.
Documentation of Concurrent Medical Conditions...............................................47
8.1.11.
Procedures for Clinical Laboratory Samples.........................................................47
8.1.12.
Contraception and Pregnancy Avoidance Procedure.............................................48
8.1.13.
ECG Procedure....................................................................................................49
8.1.14.
Clinical Assessment of Suicidal Ideation and Behavior ........................................49
8.1.15.
Aberrant Behavior Checklist ................................................................................49
8.1.16.
Vineland Adaptive Behavior Scale.......................................................................50
8.1.17.
Quality of Life in Childhood Epilepsy..................................................................50
8.1.18.
Sleep Disruption Numerical Rating Scale.............................................................50
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Date: 11 February 2019 
Page 20 of 106
8.1.19.
Caregiver Global Impression of Change (Care GI-C) ...........................................50
8.1.20.
Clinician’s Clinical Global Impression of Severity and Change (CGI-S/C) ..........51
8.1.21.
Early Termination................................................................................................51
8.1.22.
Pharmacokinetic Sample Collection and Analysis ................................................51
8.1.22.1.
Collection of Plasma Samples for TAK-935 and M-I PK Evaluation.............51
8.1.22.2.
Bioanalytical Methods for TAK-935 and M-I ...............................................52
8.1.22.3.
Pharmacokinetic Parameters .........................................................................52
8.1.23.
Pharmacodynamic Sample Collection and Analysis .............................................52
8.1.23.1.
Collection of Plasma Samples for Pharmacodynamic Evaluation ..................52
8.1.23.2.
Bioanalytical Methods for 24HC...................................................................53
8.1.23.3.
Pharmacodynamic Parameters.......................................................................53
8.1.23.4.
Documentation of Screen Failure ..................................................................53
8.1.23.5.
Documentation of Study Entrance.................................................................53
8.2.
Sample Collection and Testing....................................................................................54
8.2.1.
Optional Blood Samples for Storage: Potential Exploratory Research ..................54
8.3.
Safety Evaluations ......................................................................................................54
8.3.1.
Adverse Events....................................................................................................54
8.3.1.1.
Severity Assessment .....................................................................................56
8.3.1.2.
Causality Assessment....................................................................................56
8.3.1.3.
Serious Adverse Events ................................................................................56
8.3.1.4.
Suspected Unexpected Serious Adverse Reactions........................................57
8.3.1.5.
Reporting Adverse Events.............................................................................58
8.3.1.6.
Sponsor Reporting Requirements..................................................................58
8.3.1.7.
Investigator Reporting Requirements ............................................................58
8.3.2.
Exposure During Pregnancy and/or Lactation ......................................................59
8.3.3.
Safety Monitoring................................................................................................59
8.3.3.1.
Reporting of Abnormal Liver Function Tests................................................59
8.4.
Appropriateness of Measurements...............................................................................60
9.
DATA QUALITY ASSURANCE......................................................................................61
9.1.
Data Collection and Storage........................................................................................61
10. STATISTICAL METHODS AND PLANNED ANALYSES.............................................63
10.1.
General Considerations............................................................................................63
10.2.
Stratification by Seizure Type..................................................................................63
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Date: 11 February 2019 
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10.3.
Determination of Sample Size .................................................................................63
10.4.
Analysis Sets...........................................................................................................64
10.4.1.
Modified Intent-to-Treat Analysis Set ..................................................................64
10.4.2.
Efficacy Analysis Set...........................................................................................64
10.4.3.
Safety Analysis Set ..............................................................................................65
10.5.
Demographics and Baseline Characteristics.............................................................65
10.6.
Patient Disposition ..................................................................................................65
10.7.
Concomitant Medications and Non-Pharmacologic Therapies and Procedures.........65
10.8.
Treatment Compliance.............................................................................................65
10.9.
Efficacy Analyses....................................................................................................66
10.9.1.
Primary Efficacy Analyses...................................................................................66
10.9.2.
Secondary Efficacy Analyses...............................................................................66
10.9.3.
Exploratory Analysis............................................................................................67
10.10.
Safety Analyses.......................................................................................................67
10.10.1.
Physical Examination, Vital Signs, and Other Physical Findings ......................67
10.10.2.
Clinical Laboratory Tests .................................................................................68
10.10.3.
Adverse Events.................................................................................................68
10.11.
Pharmacokinetic/Pharmacodynamic Analyses .........................................................68
10.12.
Other Statistical Issues.............................................................................................68
10.12.1.
Significance Levels ..........................................................................................68
10.12.2.
Missing or Invalid Data ....................................................................................68
10.13.
Interim Analyses .....................................................................................................69
11. INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ................................................................................................................70
11.1.
Informed Consent....................................................................................................70
11.2.
Data Monitoring Committee....................................................................................70
11.3.
Ethical Review ........................................................................................................70
11.4.
Regulatory Considerations.......................................................................................71
11.4.1.
Confidentiality.....................................................................................................71
11.4.2.
Investigator Information.......................................................................................72
11.4.3.
Protocol Signatures..............................................................................................72
11.4.4.
Final Report Signature .........................................................................................72
11.5.
Publication Policy....................................................................................................72
12. LIST OF REFERENCES...................................................................................................73
Appendix 1. Schedule of Assessments.....................................................................................75
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 22 of 106
Appendix 2. STUDY TAK-935-2002 (OV935): CLINICAL LABORATORY TESTS............79
Appendix 3. STUDY TAK-935-2002 (OV935): SAMPLING SUMMARY.............................80
Appendix 4. STRONG CYP3A4 INDUCERS AND INHIBITORS .........................................81
Appendix 5. OVERVIEW OF MAJOR CHANGES IMPLEMENTED BY AMENDMENTs..82
LIST OF TABLES
Table 1
Dosing Schedule by Weight ......................................................................................41
Table 2
Within-Stratum Sample Size Calculations.................................................................64
Table 3
Schedule of Assessments ..........................................................................................76
LIST OF FIGURES
Figure 1: Study Design for Clinical Protocol OV/TAK-935-2002 (OV935)..............................32
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 23 of 106
2.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
24HC
24S-hydroxycholesterol
AED
antiepileptic drugs
APP/PS-1 dTg
amyloid precursor protein and presenilin-1 double transgenic
AUC
area under the plasma concentration-time curve
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
AUC24,ss
area under the plasma concentration-time curve from time 0 to 24 hours at steady state
AUCτ
area under the plasma concentration-time curve during a dosing interval
BID
twice daily
CGI-S/C
Clinician’s Clinical Global Impression of Severity and Change
Care GI-C
Caregiver Global Impression of Change
CH24H
cholesterol 24S hydroxylase
Cmax
maximum observed plasma concentration
Cmax.ss
maximum observed plasma concentration during a dosing interval, at steady state
CNS
central nervous system
C-SSRS
Columbia–Suicide Severity Rating Scale
CYP
cytochrome P-450
DEE
developmental and epileptic encephalopathy
DRF
dose range–finding
DS
Dravet syndrome
ED50
median effective dose
EE
epileptic encephalopathy
EEG
Electroencephalogram
EO
enzyme occupancy
FDA
Food and Drug Administration
GABA
γ-amino butyric acid
GABAA
γ-amino butyric acid subunit A
HIE
hypoxic-ischemic-encephalopathy
I
steady state total Cmax at the highest dose of the inhibitor
IB
Investigator’s Brochure.
IC50
50% inhibitory concentration
iDMC
independent Data Monitoring Committee
ILAE
International League Against Epilepsy
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Term
Definition
IND
Investigational New Drug
IS
infantile spasms
KCl
potassium chloride
KO
Knockout
LGS
Lennox-Gastaut syndrome
M-I
N-oxide metabolite of TAK-935
NMDA
N-methyl-D-aspartate
OLE
open-label extension
PET
positron emission tomography
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PO
Oral
QD
once daily
SRS
spontaneous recurrent seizures
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of Cmax
TMEV
Theiler’s murine encephalomyelitis virus
TSC
tuberous sclerosis complex
UGT
uridine diphosphate glucuronosyltransferase
VNS
vagal nerve stimulator
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3.
INTRODUCTION
3.1.
Background
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of TAK-935 may be found in the current edition of the Investigator’s 
Brochure (IB).
3.2.
Study Rationale
Epileptic encephalopathies (EE) are a group of rare disorders in which the unremitting epileptic 
activity contributes to severe cognitive and behavioral impairment and these can worsen 
overtime leading to progressive cerebral dysfunction.4 Epileptic encephalopathies start at an early 
age and manifest with seizures, which are usually intractable, have aggressive 
electroencephalogram (EEG) paroxysmal abnormalities, and severe neurocognitive deficits. 
Potential to halt or improve the neurocognitive consequences of epilepsy with a successful 
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treatment is a fundamental concept behind clustering of these disorders. In a group of severe 
genetic disorders causing EE, the underlying genetic mutation also contributes to developmental 
delay, in addition to severe epilepsy in these patients. Hence, the International League Against
Epilepsy (ILAE) expanded the concept of EE from the severe epilepsies with onset in infancy 
and childhood to epilepsy syndromes associated with encephalopathy including those that have a 
genetic etiology.5 The revised classification now refers to DEEs. Dravet syndrome (DS) or severe 
myoclonic epilepsy in infancy is one of the most well-known disorders of the epileptic 
encephalopathies. Clinically, DS is characterized by frequent convulsive febrile seizures, 
followed later by nonfebrile seizures, mainly clonic and unilateral, of long duration and frequent 
status epilepticus (SE). Lennox Gastaut syndrome (LGS) is rare and is one of the most severe 
forms of childhood epilepsy. The syndrome usually has its onset between the ages of 1 and 
8 years (typically between 3 and 5 years), but occasionally it occurs in children who are more 
than 8 years old, even into adulthood. The hallmarks of the disease include: presence of multiple 
seizure types: the hallmark tonic-atonic seizures; the most hazardous are drop seizures/attacks, 
which can lead to serious injuries and occur in about 56% of patients. Other seizure types include 
atypical absences, but tonic-clonic, myoclonic, and partial seizures are also frequently present.
The current study is designed to further characterize the effects of TAK-935 on seizure 
frequency using a seizure diary. An additional aim is to explore the safety, tolerability, PK, and 
PD of multiple-dose TAK-935 administration in pediatric patients with developmental and/or 
epileptic encephalopathies.
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4.
STUDY OBJECTIVES AND ENDPOINTS
Study objectives and associated endpoints are presented in Section 4.1 and Section 4.2, 
respectively; the frequency and timing of study measurements is provided in the Schedule of 
Assessments (Table 3). Information regarding sample collection and safety data collection are 
presented in Section 8.
4.1.
Objectives
4.1.1.
Primary Objective
The primary objective of this study is to investigate the effect on the frequency of all seizures 
(convulsive and drop) in patients treated with TAK-935 as an adjunctive therapy compared to 
placebo in the Maintenance Period.
4.1.2.
Secondary Objectives

To investigate the effect on the frequency of all seizures (convulsive and drop) in 
patients treated with TAK-935 as an adjunctive therapy compared to placebo 
throughout the Treatment Period

To investigate the effect on the frequency of convulsive seizure in patients with 
Dravet Syndrome treated with TAK-935 as an adjunctive therapy compared to 
placebo in the Maintenance Period

To investigate the effect on the frequency of drop seizure in patients with LGS treated 
with TAK-935 as an adjunctive therapy compared to placebo in the Maintenance
Period

To investigate the seizure frequency of LGS patients considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with:

Worsening of 25% or more in drop seizures from baseline

Worsening of 1% to 25% in drop seizures from baseline

No change in drop seizures from baseline (Worsening of 1% to Reduction of 1%)

Reduction of 25% or more in drop seizures from baseline

Reduction of 50% or more in drop seizures from baseline

Reduction of 75% or more in drop seizures from baseline

Reduction of 100% in drop seizures from baseline

To investigate the seizure frequency of Dravet patients considered treatment 
responders throughout the Maintenance Period; treatment responders are defined as 
those with:

Worsening of 25% or more in convulsive seizures from baseline

Worsening of 1% to 25% in convulsive seizures from baseline
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∀
No change in convulsive seizures from baseline (Worsening of 1% to Reduction 
of 1%)
∀
Reduction of 25% or more in convulsive seizures from baseline
∀
Reduction of 50% or more in convulsive seizures from baseline
∀
Reduction of 75% or more in convulsive seizures from baseline
∀
Reduction of 100% in convulsive seizures from baseline
!
To investigate the change in Clinical Global Impression of Severity and Change 
assessment (CGI-S/C) responses of Investigator and Caregiver Clinical Global 
Impression of Change (Care GI-C) in patients treated with TAK-935 as an adjunctive 
therapy compared to placebo
!
To characterize the relationship between plasma 24HC levels and seizure frequency
4.1.3.
Exploratory Objectives
4.1.4.
Safety Objectives
!
To evaluate safety and tolerability of TAK-935 as adjunctive therapy as compared to 
placebo
!
To investigate the effect on behavior and adaptive function in patients treated with 
TAK-935 as adjunctive therapy compared to placebo using the Vineland Adaptive 
Behavioral scales (VABS) and Aberrant Behavior Checklist-Community 
questionnaire (ABC-C)
!
To evaluate the occurrence of myoclonic and atypical absence-free days to determine 
if there is worsening of these seizure types during treatment with TAK-935
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4.2.
Endpoints
4.2.1.
Primary Endpoint
The primary endpoint for this study is the percent change from Baseline in seizure frequency per
28 days (based only on convulsive seizures for the patients in the Dravet syndrome stratum and 
drop seizures for the patients in the LGS stratum) in patients receiving TAK-935 as compared to 
placebo during the Maintenance Period.
4.2.2.
Secondary Efficacy Endpoints

Percent change from Baseline in seizure frequency per 28 days (based only on 
convulsive seizures for the patients in the Dravet syndrome stratum and drop seizures 
for the patients in the LGS stratum) in patients receiving TAK-935 as compared to 
placebo during the Treatment Period

Percent change from Baseline in convulsive seizure frequency per 28 days in patients 
randomized to the Dravet syndrome stratum and receiving TAK-935 as compared to 
placebo during the Maintenance Period

Percent change from Baseline in drop seizure frequency per 28 days in patients 
randomized to the LGS stratum and receiving TAK-935 as compared to placebo 
during the Maintenance Period

Proportion of patients in the LGS stratum considered treatment responders throughout 
the Maintenance Period; treatment responders defined as those with: 
-
Worsening of 25% or more in drop seizures from baseline
-
Worsening of 1% to 25% in drop seizures from baseline
-
No change in drop seizures from baseline (Worsening of 1% to Reduction of 1%)
-
Reduction of 25% or more in drop seizures from baseline
-
Reduction of 50% or more in drop seizures from baseline
-
Reduction of 75% or more in drop seizures from baseline
-
Reduction of 100% in drop seizures from baseline

Proportion of patients in the Dravet syndrome stratum considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with: 
-
Worsening of 25% or more in convulsive seizures from baseline
-
Worsening of 1% to 25% in convulsive seizures from baseline
-
No change in convulsive seizures from baseline (Worsening of 1% to Reduction 
of 1%)
-
Reduction of 25% or more in convulsive seizures from baseline
-
Reduction of 50% or more in convulsive seizures from baseline
-
Reduction of 75% or more in convulsive seizures from baseline
-
Reduction of 100% in convulsive seizures from baseline

Change in CGI-S/C responses of Investigator reported impression of efficacy and 
tolerability of study drug
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!
Change in Care GI-C responses of parent/family reported impression of efficacy and 
tolerability of study drug
!
To characterize plasma 24HC levels and change in seizure frequency in patients 
treated with TAK-935 as an adjunctive therapy
4.2.4.
Pharmacokinetic Endpoints
!
To determine the plasma concentrations of TAK-935 and the TAK-935 metabolite 
(M-I) at multiple time points
!
Estimate exposure parameters from sparse PK samples using population modelling 
!
Determine any potential relationship with estimated TAK-935 exposure parameters 
with changes in seizure frequency 
4.2.5.
Safety Endpoints
!
Incidence of treatment-emergent adverse events (TEAEs)
!
Change in behavioral and adaptive functional measures using the VABS
!
Change in behavior measures using total scores and subscale scores of ABC-C for 
patients ≥6 years of age
!
Incidence of abnormal values for clinical laboratory evaluations, vital signs, body 
weight and height, and electrocardiogram (ECG) parameters after TAK-935 treatment
!
Change from Baseline in clinical laboratory evaluations, vital signs, body weight, 
Columbia–Suicide Severity Rating Scale (C-SSRS), and ECG parameter values after 
TAK-935 treatment
!
Mean percent of myoclonic- and atypical-absence free days in patients receiving
TAK-935 as compared to placebo during the Maintenance Period
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5.
INVESTIGATIONAL PLAN
5.1.
Summary of Study Design
Study TAK-935-2002 (OV935) is a Phase 2, multicenter, randomized, double-blind, placebo-
controlled, parallel-group, study in pediatric patients (aged ≥2 and ≤17 years) with Dravet 
syndrome and LGS demonstrating ≥3 convulsive or ≥4 drop seizures, respectively, per month 
during the 3 months immediately prior to Screening (based on historical information) and 
≥3 convulsive or ≥4 drop seizures, respectively, during a minimum of 4 weeks during the 
prospective Baseline Period (based on the seizure diary records). Convulsive seizures include 
generalized tonic-clonic, focal to bilateral tonic-clonic with impaired awareness, hemi-clonic and 
simultaneous bilateral clonic (generalized clonic) seizures. Drop seizures are defined as 
involving the entire body, trunk, or head that leads to a fall, injury, slumping in a chair, or head 
hitting a surface, or that could have led to a fall or injury, depending on the position of the 
patient at the time of the seizure or spell. Examples of seizures causing drop include, but are not 
limited to, atonic, clonic, and tonic seizures.
Approximately 126 patients will be randomized to ensure 112 evaluable patients. Randomization 
will be stratified by 2 categories: Dravet syndrome patients with convulsive seizures and LGS 
patients with drop seizures. Stratification will be performed to ensure balance of treatments 
within each stratum.
The study will begin with a phased enrollment based on age. Patients aged ≥9 years will be 
enrolled first, prior to open enrollment in the study, for assessment of safety. The independent 
Data Monitoring Committee (iDMC) will review the adverse event (AE) profiles of the first
12 patients aged ≥9 years completing 4 weeks of treatment across all ongoing pediatric TAK-935 
studies, prior to recommending treatment for patients aged <9 years.
This study consists of 2 main periods:

4- to 6-week Screening/Baseline Period

20-week Treatment Period
-
8-week Dose Optimization Period
-
12-week Maintenance Period
The Treatment Period consists of the Dose Optimization Period and Maintenance Period. 
Figure 1 illustrates the study design.
Dravet syndrome patients who have had, on average, ≥3 convulsive or LGS patients who have 
had on average ≥4 drop seizures per month during the 3 months immediately prior to Screening 
(based on historical information) and ≥3 convulsive or ≥4 drop seizures, respectively, during a 
minimum of 4 weeks during the Baseline Period (based on the seizure diary records) will be 
eligible for entry into the study.
At the end of the prospective 4- to 6-week Screening/Baseline Period, patients will return to the 
clinic (Visit 2). Seizure diaries will be reviewed by the Medical Monitor or delegated staff and if 
a patient did not meet the eligibility criteria, including minimum number of seizures required for 
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the study and seizure stratum, the patient will be discontinued from the study and considered a 
screen failure.
Figure 1:
Study Design for Clinical Protocol OV/TAK-935-2002 (OV935)
Patients and/or patients’ caregivers will be provided with a seizure diary and will be instructed to 
record seizure data daily starting at Visit 1 (screening visit) and to continue throughout the study. 
The seizure diary data will be collected during the prospective Baseline Period and will be used 
as the baseline seizure data for endpoint analyses. An external independent or Sponsor’s 
reviewer(s) will confirm the patient’s diagnosis prior to randomization.
Patients who cannot tolerate Dose 1 will be withdrawn from the study.
5.1.1.
End of Study Definition
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient ongoing in the study.
5.1.2.
Study Extension
Following completion of the study, patients will have the option to enroll in a long-term,
open-label extension (OLE) study (under a separate protocol, TAK-935-18-001 [OV935]). 
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5.2.
Selection and Timing of Doses in the Study
Preclinical data from rodent epilepsy models suggest potentially efficacious exposures, and 
safety data from nonclinical studies were used to determine exposure-based safety margins. 
Clinical safety and tolerability data from single- and multiple-dose Phase 1 studies in adult 
healthy volunteers were used to perform PK, PD, and enzyme occupancy (EO) analyses with 
allometric scaling to determine an appropriate dose of TAK-935 for pediatric patients.
5.2.1.
Modeling and Simulation of Clinical Data
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6.
STUDY POPULATION
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened. Refer to Section 8.1.23.4 for additional information on recording screen failures.
Individuals may be re-screened up to 2 times, after consultation with the Medical Monitor. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all the following criteria and 
none of the exclusion criteria:
1. The patient and patient’s legal representative (i.e., parent or legal guardian) are willing 
and able to read, understand, and sign the informed consent form and assent, if applicable
2. Male and female patients aged ≥2 and ≤17 years at the time of informed consent and the
first dose of study drug
3. Clinical diagnosis of LGS and a history of, on average, ≥4 drop seizures per month 
during the 3 months immediately prior to Screening based on historical information, and 
the patient has ≥4 drop seizures during a minimum of 4 weeks of seizure data collection 
during the prospective Baseline Period
- OR -
Clinical diagnosis of Dravet syndrome and a history of, on average, ≥3 convulsive 
seizures per month during the past 3 months based on the historical information, and the 
patient has ≥3 convulsive seizures during a minimum of 4 weeks of seizure data 
collection during the prospective Baseline Period
4. Weight of ≥10 kg at the Screening visit (Visit 1)
5. Currently taking 1 to 4 AEDs at a stable dose for 4 weeks prior to the Screening visit
(Visit 1); benzodiazepines used chronically (on daily frequency) to treat seizures are 
considered AEDs
6. If using a vagal nerve stimulator (VNS), must have VNS placed at least 3 months prior to 
the Screening visit with stable settings for >1 month; VNS parameters must remain 
constant throughout the study (VNS will not be counted as an AED)
7. If on a ketogenic diet, must have started the ketogenic diet at least 3 months prior to the 
Screening visit (Visit 1), diet should be stable for 4 weeks before the Screening visit 
(Visit 1); and should continue through the duration of the study (ketogenic diet will not 
be counted as an AED)
8. Failed to become and remain seizure free with trials of at least 2 AEDs
9. The patient and patient’s legal representative (i.e., parent or legal guardian) are willing to 
keep the AED, VNS, and ketogenic diet regimen(s) stable throughout the study
10. The patient is able to carry out all appropriate assessments and take study drug in the 
opinion of the Investigator and parent/caregiver
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11. The patient has a documented clinical diagnosis of Dravet syndrome or LGS:
Diagnosis of Dravet syndrome supported by:

Onset of seizures around 6 months of age

Initial seizures
-
Fever-induced or fever-triggered seizures
-
Hemiclonic or generalized tonic seizure
-
Prolonged seizures (approximately 15 minutes or longer, some >30 min)

Between 1 and 5 years, other seizure types emerge:
-
Myoclonic seizures
-
Focal awareness altered
-
Absence
-
Non-convulsive status (absence or myoclonic)
-
Convulsive status epilepticus

Development normal within 1st year of life, then intellectual disability emerges
-
May regress with recurrent status epilepticus
Diagnosis of Lennox-Gastaut syndrome supported by:

History of abnormal EEG consistent with LGS 
-
EEG with slow and/or disorganized background AND one of the following:
o
EEG with bursts of generalized 2.5 Hz (or less) spike and wave activity, -
- OR -
o
Generalized paroxysmal fast activity (GPFA)

Greater than 1 type of generalized seizure for at least 6 months
-
At least one seizure type with drop seizures

Less than 11 years of age at the onset of LGS
-
Evidence of development delay or regression OR history of special education 
classed OR measured IQ <70
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12. Sexually active female patients of childbearing potential (defined as first menarche) must 
agree to use a highly effective method of birth control during the study and for 30 days
following the last dose of 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
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
Sexually active male patients (post-pubertal unless permanently sterilized by bilateral 
orchidectomy) must agree to use male contraception (condom) during the study and for a 
minimum of 90 days following the last dose of study drug. Male patients must also not
donate sperm during the Screening and Treatment Periods and for at least 90 days after 
the last dose of study drug.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
1. The patient has been admitted to a medical facility and intubated for treatment of status 
epilepticus 2 or more times in the 3 months immediately prior to the screening visit
2. Non-epileptic events that cannot be reliably distinguished from epileptic seizures
(e.g., gastroesophageal reflux, muscle cramps, etc.)
3. Patient with history of confirmed cataract (untreated with surgery)
4. Unstable, clinically significant neurologic (other than the disease being studied), 
psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, urologic, immunologic, hematopoietic, endocrine disease, malignancy 
including progressive tumors, or other abnormality, which may impact the ability to 
participate in the study or that may potentially confound the study results. It is the 
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responsibility of the Investigator to assess the clinical significance; however, consultation 
with the Medical Monitor may be warranted
5. Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), within the 2 years 
immediately prior to the Screening Visit (Visit 1)
6. Suicide attempt within the last year, at significant risk of suicide (either in the opinion of 
the Investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the Columbia-
Suicide Severity Rating Scale [C-SSRS] at Screening) or appearing suicidal per 
Investigator judgment
7. History of human immunodeficiency virus (HIV) infection (patient who has tested 
positive for human immunodeficiency virus antibodies (HIV)-1/2Ab), or history of active 
hepatitis B, or active hepatitis C infection. (Note that patients who have been vaccinated 
against hepatitis B [hepatitis B surface antibody {Ab}-positive] who are negative for 
other markers of prior hepatitis B infection [e.g., negative for hepatitis B Core Ab] are 
eligible)
8. Abnormal and clinically significant ECG abnormality at Screening:
a.
QT interval with Fridericia’s correction method (QTcF) >450 ms (males) or >470 ms 
(females), confirmed with 1 repeat testing, at the Screening visit
9. Abnormal clinical laboratory test results at the Screening visit that suggest a clinically 
significant underlying disease that would compromise the well-being of the patient (if the 
patient has alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]
>2.5 × the upper limit of normal [ULN], the Medical Monitor should be consulted)
10. Participated in a clinical study involving another study drug in the previous month (or
5 half-lives of the study drug, whichever is longer) or currently receiving another study 
drug
11. Received TAK-935 in a previous clinical study or as a therapeutic agent
12. Immediate family members, or in a dependent relationship with a study site employee 
who is involved in the conduct of this study (e.g., child, sibling)
13. Known hypersensitivity to any component of the TAK-935 formulation
14. Currently pregnant or breastfeeding or is planning to become pregnant within 90 days of 
the last dose of study drug
6.3.
Discontinuations
6.3.1.
Discontinuation of Patients
The criteria for enrollment must be followed explicitly. If the investigative site identifies a 
patient who did not meet enrollment criteria and who was inadvertently enrolled, the Sponsor 
must be notified immediately. If the Sponsor identifies a patient who did not meet enrollment 
criteria and who was inadvertently enrolled, the Investigator site will be notified immediately. A 
discussion must occur between the Sponsor and the Investigator to determine whether the patient 
may continue in the study, with or without study drug. Inadvertently enrolled patients may be 
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maintained in the study and on study drug when the Sponsor agrees with the Investigator that it
is medically appropriate for that patient. The patient may not continue in the study with or
without study drug if the Sponsor does not agree with the Investigator’s determination it is 
medically appropriate for the patient to continue. The Investigator must obtain documented 
approval from the Sponsor to allow the inadvertently enrolled patient to continue in the study 
with or without study drug.
In addition, patients will be discontinued from the study drug (and/or from the study) in the 
following circumstances:

Liver Function Test (LFT) Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow up 
(including repeat laboratory tests, until a patient’s laboratory profile has returned to 
normal/baseline status, see Section 8.1.11), if the following circumstances occur at 
any time during study drug treatment:
-
ALT or AST >8 × ULN, or
-
ALT or AST >5 × ULN and persists for >2 weeks, or
-
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
-
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

QTcF interval >500 ms that is confirmed with a repeat ECG
Study drug should be discontinued immediately with appropriate clinical follow up
(including repeat ECG)

Greater than a 100% increase in 28-day seizure frequency from the 4-week 
prospective Baseline Period (see formula in Section 8.1.7) and considered by the 
Investigator to be clinically significant worsening of the seizure frequency

Not tolerating Dose 1 (the lowest dose) for their weight category

Enrollment in any other clinical study involving a study drug or enrollment in any 
other type of medical research judged not to be scientifically or medically compatible 
with this study

Depression and/or Suicidal Ideation
-
Study staff trained in the administration of the C-SSRS will assess patient 
suicidality using the C-SSRS (see Section 8.1.14), eliciting answers from the 
patient or the patient’s caregiver. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the clinical judgment of the investigator
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Date: 11 February 2019 
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
Investigator Decision (Physician Decision)
-
The Investigator decides that the patient should be discontinued from the study
-
If the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Patient Decision (Withdrawal by Patient or Withdrawal by Patient’s Legal 
Representative [Parent or Legal Guardian])
-
The patient or the patient’s legal representative (i.e., parent or legal guardian)
requests to be withdrawn from the study

Sponsor Decision
-
The Sponsor or its designee discontinues the study or discontinues the patient’s 
participation in the study for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP)
-
The Sponsor or its designee stops the clinical study at a particular site

Adverse Event
-
If the Investigator decides that the patient should be withdrawn because of an 
SAE or a clinically significant laboratory value, the study drug is to be 
discontinued and appropriate measures are to be taken. The Sponsor or its 
designee is to be alerted immediately (refer to Section 8.3)
Patients who discontinue the study drug and/or study early will have early termination 
procedures performed as shown in the Schedule of Assessments (Table 3).
6.3.2.
Discontinuation of Study Sites/Site Terminated by Sponsor
Study site participation may be discontinued if the Sponsor or its designee, the Investigator, or 
the institutional review board/independent ethics committee (IRB/IEC) of the study site judges it 
necessary for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP.
6.3.3.
Discontinuation of the Study/Study Terminated by Sponsor
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
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7.
TREATMENT
7.1.
Materials and Supplies
The Sponsor will supply the study sites with TAK-935 100 mg tablets/20 mg mini-tablets and 
matching placebo tablets. TAK-935 tablets/mini-tablets and matching placebo tablets are 
manufactured by SPERA Pharma Inc. (Osaka, Japan) previously named as Takeda 
Pharmaceutical Co. Ltd. Each bottle will contain a label that includes pertinent study information 
and caution statements.
Clinical study materials will be labeled according to the country’s regulatory requirements.
If a patient is unable to come for a clinic visit to obtain study drug, the study drug will be 
shipped via a courier service.
7.1.1.
Storage
7.2.
Treatments Administered
All patients will receive TAK-935 BID orally or via gastrostomy tube (G-tube)/percutaneous 
endoscopic gastrostomy (PEG) tube with or without food (patients enrolled in clinical sites in 
China are not to receive study drug via G-tube/PEG tube).
For patients weighing <60 kg at Visit 1, the total daily dose of study drug (either placebo or 
TAK-935) is calculated based on body weight at Visit 1 and will be given twice a day (BID). 
The selected doses for the different weight groups are listed in Table 1. For patients weighing 
≥60 kg at Visit 1, dosing will be 200 mg/day followed by 400 mg/day, then 600 mg/day (Table
1). Study drug can be taken with or without food.
Patients weighing <60 kg will be dispensed 20 mg mini-tablets or matching placebo, and patients 
weighing ≥60 kg will be dispensed 100 mg tablets or matching placebo. If patients are unable to 
swallow tablets or mini-tablets, formulation can be changed. No change in formulations will be 
made after Visit 4 (Day 36).
Patients will receive the initial dose of study drug, Dose 1, for the first 7 days after
randomization at Visit 2. In the subsequent phone call and visit (phone call 1 [Day 8] and Visit 3 
[Day 15]), the study drug dose will be increased to Dose 2 and Dose 3. The maximum dose for 
any patient will be 600 mg/day. Patients will be contacted by phone within first 2 days following 
escalation to the maximum dose to assess safety and tolerability of the study drug. Study drug 
dose will be allowed to change in first 6 weeks of the Dose Optimization Period based on the 
judgment of the Investigator and with the approval of the Medical Monitor. The final dose level 
will be maintained until the end of the Maintenance Period; however, the dose may be decreased 
to the previous lower doses, for safety and tolerability issues. For example, Dose 3 may be 
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Date: 11 February 2019 
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reduced to Dose 2 and Dose 2 may be reduced to Dose 1 during Maintenance Period. If Dose 1 is 
not tolerated, the patient will be withdrawn from the study.
The dose may be increased per Investigator’s discretion with approval of the Sponsor’s Medical 
Monitor to a maximum of Dose 3 level. All dose changes must be made during the Dose
Optimization Period; dose changes during the Maintenance Period must be discussed and 
approved by the Sponsor.
Table 1
Dosing Schedule by Weight
Weight (kg)
Dose 1
Dose 2
Dose 3
(mg/day)a
No. Tablets/ 
Mini-tablets
(mg/day)a
No. Tablets/ 
Mini-tablets
(mg/day)a
No. Tablets/ 
Mini-tablets
10-14
80
0/4
160
0/8
220
0/11
15-19
120
0/6
200
0/10
260
0/13
20-24
120
0/6
240
0/12
320
0/16
25-29
120
0/6
240
0/12
360
0/18
30-34
160
0/8
280
0/14
400
0/20
35-39
160
0/8
280
0/14
440
0/22
40-44
160
0/8
320
0/16
480
0/24
45-49
200
0/10
360
0/18
480
0/24
50-54
200
0/10
360
0/18
520
0/26
55-59
200
0/10
360
0/18
560
0/28
≥60
200
2/0
400
4/0
600
6/0
a Total dose administered twice daily.
Two days after each dose titration or taper, patients will be contacted by phone to monitor study 
drug compliance, concomitant medication use, and AEs. Any change in dose will be documented 
in the patient’s clinic chart and dosing card. On Days 22, 57, and 113, patients will be contacted 
by phone to monitor compliance with study drug and seizure diary and to monitor AEs.
Tablets/mini-tablets may be crushed and mixed well in applesauce or thick liquid, for taste 
masking, prior to dosing. The amount of applesauce or liquid needed is dependent upon the 
number of tablets/mini-tablets the patient is taking. One-half teaspoon or 2.5 mL of applesauce 
or thick liquid is needed for each mini-tablet taken and 2 teaspoons or 10 mL is needed for each 
tablet taken.
For patients receiving study drug via G-tube/PEG tube, study drug will be crushed, suspended in 
water, and the suspension will be administered via the G-tube/PEG tube using a syringe.
Complete instructions will be provided to patients/caregivers in a document provided outside of 
the protocol. Other medications or enteral feeds should not be given concurrently with TAK-935. 
Patients enrolled in clinical sites in China are not to receive study drug via G-tube/PEG tube.
If a patient misses a dose, the missed dose should be skipped, and the patient should continue 
with his/her normal dosing schedule. Skipped doses should be reported as missed doses.
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Following completion of the study, patients will have the option to enroll in an OLE study (under 
a separate protocol; see Section 5.1) or to enter a double- blind taper period (maximum 14 days). 
During the taper period, the study drug dose will be de-escalated to a lower dose (taper Dose 3 to 
Dose 2, taper Dose 2 to Dose 1) every 3 days or less frequently based on Investigator’s discretion 
until there is no de-escalation and study drug dose is discontinued. After tapering, patients will 
complete a Safety Follow-up visit approximately 15 days after the last dose of study drug and 
exit the study.
The Investigator or his/her designee is responsible for the following:

Explaining the correct use of the investigational agent(s) to the patient/site 
personnel/legal representative

Verifying that instructions are followed properly

Maintaining accurate records of study drug dispensing and accountability

Returning or destroying all unused medication to the Sponsor or its designee at the 
end of the study
Patients or the patient’s legal representative (i.e., parent or legal guardian) will be instructed to 
contact the Investigator as soon as possible if he or she has a complaint or problem with the 
study drug so that the situation can be assessed.
All clinical trial material provided to the Investigator will be stored in a secure and locked place 
and allocated and dispensed by the interactive web-response system (IWRS). The allocation and 
dispensing of the study drugs will be fully documented. Detailed records of the amounts of the 
study drug received, dispensed, and remaining at the end of the study will be maintained.
TAK-935 or placebo tablets/mini-tablets should be administered at approximately the same times 
on each day. The actual time of all dose administrations prior to PK sample collection will be 
recorded in the patient’s source documents and transcribed into electronic case report form 
(eCRFs).
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2. Assignment to treatment groups will be determined by a computer-generated random 
sequence using an IWRS. The IWRS will be used to assign tablets/mini-tablets containing 
double-blind study drug to each patient.
To achieve between-group comparability, randomization will be stratified.
At Visit 2, all eligible patients will be stratified by 2 categories: patients with Dravet syndrome 
with convulsive seizures, and LGS patients with drop seizures to ensure balance of treatments 
within each stratum.
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Note that patients with the minimum number of convulsive or drop seizures will be assigned to a 
stratum following these stratification rules:
Patients with Dravet syndrome:
!
46 eligible patients diagnosed with Dravet syndrome with ≥3 convulsive seizures per
28 days during the prospective Baseline Period will be randomized into the Dravet 
syndrome stratum
Patients with LGS (Lennox Gastaut Syndrome):
!
80 eligible patients diagnosed with LGS with ≥4 drop seizures per 28 days during the 
prospective Baseline period will be randomized into the LGS stratum
If a patient does not meet any of these, the patient will be considered a screen failure.
7.4.
Continued Access to Study drug
7.5.
Blinding
This is a double-blind study.
Emergency unblinding for AEs may be performed through an IWRS. This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.
All calls resulting in an unblinding event are recorded and reported by the IWRS.
If an Investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study. In cases where there are ethical reasons to have the patient 
remain in the study, the Investigator must obtain specific approval from the Sponsor Medical 
Monitor for the patient to continue in the study.
Unblinding should only be considered for the safety of the patient. If unblinding is deemed 
necessary by the Investigator, the Investigator can unblind the patient’s treatment allocation 
using IWRS. The Investigator must note the date, time, and reason for unblinding.
The Investigator should inform the Sponsor that the patient was unblinded, however they are not 
required to reveal to the Sponsor the patient’s treatment allocation.
When an AE is an unexpected related SAE, the blind will be broken by the Sponsor only for that 
specific patient. The blind will be maintained for persons responsible for the ongoing conduct of 
the study (such as the monitors, Investigators, etc.) and those responsible for data analysis and 
interpretation of results at the conclusion of the study, such as biometrics personnel. Unblinded 
information will only be accessible to those who need to be involved in the safety reporting to 
Health Authorities, Ethics Committees, and/or IRBs.
Investigators will receive only blinded information unless unblinded information is judged 
necessary for safety reasons.
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7.6.
Concomitant Medications and Non-Pharmacologic Therapies and
Procedures
Adjunctive antiepileptic drug (AED) treatment, (medical) marijuana, cannabidiol products, VNS 
settings, and ketogenic diet should not be altered during the study. Concurrent treatment regimen 
data will be collected throughout the study.
All medication including vitamin supplements, over-the-counter medications, and herbal 
preparations including (medical) marijuana and cannabidiol products will be collected 
throughout the study.
Use of perampanel from screening through follow-up is prohibited.
Use of traditional Chinese medicines should be approved by the Medical Monitor at screening.
7.7.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit. On in-clinic dosing days, 
after administration of study drug, appropriate mouth and/or hand checks will be performed to 
ensure that the dose is swallowed and noted in the source document. If a site visit is not possible 
during the morning hours, the patient should take their morning dose prior to attending the visit 
during the afternoon hours. The date and time of dose given in the clinic will be recorded in the 
source documents and on the eCRFs.
Patients and/or patients’ caregivers will be required to bring study drug/unused study drug and 
the daily recording in the dosing card to each dispensing site visit. All patients and/or patients’ 
caregivers should be re-instructed about the dosing requirements during study contacts. The 
authorized study personnel conducting the re-education must document the process in the patient 
source records.
Patients who are significantly noncompliant will be discontinued from the study. A patient will 
be considered significantly noncompliant if he or she intentionally misses more than 20% of 
study medication during the study. Similarly, a patient will be considered significantly 
noncompliant if he or she is judged by the Investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication.
CCI
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8.
STUDY ASSESSMENTS
The following sections describe the study procedures to be performed and data to be collected. 
For each procedure, patients are to be assessed by the same Investigator or site personnel 
whenever possible. Study procedures and their timing (including tolerance limits for timing) are 
summarized in the Schedule of Assessments (Appendix 1, Table 3).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 3 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
8.1.
Study Procedures
8.1.1.
Informed Consent Procedure
The requirements of the informed consent are described in Section 11.1.
8.1.1.1.
Study Informed Consent Procedure
Informed consent must be obtained before the patient enters into the study, and before any 
protocol-directed procedures are performed.
The informed consent form must be signed by the patient’s legally authorized representative. A 
verbal or written patient assent should be obtained from the patient, if applicable, in the event the 
patient is not capable of providing an informed consent. If the patient is not capable of providing 
an assent, the reason should be documented by the Investigator.
A unique patient identification (ID) number (patient number) will be assigned to each patient and 
will be used throughout the study.
8.1.2.
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include year of birth (as allowed per local 
regulations), gender, ethnicity, and race as described by the patient/caregiver. Height and weight 
will be collected at Screening (Visit 1).
Medical history to be obtained will include determining whether the patient has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and the efficacy or safety evaluations stopped at or within 28 days before signing of 
informed consent. AED history will be collected as part of the medication history information.
8.1.3.
Physical Examination Procedure
The physical examination will consist of the following body systems: (1) head, eyes, ears, nose, 
and throat; (2) cardiovascular system; (3) respiratory system; (4) gastrointestinal system; 
(5) dermatologic system; (6) extremities; (7) musculoskeletal system; (8) lymph nodes; 
(9) psychiatric status; and (10) other. All examinations are to be performed by the Investigator or 
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a qualified site staff member. The physical examination must be captured in the source document 
and eCRF.
8.1.4.
Neurological Examination Procedure
A separate neurological examination will be performed and collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, motor function, and 
sensation.
8.1.5.
Weight and Height
Weight and height are to be measured while the patient is wearing indoor clothing and with 
shoes off. If unable to obtain height or weight, data may be collected from other sources
(e.g., medical records or the patient’s caretaker). The Investigator must document in the source 
document the reason for not obtaining height or weight (e.g., the patient is in a wheelchair).
8.1.6.
Vital Signs Procedure
Vital signs to be measured are temperature, blood pressure, heart rate (beats per minute), and 
respiratory rate. 
Vital signs should be measured at the same time of day across visits, if possible. When vital 
signs are scheduled at the same time as blood draws, the blood draw will take priority and vital 
signs will be obtained within 15 minutes before or after the scheduled blood draw, if possible.
All vital signs data collected at study visits will be recorded on the source documents and in the 
eCRF.
8.1.7.
Seizure Diary Procedure
The seizure diary is an observer-reported clinical outcome assessment measure that captures the 
total number of motor seizures (i.e., drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, 
myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor 
features) by type, in accordance with the new seizure classification system.7 Patients and/or 
patients’ caregivers will be the observers and reporters in the current study. Patients and/or 
patients’ caregivers may record seizures throughout the day and must ensure that the daily diary 
assessment is completed each evening, even if no seizures occurred.
Drop seizures are defined as a seizure involving the entire body, trunk, or head that leads to a 
fall, injury, slumping in a chair, or head hitting the surface, or could have led to a fall or injury, 
depending on the position of the patient at the time of the attack or spell. Drop seizures will be 
counted separately for patients enrolled in LGS stratum (e.g., tonic seizures or generalized tonic 
clonic seizures leading to a drop will be captured as a drop). Convulsive seizures include 
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Date: 11 February 2019 
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generalized tonic-clonic, focal to bilateral tonic-clonic with impaired awareness, hemi-clonic and 
simultaneous bilateral clonic (generalized clonic) seizures.
At the Screening visit (Visit 1) and at every clinic visit, the patient and/or patient’s caregiver will 
be given a seizure diary and specific instructions to ensure compliance with the seizure 
recording. The seizure events will be recorded starting at the Screening/Baseline Period up until 
the Follow-up Visit. At each clinic visit, the diary will be collected and reviewed by the 
Investigator with the patient and/or patient’s caregiver for proper recording.
For the prospective Baseline Period, the seizure frequency will be calculated as
(# of seizures) / (# of days seizures were assessed) 28
Seizure frequency calculated through this method will be used to confirm the eligibility. 
8.1.8.
Documentation of Study Drug
A dosing card will be provided to the patient and/or caregiver at each clinic visit to record actual 
time of the last 2 dose administrations prior to PK sample collection, to record exact time of the 
last meal relative to dosing prior to PK or PD sample collection, and to record any changes in 
dosing regimen that may occur between visits and during the de-escalation period of the study; 
these will be recorded in the patient’s source documents and transcribed into electronic case 
report forms (eCRFs).
8.1.9.
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be
prescribed by a physician or obtained by the patient over the counter. Concomitant medication is 
not provided by the Sponsor. At each study visit, patients and/or caregivers will be asked
whether patients have taken any medication other than the study drug (used from signing of
informed consent through the end of the study), and all medication including vitamin 
supplements, over-the-counter medications, and herbal preparations, must be recorded in the 
source document and eCRF. Documentation will include generic medication name, dose, unit, 
frequency, route of administration, start and end dates, and reason for use.
AED treatment, VNS settings, and ketogenic diet should not be altered during the study.
8.1.10.
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. These include clinically significant laboratory, ECG, or 
physical examination abnormalities noted at Screening (Visit 1), according the judgment of the 
Investigator. The condition (i.e., diagnosis) should be described and recorded on the Medical 
History form.
8.1.11.
Procedures for Clinical Laboratory Samples
Blood and urine samples are to be collected at the time points stipulated in the Schedule of 
Assessments (Table 3). Samples will be collected in accordance with acceptable laboratory 
procedures. Details of these procedures and required safety monitoring will be given in the 
laboratory manual.
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The clinical laboratory tests to be performed are listed in Appendix 2.
For an individual patient, the maximum volume of blood collected over the course of the study 
will be 73.2 mL (Appendix 3). As this is a pediatric study, blood volume limitations will 
sometimes preclude the collection of all samples in a particular study visit. Appendix 3
enumerates the priorities for blood collection. 
In general, existing guidelines for blood sample volume limits (ranging from 1% to 5% of total 
blood volume within 24 hours and up to 10% of total blood volume over 8 weeks) are consistent 
with the limited evidence available on “minimal risk” to children. Examples of guidelines for 
blood draw limits in pediatrics can be found at: http://www.who.int/bulletin/volumes/89/1/BLT-
10-080010-table-T2.html.
The central laboratory will perform laboratory tests for hematology, serum chemistry, and 
urinalysis. The results of clinical laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. The Investigator will maintain a copy of the 
laboratory accreditation and the reference ranges for the laboratory used.
If patients experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed preferably 
within 48 to 72 hours and no later than 5 days after the abnormality was noted. Please refer to 
Section 6.3.1 for discontinuation criteria and Section 8.3.3.1 for reporting requirements related to 
ALT or AST >3×ULN in conjunction with total bilirubin >2×ULN.
If the ALT or AST remains elevated >3 × ULN on these 2 consecutive occasions, the 
Investigator must contact the Medical Monitor for consideration of additional testing, close 
monitoring, possible discontinuation of study drug, and discussion of the relevant patient details 
and possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 8.3.3.1 for reporting requirements).
If urine cannot be collected due to the patient’s cooperation or because the patient is wearing a 
diaper, the reason should be documented in the source document and, for sexually active female 
patients, the results of the serum pregnancy test obtained at Visit 1 must be confirmed to be 
negative by the Investigator prior to randomization.
8.1.12.
Contraception and Pregnancy Avoidance Procedure
Please refer to Section 6.1 for detailed contraception requirements.
Patients will be provided with information on acceptable methods of contraception as part of the 
patient informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study and for 90 days after the last dose of study drug. This may be 
signed by the legally authorized representative of the patient.
All sexually active female patients of childbearing potential must have a negative serum/urine 
hCG pregnancy test at Screening (Visit 1) and a negative urine hCG pregnancy test on Day 1 
(Visit 2), before receiving any dose of study drug. If urine 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 
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patient can receive the first dose of study drug. During the course of the study, patients 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/urine hCG pregnancy test will be 
performed at the Final Visit.
Sexually active male patients (post-pubertal unless permanently sterilized by bilateral 
orchidectomy) must agree to use male contraception (condom) during the study and for a 
minimum of 90 days following the last dose of study drug. Male patients must also not donate 
sperm during the Screening and Treatment Periods and for at least 90 days after the last dose of 
study drug.
8.1.13.
ECG Procedure
A 12-lead ECG will be recorded at Screening (Visit 1) and at 30 min (±10 min) after the morning 
dose at other visits. If the patient cannot tolerate being supine, a sitting ECG may be obtained. 
The Investigator (or a qualified observer at the study site) will interpret the ECG using 1 of the 
following categories: within normal limits, abnormal but not clinically significant, or abnormal 
and clinically significant. The interpretation of the ECG will be recorded in the source 
documents and in the eCRF. The time that the ECG was performed will be recorded. The
following parameters will be recorded on the eCRF from the patient’s ECG trace: heart rate, RR 
interval, PR interval, QT interval, QRS interval with QTcF, and corrected QT interval. ECG 
traces recorded on thermal paper will be photocopied to avoid degradation of trace over time.
8.1.14.
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed in children aged ≥6 years by the use of the 
C-SSRS. The C-SSRS is a 3-part scale that measures suicidal ideation (e.g., patient endorses 
thoughts about a wish to be dead or has other thoughts of suicide), intensity of ideation 
(frequency), and suicidal behavior (actually, interrupted, and aborted attempts at suicide).8
Two versions of the C-SSRS will be used in this study, the Screening/Baseline C-SSRS Lifetime 
and the Since-Last-Visit C-SSRS.
Study staff trained in the administration of the C-SSRS will assess patient suicidality using the 
C-SSRS, eliciting answers from the patient or the patient’s caregiver. Ultimately, the 
determination of the presence of suicidal ideation or behavior depends on the clinical judgment 
of the investigator.
If a patient exhibits signs of suicidal ideation, the patient may be discontinued as described in 
Section 6.3.1.
8.1.15.
Aberrant Behavior Checklist
Behavior will be assessed by the use of the ABC-C questionnaire, which is a rating scale that 
measures the severity of a range of problem behaviors commonly observed in individuals with 
intellectual and developmental disabilities.9 It is completed by the caregiver. It is an empirically 
developed scale designed to measure psychiatric symptoms and behavioral disturbance exhibited 
by individuals across 5 domains with 58 items: irritability, agitation, and crying (15 items); 
lethargy, social withdrawal (16 items); stereotypy (7 items); hyperactivity/noncompliance 
(16 items); and inappropriate speech (4 items).
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If the patient is unable to comply with the ABC-C, for example due to the language barrier 
(e.g., unavailability of validated test in patient’s language), the Investigator may also use clinical 
judgment to assess for behavior.
8.1.16.
Vineland Adaptive Behavior Scale
The Vineland Adaptive Behavior Scales, 3rd Edition, Parent Caregiver Form (VABS-3 Parent 
Caregiver Form), is a parent-report questionnaire of adaptive functioning or how an individual 
behaves in their day-to-day life at home and in the community.10 It assesses adaptive functioning 
across 4 domains: problem behavior, communication, daily living, and socialization. The 
questionnaire takes about 20 minutes to complete.
If the patient is unable to comply with the VABS, for example due to the language barrier 
(e.g., unavailability of validated test in patient’s language), the Investigator may also use clinical 
judgment to assess for adaptive function and behavior.
8.1.17.
Quality of Life in Childhood Epilepsy
The Quality of Life in Childhood Epilepsy is a parent-reported questionnaire that evaluates 
health related quality of life in children ages 4 to 18 years old. It contains 76 items with 
16 subscales covering 7 domains of life function: physical activities, social activities, cognition, 
emotional wellbeing, behavior, general health, and general quality of life.
8.1.18.
Sleep Disruption Numerical Rating Scale
The patient’s caregiver will be asked:
“On a scale of ‘0 to 10’, please circle the number that best describes your child’s sleep 
disruption in the last week.”
The markers range from 0 (slept extremely well) to 10 (unable to sleep at all). If the main 
caregiver is not available at the appropriate visit then this information can be captured over the 
telephone, ideally on the day of the visit or otherwise within 3 days.
8.1.19.
Caregiver Global Impression of Change (Care GI-C)
At Visit 2 (prior to administration of the first dose of study drug), the caregiver will be asked to 
write a brief description of the patient’s overall condition as a memory aid for the Care GI-C at 
subsequent visits.
The Care GI-C comprises the following question to be rated on a 7-point scale:
Since your child started treatment, please assess the status of your child’s overall condition
(comparing their condition now to their condition before treatment) using the scale below.

Very Much Improved

Much Improved

Slightly Improved

No Change

Slightly Worse
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!
Much Worse
!
Very Much Worse
If the main caregiver is not available at the appropriate visit then this information can be 
captured over the telephone, ideally on the day of the visit or otherwise within 3 days.
8.1.20.
Clinician’s Clinical Global Impression of Severity and Change (CGI-S/C)
CGI-Severity (CGI-S) is used to obtain an assessment of symptoms severity. The CGI-S focuses 
on clinicians’ observations of the patient’s cognitive, functional, and behavioral performance 
since the beginning of the study. The CGI-S/C measures improvement from the first assessment.
The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of 
responses from 1 (normal) through to 7 (amongst the most severely ill patients).
For the CGI-Change (CGI-C) treatment response ratings should take account of both therapeutic 
efficacy and treatment-related AEs and range from 0 (marked improvement and no side-effects) 
and 4 (unchanged or worse and side-effects outweigh the therapeutic effects). Each component 
of the CGI is rated separately; the instrument does not yield a global score.
The PI or designee will complete the CGI-S/C at the timepoints specified in Table 3.
8.1.21.
Early Termination
Early Termination/Exit survey will be conducted at Visit 6 and takes approximately 2 minutes. 
The survey captures the parent’s (and caregiver’s) experiences with TAK-935 including impact 
of treatment with TAK-935 on daily life/functioning and on most important bothersome 
symptoms.
8.1.22.
Pharmacokinetic Sample Collection and Analysis
8.1.22.1.
Collection of Plasma Samples for TAK-935 and M-I PK Evaluation
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8.1.22.2.
Bioanalytical Methods for TAK-935 and M-I
Plasma concentrations of TAK-935 and M-I will be measured by high-performance liquid 
chromatography with tandem mass spectrometry.
8.1.22.3.
Pharmacokinetic Parameters
8.1.23.
Pharmacodynamic Sample Collection and Analysis
8.1.23.1.
Collection of Plasma Samples for Pharmacodynamic Evaluation
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8.1.23.2.
Bioanalytical Methods for 24HC
8.1.23.3.
Pharmacodynamic Parameters
The PD parameter of change from Baseline in plasma 24HC levels will be summarized. 
Additional PD parameters may be calculated, as appropriate.
8.1.23.4.
Documentation of Screen Failure
Investigators must account for all patients with a signed informed consent. If the patient is found 
to be ineligible for the study at this visit, the Investigator will enter the reason in the IWRS. The 
IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is to be recorded in the IWRS. Patients may be re-screened 
after consultation with the Medical Monitor.
Patient ID numbers assigned to patients who fail screening should not be reused. If a patient fails 
screening, but is later successfully rescreened, the data for the patient will be entered as if these 
were 2 separate patients. Therefore, the data should be entered as follows:
1. The screen failure data should be entered as a screen failure patient.
2. Rescreened patients should be assigned a new patient ID number and treated as a 
stand-alone patient.
8.1.23.5.
Documentation of Study Entrance
Only patients who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the study.
If the patient is found to be not eligible, the Investigator should record the primary reason for 
failure on the applicable IWRS.
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8.2.
Sample Collection and Testing
Appendix 1 lists the schedule for sample collections in this study. 
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 3 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
8.2.1.
Optional Blood Samples for Storage: 
Samples for research purposes are optional and will be collected as specified in the Schedule of 
Assessments (Table 3). 
The optional blood samples will be coded with the patient number and stored for up to a 
maximum 15 years after the last patient visit for the study at a facility selected by the sponsor. 
The samples and any data generated from them can only be linked back to the patient by the 
Investigator or site personnel. The duration allows the sponsor to respond to regulatory requests 
related to the study drug.
Samples will be destroyed according to a process consistent with local regulation. Patients may 
request to have their samples destroyed at any time.
8.3.
Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or designee to any event that seems unusual, even if this event may 
be considered an unanticipated benefit to the patient.
The Investigator is responsible for the appropriate medical care of patients during the study. The 
Investigator remains responsible for following, through an appropriate health care option, AEs 
that are serious, considered related to the study treatment or the study, or that caused the patient 
to discontinue before completing the study. The patient should be followed until the event is 
resolved or explained. Frequency of follow-up evaluation is left to the discretion of the 
Investigator.
8.3.1.
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical study patient administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (for example, an abnormal 
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laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related to this medicinal product.
The definition of an AE also covers medication errors and uses outside what is foreseen in the 
protocol only if an AE results from the error, including intentional misuse, abuse, and overdose 
of the product. Adverse events (including SAEs) associated with overdose should be reported 
according to the procedure outlined in Section 8.3.1.5. In the event of drug overdose, the patient 
should be treated symptomatically.
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) and anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not worsen are not AEs.
Ovid has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to study drug are to be 
reported. Data on fetal outcome and breast-feeding are collected for regulatory reporting and 
drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s pre-existing 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
Seizures in this patient population will be measured using the seizure diary and seizure frequency 
as a primary study endpoint (see Section 8.1.7). For the purpose of this study, reporting of 
seizures should meet the AE/SAE reporting requirements. As seizures are considered a baseline 
condition, seizures should be reported as an AE/SAE if: 1) there is a clear increase in the 
frequency of seizures compared to the patient’s baseline, 2) there is an emergence of a new 
seizure type, or 3) the patient experiences status epilepticus, and 4) any other time the 
Investigator feels the seizure should be captured as an AE/SAE, in which case the Investigator 
should document his/her reasoning. All seizures will be captured in the seizure diary collected at 
the site during the study and will be analyzed by the Sponsor along with the reportable SAEs in 
evaluating risk:benefit. The Sponsor will report the SAE events of seizure that meet these criteria 
in an aggregated unblinded report at the conclusion of the study.
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs. If a patient experiences an AE after 
signing informed consent, but prior to receiving study drug, the event will be reported, but will 
be included in the patient’s medical history unless the event is serious, or the Investigator feels 
the event may have been caused by a protocol procedure.
In addition, all AEs occurring after the patient receives the first dose of study drug must be 
reported to Ovid or its designee via the eCRF.
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8.3.1.1.
Severity Assessment
Investigators will be instructed to rate the severity of AEs using the following criteria:
Mild 
Events require minimal or no treatment and do not interfere with the patient’s daily 
activities.
Moderate 
Events result in a low level of inconvenience or concerns with the therapeutic measures. 
Moderate events may cause some interference with functioning.
Severe 
Events interrupt a patient’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating.
Change in severity of an AE should be documented based on specific guidelines in the eCRF 
Completion Guidelines.
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE.
8.3.1.2.
Causality Assessment
Investigators will be instructed to report to Ovid or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and/or study drug via the CRF.
An Investigator causality assessment (unrelated or related) must be provided for all AEs (both 
serious and non-serious). This assessment must be recorded in the CRF and any additional forms 
as appropriate.
Relationship of AEs to the defined study treatment (TAK-935 [after the start of TAK-935 on 
Day 1]), will be determined by the Investigator according to the following criteria. Please note 
that not all criteria must be present to be indicative of a particular relationship.
Not Related 
Exposure to the defined study treatment did not occur, or the occurrence of the AE is 
not reasonably related in time
Unlikely Related 
The AE occurred in a reasonable time after the defined study treatment and is 
doubtfully related to the investigational agent/procedure
Possibly Related
The defined study treatment and the AE were reasonably related in time, and the AE 
could be explained equally well by causes other than exposure to the defined study 
treatment
Related 
The defined study treatment and the AE were reasonably related in time, and the AE 
was more likely explained by exposure to the defined study treatment than by other 
causes, or the defined study treatment was the most likely cause of the AE
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Ovid or its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.
8.3.1.3.
Serious Adverse Events
Serious adverse event collection begins after the patient has signed informed consent. If a patient 
experiences an SAE after signing informed consent, but prior to receiving study drug, the event 
will be reported, but will be classified as a pre-treatment SAE unless the Investigator feels the 
event may have been caused by a protocol procedure.
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Planned surgeries and/or hospitalizations should not be reported as SAEs unless the underlying 
medical condition has worsened during the course of the study.
Study site personnel must alert Ovid or its designee of any SAE within 24 hours of Investigator 
awareness of the event via a sponsor-approved method. If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms. This
24-hour notification requirement refers to the initial SAE information and all follow-up SAE
information.
An SAE is any AE from this study that results in 1 or more of the following outcomes:

Results in death

Requires or prolongs hospitalization

Is life threatening (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly or birth defect

Other medically important serious event
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse events occurring up to and including the patient’s last study visit will be 
collected, regardless of the Investigator’s opinion of causation.
If an Investigator becomes aware of SAEs occurring to a patient after the patient’s participation 
in the study has ended (including any protocol-required post-treatment follow-up), the 
Investigator should report the SAEs to the sponsor, regardless of the Investigator’s opinion of 
causation.
8.3.1.4.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the Investigator identifies as related to study drug or procedure. United States
21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated 
detailed guidance or national regulatory requirements in participating countries require the 
reporting of SUSARs. Ovid has procedures that will be followed for the recording and expedited 
reporting of SUSARs that are consistent with global regulations and the associated detailed 
guidance.
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8.3.1.5.
Reporting Adverse Events
All non-serious AEs must be recorded in the eCRF upon awareness.
Any AE that meets SAE criteria (Section 8.3.1.3) must immediately (i.e., within 1 business day) 
be sent to the Sponsor 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 
following fax number or email. All supporting source information concerning the SAE 
(e.g., hospital records) should also be provided by fax or email.
Country-specific fax numbers will be provided in a separate document.
Email: 
If there is a question concerning an SAE, the site needs guidance regarding reporting of an SAE, 
the site is returning a call from the Sponsor’s safety specialist, or the site urgently needs to report 
an SAE or make the Sponsor aware of an SAE, the safety hotline should be used
(country-specific hotline numbers provided in a separate document).
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 must be entered into the EDC 
system immediately (i.e., within 1 business day) after site personnel first learns about the event 
in addition to faxing/emailing the SAE Report form. Once the qualifying SAE data are entered 
into EDC, the Sponsor will be notified by an email alert, which 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 patient’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 patient or health care practitioner is unable to provide additional information, or 
the patient is lost to follow up). Serious AEs that occur more than 30 days after the last dose of 
study drug need not be reported unless the Investigator considers them related to study drug.
8.3.1.6.
Sponsor Reporting Requirements
The Sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use Appendix A of the 
current IB as the Reference Safety Document. The expectedness and reporting criteria of an SAE 
will be determined by the Sponsor from the Reference Safety Information.
8.3.1.7.
Investigator Reporting Requirements
The Investigator must fulfill all local regulatory obligations required for the study Investigators. 
It is the Principal Investigator’s responsibility to notify the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) of all SAEs that occur at his or her site. Investigators will 
also be notified of all SUSAR events that occur during the clinical study. Each site is responsible 
for notifying its IRB/IEC of these additional SAEs.
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Investigators will receive blinded information unless unblinded information is judged necessary 
for safety reasons.
8.3.2.
Exposure During Pregnancy and/or Lactation
TAK-935 should not be administered to pregnant and lactating females because the potential for 
adverse reactions to TAK-935 in pregnant females, fetuses, and nursing infants is unknown.
Pregnancy data will be collected during this study for all patients. Exposure during pregnancy 
(also referred to as exposure in-utero [EIU]) can be the result of either maternal exposure or 
transmission of drug product via semen following paternal exposure.
For all Ovid products, both in development or post-approval, exposure during pregnancy must be 
recorded and the patient followed until the outcome of the pregnancy is known (spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality), even if the patient 
discontinues study drug or discontinues from the study.
If a patient within this study or a patient’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. Pharmacovigilance will supply the Investigator with a copy of a “Pregnancy Reporting 
and Outcome Form/Breast Feeding.” 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 or fax (Section 8.3.1.5).
Pregnancy is not regarded 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.
8.3.3.
Safety Monitoring
The Sponsor’s Medical Monitor and/or Pharmacovigilance physician will monitor safety data 
throughout the course of the study.
8.3.3.1.
Reporting of Abnormal Liver Function Tests
If a patient is noted to have ALT or AST elevated >3 × ULN on 2 consecutive occasions, as 
specified in Section 8.1.11, the abnormality should be recorded as an AE.
If a patient is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 8.3.1.5. The Investigator must contact the Medical Monitor for discussion of the 
relevant patient details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 8.1.11 must also be performed.
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8.4.
Appropriateness of Measurements
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
Dravet syndrome and LGS.
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9.
DATA QUALITY ASSURANCE
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following:

Provide instructional material to the study sites, as appropriate

Sponsor start-up training to instruct the Investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and study 
procedures

Make periodic visits to the study site

Be available for consultation and stay in contact with the study site personnel by
Email, telephone, and/or fax

Review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

Conduct a quality review of the database
In addition, the Sponsor or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by the Sponsor or 
its representatives, and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the 
Investigator will provide the sponsor, applicable regulatory agencies, and applicable IRBs/IECs 
with direct access to original source documents.
9.1.
Data Collection and Storage
All clinical raw data will be recorded promptly, accurately, and legibly, either directly into the 
source document or indelibly on paper (e.g., ECG readings). When recorded electronically, case 
report forms will be electronically generated. All raw data will be preserved to maintain data 
integrity. The Investigator or designee will assume the responsibility of ensuring the 
completeness, accuracy, and timeliness of the clinical data.
The electronic data capture system is fully validated and Code of Federal Regulations Title 21
Part 11 compliant. The electronic data capture system will maintain a complete audit trail of all 
data changes. At each scheduled monitoring visit, the Investigator or designee will cooperate 
with the Sponsor’s representative(s) for the frequent review of study documents to ensure the 
accuracy and completeness of the data capture system.
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries.
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The Investigator or designee will prepare and maintain adequate and accurate study documents
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms)
designed to record all observations and other pertinent data for each patient receiving study drug 
or placebo.
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/IEC to have direct access to all documents pertaining to the 
study.
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10.
STATISTICAL METHODS AND PLANNED ANALYSES
10.1.
General Considerations
All statistical analyses will be performed using SAS® Version 9.3 or higher. All clinical study 
data will be presented in patient data listings. Data summaries will be presented for all endpoints 
and will include descriptive statistics (number of patients [n], mean, standard deviation [SD], 
first quartile [Q1], median, third quartile [Q3], minimum and maximum) for continuous 
variables, and frequency and percentage for categorical and ordinal variables. If there are
missing values, the number of missing will be presented, but without a percentage. For all 
analyses, ‘Baseline’ refers to the prospective 4-week Baseline Period.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) which will be finalized and approved prior to database lock. 
Additional exploratory analyses of the data may be conducted as deemed appropriate.
10.2.
Stratification by Seizure Type
At Visit 2, all eligible patients will be stratified by 2 categories: patients with Dravet syndrome 
with convulsive seizures, and patients with LGS with drop seizures to ensure balance of 
treatments within each stratum. Note that patients with both the minimum number of convulsive 
and drop seizures will be assigned to a stratum following the noted rules.
Patients with Dravet syndrome:
!
46 eligible patients diagnosed with Dravet syndrome with ≥3 convulsive seizures per
28 days during the prospective Baseline period will be randomized into the Dravet 
syndrome stratum
Patients with LGS:
!
80 eligible patients diagnosed with LGS with ≥4 drop seizures per 28 days during the 
prospective Baseline period will be randomized into the LGS stratum
If a patient does not meet any of these criteria, the patient will be considered a screen failure.
10.3.
Determination of Sample Size
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Date: 11 February 2019 
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10.4.
Analysis Sets
10.4.1.
Modified Intent-to-Treat Analysis Set
All randomized patients who have received at least 1 dose of study drug and have been assessed 
for at least 1 day in the Treatment Period will be included in the modified intent-to-treat (mITT) 
analysis set. All mITT analyses will be based on each patient’s randomized treatment 
assignment.
10.4.2.
Efficacy Analysis Set
All mITT patients whose efficacy assessments are compliant with Protocol Amendment 2 will be 
included in the efficacy analysis set. Efficacy analyses for primary and secondary efficacy 
endpoints will be based on the efficacy analysis set. 
 
Efficacy analyses will be based on each patient’s
randomized treatment assignment.
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Date: 11 February 2019 
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10.4.3.
Safety Analysis Set
All randomized patients who take at least 1 dose of study medication will be included in the 
Safety Analysis Set. Safety analyses will be based on the medication that was actually 
administered to each patient.
10.5.
Demographics and Baseline Characteristics
Demographic characteristics include age, gender, race, ethnicity, and study center. Baseline 
characteristics include baseline body weight, height, and the randomization stratum. Summary 
statistics by treatment group and overall will include counts and percentages for discrete 
variables, and means, SD, Q1, medians, Q3, minimum and maximum for continuous variables.
10.6.
Patient Disposition
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given.
Disposition data will be summarized and provided in patient listings.
10.7.
Concomitant Medications and Non-Pharmacologic Therapies and
Procedures
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). A by-patient listing of concomitant medications will include all medications taken 
during the study regardless of the timing for the start of the medication. All medications started 
prior to the administration of the study drug will be included in the data but will be identified as 
prior in the listing. Only the concomitant medication use will be summarized.
The number and percentage of patients who took at least 1 medication during the double-blind 
period as well as the number and percentage of patients who took each type of medication will 
be presented for each treatment group. Medications will be listed according to their WHO-DD 
anatomic therapeutic chemical (ATC) class level 4 and preferred drug name within ATC class 
level 4 by decreasing frequency of incidence for all active treatment groups combined.
10.8.
Treatment Compliance
Treatment compliance will be summarized by treatment group over the entire treatment period. 
Compliance rates during the treatment period will be derived using the following formula:
100*(Total number of tablets/mini-tablets dispensed – Total number of tablets/mini-tablets 
returned) / (Expected number of tablets/mini-tablets)
Expected number of tablets/mini-tablets to be taken is based on the date of first study medication 
dose and the date of last study medication dose (ie, [date of last study medication dose – date of 
first study medication dose] +1). Compliance rates will be presented for the safety analysis set 
using summary statistics and percentage for the frequency distributions (0% to <20%, 20% to
40%, 40% to <60%, 60% to <80%, 80% to <100%, 100% to ≤120%) by treatment group and
overall.
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10.9.
Efficacy Analyses
10.9.1.
Primary Efficacy Analyses
For the patients randomized to the Dravet syndrome stratum (≥3 convulsive seizures per 
28 days), convulsive seizure frequencies per 28 days for the 4-week prospective Baseline Period
and the Maintenance Period will be calculated.
For the patients randomized to the LGS stratum (≥4 drop seizures per 28 days), drop seizure 
frequencies per 28 days for the 4-week prospective Baseline Period and the Maintenance Period 
will be calculated.
The seizure frequency per 28 days in a study period will be calculated as
(# of seizures) / (# of days seizures were assessed) 28
For each patient, percent change from Baseline to the frequency during Maintenance Period (per 
28 days) will be calculated for the seizure type corresponding to the assigned stratum of that 
patient (convulsive for the Dravet and drop for the LGS stratum). Percent change from Baseline 
will be compared between TAK-935 and placebo using a Mann-Whitney (Wilcoxon) test 
adjusting for Baseline seizure frequency and randomization stratum.
The null hypothesis of no treatment difference will be tested at a two-sided 0.05 level of 
significance. The Mann-Whitney estimator and the corresponding 95% confidence interval (CI) 
comparing TAK-935 with placebo will also be displayed.
10.9.2.
Secondary Efficacy Analyses
For Dravet stratum, percent change in convulsive seizure frequency from Baseline to the 
frequency of convulsive seizures during the Maintenance Period will be compared between 
TAK-935 and placebo using a Mann-Whitney test adjusting for Baseline convulsive seizure 
frequency and randomization stratum. For the LGS stratum, percent change in drop seizure
frequency from Baseline to the frequency of drop seizures during the Maintenance Period will be 
compared between TAK-935 and placebo using a Mann-Whitney test adjusting for Baseline drop 
seizure frequency. The Mann-Whitney estimator and the corresponding 95% CI comparing 
TAK-935 with placebo will also be displayed.
The primary efficacy analysis will be repeated for the 20-week Treatment Period.
For the Dravet syndrome strata, the proportion of treatment responders based on ≥25% 
worsening, <25% and >1% worsening, no change (Worsening of 1% to Reduction of 1%), ≥25% 
reduction, ≥50% reduction, ≥75% reduction, and 100% reduction from Baseline in convulsive 
seizure frequency for the Maintenance Period will be summarized for TAK-935 and placebo. 
The 95% CIs for the difference of proportions will be displayed for each responder category. For 
the LGS stratum, the proportion of treatment responders based on ≥25% worsening, <25% and 
>1% worsening, no change (Worsening of 1% to Reduction of 1%), ≥25% reduction, ≥50% 
reduction, ≥75% reduction, and 100% reduction from Baseline in drop seizure frequency for the 
Maintenance Period will be summarized for TAK-935 and placebo; 95% CIs for the difference 
of proportions will be displayed for each responder category.
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Change in CGI-S/C responses of Investigator reported impression of efficacy and tolerability of
study drug and change in Care GI-C responses of parent/family reported impression of efficacy 
and tolerability of study drug will be analyzed descriptively.
Correlation of seizure frequency reduction and plasma 24 HC level will be explored.
Techniques for handling missing information with respect to reporting of seizures in the 
treatment period (Dose Optimization and Maintenance) will be specified in detail in the 
statistical analysis plan (SAP).
10.10.
Safety Analyses
All safety analyses will be conducted based on the Safety Analysis Set.
Descriptive statistics will be used to summarize all safety endpoints by treatment group.
Two-sided 95% CIs will be presented where meaningful. Data summaries will be displayed for 
incidence of AEs, clinical laboratory variables, vital signs, body weight and height, ECG 
parameters, percent myoclonic- and atypical absence-free days, as well as changes in behavioral 
and adaptive functioning measures using VABS and sub-scales of ABC-C, as appropriate.
All data will be listed by patient.
10.10.1.
Physical Examination, Vital Signs, and Other Physical Findings
Physical examinations (general appearance; skin; head, ear, eye, nose, and throat; neck; lymph 
node; chest; heart; abdominal cavity; limb; central nervous system; and musculoskeletal) at 
Baseline will be summarized. Shifts from Baseline to post-baseline study visits in each body 
system/site will be summarized by treatment group.
Vital signs (temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure), 
weight, and height will be summarized descriptively at Baseline and all post-baseline study visits 
by treatment group. Change from Baseline to all post-baseline study visits also will be 
summarized descriptively by treatment group.
Data listings will be provided.
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Date: 11 February 2019 
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10.10.2.
Clinical Laboratory Tests
Changes from Baseline to study timepoints in clinical chemistry, hematology, and urinalysis 
results will be summarized descriptively. Each laboratory parameter will be classified as low, 
normal, or high relative to the parameter’s reference range. Laboratory abnormalities for each 
treatment will also be summarized with shift tables. Listings of patients with abnormal results 
will be provided.
10.10.3.
Adverse Events
The following definitions will be used for AEs:
!
Treatment-emergent adverse event (TEAE): Any AE that starts or increases in 
severity during or after the first dose of study drug
!
Treatment-emergent SAE: A TEAE that is serious
The incidence of TEAEs, discontinuations due to TEAEs, drug-related, serious, and severe
TEAEs will be summarized. All AEs will be coded using MedDRA and will be summarized by
SOC and PT and treatment group. Detailed listings of AEs, SAEs, IARs, related AEs, and 
discontinuations due to AEs will be provided.
10.11.
Pharmacokinetic/Pharmacodynamic Analyses
10.12.
Other Statistical Issues
10.12.1.
Significance Levels
A primary endpoint is defined and will be tested at 0.05 level of significance.
 
10.12.2.
Missing or Invalid Data
Techniques for handling missing information with respect to reporting of seizures in the 
treatment period (Dose Optimization and Maintenance) will be specified in detail in the 
statistical analysis plan (SAP).
CCI
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Date: 11 February 2019 
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10.13.
Interim Analyses
Plasma concentrations of TAK-935 in first 12 patients within each category of aged ≥9 years and 
aged <9 years will be used to estimate PK parameters using the current population PK model. If 
needed, the dose will be adjusted. The frequency of PK sample collection may be changed based 
on results of interim analysis.
Overall and by-stratum futility and interim analyses may be performed. Enrollment may be 
stopped for 1 of the strata if the treatment effect is not sufficiently strong. If one stratum is 
discontinued, then the remaining patients may be re-allocated to continuing stratum. Thresholds 
for stopping enrollment will be pre-specified in the interim analysis plan.
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11.
INFORMED CONSENT, ETHICAL REVIEW, AND 
REGULATORY CONSIDERATIONS
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient 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 patient and/or patient’s legal representative (i.e., parent or legal guardian), except as 
necessary for monitoring and auditing by the sponsor, its designee, US Food and Drug 
Administration, Health Authorities, Ethics Committees, and/or IRBs. 
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.
11.1.
Informed Consent
The Investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The Investigator is responsible for ensuring that informed consent is given by each patient or
legal representative. This includes obtaining the appropriate signatures and dates on the ICF prior 
to the performance of any protocol procedures and prior to the administration of study drug.
A legal representative must give informed consent for a child to participate in this study. In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
11.2.
Data Monitoring Committee
The specific responsibilities of the iDMC are described in the DMC Charter, which is maintained 
as a separate document.
11.3.
Ethical Review
The Sponsor or its representatives must approve all ICFs before they are used at investigative 
sites(s). All ICFs must be compliant with the ICH guideline on GCP.
Documentation of IRB/IEC approval of the protocol and the ICF must be provided to the 
Sponsor before the study may begin at the investigative site(s). The IRB/IEC(s) will review the 
protocol as required.
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The study site’s IRB/IEC(s) should also be provided with the following:

The current IB and updates during the study

ICF

Relevant curricula vitae
11.4.
Regulatory Considerations
This study will be conducted in accordance with:

Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

The ICH GCP Guideline (E6)

Applicable laws and regulations
The Investigator or designee will promptly submit the protocol to applicable IRB/IEC(s). Some 
of the obligations of the Sponsor may be assigned to a Third-Party Organization.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other study-related data.
11.4.1.
Confidentiality
The Sponsor affirms that subject’s rights to protection against invasion of privacy are in 
compliance with ICH and other local regulations (whichever is most stringent). Information 
about patients and their records will be kept confidential by the Sponsor and its representatives. 
Study related records identifying patients will be kept confidential and, to the extent permitted by 
applicable laws and/or regulations will not be made publicly available. 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject 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 patient and/or patient's custodial parent or guardian, except as necessary for monitoring 
and auditing by the sponsor, its designee, FDA, Health Authorities, Ethics Committees, and/or 
IRBs.
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.
If any of the results of the study are published, patient’s identity will remain confidential.
The Sponsor requires the Investigator to permit sponsor representatives and, when necessary, 
representatives from FDA and other regulatory authorities, monitor, auditor, IRB to have access 
to study related medical records in accordance with local privacy laws.
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11.4.2.
Investigator Information
Physicians with a specialty in neurology and/or epilepsy disorders will participate as
investigators in this clinical study.
11.4.3.
Protocol Signatures
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each Principal Investigator will sign the protocol signature page and 
send a copy of the signed page to a Sponsor representative.
11.4.4.
Final Report Signature
The clinical study report Coordinating Investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The Sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
11.5.
Publication Policy
The full terms regarding publication of the results of this study are outlined in the Clinical Study 
Agreement, Statement of Agreement, or the Master Clinical Study Agreement. Publication is 
permitted only after multi-center results are available and all disclosure requirements for clinical 
study registries have been met. Any data to be submitted for publication, including abstract 
submissions or presentations, are required to be submitted to Ovid for review at least 30 days 
prior to submission.
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12.
LIST OF REFERENCES
1. Howie S. Blood sample volumes in child health research: review of safe limits. Bulletin 
of the World Health Organization, 2011;89:46-53. doi: 10.2471/BLT.10.080010.
2. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: 
Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus 
Conference. Pediatr Neurol. 2013;49(4):243-54.
3. Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, et al. The 
major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric 
modulator of N-methyl-D-aspartate receptors. J Neurosci 2013;33(44):17290-300.
4. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al.
Revised terminology and concepts for organization of seizures and epilepsies: report of 
the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia
2010;51(4):676-85.
5. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE 
classification of the epilepsies: Position paper of the ILAE Commission for Classification 
and Terminology. Epilepsia 2017;58(4):512-21.
6. Wagner T, Tsai M, et al. Clinical trial simulations using a pharmacokinetic/enzyme 
occupancy/pharmacodynamic model of TAK-935, a cholesterol 24S-hydroxylase 
inhibitor; poster presented at the American Epilepsy Society 71st Annual Meeting 
(Washington, D.C. 2017).
7. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational 
classification of seizure types by the International League Against Epilepsy: Position 
Paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017.
8. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry
2011;168(12):1266-77.
9. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a 
behavior rating scale for the assessment of treatment effects. Am J Ment Defic
1985;89(5):485-91.
10. de Bildt A, Kraijer D, Sytema S, Minderaa R. The Psychometric Properties of the 
Vineland Adaptive Behavior Scales in Children and Adolescents with Mental 
Retardation. J Autism Dev Disord. 2005;35(1):53-62.
11. Bretillon L, Lutjohann D, Stahle L, Widhe T, Bindl L, Eggertsen G, et al. Plasma levels 
of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic 
metabolism and are inversely related to body surface. J Lipid Res 2000;41(5):840-5.
12. Cartagena CM, Ahmed F, Burns MP, Pajoohesh-Ganji A, Pak DT, Faden AI, et al.
Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J 
Neurotrauma 2008;25(9):1087-98.
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Date: 11 February 2019 
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13. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CG. Increased expression of cholesterol
24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association 
with lipid rafts: a potential role in Alzheimer's disease. J Neurochem 2010;113(4):978-89.
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APPENDIX 1. SCHEDULE OF ASSESSMENTS
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Page 76 of 106
CONFIDENTIAL
Table 3
Schedule of Assessments
Screening/ 
Baseline 
Period
Double-blind Treatment Period
Follow-
up
Period
Rand/
Dosing
Day
Visit (V) or Phone Call (P) 
Numberk
V1
V2
P1
V3
P2
V4
P3
V5
P4
V6
V7
Study Day
Days -42 to -1
Day 1a
Day 8a,l/
phone 
call
Day 15a
Day 22l/
phone 
call
Day 36
Day 57l/
phone 
call
Day 85
Day 113l/
phone 
call
Day 141/ 
ETa,b,d
Day 169/
Follow-
upc
Visit Window (days)
±2
±2
±2
+2
±7
+2
±7
+2
±7
-7
Informed consent and assent 
(if applicable)
X
Inclusion/exclusion criteria
X
X
Randomization
X
Demographics, medical 
history, medication history
X
Height, weight
X
X
X
X
X
X
Concurrent medical 
conditions
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
CGI-S/C & Care GI-Cj
X
X
X
X
C-SSRS
X
X
X
X
Vineland Adaptive 
Behavioral Scale (VABS)
X
X
Aberrant behavior checklist 
(ABC-C)
X
X
Quality of Life in Childhood 
Epilepsy
X
X
Sleep Disruption Numerical 
Rating Scale
X
X
Exit surveyj
X
Serum/urine pregnancy teste
X
X
X
Vital signs
X
X
X
X
X
X
X
Physical examination
X
X
Xf
Xf
X
X
Neurological examination, 
 
X
X
X
X
X
X
X
12-lead ECGn
X
X
X
X
CCI
Property of Taked
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 77 of 106
CONFIDENTIAL
Screening/ 
Baseline 
Period
Double-blind Treatment Period
Follow-
up
Period
Rand/
Dosing
Day
Visit (V) or Phone Call (P) 
Numberk
V1
V2
P1
V3
P2
V4
P3
V5
P4
V6
V7
Study Day
Days -42 to -1
Day 1a
Day 8a,l/
phone 
call
Day 15a
Day 22l/
phone 
call
Day 36
Day 57l/
phone 
call
Day 85
Day 113l/
phone 
call
Day 141/ 
ETa,b,d
Day 169/
Follow-
upc
Visit Window (days)
±2
±2
±2
+2
±7
+2
±7
+2
±7
-7
Clinical laboratory tests 
(Chemistry, hematology, and 
urine analysis)
X
X
X
X
X
X
Distribute seizure diary and 
provide instructions on use
X
X
X
X
X
X
Collect seizure diary data
X
X
X
X
X
X
Plasma sample for TAK-935 
PKg
X
X
X
X
X
Plasma sample for AED 
analysis
X
X
X
Plasma sample for PD 
(plasma 24HC)h
X
X
X
X
X
X
IWRS to obtain patient 
ID/medication
ID/patient status
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
Xm
In-clinic administration of 
morning dose of study drug
X
X
X
X
X
Study drug return/
accountability/compliance
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Abbreviations: AED=antiepileptic drug; Care GI-C=Caregiver Global Impression of Change; CGI-S/=Clinician’s Clinical Global Impression of Severity and 
Change; C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; ET=Early Termination; ID=identification; IWRS=interactive web 
response system; P=phone call; PD=pharmacodynamics; Rand=randomization; V=visit.
a Two days after each dose escalation or taper, patients will be contacted by phone to monitor study drug compliance, concomitant medication use, and AEs. 
Patients will be contacted by phone within first two days following escalation to the maximum dose to assess safety and tolerability of the study drug.
b Patients who do not continue into the open-label extension (OLE) study will undergo the dose taper procedures and will then proceed to the Follow-up Period.
Patients who continue in OLE may do a combined visit, i.e., the last visit of this trial may be combined with the first visit of the OLE
c The timing of the Follow-up Period and Follow-up Visit will depend on the dose taper procedures followed. Patients who are on Dose 1 (the lowest 
administered dose) of TAK-935 during the Maintenance Period will not undergo dose taper. Visit may be eliminated for patients enrolled in OLE.
CCI
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 78 of 106
CONFIDENTIAL
d Patients who withdraw early from the study should complete all Final Visit procedures at the ET Visit.
e For sexually active female patients of childbearing potential, a serum pregnancy (hCG) test will be performed at the Screening visit. If urine 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 the results of a serum pregnancy test at Visit 2 must be confirmed to be negative before the patient can 
receive the first dose of study drug. Additional pregnancy tests (serum or urine) may be performed throughout the study at the Investigator’s discretion.
f Physical examination can be limited to general appearance; head, eyes, ears, nose, and throat [HEENT]; cardiovascular; respiratory, and abdominal at Day 15 
and Day 85.
g For the first 12 randomized patients aged ≥9 years and 12 randomized patients aged <9 years, PK blood samples for measurement of TAK-935 and M-I 
concentrations in plasma will be collected within 1 hour before the morning dose (pre-morning dose) and 30 min (±10 min) and 1, 2, and 4 hours (± 10 min) 
after the morning dose at Visit 2 (Day 1); within 1 hour before the morning dose (pre-morning dose) and 30 min (±10 min) post-dose at Visits 3, 4, 5, and 6. In 
the remaining randomized patients, PK blood draws will occur within 1 hour before the morning dose (pre-dose) and 30 min (±10 min) post-morning dose at 
Visits 2, 3, 4, 5, and 6 (Days 1, 15, 36, 85, and 141, respectively) during the study. An intravenous line (IV) line may be inserted for collection of all blood 
samples during the visit.
h PD blood samples for measurement of 24HC levels in plasma will be collected at pre-morning dose on Visits 2, 4, 5, and 6 (Days 1, 36, 85, 141, and 169,
respectively).
i
 
j The ET/Exit survey will be conducted at Visit 6.
k Based on local country regulations and Sponsor approval, some study visits may be conducted at home.
l The study visits on Days 8, 22, 57, and 113 (phone calls 1 through 4) will be conducted via telephone.
m At Visit 6 (Day 141), dispensing study drug is applicable only for patients not entering the Open-label Extension study.
n A 12-lead ECG will be recorded at Screening (Visit 1) and at 30 min (±10 min) after the morning dose at Visits 2, 4, and 6.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 79 of 106
APPENDIX 2. STUDY TAK-935-2002 (OV935): CLINICAL 
LABORATORY TESTS
Hematology
Serum Chemistry
Urinalysis (a)
Study Specific
RBC
ALT
pH
Plasma
WBC with 
differential
(% and absolute)
Albumin
Specific gravity
24HC
Hemoglobin
Alpha-1-acid 
glycoprotein
Protein
Hematocrit
Alkaline phosphatase
Glucose
Platelets
AST
Blood
Plasma (Concomitant AEDs)
PT/INR
Total bilirubin
Nitrite
Carbamazepine
aPTT
Total protein
Clobazam
Creatinine
N-desmethylclobazam
Blood urea nitrogen
Microscopic Analysis: (b)
Valproic acid
Creatine kinase
RBC/high power field
Phenytoin
GGT
WBC/high power field
Topiramate
Potassium
Epithelial cells, casts etc.
Lamotrigine
Sodium
Rufinamide
Glucose
Zonizamide
Chloride
Phenobarbital
Bicarbonate
Levetiracetam
Calcium
Lacosamide
Total cholesterol
10-hydroxycabazepine 
(metabolite
HDL cholesterol
of oxcarbazepine)
LDL cholesterol
Trileptal
Triglycerides
Epidiolex
Diagnostic Screening
Serum
Urine (a)
hCG (for pregnancy) (c)
hCG (for pregnancy) (c)
Abbreviations: AED=antiepileptic drug; aPTT= activated partial thromboplastin time, GGT=γ-glutamyl transferase, 
HDL=high-density lipoprotein, LDL=low-density lipoprotein, PT=prothrombin time, RBC=red blood cell; WBC=white blood 
cell.
(a) If urine cannot be collected at the time of the Screening Visit or other Visits due to the patient’s cooperation or because the 
patient is wearing a diaper, it is acceptable for the patient to continue in the study and the reason should be documented in the 
source document.
(b) Only if dipstick results are positive.
(c) Only for sexually active female patients of childbearing potential. If urine 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 patient can receive the first dose of study drug. An additional serum hCG pregnancy test will be performed 
at the Final Visit.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 80 of 106
APPENDIX 3. STUDY TAK-935-2002 (OV935): SAMPLING 
SUMMARY
This table summarizes the maximum number of samples and volumes for all sampling and tests 
during the study. Fewer samples may be taken, but this will not require a protocol amendment.
Protocol TAK-935-2002: Sampling Summary for Patients Weighing ≥10 kg 
Purpose
Sample 
Type
Maximum 
Amount per 
Sampleb
Maximum 
Number 
Samples
Maximum 
Volume in 
30-day Period
Maximum 
Total 
Amount
Standard laboratory testsa
Blood
5.7 mL
6
11.4
34.2 mL
Pharmacokinetic samples
Blood
1 mL
13
7
13 mL
AED Drug concentration
Blood
4 mL
3
4
12 mL
Plasma Biomarker (24HC 
)samples (PD)
Blood
2 mL
6
4
12 mL
Optional blood sample for 
research
Blood
2 mL
1
2
2 mL
Total 
Blood
14.7 mL
41 mL
28.4 mL
73.2 mL
a
Additional samples may be drawn if needed for safety purposes.
b
Maximum volume per sample is 14.7 mL.
Howie SR. Blood sample volumes in child health research: review of safe limits. Bulletin of the World Health Organization. 
2011;89(1):46-53. doi:10.2471/BLT.10.080010.
Blood Collection: Priority Order

Coagulation

Chemistry

Pregnancy test

Serum sample for AED analysis

Hematology

Plasma sample for TAK-935 PK

Plasma sample for PD (plasma 24HC)
Optional blood sample for research analysis: Blood volume limitations will sometimes preclude 
the collection of all samples in a particular study visit. In case this happens, for blood sample 
analysis, safety labs should be prioritized over labs for efficacy and exploratory analyses.
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 81 of 106
APPENDIX 4. STRONG CYP3A4 INDUCERS AND INHIBITORS
Use of perampanel from screening through follow-up is prohibited.
The strong inducers and inhibitors of CYP 3A4 listed below also are prohibited:
Strong CYP3A4 INDUCERS
Strong CYP3A4 INHIBITORS
Bosentan
Clarithromycin
Efavirenz
Telithromycin
Etravirine
Nefazodone
Modafinil
Itraconazole
Nafcillin
Ketoconazole
Nevirapine
Following antivirals: atazanavir, darunavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, and 
tipranavir.
Rifampin
Rifabutin
St. John’s Wort
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 82 of 106
APPENDIX 5. OVERVIEW OF MAJOR CHANGES 
IMPLEMENTED BY AMENDMENTS
AMENDMENT 2
1.
Clarified that iDMC will review the AE profiles of the first 12 patients aged
≥9 years completing 4 weeks of treatment
Description of Change: The iDMC will review the AE profiles of the first 12 patients 
(previously first 20) aged ≥9 years completing 4 weeks of treatment prior to recommending
treatment for patients aged <9 years
Rationale for Change: iDMC has reviewed the data of patients aged ≥9 years from another 
study (TAK-935-18-002) who were treated with TAK-935, and iDMC have approved to 
initiate treatment of patients aged 2-9 years old in the study. As TAK-935 is deemed safe in 
patients aged ≥9 years in TAK-935-18-002, it will be appropriate to decrease the number of 
patients aged ≥9 years needed before initiation treatment of 2-9 years old patients. 
Sections Impacted:

Synopsis

Section 5.1
2.
Renamed the Titration Period to the Dose Optimization Period and increased the 
period duration from 2 weeks to 8 weeks
Description of Change: Changed the period during which patients will titrate to the optimal 
dose from 2 weeks to 8 weeks in order to allow for 6 weeks of dose optimization. This 
revision resulted in a change in the Treatment Period from 14 weeks to 20 weeks. Updated 
Figure 1 to reflect the name change and the extension of the Dose Optimization Period. 
Updated the Schedule of Assessments to reflect the increase in the number of days on study. 
Updated the total duration of the study to approximately 30 weeks.
Rationale for Change: To allow for an additional 6 weeks to adjust patient dosing to optimal 
levels after the maximum dose had been reached, based on Investigator judgment and with 
approval of the Medical Monitor. 
Sections Impacted:

Synopsis

Section 5.1

Figure 1

Section 7.2

Section 10.9.2

Section 10.12.2

Appendix 1 (Table 3)
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 83 of 106
3
Added additional phone calls to monitor dose optimization and safety
Description of Change: Phone calls were added due to the increase in the duration of the 
Dose Optimization Period (formerly Titration Period) to 6 weeks. Updated the Schedule of 
Assessments to reflect the increase in the number of days on study. Phone calls will be made 
at Days 8, 22, 57, and 113. Clinic visits will occur at Screening (Visit 1), Day 1 (Visit 2), 
Day 15 (Visit 3), Day 36 (Visit 4), Day 85 (Visit 5), Day 141 (Visit 6), and Day 169 (Visit 7; 
follow-up).
Rationale for Change: To allow for an additional 6 weeks to adjust patient dosing to optimal 
and to monitor safety and compliance. 
Sections Impacted:

Synopsis

Section 5.1 (Figure 1)

Section 7.2

Appendix 1 (Table 3)
4.
Removed hepatitis B and C serology panel
Description of Change: Removed clinical laboratory tests for hepatitis B and C, including an 
additional blood sample for HCV qPCR for patients who are positive for hepatitis C Ab. 
Removed from exclusion criterion #7 that patients who are positive for hepatitis C Ab are 
eligible if they have a negative hepatitis C viral load by qPCR. 
Rationale for Change: There is no need to actively screen for hepatitis B and C.
Sections Impacted:

Synopsis

Section 6.2

Appendix 2
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 84 of 106
5.
Changed the follow-up visit from a phone call to a clinic visit
Description of Change: The Follow-up Period previously consisted of a phone call with the 
option to have follow-up assessment performed at the clinic. This Follow-up Visit is now a 
clinic visit with final assessments for concomitant medications, vital signs, physical 
examination, neurological examination, collection of seizure diary, plasma sample for 24HC, 
IWRS for patient status, study drug accountability, and AEs.
Rationale for Change: Because this amendment added an assessment of 24HC at the 
Follow-up Visit, it is necessary for patients to visit the clinic to have samples obtained for 
24HC. Additionally, the patient can return any unused study drug to the site. 
Sections Impacted:

Synopsis

Section 7.2 

Appendix 1 (Table 3)
6.
Revised the PK collection timepoints and added sampling windows
Description of Change: The PK collection text was revised as follows: 
Pharmacokinetic (PK) sample collection will start at Visit 2 (Day 1), and it is designed to 
investigate the PK in all patients. The first 16 12 randomized patients aged ≥9 years and the 
first 16 12 randomized patients aged <9 years will receive the first dose of TAK-935 or 
placebo in the clinic; PK blood draws will occur within 1 hour before the morning dose (pre-
morning-dose) and 30 min (±10 min) and 1, 2, and 4 3, and 5 hours (±10 min) after the first
morning dose. After Visit 2 (Day 1), additional PK samples will be collected within 1 hour 
before the morning dose (pre-morning-dose) and 30 min (±10 min) post-morning-dose (1 to 5
hours after the dose) at Visits 3, 4, 5, and 6 7 4, 5, 6, and 7 during the study.
The remaining randomized patients in the study will receive the first dose of TAK-935 or 
placebo in the clinic, with PK blood draws occurring within 1 hour before the morning dose
(pre-dose) and 30 min (±10 min) one draw post-dose (1 to 5 hours after the dose) at Visits 2, 3, 
4, 5, and 6 4, 5, 6, and 7 during the study.
Rationale for Change: No window was previously provided in the protocol; adding a window 
grants flexibility to the sites in collection of this sample. The phrase “within 1 hour before 
dose” was not previously consistent throughout the protocol. Adjusted the visit days to reflect 
new schedule of phone calls and visits. The PK sampling times were changed to better capture 
the PK profile and when Cmax is reached.
Sections Impacted:

Synopsis

Section 8.1.22.1

Section 10.13

Appendix 1 (Table 3)
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 85 of 106
7.
Added concomitant medications that should not be altered during study or that 
require approval
Description of Change:  Medical marijuana and cannabidiol products were added to the list 
of concomitant medications that should not be altered during the study. Added that use of 
traditional Chinese medicines should be approved by the Medical Monitor at screening.
Rationale for Change: Medical marijuana and cannabidiols are used as antiepileptic drugs 
and, therefore, like other AEDs, they should not be altered during the study. Traditional 
Chinese medicine may include a number of chemical components that may potentially have a 
drug-drug interaction with TAK-935 and, therefore, must be approved by the Medical 
Monitor.
Sections Impacted:

Synopsis

Section 7.6
8.
Added perampanel as prohibited concomitant medication
Description of Change: Use of perampanel from screening through follow-up is prohibited.
Rationale for Change: The new data from the TAK-935-2001 (OV935) study in adult 
patients with epileptic encephalopathy indicated that there is a potential drug-drug interaction 
between TAK-935 and perampanel, which may compromise the efficacy of TAK-935.
Sections Impacted:

Synopsis

Section 7.6

Appendix 4
9.
Updated the approximate total blood volume collected
Description of Change: The approximately total blood volume collected from each patient 
over the course of the study was revised from 69 to 73.2 mL.
Rationale for Change: Revised based on changes in the Schedule of Assessments (Table 3)
and central laboratory requirements.
Sections Impacted:

Synopsis

Section 8.1.11
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 86 of 106
10.
Revised the primary objective
Description of Change: The primary objective was revised as follows:
To investigate the effect on the frequency of all seizures (convulsive and drop) in patients 
treated with TAK-935 as an adjunctive therapy compared to placebo at the end of the 
Treatment Period (Titration plus in the Maintenance Period periods)
Rationale for Change: The preliminary data from the TAK-935-2001 (OV935) study in adult 
patients with epileptic encephalopathy indicate that full effects of TAK-935 are observed after 
8 weeks of treatment. Accordingly, to observe the full efficacy effects, the primary endpoint 
was changed to the last 12 weeks of treatment, which is the Maintenance Period.
Sections Impacted:

Synopsis

Section 4.1.1
11.
Revised the secondary objectives
Description of Change: The secondary objective for comparing patients treated with 
TAK-935 as an adjunctive therapy to placebo for the frequency of all seizures (convulsive and 
drop) was revised from throughout the Maintenance Period to throughout the Treatment 
Period.
The secondary objective for comparing patients treated with TAK-935 as an adjunctive 
therapy to placebo for the frequency of convulsive seizure in patients with Dravet Syndrome, 
the frequency of drop seizure in patients with LGS, the frequency of patients considered 
treatment responders in patients with LGS, and the frequency of patients considered treatment 
responders with Dravet Syndrome was revised from through the Treatment Period to the 
Maintenance Period.
The PK secondary objective was revised as follows:
To characterize the relationship between the PK and plasma 24HC levels and seizure 
frequency
The following secondary objective was deleted:
To investigate changes in plasma concentrations of concomitant AEDs and their 
pharmacologically active metabolites in patients treated with TAK-935 as an 
adjunctive therapy
Rationale for Change: Secondary objectives were revised to be consistent with the primary 
objective and to evaluate the changes in seizure frequency that may potentially occur earlier, 
i.e., during the entire treatment period. The relationship between the plasma 24HC levels and 
seizure frequency was deemed to be more clinically meaningful.
Sections Impacted:

Synopsis

Section 4.1.2
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 87 of 106
13.
Updated language regarding patient’s legal representative
Description of Change: Changed “patient’s custodial parent or guardian” to “patient’s legal 
representative (i.e., parent or legal guardian).”
Rationale for Change: For consistency throughout the document.
Sections Impacted:
!
Synopsis
!
Section 6.1
!
Section 6.3.1
!
Section 7.2
!
Section 11
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Property of Takeda: For Non-Commercial U
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 88 of 106
14.
Clarified definition of benzodiazepines as AEDs
Description of Change: Added text to inclusion criterion #5 to state that benzodiazepines 
used chronically (on daily frequency) to treat seizures are considered AEDs.
Rationale for Change: For clarification and based on feedback from the clinical sites.
Sections Impacted:

Synopsis

Section 6.1
15.
Clarified diagnosis of Dravet syndrome and Lennox-Gastaut syndrome for 
inclusion
Description of Change: Revised the text of inclusion criterion #11 to update the symptoms 
that support the diagnosis of Dravet syndrome and LGS for inclusion in this study.
Rationale for Change: Based on guidelines from the Epilepsy Consortium; clarification is 
provided to enhance diagnosis of Dravet Syndrome and LGS.
Sections Impacted:

Synopsis

Section 6.1
16.
Clarified that convulsive status epilepticus requiring hospitalization is an 
exclusion criterion for this study
Description of Change: Revised exclusion criterion #1 to state that patients that have been 
admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times 
in the 3 months immediately prior to the screening visit will be excluded from the study.
Rationale for Change: Status epilepticus can be a long seizure over 5 minutes and several 
patients, especially with Dravet Syndrome, can have prolonged seizures (>5 minutes) that are 
not severe enough to exclude them from the study. Therefore, patients whose status epilepticus 
required hospitalization and intubation will be excluded.
Sections Impacted:

Synopsis

Section 6.2
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 89 of 106
18.
Added malignancy (including progressive tumors) as an exclusionary condition
Description of Change: Added to exclusion criterion #4 that malignancy (including 
progressive tumors) would be an exclusionary unstable clinically significant condition
Rationale for Change: Based on unpredictable effects on efficacy and that progressive 
tumors have poor prognosis.
Sections Impacted:
!
Synopsis
!
Section 6.2
19.
Clarified the duration for avoidance of pregnancy and donation of ova and sperm 
for female and male patients, respectively
Description of Change: Added text to clarify that avoidance of pregnancy and donation of 
ova and sperm should be up to 90 days (previously 30 days) after the last dose of study drug.
Rationale for Change: The original text was not consistent with other sections of the 
protocol.
Sections Impacted:
!
Section 10.1.12
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Appl
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 90 of 106
19.
Revised the primary endpoint
Description of Change: Changed the primary endpoint from percent change from Baseline in 
seizure frequency during the Treatment Period to percent change from Baseline in seizure 
frequency during the Maintenance Period. 
Rationale for Change: The preliminary data from the TAK-935-2001 (OV935) study in adult 
patients with epileptic encephalopathy may indicate that full effects of TAK-935 are observed 
after 8 weeks of treatment. Accordingly, because treatment duration is extended to 20 weeks 
and to observe the full effects, the primary endpoint was changed to the last 12 weeks of 
treatment, which is the Maintenance Period.
Sections Impacted:

Synopsis

Section 4.2.1

Section 10.9.1
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 91 of 106
20.
Revised the secondary endpoints
Description of Change: The secondary endpoint for percent change from Baseline in seizure 
frequency per 28 days (convulsive and drop) was revised from during the Maintenance Period 
to during the Treatment Period.
The secondary endpoints for percent change from Baseline frequency of convulsive seizure in 
patients with Dravet Syndrome and the frequency of drop seizure in patients with LGS was 
revised from during the Treatment Period to during the Maintenance Period, and the 
proportion of patients with LGS considered treatment responders in patients and patients with 
Dravet Syndrome considered treatment responders was revised from during the Treatment 
Period to during the Maintenance Period. 
The PK secondary endpoint was revised as follows:
Correlation of TAK-935 concentration and plasma 24HC levels with seizure frequency
To characterize plasma 24HC levels and change in seizure frequency in patients treated 
with TAK-935 as an adjunctive therapy
Rationale for Change: Because the primary objective was changed to the Maintenance 
Period, the secondary objective was changed to the Treatment period to evaluate the changes 
in seizure frequency that may potentially occur earlier, ie, during the entire treatment period.
Consistent with the primary objective/endpoint and given the importance of the responder 
analysis, the frequency of patients considered as treatment responders was changed to the 
Maintenance Period (last 12 weeks of treatment).
The PK secondary objective of the correlation of 24HC levels with seizure frequency is more 
clinically meaningful.
Sections Impacted:

Synopsis

Section 4.2.2

Section 10.9.2
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 92 of 106
22.
Revised the pharmacokinetic endpoints
Description of Change: The PK endpoints were revised as follows:
To determine the plasma concentrations of the TAK-935 and the TAK-935 metabolite 
(M-I) at multiple time points
Estimate exposure parameters from sparse PK samples using population modelling
Determine any potential relationship with estimated TAK-935 exposure parameters 
with changes in seizure frequency
Population pharmacokinetic parameter estimates (eg apparent clearance CL/F, apparent 
volume of distribution VD/F, Cmax, AUC, Cavg within dosing interval) at steady-state 
for TAK-935
Correlation of TAK-935 concentrations on the serum levels of concomitant AEDs and 
their pharmacologically active metabolites
Outcome from an exposure-response model utilizing reduction in seizure rate for 
convulsive and drop seizures and TAK-935 concentrations
Rationale for Change: Estimate of exposure parameters using population modeling provides 
more clarification. Relationship between exposure and seizure frequency is more clinically 
meaningful.
Sections Impacted:
!
Synopsis
!
Section 4.2.4
!
Section 10.11
CCI
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Subject to the Applicable Terms


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 93 of 106
23.
Revised and added analysis sets
Description of Change: Deleted the statement that efficacy analysis would be based on the 
modified intent-to-treat (mITT) analysis set. Added a definition for the new efficacy analysis 
set, defined as all mITT patients whose efficacy assessments are compliant with protocol 
amendment 2.
Rationale for Change: To provide further clarification on efficacy analysis data set.
Sections Impacted:

Synopsis

Section 10.4
24.
Clarified and revised PK analyses
Description of Change: The plasma concentration-time and PD (24HC) data obtained in this 
study will be used to estimate TAK-935 exposure parameters, analyze target engagement in 
terms of 24HC reduction, and evaluate potential relationships between TAK-935 exposure or 
24HC responses and clinical and safety endpoints. Details will be included in a separate data 
analysis plan, and results will be reported separately.
Rationale for Change: To provide clarification on those parameters that are considered 
clinically meaningful.
Sections Impacted:

Synopsis

Section 8.1.22.3

Section 10.11
25.
Updated study rationale 
Description of Change: Revised the summary statements for clinical study TAK-935-2001 
(OV935) (Phase 2a study) to state that the study has been completed.
Rationale for Change: Updated text to reflect the current status of the study
Sections Impacted:

Section 3.2
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 94 of 106
26.
Add new section to define end of the study
Description of Change: Added the following text:
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient ongoing in the study.
Rationale for Change: To ensure sites had a clear understanding of what defined the end of 
the study and to ensure consistency with antecedent studies.
Sections Impacted:

Section 5.1.1
27.
Simplified the background information provided for selection and timing of doses
Description of Change: Deleted Section 5.2.1 (Nonclinical Efficacy and Safety) and 
Section 5.2.2 (Clinical Safety)
Rationale for Change: To remove information that is already provided in the IB.
Sections Impacted:

Section 5.2.1

Section 5.2.2
28.
Added 2 new forms of approved contraceptive methods
Description of Change: Added vasectomized partner and sexual abstinence as approved 
contraceptive methods.
Rationale for Change: Based on feedback from the clinical sites and IRBs.
Sections Impacted:

Section 6.1
29.
Added depression and/or suicidal ideation as a reason for study drug 
discontinuation
Description of Change: Added that depression and/or suicidal ideation could be a reason for 
study drug discontinuation as assessed using the C-SSRS and with ultimate determination of 
the presence of suicidal ideation or behavior depending on the clinical judgment of the 
investigator
Rationale for Change: To be compliant with patient safety guidelines and for consistency 
within the protocol.
Sections Impacted:

Section 6.3.1

Section 8.1.14
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 95 of 106
30.
Added storage temperatures for ex-US sites
Description of Change: Added the following language: 
For US sites, TAK-935 tablets/mini-tablets must be stored at 20°C to 25°C (USP controlled 
room temperature), with excursions permitted from 15°C to 30°C. For sites in all other 
countries, TAK-935 tablets must be stored at 1°C to 25°C.
Rationale for Change: The previous version of the protocol did not include storage 
temperatures for ex-US sites, which are different from the recommended storage temperatures 
in the United States.
Sections Impacted:

Section 7.1.1
31.
Added that study drug may be shipped via courier service if patient is unable to 
come for clinic visit to obtain resupply
Description of Change: If a patient is unable to come for a clinic visit to obtain study drug, 
the study drug may be shipped via a courier service.
Rationale for Change: To ensure patients do not run out of study drug in the event that they 
are unable to return to the clinic. 
Sections Impacted:

Section 7.1
32.
Clarified the handling of missed doses
Description of Change: Added the following text:
If a patient misses a dose, the missed dose should be skipped, and the patient should continue 
with his/her normal dosing schedule. Skipped doses should be reported as missed doses.
Rationale for Change: Based on inquiries from clinical sites, clarification was required for 
proper instructions to study patients on how to handle missing doses. Skipped doses should be 
reported as missed doses.
Sections Impacted:

Section 7.2
33.
Clarified how unblinding events will be recorded and reported
Description of Change: Emergency unblinding for AEs may be performed through an IWRS. 
Rationale for Change: Removed reference to emergency codes being generated by a 
computer drug-labeling system, as IWRS will serve this role.
Sections Impacted:

Section 7.5
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 96 of 106
34.
Changed demographic collection from “date of birth” to “year of birth”
Description of Change: Updated the text clarifying that only year of birth will be collected 
for demographics data collection.
Rationale for Change: To be compliant with current patient privacy standards.
Sections Impacted:

Section 8.1.2
35.
Revised requirement for heart rate and blood pressure collection
Description of Change: Removed text that stated that heart rate and blood pressure will also 
be measured after 5 minutes supine and after 1 to 3 minutes standing, if possible.
Rationale for Change: Based on feedback from the clinical sites and to provide further 
clarification.
Sections Impacted:

Section 8.1.6
36.
Added a formula for assessment of seizure frequency
Description of Change: Added the following formula for assessment of seizure frequency: 
(# of seizures) / (# of days seizures were assessed) 28
Rationale for Change: The formula for seizure frequency was not previously noted in the 
protocol.
Sections Impacted:

Section 8.1.7
37.
Clarified the use of the dosing card
Description of Change: Added the text as follows to clarify the use of the dosing card: A 
dosing card will be provided to the patient and/or caregiver at each clinic visit to record actual 
time of the last 2 dose administrations prior to PK sample collection, to record exact time of 
the last meal relative to dosing prior to PK or PD sample collection, and to record any changes 
in dosing regimen that may occur between visits and during the de-escalation period of the 
study; these will be recorded in the patient’s source documents and transcribed into electronic 
case report forms (eCRFs), including changes in dosing regimen (de-escalation) that may 
occur between visits and during the de-escalation period of the study.
Rationale for Change: The description of the dosing card was incomplete.
Sections Impacted:

Section 8.1.8
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 97 of 106
38.
Clarified that only sexually active female patients of childbearing potential will 
have pregnancy tests performed
Description of Change: Added the phrase “sexually active” where needed to clarify that only 
sexually active female patients of childbearing potential will have pregnancy tests performed.
Rationale for Change: As this patient population includes patients of severely impaired 
faculties, this change was made to reduce the clinical test burden on patients.
Sections Impacted:

Section 8.1.11

Section 8.1.12

Appendix 1 (Table 3)

Appendix 2
39.
Clarified the duration for avoidance of pregnancy and donation of ova/sperm for 
female and male patients
Description of Change: Added text to clarify that avoidance of pregnancy and donation of 
ova/sperm should be 90 days after the last dose of study drug.
Rationale for Change: The original text was not consistent with other sections of the 
protocol.
Sections Impacted:

Section 8.1.12
40.
Clarified pregnancy testing at Day 1
Description of Change: Added the following language: If urine 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 the results of a serum pregnancy test at Visit 2 must be confirmed to be 
negative before the patient can receive the first dose of study drug.
Rationale for Change: Much of this language was already present in Appendix 2 (now 
footnote c). Language was added to the other sections to ensure consistency, and all 3 sections 
were updated to ensure that pregnancy test results are obtained before female patients of 
childbearing potential receive study drug.
Sections Impacted:

Section 8.1.12

Appendix 1 (Table 3)

Appendix 2 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 98 of 106
41.
Adding window for ECGs
Description of Change: For ECGs performed after the screening ECG (ie, after the start of 
dosing), the ECG will be recorded 30 min (±10 min) after the morning dose.
Rationale for Change: This sampling time point coincides with the Cmax and Tmax of 
TAK-935.
Sections Impacted:
!
Section 8.1.13
!
Appendix 1 (Table 3)
42.
Clarified language for the C-SSRS administration
Description of Change: Removed text that indicated that a parent proxy could complete the 
C-SSRS. Clarified that trained study staff will administer the C-SSRS and that determination 
of the presence of suicidal ideation or behavior depends on the clinical judgment of the 
investigator.
Rationale for Change: Revised for consistency with the instructional language on the 
C-SSRS.
Sections Impacted:
!
Section 8.1.14
43.
Clarified that the Exit survey is a separate questionnaire from the Care GI-C
Description of Change: Removed reference to the Care GI-C in description of the Exit survey
Rationale for Change: Wording for exit survey previously was misinterpreted in the clinic.
Sections Impacted:
!
Section 8.1.21
!
Appendix 1 (Table 3)
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 99 of 106
45.
Added statement about AEs or SAEs associated with overdose
Description of Change: Added the following text:
Adverse events (including SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 8.3.1.5. In the event of drug overdose, the patient should be 
treated symptomatically.
Rationale for Change: Based on safety guidelines, clarification on overdose is provided.
Sections Impacted:

Section 8.3.1
46.
Clarified reporting seizures as AEs/SAEs
Description of Change: Instruction text for reporting seizures as AEs was revised from the 
following: 
For the purpose of this study, seizures will not be considered immediately reportable as 
an(S)AEs unless: 1) there is a clear increase in frequency of seizures compared to the patient’s 
baseline, 2) there is an emergence of a new seizure type, or 3) the patient experiences status 
epilepticus, and any other time the investigator feels the seizure should be captured as an 
(S)AE in which case the investigator should document her/his reasoning.
To:
Seizures in this patient population will be measured using the seizure diary and seizure 
frequency as a primary study endpoint (see Section 8.1.7). For the purpose of this study, 
reporting of seizures should meet the AE/SAE reporting requirements. As seizures are 
considered a baseline condition, seizures should be reported as an AE/SAE if: 1) there is a 
clear increase in the frequency of seizures compared to the patient’s baseline, 2) there is an 
emergence of a new seizure type, or 3) the patient experiences status epilepticus, and any other 
time the Investigator feels the seizure should be captured as an AE/SAE, in which case the 
Investigator should document his/her reasoning..
Rationale for Change: To provide clarification for the clinical sites on when seizures can be 
considered as AEs or SAEs.
Sections Impacted:

Section 8.3.1
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 100 of 106
47.
Removed text that stated that expected SAEs were provided in the Investigator’s 
Brochure
Description of Change: Deleted the following text:
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the study may be 
found in Appendix A of the current Investigator’s Brochure.
Rationale for Change: The current version of the Investigator’s Brochure does not include 
Appendix A, and the SAE information indicating as being included in The Investigator’s 
Brochure is not provided.
Sections Impacted:
!
Section 8.3.1.3
48.
Clarified SAE reporting process 
Description of Change: Clarified that AEs must be recorded in the eCRF upon awareness. 
Any AE that meets the criteria of an SAE must be reported to sponsor immediately using fax 
or email. Email address was updated to 
. If sites use the safety 
hotline telephone number to report an SAE, the site should first submit the SAE paper form 
and then enter the SAE in the eCRF. 
Removed AE reporting FAX numbers from the protocol and added a sentence stating that 
“country-specific FAX numbers will be provided in a separate document.” Also removed AE 
reporting safety hotline telephone number from the protocol, and added a sentence stating 
“country-specific hotline numbers will be provided in a separate document.”
Rationale for Change: To clarify that sites should submit the SAE paper form before entering 
the SAE in the eCRF and to state that country-specific FAX and safety hotline numbers will 
be provided to sites in a separate document.
Sections Impacted:
!
Section 8.3.1.5
49.
Added text stating that TAK-935 should not be administered to pregnant or 
lactating females 
Description of Change: Added the following text:
TAK-935 should not be administered to pregnant and lactating females because the potential 
for adverse reactions to TAK-935 in pregnant females, fetuses, and nursing infants is 
unknown.
Rationale for Change: Based on guidelines and feedback from the clinical sites.
Sections Impacted:
!
Section 8.3.2
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 101 of 106
50.
Added text on site responsibilities for record keeping
Description of Change: Added general text on how data records are to be kept or released 
during and after the study.
Rationale for Change: Based on GCP Guidelines.
Sections Impacted:

Section 11
51.
Updated the schedule of assessments 
Description of Change: All applicable revisions made in the body of the protocol were 
implemented in the schedule of events, including the following:
Add additional phone calls
Clearly identify clinic visits and phone calls
Revise study day number to account for added weeks in Dose Optimization Period
Update time point and window for PK sampling and 12-lead ECGs 
Dispensing study drug was added to Day 141/ET (Visit 6) for patients not entering the 
OLE; study drug return/accountability/compliance was removed from Day 1
Changed follow-up from a phone call to clinic visit and added assessments to be 
performed at this visit
Rationale for Change: Because the duration of treatment was changed to 20 weeks, 
additional study visits were incorporated. Other changes were implemented for clarification.
Sections Impacted:

Appendix 1 (Table 3)
52.
Updated Appendix 2
Description of Change: Removed Perampanel and added Trileptal and Epidiolex to the list of 
concomitant AEDs and added alpha-1-acid glycoprotein to the list of serum chemistry 
analytes.
Rationale for Change: To ensure the table shown in Appendix 2 accurately reflects the tests 
that will be performed by the central laboratory. Perampanel was removed because it is now a 
prohibited medication.
Sections Impacted:

Appendix 2
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 102 of 106
53.
Updated the Appendix 3 study sampling summary
Description of Change: Updated the maximum amounts per sample and the maximum 
number of samples.
Rationale for Change: To be consistent with the current laboratory manual for the study.
Sections Impacted:

Appendix 3
54.
Replaced table in Appendix 3
Description of Change: Removed the previous table and inserted a new table for blood 
volume collection of pediatric patients.
Rationale for Change: The previous table did not accurately reflect the blood volumes for the 
primarily pediatric populations in this study.
Sections Impacted:

Appendix 3
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 103 of 106
AMENDMENT 1
1.
Removal of ‘Non-Dravet patients with convulsive seizures”
Description of Change: Third stratum of the study is removed, and there will be only two 
strata Dravet syndrome and Lennox Gastaut syndrome.
Rationale for Change: Third stratum of the study was removed based on feedback received 
from the FDA to stratify patients according to their individual DEE syndromes and reduce the 
number of syndromes in the study.
Sections Impacted:
Synopsis: Section 6.2.1
Section 6.2.2
Section 7.1
Section 9.3
Section 12.2
Section 12.3
Section 12.9.1
Section 12.9.2
Section 12.13
2.
To change name of ‘Drop seizure’ stratum to ‘LGS stratum’
Description of Change: Name of Drop seizure stratum will be changed to LGS stratum
Rationale for Change: Based on feedback from the FDA the study is limited to two 
syndromes only, LGS and Dravet syndrome. Drop seizure stratum will only be limited to LGS 
patients and the name is changed accordingly.
Sections Impacted:
Synopsis
Section 6.2.1
Section 6.2.2
Section 7.1
Section 9.3
Section 12.2
Section 12.3
Section 12.9.1
Section 12.9.2
Section 12.13
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 104 of 106
3.
To increase duration of maintenance period from 10 weeks to 12 weeks
Description of Change: Maintenance period of the study is increase from 10 weeks to 12 
weeks.
Rationale for Change: A 12-week efficacy assessment is an FDA requirement to properly 
evaluate maintenance of treatment effect. With the availability of 9-month chronic toxicity 
data, it is now justified to extend the maintenance duration to 12 weeks.
Sections Impacted:
Synopsis
Section 7.1
Section 12.9.1
Section 12.9.2
Appendix 1 (Schedule of Assessments)
4.
To allow administration of TAK-935 via gastrostomy tube (G-tube)/percutaneous 
endoscopic gastrostomy (PEG) tube
Description of Change: To clarify administration of TAK-935 in patients with G- or PEG-
tube.
Rationale for Change:
Approximately 30% of pts with DEE can’t swallow oral medications or eat food orally, so 
these patients are fed and administered medication via gastric tube. With the availability of a 
CMC study report showing that administration of TAK-935 is viable through G- or PEG-tube, 
this option is justified.
Sections Impacted:
Section 9.2
5.
Change in sample size the sample size
Description of Change:
The total sample size was changed from 152 to 112.
Rationale for Change:
Due to the reduction in the number of strata from 3 to 2 (above Changes 1 and 2), the total 
sample size was recalculated (Dravet stratum: 46 and LGS stratum: 80).
Sections Impacted:
Synopsis
Section 12.3
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 105 of 106
6.
Remove exclusion criterion for status epilepticus (exclusion criterion #1)
Description of Change: To remove exclusion of patients admitted to a medical facility and 
intubated for treatment of status epilepticus within 1 month of the Screening visit.
Rationale for Change: It was a repetitive and created confusion. Patients with frequent status 
epilepticus will be excluded per exclusion criterion #2
Section Impacted:
Synopsis
Section 8.2
7.
Remove exclusion criterion for inability to swallow study drug safety (exclusion 
criterion #3)
Description of Change: Remove exclusion based on the inability to swallow study drug 
safety by mouth
Rationale for Change: To allow administration of TAK-935 or placebo via G-tube/PEG tube 
after finalization of CMC in vitro studies demonstrating nearly 100% drug delivery through a 
G-tube when crushed and suspended in water.
Sections Impacted:
Synopsis
Section 8.2
8.
Remove exclusion criterion for positive drug screen at screening
Description of Change: Remove exclusion based on positive drug screen at Screening
Rationale for Change: Patients with history of drug use disorder would continue to be 
ineligible for the study, but screening for illicit drugs is removed. We were advised by clinical 
advisors and representative of patient foundations that majority of Dravet and LGS syndromes 
who have treatment resistant seizures will not be capable of buying and using illicit drugs. 
And this test would result in an unnecessary blood draw.
Sections Impacted:
Synopsis
Section 8.2
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Protocol TAK-935-2002 (OV935) Amendment 2
Ovid Therapeutics, Inc.
Date: 11 February 2019 
Page 106 of 106
9.
BMI assessment removed
Description of Change: Measurement of BMI at screening removed
Rationale for Change: Changes in percentile and absolute weight and height of pediatric 
patients will be used for assessment. BMI assessment was repetitive, and its utility is less 
useful in pediatric patients compared to adult patients.
Sections Impacted:
Synopsis
Section 6.2.5
Section 10.1.5
Section 12.5
Section 12.10
Section 12.10.1
Appendix 1 (Schedule of assessments)
10.
Perampanel added as a concomitant AED medication
Description of Change: Perampanel was added as a concomitant AED medication for which 
plasma concentrations will be investigated
Rationale for Change: Level of perampanel was missed from the list of AEDs in the original 
protocol.
Section Impacted:
Appendix 2
11.
Patients with Hepatitis B and C are excluded
Description of Change: Patients will be excluded based on a history of active hepatitis B or 
active hepatitis C infection.
Rationale for Change: Active Hepatitis B and C infection would not interfere with TAK-935 
administration or metabolism or effectiveness, therefore, patients will not be tested for 
hepatitis infection. However, patients with known hepatitis infection will be excluded. Other 
exclusion criteria exclude patients with abnormal liver enzymes or unstable medical conditions 
that could be caused by Hepatitis infection. Patients with Dravet and LGS syndromes with 
active hepatitis B and C would be known to their treating physicians because these are 
frequently seen in the clinics for their treatment resistant seizures.
Sections Impacted:
Synopsis
Section 8.2
Appendix 3 (Sampling summary)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF TAK-935 (OV935) AS AN ADJUNCTIVE THERAPY IN PEDIATRIC 
PATIENTS WITH DEVELOPMENTAL AND/OR EPILEPTIC ENCEPHALOPATHIES (ELEKTRA)
NCT Number: NCT03650452
SAP Approve Date: 15 June 2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Please note that the statistical output shells have been removed for brevity, since they are not a
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
1
Ovid Therapeutics, Inc.
TAK-935-2002 (OV935)
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy, Safety, and Tolerability of TAK-935 (OV935) as an Adjunctive Therapy in 
Pediatric Patients with Developmental and/or Epileptic Encephalopathies (ELEKTRA)
15 June 2020
Statistical Analysis Plan
Version Final 1.0
Ovid Therapeutics, Inc.
1460 Broadway
New York, NY10036
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
2
Approved by 
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
nd Subject to the Applicable T


Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
3
TABLE OF CONTENTS
List of Abbreviations and Definition of Terms
7
1.
INTRODUCTION
9
2.
OBJECTIVES
10
2.1.
Primary Objective
10
2.2.
Secondary Objectives
10
2.3.
Exploratory Objectives
11
2.4.
Safety Objectives
11
3.
INVESTIGATIONAL PLAN
11
3.1.
Overall Study Design and Plan
11
Figure 1:
Study Design for Clinical Protocol OV/TAK-935-2002
13
Figure 2: 
Study Design for Clinical Protocol OV/TAK-935-2002 (Protocol 
Amendment 2)
14
3.2.
Study Endpoints
15
3.2.1 Primary Efficacy Endpoints
15
3.2.2 Secondary Efficacy Endpoint
15
3.2.3 Exploratory Endpoints
16
3.2.4 Pharmacokinetic Endpoints
17
3.2.5 Safety Endpoints
17
3.3.
Treatments
17
Table 1: 
Dosing Schedule by Weight
18
3.4.
Dose Adjustment/Modification
19
4.
GENERAL STATISTICAL CONSIDERATIONS
19
4.1.
Visits and Day Ranges
20
4.2.
Sample Size
21
Table 2: 
Within-Stratum Size Calculations
22
4.3.
Randomization, Stratification and Blinding
22
4.4.
Analysis Set
23
4.4.1 All Randomized Analysis Set
23
4.4.2 Modified Intent-to-Treat Analysis Set
23
4.4.3 Efficacy Analysis Set
23
4.4.4 Per-protocol Analysis Set
23
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
4
4.4.5 Safety Analysis Set
23
5.
PATIENT DISPOSITION
24
5.1.
Study Enrollment
24
5.2.
Inclusion and Exclusion Criteria
24
5.3.
Disposition
24
5.4.
Protocol Deviations
26
6.
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
26
6.1.
Demographics
26
6.2.
Baseline Characteristics
26
7.
MEDICAL HISTORY
27
8.
Prior and Concomitant Medications and Procedures
27
8.1.
Prior and Concomitant Medications
27
8.2.
Prior and Concomitant Procedures
28
9.
STUDY TREATMENTS
28
9.1.
Extent of Exposure
28
9.2.
Treatment Compliance
28
10.
EFFICACY ANALYSES
28
10.1.
Analyses of the Primary Endpoint
28
10.1.1 Primary Analysis
28
10.1.2 Supportive Analysis
30
10.1.3 Sensitivity Analysis
30
10.2.
Analyses of the Secondary Efficacy Endpoints
30
10.3.
Exploratory Analysis
33
10.3.1 Proportion of Patients with reduction in frequency of seizures requiring rescue 
medication
34
10.3.2 Seizure Frequency Reduction
34
10.3.3 Proportion of Seizure-free Days
34
10.3.4 Seizure Frequency Reduction Time Effect
35
10.3.5 Seizure Frequency at Weeks 4, 8, 12, 16, and 20
35
10.3.6 Longest Seizure-free Days
35
10.3.7 Use of Rescue Medication
35
10.3.8 New Seizure Type
35
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
5
10.3.9 Subgroup Analysis for Chinese Sites on the Seizure Frequency
35
10.3.10 Quality of Life in Childhood Epilepsy (QoLCE)
36
10.4.
Pharmacokinetic Analysis
36
11.
SAFETY ANALYSES
36
11.1.
Adverse Events
36
11.1.1 Incidence of Adverse Events
36
11.1.2 Study Medication-related TEAEs
37
11.1.3 Severity of TEAEs
37
11.1.4 Serious TEAEs
37
11.1.5 TEAEs Leading to Treatment Discontinuation/Study Termination
37
11.1.6 Death
38
11.1.7 TEAEs of Special Interest
38
11.2.
Clinical Laboratory Evaluations
38
11.2.1 Hematology
38
11.2.2 Clinical Chemistry
39
11.2.3 Urinalysis
39
11.2.4 Microscopic Results
39
11.3.
Vital Signs
39
11.4.
Physical Examination
39
11.5.
Safety ECG (12-lead ECG)
40
11.6.
Clinical Assessment of Suicidal Ideation and behavior
40
11.7.
Myoclonic and Atypical Absence Free Days Seizures
40
11.8.
Neurological and Ophthalmic Examination
41
11.9.
Sleep Disruption Numerical Rating Scale
41
11.10.
Vineland Adaptive Behavior Scale
41
11.11.
Behavior Checklist – Community Edition (ABC-C)
42
11.12.
Investigator’s assessments of VABS and ABC-C
43
11.13.
Exit Survey
43
11.14.
Pharmacodynamic Biomarker
43
11.15.
Subgroup of All Patients from Chinese Sites
43
12.
OTHER STATISTICAL ISSUES
44
12.1.
Significance Levels
44
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
6
12.2.
Handling of Missing Data
44
13.
REFERENCES
45
14.
APPENDICES
46
14.1.
Listing of Planned Tables
46
14.2.
Listing of Planned Listings
53
14.3.
Listing of Planned Figures
54
14.4.
Imputation Algorithm for Partial and Missing Dates
55
14.5.
Schedule of Study Procedures
56
14.6.
List of AEs of Special Interest Preferred Terms
60
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
7
List of Abbreviations and Definition of Terms
Term
Definition
24HC
24S-hydroxycholesterol
ABC-C
Aberrant Behavior Checklist-Community
AE
Adverse Event
AED
antiepileptic drugs
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BID
twice daily
CGI-S/C
Clinician’s Clinical Global Impression of Severity and Change
Care GI-C
Caregiver Global Impression of Change
CI
confidence interval
CNS
central nervous system
CSR
Clinical Study Report
C-SSRS
Columbia–Suicide Severity Rating Scale
CYP
cytochrome P-450
DEE
developmental and epileptic encephalopathy
DS
Dravet syndrome
ECG
electrocardiogram
EE
epileptic encephalopathy
EEG
electroencephalogram
GGT
Gamma-glutamyl transferase
HDL
High-density lipoproteins
HLGT
High Level Group Term
HLT
High Level Term
ICH
International Conference on Harmonization
iDMC
independent Data Monitoring Committee
IEC
Independent Ethics Committee
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
8
Term
Definition
ILAE
International League Against Epilepsy
IRB
Institutional Review Board
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LDL
Low-density lipoproteins
LGS
Lennox-Gastaut syndrome
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMRM
Mixed Model for Repeated Measure 
PA1
Protocol Amendment 1
PA2
Protocol Amendment 2
PD
pharmacodynamic(s)
PEG
percutaneous endoscopic gastrostomy
PK
Pharmacokinetic(s)
PT
Preferred Term
RBC
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
VABS
Vineland Adaptive Behavior Scale
VNS
Vagal Nerve Stimulator
WBC
White Blood Cells
WHO-DD
World Health Organization Drug Dictionary
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
9
1. INTRODUCTION
Epileptic encephalopathies (EE) refer to a group of rare disorders in which the unremitting 
epileptic activity contributes to severe cognitive and behavioral impairment and these can 
worsen overtime leading to progressive cerebral dysfunction. Epileptic encephalopathies start 
at an early age and manifest with seizures, which are usually intractable, have aggressive 
electroencephalogram (EEG) paroxysmal abnormalities and severe neurocognitive deficits. 
Potential to halt or improve the neurocognitive consequences of epilepsy with a successful 
treatment is a fundamental concept behind clustering of these disorders. In a group of severe 
genetic disorders causing EE, the underlying genetic mutation also contributes to 
developmental delay, in addition to severe epilepsy in these patients. Hence, the International 
League Against Epilepsy (ILAE) expanded the concept of EE from the severe epilepsies with 
onset in infancy and childhood to epilepsy syndromes associated with encephalopathy 
including those that have a genetic etiology. The revised classification now refers to 
Developmental Epileptic Encephalopathies (DEEs). Dravet syndrome (DS) or severe 
myoclonic epilepsy in infancy is one of the most well--known disorders of the epileptic 
encephalopathies. Clinically, DS is characterized by frequent convulsive febrile seizures, 
followed later by nonfebrile seizures, mainly clonic and unilateral, of long duration and 
frequent status epilepticus (SE). LGS is rare and is one of the most severe forms of childhood 
epilepsy. The syndrome usually has its onset between the ages of 1 and 8 years (typically 
between 3 and 5 years), but occasionally it occurs in children who are more than 8 years old, 
even into adulthood. The hallmarks of the disease include: presence of multiple seizure types: 
the hallmark tonic-atonic seizures; the most hazardous are drop seizures/attacks, which can 
lead to serious injuries and occur in about 56% of patients. Other seizure types include
atypical absences, but tonic-clonic, myoclonic, and partial seizures are also frequently 
present. 
The current study is designed to further characterize the effects of TAK-935 on seizure 
frequency using a seizure diary. An additional aim is to explore the safety, tolerability, PK, 
and PD of multiple-dose TAK-935 administration in pediatric patients with developmental 
and/or epileptic encephalopathies. 
This Statistical Analysis Plan (SAP) describes the data-handling and statistical procedures to 
be used for the statistical analysis and reporting of efficacy and safety data collected under 
the Ovid Protocol TAK-935-2002 (OV935) Amendment 2 (February 11, 2019). The methods 
of analysis in this SAP expand on statistical considerations identified in the protocol; where 
considerations are substantially different, they will be identified as such in this document. 
CCI
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
10
This SAP has been developed and finalized prior to locking the clinical database for the 
primary analysis. Any additional analyses required to supplement the analyses specified in 
this SAP will be considered exploratory and will be identified in the Clinical Study Report 
(CSR).
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principals for Clinical Trials” and the most recent ICH-E3 Guideline entitled “Guidance for 
Industry: Structure and Content of Clinical Study Reports.”
2. OBJECTIVES
2.1. Primary Objective
●
To investigate the effect on the frequency of all seizures (convulsive and drop) in 
patients treated with TAK-935 as an adjunctive therapy compared to placebo in the 
Maintenance Period.
2.2. Secondary Objectives
●
To investigate the effect on the frequency of all seizures (convulsive and drop) in 
patients treated with TAK-935 as an adjunctive therapy compared to placebo throughout 
the Treatment Period
●
To investigate the effect on the frequency of convulsive seizure in patients with Dravet 
Syndrome treated with TAK-935 as an adjunctive therapy compared to placebo in the 
Maintenance Period
●
To investigate the effect on the frequency of drop seizure in patients with LGS treated 
with TAK-935 as an adjunctive therapy compared to placebo in the Maintenance Period
●
To investigate the seizure frequency of LGS patients considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with:
-
Reduction of 25% or more in drop seizures from baseline
-
Reduction of 50% or more in drop seizures from baseline
-
Reduction of 75% or more in drop seizures from baseline
-
Reduction of 100% in drop seizures from baseline
●
To investigate the seizure frequency of Dravet patients considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with:
-
Reduction of 25% or more in convulsive seizures from baseline
-
Reduction of 50% or more in convulsive seizures from baseline
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
11
-
Reduction of 75% or more in convulsive seizures from baseline
-
Reduction of 100% in convulsive seizures from baseline
●
To investigate change in Clinical Global Impression of Severity and Change assessment 
(CGI-S/C) responses of Investigator and Caregiver Clinical Global Impression of 
Change assessment (Care GI-C) in patients treated with TAK-935 as an adjunctive 
therapy compared to placebo
●
To characterize the relationship between plasma 24HC levels and seizure frequency
2.3. Exploratory Objectives
2.4. Safety Objectives
●
To evaluate safety and tolerability of TAK-935 as adjunctive therapy as compared to 
placebo
●
To evaluate the occurrence of myoclonic and atypical absence-free days to determine if 
there is worsening of these seizure types during treatment with TAK-935
●
To investigate the effect on behavior and adaptive function in patients treated with TAK-
935 as adjunctive therapy compared to placebo using the Vineland Adaptive Behavioral 
scales (VABS) and Aberrant Behavior Checklist-Community questionnaire (ABC-C)
3. INVESTIGATIONAL PLAN
3.1. Overall Study Design and Plan
Study TAK-935-2002 (OV935) is a Phase 2, multicenter, randomized, double-blind, placebo-
controlled, parallel-group, study in pediatric patients (aged ≥2 and ≤17 years) with Dravet 
syndrome and LGS demonstrating ≥3 convulsive and ≥4 drop seizures, respectively, per 
month during the 3 months immediately prior to Screening (based on historical information) 
and ≥3 convulsive or ≥4 drop seizures, respectively, during a minimum of 4 weeks during the 
CCI
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f 
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NVES
3.1.
3.1 O
Only and Subject to the Applic


Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
12
prospective Baseline Period (based on the seizure diary records). Convulsive seizures include 
generalized tonic-clonic, focal to bilateral tonic-clonic with impaired awareness, hemi-clonic 
and simultaneous bilateral clonic (generalized clonic) seizures. Drop seizures are defined as 
involving the entire body, trunk, or head that leads to a fall, injury, slumping in a chair, or 
head hitting a surface, or that could have led to a fall or injury, depending on the position of 
the patient at the time of the seizure or spell. Examples of seizures causing drop include, but 
are not limited to, atonic, clonic, and tonic seizures.
Approximately 126 patients will be randomized to ensure 112 patients with evaluable 
primary endpoint. Randomization will be stratified by 2 categories: Dravet syndrome patients 
with convulsive seizures and LGS patients with drop seizures. Stratification will be 
performed to ensure balance of treatments within each stratum.
The study will begin with a phased enrollment based on age. Patients aged ≥9 years will be 
enrolled first, prior to open enrollment in the study, for assessment of safety. The 
independent Data Monitoring Committee (iDMC) will review the adverse event (AE) 
profiles of the first 12 patients aged ≥9 years completing 4 weeks of treatment across all 
ongoing pediatric TAK-935 studies, prior to recommending treatment for patients aged <9 
years.
For patients consented to protocol amendment 1 (PA1) and terminated prior to protocol 
amendment 2 (PA2), the study consists of 2 main periods:

4- to 6-week Screening/Baseline Period

14-week Treatment Period

2-week Titration Period

12-week Maintenance Period 
The 4-week minimum baseline period will be used to collect seizure diary data.  All the data 
collected prior to first dose date will be used to calculate baseline seizure data.
The Treatment Period consists of Titration Period and Maintenance Period. Figure 1
illustrates the study design.
For patients enrolled in, or reconsented from protocol amendment 1 to, protocol amendment 
2, the study consists of 2 main periods:

4- to 6-week Screening/Baseline Period

20-week Treatment Period
-
8-week Dose Optimization Period
-
12-week Maintenance Period
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
13
The Treatment Period consists of the Dose Optimization Period and Maintenance Period. 
Figure 2 illustrates the study design. 
Figure 1:
Study Design for Clinical Protocol OV/TAK-935-2002
Dravet Syndrome patients who have had, on average, ≥3 convulsive or LGS patients who 
have had on average ≥4 drop seizures per month during the 3 months immediately prior to 
Screening (based on historical information) and ≥3convulsive or ≥4 drop seizures, 
respectively, during a minimum of 4 weeks during the Baseline Period (based on the seizure 
diary records) will be eligible for entry into the study.
For subjects who completed PA1 only the titration and maintenance periods are defined by 
the PA1 visit schedule (Day 1 to 14 for the Titration Period and Day 15 to Day 98 for the 
Maintenance Period). For subjects who are randomized under PA2, Dose Optimisation (Day 
1 to 56) and Maintenance periods (Day 57 to 141) are defined as per the PA2 visit schedule.
For subject who randomized in PA1 and subsequently reconsents to PA2, the Titration period 
will be from Day 1 to 14, Dose Optimization will be from Day 15 to 56 and Maintenance 
will be from Day 57 to 141. Subjects in PA1 will be treated as being in the maintenance 
phase from Week 3 (Day 15) and subjects who reconsent to PA2 or who randomized in PA2 
will be treated as being in the maintenance phase from Week 9 (Day 57). 
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
14
At the end of the prospective 4- to 6-week Screening/Baseline Period, patients will return to 
the clinic (Visit 2). Seizure diaries will be reviewed by the Medical Monitor or delegated 
staff and if a patient did not meet the eligibility criteria, including minimum number of 
seizures required for the study and seizure stratum, the patient will be discontinued from the 
study and considered a screen failure.
Figure 2:
Study Design for Clinical Protocol OV/TAK-935-2002
(Protocol 
Amendment 2)
Patients and/or patients’ caregivers will be provided with a seizure diary and will be 
instructed to record seizure data daily starting at Visit 1 (screening visit) and to continue 
throughout the study. The seizure diary data will be collected during the prospective Baseline 
Period and will be used as the baseline seizure data for endpoint analyses. An external 
independent or Sponsor’s reviewer(s) will confirm the patient’s diagnosis prior to 
randomization.
Patients who cannot tolerate Dose 1 will be withdrawn from the study. 
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
15
3.2. Study Endpoints
3.2.1 Primary Efficacy Endpoints
The primary endpoint for this study is the percent change from Baseline in seizure frequency 
per 28 days (based only on convulsive seizures for the patients in the Dravet syndrome 
stratum and drop seizures for the patients in the LGS stratum) in patients receiving TAK-935 
as compared to placebo during the Maintenance Period. 
3.2.2 Secondary Efficacy Endpoint
Percent change from Baseline in seizure frequency per 28 days (based only on convulsive 
seizures for patients in the Dravet syndrome stratum and drop seizures for patients in the 
LGS stratum) in patients receiving TAK-935 as compared to placebo during the 
Treatment Period
Percent change from Baseline in convulsive seizure frequency per 28 days in patients in
the Dravet syndrome stratum and receiving TAK-935 as compared to placebo during the 
Maintenance Period
Percent change from Baseline in drop seizure frequency per 28 days in patients in the LGS 
stratum and receiving TAK-935 as compared to placebo during the Maintenance Period
Proportion of patients in the LGS stratum considered treatment responders throughout the 
Maintenance Period; treatment responders are defined as those with:
-
Reduction of 25% or more in drop seizures from baseline 
-
Reduction of 50% or more in drop seizures from baseline 
-
Reduction of 75% or more in drop seizures from baseline 
-
Reduction of 100% in drop seizures from baseline 
Proportion of patients in the Dravet syndrome stratum considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with: 
-
Reduction of 25% or more in convulsive seizures from baseline 
-
Reduction of 50% or more in convulsive seizures from baseline 
-
Reduction of 75% or more in convulsive seizures from baseline 
-
Reduction of 100% in convulsive seizures from baseline 
Change in CGI-S responses of Investigator reported impression of efficacy and tolerability 
of study drug
Summary of CGI-C responses reported impression of efficacy and tolerability of study 
drug 
Summary of Care GI-C responses of parent/family reported impression of efficacy and 
tolerability of study drug 
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
16
! To characterize plasma 24HC levels and change in seizure frequency in patients treated with 
TAK-935 as an adjunctive therapy 
3.2.3 Exploratory Endpoints
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
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3.2.4 Pharmacokinetic Endpoints
! To determine the plasma concentrations of TAK-935 and the TAK-935 metabolite (M-I) 
at multiple time points 
! Estimate exposure parameters from sparse PK samples using population modelling 
! Determine any potential relationship with estimated TAK-935 exposure parameters with 
changes in seizure frequency 
3.2.5 Safety Endpoints
! Incidence of treatment-emergent adverse events (TEAEs) 
! Incidence of abnormal values for clinical laboratory evaluations, vital signs, body weight 
and height, and electrocardiogram (ECG) parameters after TAK935 treatment
! Change from Baseline in clinical laboratory evaluations, vital signs, body weight, 
Columbia-Suicide Severity Rating Scale (C-SSRS), and ECG parameter values after 
TAK-935 treatment
! Mean percent of myoclonic- and atypical-absence free days in patients receiving TAK-
935 as compared to placebo during the Maintenance Period
!
Change in behavioral and adaptive functional measures using the VABS
!
Change in behavior measures using total scores and subscale scores of ABC-C for 
patients ≥6 years of age 
3.3. Treatments
All patients will receive TAK-935 BID orally or via gastrostomy tube (G-tube)/percutaneous 
endoscopic gastrostomy (PEG) tube with or without food (patients enrolled in clinical sites in 
China are not to receive study drug via G-tube/PEG tube).
For patients weighing <60 kg at Visit 1, the total daily dose of study drug (either placebo or 
TAK-935) is calculated based on body weight at Visit 1 and will be given twice a day (BID). 
The selected doses for the different weight groups are listed in Table 1. For patients weighing 
≥60 kg at Visit 1, dosing will be 200 mg/day followed by 400 mg/day, then 600 mg/day 
(Table 1). Study drug can be taken with or without food.
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Ovid Therapeutics Inc.
Final Statistical Analysis Plan, Version 1.0
TAK-935-2002 (OV935)
Date Issued: 15June2020
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Patients weighing <60 kg will be dispensed 20 mg mini-tablets or matching placebo, and 
patients weighing ≥60 kg will be dispensed 100 mg tablets or matching placebo. If patients 
are unable to swallow tablets or mini-tablets, formulation can be changed. No change in 
formulations will be made after Visit 5 (Day 29) for patients consented on protocol 
amendment 1 and early terminated prior to protocol amendment 2 and Visit 4 (Day 36) for 
patients randomized/reconsented to protocol amendment 2.
Patients randomized in protocol amendment 1 will receive the initial dose of study drug, 
Dose 1, for the first 7 days after randomization at Visit 2. In the two subsequent visits 
(Visit 3 and Visit 4) the study drug dose will be increased to Dose 2 and Dose 3, respectively. 
The maximum dose for any patient will be 600 mg/day. The final dose level will be 
maintained until the end of the Maintenance Period; however, the dose may be decreased 1 
time to the previous lower doses, for safety and tolerability issues. For example, Dose 3 may 
be reduced to Dose 2 and Dose 2 may be reduced to Dose 1. If Dose 1 is not tolerated, the 
patient will be withdrawn from the study. 
Patients randomized in protocol amendment 2 will receive the initial dose of study drug, 
Dose 1, for the first 7 days after randomization at Visit 2. In the subsequent phone call and 
visit (phone call 1 [Day 8] and Visit 3[Day 15]), the study drug dose will be increased to 
Dose 2 and Dose 3, respectively. The maximum dose for any patient will be 600 mg/day. 
Patients will be contacted by phone within first 2 days following escalation to the maximum 
dose to assess safety and tolerability of the study drug. Study drug dose will be allowed to 
change in the first 6 weeks of the Dose Optimization Period based on the judgment of the 
Investigator and with the approval of the Medical Monitor. The final dose level will be 
maintained until the end of the Maintenance Period; however, the dose may be decreased to 
the previous lower doses, for safety and tolerability issues. For example, Dose 3 may be 
reduced to Dose 2 and Dose 2 may be reduced to Dose 1 during Maintenance Period. If Dose 
1 is not tolerated, the patient will be withdrawn from the study.
Table 1:
Dosing Schedule by Weight
Weight (kg)
Dose 1 
Dose 2 
Dose 3 
(mg/day)a
No. Tablets/ 
Mini-tablets
(mg/day)a
No. 
Tablets/ 
Mini-tablets
(mg/day)a
No. 
Tablets/ 
Mini-tablets
10-14
80
0/4
160
0/8
220
0/11
15-19
120
0/6
200
0/10
260
0/13
20-24
120
0/6
240
0/12
320
0/16
25-29
120
0/6
240
0/12
360
0/18
30-34
160
0/8
280
0/14
400
0/20
35-39
160
0/8
280
0/14
440
0/22
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Weight (kg)
Dose 1 
Dose 2 
Dose 3 
(mg/day)a
No. Tablets/ 
Mini-tablets
(mg/day)a
No. 
Tablets/ 
Mini-tablets
(mg/day)a
No. 
Tablets/ 
Mini-tablets
40-44
160
0/8
320
0/16
480
0/24
45-49
200
0/10
360
0/18
480
0/24
50-54
200
0/10
360
0/18
520
0/26
55-59
200
0/10
360
0/18
560
0/28
≥60
200
2/0
400
4/0
600
6/0
a Total dose administered twice daily.
3.4. Dose Adjustment/Modification
The dose may be increased per Investigator’s discretion with approval of the Sponsor’s 
Medical Monitor to a maximum of Dose 3 level. All dose changes must be made during the 
Titration Period for patients consented to protocol amendment 1 and Dose Optimization 
Period for patients consented to protocol amendment 2; dose changes during the Maintenance 
Period must be discussed and approved by the Sponsor.
4. GENERAL STATISTICAL CONSIDERATIONS
All statistical analyses will be performed using SAS® Version 9.4 or higher. All clinical 
study data will be presented in patient data listings. Data summaries will be presented for all 
endpoints and will include descriptive statistics (number of patients [n], mean, standard 
deviation [SD], first quartile [Q1], median, third quartile [Q3], minimum and maximum) for 
continuous variables, and frequency and percentage for categorical and ordinal variables. If 
there are missing values, the number of missing will be presented, but without a percentage.
For all analyses, ‘Baseline’ refers to the prospective 4-week Baseline Period.  Unless 
otherwise stated the baseline observation will be defined as the last non-missing observation 
on or before the date of first dose of study medication. Baseline seizure frequency 
normalized to 28 days will use all the seizure diary data prior to first dose date (4 – 6 weeks).
If there are multiple records within a pre-specified visit window the non-missing visit closest 
to the scheduled visit day will be included in the summary tables. The assessment record(s) 
from the unscheduled visit(s) will be used only if there is no assessment record available 
from any scheduled visit.
The following reporting conventions apply generally to tables, listings and figures:
●
All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
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places than the measured value. Minimum and maximum will be formatted to the 
same decimal as the measured value;
●
All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses. In the case the numerator is equal to the denominator, the percentage 
should be presented as (100) instead of (100.0). For TEAEs, the number, percentage, 
and event incidence will be presented in the form of xx (xx.x) [E], where E is the 
number of events;
●
All listings will be sorted for presentation in order of randomized treatment group, 
study center, subject, and date of procedure or event;
●
All analysis and summary tables will have the analysis population sample size for 
each treatment group in the column heading (i.e., number of subjects);
●
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as “<0.0001” and p-values that round to 1.0000 will be presented as 
“>0.9999”;
●
The day of first dose of study drug, TAK-935, will be defined as Day 1. For day 
calculation, if date is before first dose date then day=date - first dose date, if date is 
after first dose date then day=date - first dose date + 1;
●
Listings of all data will identify the age group (adolescent/adult) of each subject.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be 
described in the statistical analysis plan (SAP) which will be finalized and approved prior to 
database lock. Additional exploratory analyses of the data may be conducted as deemed 
appropriate.
4.1. Visits and Day Ranges
Since it is not always possible for all study participants to come in for their clinic visits on 
the exact day specified in the protocol schedule, the subject’s visit will be defined by the 
following relative day ranges. Study days below will be used for Unscheduled visits.
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For patients consented under protocol v1.0 and terminated prior to protocol v2.0.
Visit
Target
Study Days 
V2 Day 1
Day 1
Day 1
V3 Day 8
Day 8
Days 2 to 12
V4 Day 15
Day 15
Days 13 to 21
V5 Day 29
Day 29
Days 22 to 52
V6 Day 60
Day 60
Days 53 to 90
V7 Day 98
Day 98
Day 91 to 120
V8 Day 128
Day 128
Day 121 onwards
For patients randomized or reconsented to protocol v2.0. 
Visit
Target
Study Days 
V2 Day 1
Day 1
Day 1
P1 Day 8
Day 8
Days 2 to 12
V3 Day 15
Day 15
Days 13 to 21
P2 Day 22
Day 22
Days 22 to 28
V4 Day 36
Day 36
Days 29 to 54
P3 Day 57
Day 57
Days 55 to 77
V5 Day 85
Day 85
Days 78 to 110
P4 Day 113
Day 113
Days 111 to 133
V6 Day 141
Day 141
Days 134 to 161
V7 Day 169
Day 169
Day 162 onwards
All visits prior to reconsent date will follow protocol Version 1.0 visit structure and all visits 
after the reconsent date will follow protocol Version 2.0 visit structure.  All patients 
reconsented to protocol Version 2.0 from protocol Version 1.0, the maintenance period starts
at Week 9.
4.2. Sample Size
The sample size calculations are based on unadjusted Mann-Whitney (Wilcoxon rank-sum) 
test. 
Randomization will be stratified by 2 categories: 
• Dravet syndrome stratum 
• LGS stratum 
The primary endpoint is defined as percent change in convulsive seizures for the patients in 
the Dravet syndrome and percent change in drop seizures for those in the LGS stratum. 
If the mean difference in percentage change from baseline between active and placebo arms 
is 29% for the 2 strata combined and the standard deviation is 42.3%, with 56 patients per 
treatment group, there will be 92% power to test the treatment difference at a two-sided 0.05 
level of significance. Assuming a 10% drop-out rate, 63 patients per arm will be randomized. 
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Within the 2 randomization strata, hypothesis tests will be performed at levels of significance 
higher than 0.05 in this Phase 2 proof of concept study and will have power of 80%. Table 2
shows the within-stratum sample size calculations:
Table 2:
Within-Stratum Size Calculations
Dravet 
Syndrome 
Stratum
Drop 
Seizure 
Stratum
Alpha
0.1
0.1
1-sided or 2-sided
2
2
Treatment Difference
0.30
0.28
Standard Deviation
0.35
0.45
Power
80%
80%
N per group
20
36
N per group (after 10% adjustment)
23
40
Total N
46
80
A minimum of 46 patients (23 per treatment group) will be randomized to the Dravet 
syndrome stratum. A minimum of 80 patients (40 per treatment group) will be enrolled in the 
LGS stratum.
4.3. Randomization, Stratification and Blinding
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2. Assignment to treatment groups will be determined by a computer-generated random 
sequence using an IWRS. The IWRS will be used to assign tablets/mini-tablets containing 
double-blind study drug to each patient. 
To achieve between-group comparability, randomization will be stratified. 
At Visit 2, all eligible patients will be stratified by 2 categories: patients with Dravet 
syndrome with convulsive seizures, and LGS patients with drop seizures to ensure balance of 
treatments within each stratum.
Note that patients with the minimum number of convulsive or drop seizures will be assigned 
to a stratum following these stratification rules: 
Patients with Dravet syndrome: 
• 46 eligible patients diagnosed with Dravet syndrome with ≥3 convulsive seizures per 28 
days during the prospective Baseline Period will be randomized into the Dravet syndrome 
stratum 
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Patients with LGS (Lennox Gastaut Syndrome): 
• 80 eligible patients diagnosed with LGS with ≥4 drop seizures per 28 days during the 
prospective Baseline period will be randomized into the LGS stratum 
If a patient does not meet any of these, the patient will be considered a screen failure.
4.4. Analysis Set
4.4.1 All Randomized Analysis Set
The all randomized analysis set includes all patients who are randomized into the study.  This 
includes all patients who are randomized into study based on protocol amendment 1 or
protocol amendment 2.
4.4.2 Modified Intent-to-Treat Analysis Set
All Randomized Analysis Set who have received at least one dose of study drug and have 
been assessed for at least one day in the Treatment period will be included in the modified 
intent-to-treat (mITT) analysis set. All mITT analyses will be based on each patient’s 
randomized treatment assignment.
4.4.3 Efficacy Analysis Set
All mITT patients whose efficacy assessments are compliant with Protocol Amendment 2 
will be included in the efficacy analysis set. The primary efficacy analyses for the primary 
and secondary efficacy endpoints will be based on the efficacy analysis set. All analyses 
performed on Efficacy Analysis Set will be based on each patient’s randomized treatment 
assignment.
This analysis set includes all patients who are randomized or reconsented into protocol 
amendment 2 with 20 weeks of treatment period.
4.4.4 Per-protocol Analysis Set
All mITT patients who did not deviate from the protocol in any major way. Per-protocol
analyses will be based on each patient’s treatment actually administered.
4.4.5 Safety Analysis Set
All Randomized Analysis Set who take at least one dose of study medication will be included 
in the Safety Analysis Set. Safety analyses will be based on the medication that was actually 
administered to each patient.
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5. PATIENT DISPOSITION
5.1. Study Enrollment
Study enrollment will be summarized by site and stratum, by site and protocol group.  These 
summaries will be presented for All Randomized Analysis Set.
5.2. Inclusion and Exclusion Criteria 
All inclusion/exclusion information on enrolled subjects will be included in a by-patient 
listing.  The listing will include whether all criteria were satisfied.  For subjects who did not 
satisfy the criteria, the criterion number will be listed with the deviation, along with whether 
an exception was obtained. 
5.3. Disposition
The number of patients enrolled in the study by investigator and treatment group as well as 
overall/total columns will be tabulated.  Tables showing study participant accounting will be 
provided.  Tables will indicate number of patients who were randomized into the study, the 
number of patients who completed the study, number of patients who completed the 
treatment, and the number of patients who discontinued treatment for any of the following 
reasons: 

Liver function test abnormalities

QTcF interval > 500 ms

Greater than 100% increase in 28-day seizure frequency

Not tolerating dose 1

Enrollment in other clinical study

Depression and/or suicidal ideation

Physician decision

Withdrawal by patient

Withdrawal by parent/guardian

Sponsor decision

Adverse event

Lack of Efficacy

Lost to follow-up

Non-compliance with study drug
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
Protocol deviation

Death

Other
Also, the number of patients who discontinued study for any of the following reasons will be 
summarized:

Liver function test abnormalities

QTcF interval > 500 ms

Greater than 100% increase in 28-day seizure frequency

Not tolerating dose 1

Enrollment in other clinical study

Depression and/or suicidal ideation

Physician decision

Withdrawal by patient

Withdrawal by parent/guardian

Sponsor decision

Adverse event

Lost to follow-up

Non-compliance with study drug

Protocol deviation

Death

Other
Disposition data will be provided in patient listings. Also, disposition tables will be 
summarized for subjects who did not reconsent to PA2 or completed/early terminated to 
PA1, PA1 subjects reconsented to PA2, and subjects randomized under PA2 and by stratum.
All analyses on disposition will be based on All Randomized Analysis Set.
A separate summary of disposition will also be presented for patients whose participation of 
this trial was affected by COVID 19 in anyway (visit schedule, discontinuation, etc.).
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5.4. Protocol Deviations
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) and agreed to by the investigator. Major protocol 
deviations will be classified by categories and will be summarized in a table by treatment 
group and total column and will be displayed in a listing.  All protocol deviations will be 
presented in a by-patient listing.
A separate listing of all protocol deviations due to COVID19 and a listing of visits affected 
by COVID19 will be presented.
All analyses on protocol deviations will be based on All Randomized Analysis Set.
6. DEMOGRAPHIC AND BASELINE CHARACTERISTICS
6.1. Demographics 
Demographic characteristics include age, gender, race, ethnicity, and study center. Summary 
statistics by treatment group and overall will include counts and percentages for discrete 
variables, and means, SD, Q1, medians, Q3, minimum and maximum for continuous 
variables.
The following variables will be summarized by treatment group and by randomization 
stratum:
1) Continuous variable: age (years)
2) Categorical/discrete baseline and demographic variables: gender (female or male), 
ethnicity (Hispanic or Latino, Not Hispanic or Latino), race (American Indian or 
Alaska Native, Asian, Black or African-American, Native Hawaiian or Other Pacific 
Islander, White or Caucasian, or Other) 
6.2. Baseline Characteristics 
Baseline characteristics include baseline body weight (kg), height (cm), BMI, disease 
characteristics, number of AEDs (categorized as 1, 2, 3, 4 etc.) at baseline, reproductive 
system, neurologic examination, ophthalmic examination. Summary statistics by treatment 
group and overall will include counts and percentages for discrete variables, and means, SD, 
Q1, medians, Q3, minimum and maximum for continuous variables.
All analyses on Demographics and baseline characteristics will be performed on the
following populations,

All Randomized Analysis Set

Efficacy Analysis Set.
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
mITT

The subgroup of all patients from Chinese sites
7. MEDICAL HISTORY
All medical history will be coded using the most current Medical Dictionary for  Regulatory 
Activities (MedDRA, version 21.0 or later) and will be summarized by Stratum and by SOC 
and PT.
Patient medical history including specific details will be presented in a listing.
Analyses on medical history will be performed on mITT, Efficacy Analysis Set and the 
subgroup of all patients from Chinese sites.
8. Prior and Concomitant Medications and Procedures
8.1. Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD), June 2017. A by-patient listing of concomitant medications will 
include all medications taken during the study regardless of the timing for the start of the 
medication. All medications ended prior to the administration of the study drug will be 
included in the data but will be identified as prior in the listing. Only concomitant medication 
use will be summarized.
The number and percentage of patients who took at least 1 medication during the double-
blind period as well as the number and percentage of patients who took each type of 
medication will be presented for each treatment group. Medications will be listed according 
to their WHO-DD anatomic therapeutic chemical (ATC) class level 2 and level 4 and 
preferred drug name within ATC class level 4 by decreasing frequency of incidence for all 
active treatment groups combined.
Summary of Concomitant medication will be performed on the mITT, Efficacy Analysis Set
and the subgroup of all patients from Chinese sites.
Anti-epileptic drugs (AED) and rescue medications will also be summarized. List of AEDs is 
in Appendix 2 of the protocol. The total number of AEDs and rescue medications will be 
presented as well as the number and percentage of patients with at least 1 AED and rescue 
medication.  AED listing will also be presented.
The summary of AED and seizure rescue medication will be based on the All, Randomized
Set, mITT Analysis Set and Efficacy Analysis Set.
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8.2. Prior and Concomitant Procedures 
All prior and concomitant procedures or clinically significant non-drug therapies will be 
presented in a listing.   
9. STUDY TREATMENTS 
Analyses on study treatment will be based on Safety Analysis Set.
9.1. Extent of Exposure
Total dose given, average daily dose, duration of exposure (days), total missed doses, and 
total doses not fully administered will be summarized for all patients by stratum, treatment,
and overall for the safety analysis set using mean, median, standard deviation, 1st quartile, 3rd
quartile and range. Total dose is the sum of the actual dose (All non-missed doses are 
considered full dose) and the duration of exposure will be computed as the last dose date –
first dose date +1. Dose type (tablets/mini-tablets) will also be summarized. 
9.2. Treatment Compliance 
Treatment compliance will be summarized by treatment group, stratum and overall over the 
treatment period. Compliance rates will be derived using the following formula:
100*(Total dose administered) / (total planned dose)
Total planned dose will be derived as (date of last study medication dose – date of first 
maintenance dose + 1)*(planned dosage during the treatment period). Total dose 
administered will primarily be based on the drug accountability (Total dose dispensed – total 
dose returned).  Compliance rates will be presented for the safety analysis set using summary 
statistics and percentage for the frequency distributions (0 to ≤20%, 20% to ≤40%, 40% to 
≤60%, 60% to ≤80%, 80% to ≤100%, 100% to ≤ 120%) by treatment group, and overall. 
Also, number and percentage of patients who are compliant (compliance ≥ 80%) and non-
compliant will be summarized.
10. EFFICACY ANALYSES
10.1.
Analyses of the Primary Endpoint
10.1.1 Primary Analysis
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The analysis performed on Efficacy Analysis Set is considered the primary analysis.
For the patients randomized to the Dravet syndrome stratum (≥3 convulsive seizures per 28 
days), convulsive seizure frequencies per 28 days for the 4-week prospective Baseline Period 
and the Maintenance Period will be calculated. 
For the patients randomized to the LGS stratum (≥4 drop seizures per 28 days), drop seizure 
frequencies per 28 days for the 4-week prospective Baseline Period and the Maintenance 
Period will be calculated. 
The seizure frequency per 28 days in a study period will be calculated as:
(# of seizures) / (# of days seizures were assessed) × 28
where:
# of seizures=Total number of Seizures (either convulsive or drop depending on the strata) 
reported from Start date to the End Date
# days seizures were assessed = Number of days during the period seizures were assessed.
Baseline Period:
From up to 6 weeks prior to the day before first dose.
Maintenance Period:
For PA1 patients, between Day 15 and Day 84 (inclusive), and for PA2 and PA1 reconsented 
to PA2, between Day 57 and Day 140 (inclusive).
Treatment Period:
For PA1 patients, between Day 1 and Day 84 (inclusive), and for PA2 and PA1 reconsented 
to PA2, between Day 1 and Day 140 (inclusive).
For each patient, percent change from Baseline to Maintenance Period of seizure frequencies 
(per 28 days) will be calculated for the seizure type corresponding to the assigned stratum of 
that patient (convulsive for the Dravet and drop for the LGS stratum). Percent change from 
Baseline will be compared between TAK-935 and placebo using a rank test adjusting for 
Baseline seizure frequency and randomization stratum. 
Percentage change from baseline will be defined as:
((Frequency of seizures per 28 days during maintenance period – Frequency of seizures per 
28 days at baseline)/ Frequency of seizures per 28 days at baseline) * 100
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The null hypothesis of no treatment difference will be tested at a two-sided 0.05 level of 
significance. 
The Hodges-Lehmann confidence interval based on unadjusted rank statistic will also be 
presented.
For convenience from here on in this document, all references to the “number of seizures” in 
percent change calculations will imply “number of seizures per 28 days” even without the 
explicit expression.
10.1.2 Supportive Analysis
The analysis performed in 10.1.1 will also be repeated for mITT and Per-protocol analysis set 
as supportive analysis.
The model for the mITT and Per-protocol population will include treatment, baseline, 
randomization stratum, and treatment cohort (14 weeks vs 20 weeks) so that it could produce 
an estimate of the treatment difference for the combined cohorts under the assumption that 
the treatment differences within the separate cohorts are similar. That assumption would be 
addressed by additionally including treatment*cohort in the model so that its assessment can 
confirm similarity of the treatment differences for the separate cohorts through a sufficiently 
large p-value such as p > 0.15.
10.1.3 Sensitivity Analysis
Sensitivity analysis will be conducted using multiple imputation method to impute seizure 
dairy data during maintenance period.  The imputation model (proc mi) will include the 
following variables, seizure count from seizure dairy (convulsive or drop), age, gender, 
treatment group, randomization stratum, and study day for the impact of missing data.
The analysis model in 10.1.1 will be applied for multiple imputation analysis (PROC
MIANALYZE).
The compliance of seizure dairy completion for each patient will be summarized 
descriptively.  The compliance is defined as Number of days dairy are available/Number of 
days dairy are expected.  A listing of seizure diary compliance will also be presented.
10.2.
Analyses of the Secondary Efficacy Endpoints
All analyses on the secondary endpoints will be performed for both Efficacy Analysis Set 
and mITT Analysis Set.
Percent change from Baseline in seizure frequency per 28 days (based only on convulsive 
seizures for the patients in the Dravet syndrome stratum and drop seizures for the patients 
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in the LGS stratum) in patients receiving TAK-935 as compared to placebo during the 
Treatment Period
The percent change from baseline will be calculated as 
((Frequency of seizures per 28 days during treatment period – Frequency of seizures per 28 
days at baseline)/ Frequency of seizures per 28 days at baseline) * 100
The same calculation for the number of seizures and the same statistical approach as 
described in 10.1.1 and 10.1.2 will be used for the analysis of percent change in seizure 
frequency from baseline to treatment period.
Percent change from Baseline in convulsive seizure frequency per 28 days in patients 
randomized to the Dravet syndrome stratum and receiving TAK-935 as compared to 
placebo during the Maintenance Period
For the Dravet stratum, the percent change in convulsive seizure frequency from Baseline to the 
frequency of convulsive seizures during the Maintenance Period will be calculated as
((Number of convulsive seizures during treatment period – Number of convulsive 
seizures at baseline)/ Number of convulsive seizures at baseline) * 100
The same statistical approach as described in 10.1.1 and 10.1.2 will also be applied to this 
endpoint.
Percent change from Baseline in drop seizure frequency per 28 days in patients 
randomized to the LGS stratum and receiving TAK-935 as compared to placebo during 
the Maintenance Period
For the LGS stratum, the percent change in convulsive seizure frequency from Baseline to the 
frequency of convulsive seizures during the Maintenance Period will be calculated as
((Number of drop seizures during treatment period – Number of drop seizures at 
baseline)/ Number of drop seizures at baseline) * 100
The same statistical approach as described in 10.1.1 and 10.1.2 will also be applied to this 
endpoint.
Proportion of patients in the LGS stratum considered treatment responders throughout the 
Maintenance Period; treatment responders defined as those with:
-
Reduction of 25% or more in drop seizures from baseline 
-
Reduction of 50% or more in drop seizures from baseline 
-
Reduction of 75% or more in drop seizures from baseline 
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-
Reduction of 100% in drop seizures from baseline 
For each response category, the proportion of responders will be summarized by treatment 
groups and the 95% confidence intervals will be calculated.
A bar chart representing proportion of subjects in each of the following percent change 
categories will also be presented, ≤0; >0 to ≤25; >25 to ≤50; >50 to ≤75; >75 to ≤100.
Proportion of patients in the Dravet syndrome stratum considered treatment responders 
throughout the Maintenance Period; treatment responders are defined as those with: 
-
Reduction of 25% or more in convulsive seizures from baseline
-
Reduction of 50% or more in convulsive seizures from baseline 
-
Reduction of 75% or more in convulsive seizures from baseline 
-
Reduction of 100% in convulsive seizures from baseline 
For each response category, the proportion of responders will be summarized by treatment 
groups and the 95% confidence intervals will be calculated.
A bar chart representing proportion of subjects in each of the following percent change 
categories will also be presented, ≤0; >0 to ≤25; >25 to ≤50; >50 to ≤75; >75 to ≤100.
Change in CGI-S responses of Investigator reported impression of efficacy
Observed and change from baseline in CGI-S scores will be summarized with descriptive 
statistics (N, mean, standard deviation, median, minimum, maximum) treatment groups and by 
visit.  Additionally, the number and percentage of patients with each score level will also be 
summarized by treatment group and by visit.
Shift tables representing best and worst changes will be presented.
The change from baseline scores will be compared between the 2 treatment groups.  The 
comparison will be based on mixed model repeated measures (MMRM) to account for the 
repeated assessments at multiple visits.  The model will include treatment, visit and 
randomization stratum as factors along with treatment*visit interaction and baseline score as a 
covariate.
Summary of CGI-C responses (0, 1, 2, 3 and 4) reported impression of efficacy and 
tolerability of study drug 
The number and percentage of patients with each CGI-C score level will be summarized by 
treatment groups and by visit.
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The number and percentage of patients with the combine score levels of improvement (0, 1) 
and no improvement or worse (2, 3, 4) will also be summarized by treatment groups, stratum 
and by visit.  The treatment groups will be compared using a generalized linear mixed model
to account for the repeated measures.  The model will be based on the binomial distribution 
(logit link function) with treatment group, stratum and visit as factors along with
treatment*visit interaction.
! Summary of Care GI-C responses (1, 2, and 3 vs 4, 5, 6, and 7) of parent/family reported 
impression of efficacy and tolerability of study drug 
The number and percentage of patients in each Care GI-C score level will be summarized by 
treatment groups, stratum and by visit.
The number and percentage of patients with the combine score levels of improvement (1, 2, 
3) and no improvement or worse (4, 5, 6, 7) will also be summarized by treatment groups, 
stratum and by visit.  The treatment groups will be compared using a generalized linear 
mixed model to account for the repeated measures.  The model will be based on the binomial 
distribution (logit link function) with treatment group, stratum and visit as factors along with 
treatment*visit interaction.
! To characterize plasma 24HC levels and change in seizure frequency in patients treated with 
TAK-935 as an adjunctive therapy 
Observed and change from baseline in plasma 24HC levels will be summarized by treatment 
groups and by visit. The level of plasma 24HC at each visit will be listed by patient.
Concentration values below the limit of quantitation (BLQ) will be listed as not detectable in 
the listing and treated as missing values in the summary.
The relationship between the plasma 24HC level and the seizure count will be explored by 
summarizing the seizure count per 28 day by 24HC collection time points.
10.3.
Exploratory Analysis
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10.3.1 Proportion of Patients with reduction in frequency of seizures requiring rescue 
medication
The analysis performed on this endpoint will depend on the availability of rescue medication 
data.
10.3.2 Seizure Frequency Reduction
The reduction in seizure frequency in each period is calculated as follows:
Baseline seizure frequency per 28 days minus Treatment Period seizure frequency per 28 
days as calculated in 10.1.1.
The reduction in seizure frequency will be compared between TAK-935 and placebo using 
the same statistical model as in 10.1.1 and 10.1.2.
Proportion of patients with reduction in seizure frequency will be compared between TAK-
935 and Placebo using exact test to test for the difference of the treatments.
10.3.3 Proportion of Seizure-free Days
The proportion of seizure-free days during the Treatment period will be calculated as:
(Days with number of seizures=0 during the Treatment period)/(Days with recorded/non-
missing data in seizure diary during the Treatment period).
The proportion of seizure-free during the Maintenance period will be calculated as:
(Days with number of seizures=0 during the Maintenance period)/(Days with recorded/non-
missing data in seizure diary during the Maintenance period).
Proportion of seizure-free days will be compared between TAK-935 and Placebo using 
ANCOVA model with treatment group, stratum as factors and baseline values as a covariate.  
For analyses on mITT population, the treatment cohort and treatment*cohort effect will be 
included.
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10.3.4 Seizure Frequency Reduction Time Effect
The seizure frequency reduction in the treatment Period will be divided to 4-week intervals
starting from Day 1. Seizure frequency (per 28 days) reductions from baseline to each period
will be summarized by treatment groups and overall.  
This endpoint will be analyzed for both Efficacy Analysis Set and mITT Analysis Set.
10.3.5 Seizure Frequency at Weeks 4, 8, 12, 16, and 20
The seizure frequency at weeks 4 (weeks 1-4), 8 (weeks 5-8), 12 (weeks 9-12), 16 (weeks 
13-16) and 20 (weeks 17-20) will be analyzed using the same statistical approach as in 
10.3.4. 
This analysis will be performed on the Efficacy Analysis Set and mITT Analysis set.
10.3.6 Longest Seizure-free Days
The longest of consecutive seizure-free days during the Treatment period will be calculated 
as the maximum number of consecutive days with number of seizures=0 during the 
Treatment period. The longest seizure-free days during the Treatment Period will be
summarized descriptively by treatment groups and compared between TAK-935 and placebo 
using a Mann-Whitney test.
10.3.7 Use of Rescue Medication
The analyses on rescue medication will be performed based on data availability.
10.3.8 New Seizure Type
New seizure type development post baseline
The number and percentage of patients who develop new seizure types post baseline will be 
summarized by treatment group.
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10.3.10 Quality of Life in Childhood Epilepsy (QoLCE)
The Quality of Life in Childhood Epilepsy is a parent-reported questionnaire that evaluates 
health related quality of life in children ages 4 to 18 years old. It contains 76 items with 16 
subscales covering 7 domains of life function: physical activities, social activities, cognition, 
emotional wellbeing, behavior, general health, and general quality of life. Based on the data 
availability, patient listing will be provided.
10.4. Pharmacokinetic Analysis
The details of PK analysis will be described in a separate document.
11. SAFETY ANALYSES
All safety analyses will be conducted based on the Safety Analysis Set. 
Data summaries will be displayed for incidence of AEs, clinical laboratory variables, vital 
signs, body weight and height, ECG parameters, percent myoclonic- and atypical absence-
free days, as well as changes in behavioral and adaptive functioning measures using VABS 
and sub-scales of ABC-C, as appropriate. 
11.1.
Adverse Events
11.1.1 Incidence of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical study patient administered 
a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable or unintended sign (for example, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether considered related to this medicinal product.
The definition of an AE also covers medication errors and uses outside what is foreseen in 
the protocol only if an AE results from the error, including intentional misuse, abuse, and 
overdose of the product.
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) and anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not worsen are not AEs.
Ovid has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study 
is to establish drug effect.
The following definitions will be used for AEs:
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
Treatment-emergent adverse event (TEAE): Any AE that starts or increases in 
severity during or after the first dose of study drug and within 15 days of last 
study medication.

Treatment-emergent SAE: A serious AE that starts or increases in severity during 
or after the first dose of study drug and within 30 days of last study medication.
The incidence of TEAEs, non-serious TEAEs with incidence > 5%, discontinuations due to 
TEAEs, drug-related, serious, and severe TEAEs will be summarized. All AEs will be coded 
using MedDRA Version 21.0 and will be summarized by SOC and PT and treatment group. 
Detailed listings of AEs, SAEs, related AEs, and discontinuations due to AEs will be 
provided.
11.1.2 Study Medication-related TEAEs
A TEAE is considered a study medication-related if the relationship is judged as either 
possibly related or related. If the relationship of a TEAE is missing, the TEAE is reported as 
related. The number and percentage of patients experiencing TEAEs which are related to the 
study medication will be summarized. 
11.1.3 Severity of TEAEs
A summary of TEAEs by severity will be presented in a table. The severity that will be 
presented represents the most extreme severity captured on the CRF page. The possible 
severities are ‘Mild,’ ‘Moderate,’ and ‘Severe’. In the TEAE severity table, if a patient 
reported multiple occurrences of the same TEAE, only the most severe TEAE is presented. 
TEAEs that are missing severity will be presented in tables as ‘Severe’ but will be presented 
in the data listing with a missing severity. 
11.1.4 Serious TEAEs
A serious treatment-emergent adverse event is any untoward medical occurrence that, at any 
dose, results in death, life-threatening, requires hospitalization or prolongation of existing 
hospitalization, hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE, results in disability/incapacity, and congenital 
anomaly/birth defect.
Serious TEAEs will be categorized and presented by SOC and PT in the same manner to that 
described in Section 9.1.1.
11.1.5 TEAEs Leading to Treatment Discontinuation/Study Termination
The number and percentage of patients with TEAEs leading to treatment and study 
discontinuation will be categorized and presented by SOC and PT in the same manner to that 
described in Section 9.1.1.
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11.1.6 Death
The number and percentage of deaths will be tabulated by treatment. Adverse events leading 
to death will be categorized and presented by SOC and PT in the same manner to that 
described in Section 9.1.1.
11.2. Clinical Laboratory Evaluations
All laboratory results are from PPD central laboratory and only standard results in SI unit 
will be summarized in the outputs. 
Descriptive statistics for laboratory values at each visit and change from Baseline values to 
each post-baseline visits in clinical chemistry, hematology, urinalysis, and microscopic 
results will be summarized. 
Shift tables for laboratory parameters will be presented to show the change of normality from 
baseline to each post-baseline time point. For each continuous laboratory parameter, results 
will be classified as low, normal, or high relative to the parameter’s reference range. 
Listings of subjects with abnormal results will be provided.
11.2.1 Hematology
The parameters to be analyzed for hematology includes red blood cell count (RBC), 
hemoglobin, white blood cell count (WBC) and differential, hemoglobin, hematocrit, 
platelets, prothrombin time and international normalized ratio (PT/INR), and activated partial 
thromboplastin time (aPTT).
A summary of the descriptive statistics of the hematology parameters in SI units, together 
with changes from baseline, will be presented for each visit by treatment. In addition, shift
tables will be produced, one with the results categorized using the normal ranges. This 
categorical data will be summarized in shift tables comparing the results at each scheduled 
post-baseline visit with those at the baseline visit. 
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11.2.2 Clinical Chemistry
The parameters to be analyzed for clinical chemistry are ALT, albumin, alpha-1acid 
glycoprotein, alkaline phosphatase, AST, total bilirubin, total protein, creatinine, blood urea 
nitrogen, creatinine kinase, GGT, potassium, sodium, glucose, chloride, bicarbonate, 
calcium, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides.
A summary of the descriptive statistics of the serum chemistry parameters in SI units, 
together with changes from baseline, will be presented for each visit by treatment. In 
addition, shift tables will be produced, one with the results categorized using the normal 
ranges. This categorical data will be summarized in shift tables comparing the results at each 
scheduled post-baseline visit with those at the baseline visit. 
11.2.3 Urinalysis
The parameters to be analyzed for urinalysis includes pH, specific gravity, protein, glucose, 
blood, and nitrite. These parameters will be summarized by treatment in shift tables 
comparing the results at each scheduled post-baseline visit with those at the baseline visit.
11.2.4 Microscopic Results
Microscopic results will be presented in a listing. 
11.3. Vital Signs 
Vital signs (temperature in °C, heart rate [beats per minute], respiratory rate [breaths per 
minute], and systolic and diastolic blood pressure [mmHg]), weight (kg), and height (cm) 
will be summarized descriptively at Baseline and all post-baseline study time points by 
treatment group and overall. Change from baseline and post-baseline study time points will 
be summarized descriptively by treatment group and overall. 
Data listings will be provided.
11.4. Physical Examination 
Physical examinations (general appearance; skin; head, eyes, ears, nose, throat; respiratory; 
cardiovascular; gastrointestinal/abdominal; neurological; lymph node; musculoskeletal; 
extremities; other)) will be summarized descriptively at Baseline and all post-baseline study 
time points as well as shifts from baseline to post-baseline will be summarized by treatment 
group and overall.
Data listings will be provided.
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11.5. Safety ECG (12-lead ECG) 
Individual safety ECG values will be listed by treatment and visit and will be summarized 
using descriptive statistics.  Intervals to be provided for each ECG are: heart rate, RR 
interval, PR.  Post-baseline ECGs will be compared with the baseline ECG.  Summary 
statistics will also be provided for change from baseline in ECG values.  
Additionally, each ECG reading will be interpreted as ‘abnormal’ or ‘within normal limits’ or 
‘not evaluable’, and the relevance of the abnormality will be summarized as ‘clinically 
significant’ or ‘not clinically significant’. This categorical data will be summarized in shift 
tables comparing the results at each scheduled post-baseline visit with those at the baseline 
visit by dose cohort.
11.6. Clinical Assessment of Suicidal Ideation and behavior
Suicidal ideation and behavior will be assessed in children aged ≥6 years by the use of the 
C-SSRS. The C-SSRS is a 3-part scale that measures suicidal ideation (e.g., patient endorses 
thoughts about a wish to be dead or has other thoughts of suicide), intensity of ideation 
(frequency), and suicidal behavior (actually, interrupted, and aborted attempts at suicide). 
• Suicidal Ideation and Intensity of Ideation 
The number and percentage of patients with suicidal ideation will be presented for each visit 
by treatment groups and overall. A patient is considered to have suicidal ideation if the 
answer to either C-SSRS Suicidal Ideation Question 1 or 2 (Wish to be dead, Non-specific 
Active Suicidal Thoughts) was “Yes”.
• Suicidal Behavior 
The number of percentage of patients with suicidal behavior will be presented for each visit 
by treatment groups and overall.  A patient is considered to have suicidal behavior if the 
response to any of the six Suicidal Behavior questions (Actual attempt; Interrupted attempt; 
Aborted attempt; Preparatory acts or behavior; Suicidal behavior; Completed suicide) was 
“Yes”.  
A by patient listing of C-SSRS and investigator assessment of C-SSRS will also be 
presented.
11.7. Myoclonic and Atypical Absence Free Days Seizures
Descriptive statistics will be used to summarize the percent of myoclonic- and atypical-
absence free days in patients receiving TAK-935 as compared to placebo during the 
treatment Period. The percent myoclonic- and atypical-absence free days is computed as:
(per patient number of seizure free day/total # of days seizure was assessed in the 
treatment  period)*100
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11.8. Neurological and Ophthalmic Examination
Neurological examination will include testing mental status, gait, cerebellar function, cranial 
nerves, motor function, reflex, and sensation. 
As part of the neurological exam, vision testing is recommended to include fundoscopy and 
best corrected visual acuity using a pocket vision screening card, if possible.
Worst shift from baseline in neurological and ophthalmic examination will be summarized by 
treatment.
Listing of neurological and ophthalmic examination results will be presented.
11.9. Sleep Disruption Numerical Rating Scale
Sleep disruption numerical rating scale range from 0 (slept extremely well) to 10 (unable to 
sleep at all) and summary statistics will be provided for observed and change from baseline 
in sleep disruption numerical rating scale by treatment and visit.
11.10. Vineland Adaptive Behavior Scale
The Vineland Adaptive Behavior Scale, 3rd Edition, Comprehensive Parent Caregiver Form 
(VABS-3 Parent Caregiver Form), is a caregiver-report questionnaire that assesses adaptive 
functioning across the following 4 domains and 11 subdomains.
The following domain names and subdomain names are used in the data based in Pearson’s 
Q global and will be used for reporting or clinical study report. They are consistent with 
VABS-3 Parent Caregiver form manual pages 25-26.
The Motor domain data was collected prior to the current protocol amendment and will be 
listed in the listing.
Domain 
Subdomains 
Communication 
Receptive
Expressive 
Written 
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Daily Living Skills
Personal 
Domestic 
Community 
Socialization 
Interpersonal Relationships 
Play and Leisure 
Coping Skills
Maladaptive Behaviors 
Internalizing 
Externalizing 
Each item is scored from 0 to 2. If a caregiver estimates a response, the item score is reported 
as a 97, 98, or 99 on the CRF to indicate that they are estimates, but for the calculation of 
domain and subdomain totals, 97 is mapped to 2, 98 is mapped to 1 and 99 is mapped to 0. 
For the Communication, Daily Living, and Socialization and Maladaptive behaviors
domains, each domain yields a normative-based standard score. Each subdomain within these 
three domains yields a v-scale score, age equivalent score, and total raw score. For the 
Problem Behavior domain, the Internalizing (Section A) and Externalizing (Section B) 
subdomains yield a v-scale score and total raw score. All raw score calculations respect the 
basal and ceiling rules of the scale. Scoring will be completed using the publisher’s scoring 
software program, Pearson’s Qglobal.
The VABS-3 will be administered at Screening and Day 141 EOT/ET (Day 85/ET for 
patients who completed the study under the original protocol).
Summary statistics will be provided for observed and change from baseline in VABS and in 
VABS as assessed by the investigator.  
11.11. Behavior Checklist – Community Edition (ABC-C)
Behavior will be assessed by the use of the Aberrant Behavior Checklist-Community (ABC-
C) questionnaire, which is a rating scale that measures the severity of a range of problem 
behaviors commonly observed in individuals with intellectual and developmental disabilities.  
It is completed by the caregiver. It is an empirically developed scale designed to measure 
psychiatric symptoms and behavioral disturbance exhibited by individuals across 5 domains 
with 58 items: irritability, agitation, and crying (15 items); lethargy, social withdrawal (16 
items); stereotypy (7 items); hyperactivity/noncompliance (16 items); and inappropriate 
speech (4 items). Sub scores are derived by getting the sum of the individual scores per 
domain and the total score is the sum of the scores for all domains. Changes from baseline in 
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behavior measures using total scores and subscale scores of Aberrant Behavior Checklist-
Community Edition (ABC-C) as assessed by the caregiver and the investigator for patients 
≥6 years of age will be summarized descriptively.
Total score is the sum of the scores of the 58 questions and scores for the subscales will be 
obtained as follows: 
Subscales
Sum of Questions
Irritability
2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, 57
Lethargy/Social Withdrawal
3, 5, 12, 16, 20, 23, 26, 30, 32, 37, 40, 42, 43, 53, 55, 58
Stereotypic Behavior
6,11,17,27,35,45,49
Hyperactivity
1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 51, 54, 56
Behavior
Mean of 61-74 scores
General Health
Score of question 75
General Quality of Life
Score of question 76
The change from baseline of ABC-C total and subscale scores will be summarized.
11.12. Investigator’s assessments of VABS and ABC-C
Investigator’s assessment results for VABS and ABC-C will be included in listings.
11.13. Exit Survey
The results of the exit summary will be presented with a listing.
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12. OTHER STATISTICAL ISSUES
12.1. Significance Levels
For the sample size calculation, within the 2 randomization strata, hypothesis tests will be 
performed at levels of significance higher than 0.05 in this Phase 2 proof of concept study 
and will have power of 80%.
The primary and secondary endpoints are defined and will be tested at 0.05 level of significance. 
All other testing is considered exploratory and significance level of 0.05 will be used.
12.2. Handling of Missing Data
For missing baseline, the last screened value close to baseline visit will be used. 
For the primary efficacy endpoint, observed values will be used. Sensitivity analysis will be 
conducted using multiple imputation (Rubin, 1987) based on missing at random for missing 
data in primary and key secondary efficacy endpoints. The multiple imputation method will 
be implemented using PROC MI and PROC MIANALYZE in SAS. Imputations of each 
missing value will be derived from a parametric Bayesian model using a noninformative 
prior distribution that is proportional to the inverse of the standard deviation of the observed 
values. For each timepoint at which imputation is necessary and for each imputation at that 
timepoint, a random variance and mean will be generated from the prior distribution; these 
are then used as parameters of the posterior Gaussian distribution for random selection of a 
single value. Repeating this process 50 times provides a sufficient number of replications.  
Sensitivity analyses based on the imputed data will be specified in the efficacy analysis 
section.
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