A Randomized, Double-Blind, Controlled Study to Assess the Efficacy and Safety of Intravenous Phenobarbital in Neonatal Seizures
Phase: PHASE3
Conditions: Epilepsy, Benign Neonatal
Sponsor: NEMA Research, Inc.

Protocol 
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Version: 2.0; 07-Dec-2021 
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Page 1 of 76 
 
A Randomized, Double-Blind, Controlled Study to Assess the Efficacy and Safety of 
Intravenous Phenobarbital in Neonatal Seizures 
Protocol Number: MI-5780 
National Clinical Trial (NCT) Identified Number: NCT04320940 
IND Sponsor: Hikma Pharmaceuticals USA Inc. 
Funded by: Hikma Pharmaceuticals USA Inc. 
Version Number: 2.0 
07-Dec-2021 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Significant Revisions Made 
and Rationale 
1.1 Synopsis 
Updated study duration 
1.3 Schedule of Events 
Update language for Vital Signs, Laboratory 
Safety Tests, cvEEG Monitoring and Clinical 
Seizure Assessments during the different study 
Periods 
1.3.1 Schedule of Events (Open Label 
Extension Period) 
Update language for Vital signs, Laboratory 
Safety Tests, cvEEG Monitoring and Clinical 
Seizure Assessments 
3.2.1 Primary Endpoint 
Clarified T0 
4.1 Overall Design 
Clarified qualifying seizure burden for first 
and second loading dose ((≥ 30seconds/hour) 
4.1.2 Screening Period 
Clarified length of time for screening period; 
Updated description of screening period 
assessments to match schedule of events 
4.1.3 Treatment Period 
Clarified length of time for treatment period; 
Updated description of screening period 
assessments to match schedule of events 
4.1.4 Follow-up Period 
Clarified length of time for follow-up period; 
Updated description of screening period 
assessments to match schedule of events 
4.1.5 Open-Label Extension Period 
Clarified length of time for Open-Label 
Extension Period and when study participants 
can enter the period; Updated description of 
screening period assessments to match 
schedule of events 
4.1.6 Subject Treatment Scenarios 
Section not required due to clarifications 
provided in sections 4.1.2 to 4.1.5 
5.2 Exclusion Criteria 
Added language regarding enrollment of study 
participants in other neonatal clinical trials 
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6.1.2 Dosing and Administration 
Clarified when a second loading dose of study 
drug can and cannot be administered. 
6.2.3 Product Storage and Stability 
Updated storage conditions to reference the 
study Pharmacy Manual 
6.5.2 Second Line Anticonvulsants 
Updated title from Rescue Medication to 
Second Line Anticonvulsants. There is no 
rescue medication in this study; Added the use 
of midazolam prior to study screening and 
updated time of administration from >24 h to 
>=8 h 
8.1.4 Seizure Documentation 
Added section to provide guidance on how to 
and when to review the cvEEG recordings 
8.2.1 Demographic and Medical History 
Added 
section 
to 
provide 
additional 
instructions on what to and how to record 
demographics and medical history 
8.2.2 Pregnancy and Delivery History 
Updated delivery presentation options 
8.2.5 Physical Examination 
Added neurological exam details in order to 
standardize across all sites 
8.2.8 Continuous Video EEG Monitoring 
Added section to provide guidance on how to 
and when to review the cvEEG recordings 
12.4 Appendix IV Clinical Laboratory Tests 
Added guidance on blood draw and daily 
blood volume; Updated lab safety tests and 
removed non-standard of practice exams 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Protocol Approval Form 
 
Protocol Title: A Randomized, Double-Blind, Controlled Study to Assess the Efficacy and 
Safety of Intravenous Phenobarbital in Neonatal Seizures 
 
 
Study No: MI-5780 
Original Protocol Date: 28-Aug-2020 
Protocol Version No: 2.0 
Protocol Version Date: 07-Dec-2021 
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the Sponsor. The information contained in this protocol is consistent 
with: 
x The current risk-benefit evaluation of the investigational product. 
 
x The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and principles of GCP as described in 21 CFR parts 50, 54, 56 and 
312 and according to applicable local requirements. 
The Investigator will be supplied with details of any significant or new findings, including adverse 
events, relating to treatment with the investigational product. 
 
 
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Name and Title 
Approval 
Signature 
Date 
Sponsor Representative: 
 
Naomi Donovan 
Hikma Project Manager 
Yes        
No 
 
(check 
one) 
 
 
Clinical Operations: 
 
Robert Taylor Jr, PhD 
NEMA Project Manager 
Yes        
No 
 
(check 
one) 
 
 
Biometrics: 
 
Duolao Wang, PhD 
Biostatistician 
Yes        
No 
 
(check 
one) 
 
 
Medical Lead: 
 
Sumedha Labhsetwar, MD 
Medical Monitor 
Yes        
No 
 
(check 
one) 
 
 
Regulatory Affairs: 
 
Robert Colucci, PharmD 
Clinical Development and 
Regulatory Consultant 
Yes        
No 
 
(check 
one) 
 
 
Protocol Principal Investigator: 
 
Taeun Chang, MD 
Neonatal Neurologist 
Yes        
No 
 
(check 
one) 
 
 
 
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


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MI-5780 
A Randomized, Double-Blind, Controlled Study to Assess the Efficacy and Safety of 
Intravenous Phenobarbital in Neonatal Seizures 
Confidentiality and Investigator Statement 
The information contained in this protocol and all other information relevant to MI-5780 are the 
confidential and proprietary information of Hikma, and except as may be required by federal, state 
or local laws or regulation, may not be disclosed to others without prior written permission of 
Hikma. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Conference on Harmonization guidelines and will make 
a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Hikma or specified designees. I will 
discuss the material with them to ensure that they are fully informed about MI-5780 and the study. 
 
 
 
 
 
Principal Investigator Name (printed): ________________________ 
 
 
Signature: _________________________________  
 
 
Date: ___________ 
 
 
Site Number: ___________  
 
 
 
 
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Table of Contents 
1 
Protocol Summary ................................................................................................................. 12 
1.1 
Synopsis ......................................................................................................................... 12 
1.2 
Schema ........................................................................................................................... 14 
1.3 
Schedule of Events ......................................................................................................... 15 
1.3.1 
Schedule of Events (Open Label Extension Period) ............................................... 17 
2 
Introduction ........................................................................................................................... 19 
2.1 
Study Rationale .............................................................................................................. 19 
2.2 
Background .................................................................................................................... 19 
2.2.1 
Clinical .................................................................................................................... 20 
2.2.2 
Importance of Clinical Trial .................................................................................... 20 
2.3 
Risk/Benefit Assessment ................................................................................................ 20 
2.3.1 
Known Potential Risks ............................................................................................ 20 
2.3.2 
Known Potential Benefits ....................................................................................... 21 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................... 21 
3 
Objectives and Endpoints ...................................................................................................... 23 
3.1 
Objectives ....................................................................................................................... 23 
3.1.1 
Primary Objective ................................................................................................... 23 
3.1.2 
Secondary Objectives.............................................................................................. 23 
3.1.3 
Exploratory Objectives ........................................................................................... 23 
3.2 
Endpoints ........................................................................................................................ 23 
3.2.1 
Primary Endpoint .................................................................................................... 23 
3.2.2 
Secondary Endpoints .............................................................................................. 24 
3.2.3 
Exploratory Endpoints ............................................................................................ 24 
3.2.4 
Safety Endpoints ..................................................................................................... 25 
4 
Study Design.......................................................................................................................... 25 
4.1 
Overall Design................................................................................................................ 25 
4.1.1 
Definitions............................................................................................................... 27 
4.1.2 
Screening Period ..................................................................................................... 27 
4.1.3 
Treatment Period ..................................................................................................... 28 
4.1.4 
24 Hour Follow-Up Period /Early Discontinuation/End of Study .......................... 28 
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4.1.5 
Open-Label Extension Period ................................................................................. 29 
4.2 
Scientific Rationale for Study Design ............................................................................ 29 
4.3 
Justification for Dose ..................................................................................................... 29 
4.4 
End of Study Definition ................................................................................................. 30 
5 
Study Population.................................................................................................................... 30 
5.1 
Inclusion Criteria ............................................................................................................ 30 
5.2 
Exclusion Criteria ........................................................................................................... 30 
5.3 
Lifestyle Considerations ................................................................................................. 31 
5.4 
Screen Failures ............................................................................................................... 31 
5.5 
Strategies for Recruitment and Retention ...................................................................... 31 
5.5.1 
Target Study Sample Size ....................................................................................... 31 
5.5.2 
Anticipated Accrual Rate ........................................................................................ 32 
5.5.3 
Anticipated Number of Sites ................................................................................... 32 
5.5.4 
Source of Study Participants ................................................................................... 32 
5.5.5 
Recruitment Venues ................................................................................................ 32 
5.5.6 
Identification of Potential Study Participants ......................................................... 32 
5.5.7 
Recruitment Strategies ............................................................................................ 32 
5.5.8 
Long-term Recruitment/Enrollment Strategies ....................................................... 33 
5.5.9 
Justification for Vulnerable Population Recruitment ............................................. 33 
5.5.10 
Compensation for Study Participation .................................................................... 33 
6 
Study Drug ............................................................................................................................. 33 
6.1 
Study Drug(s) Administration ........................................................................................ 33 
6.1.1 
Study Drug Description .......................................................................................... 33 
6.1.2 
Dosing and Administration ..................................................................................... 33 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 34 
6.2.1 
Acquisition and Accountability .............................................................................. 34 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 35 
6.2.3 
Product Storage and Stability.................................................................................. 35 
6.2.4 
Preparation .............................................................................................................. 35 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................... 35 
6.3.1 
Unblinding .............................................................................................................. 36 
6.4 
Study Drug Compliance ................................................................................................. 36 
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6.5 
Concomitant Therapy ..................................................................................................... 36 
6.5.1 
Allowed Concomitant Medication .......................................................................... 36 
6.5.2 
Second-line Anticonvulsants .................................................................................. 36 
7 
Study Drug Discontinuation and Participant Discontinuation/Withdrawal .......................... 37 
7.1 
Discontinuation of Study Drug ...................................................................................... 37 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 37 
7.3 
Lost to Follow-up ........................................................................................................... 37 
7.4 
Study Stopping Rules ..................................................................................................... 38 
7.4.1 
Stopping rules for study participants ...................................................................... 38 
7.4.2 
Stopping rules for Overall Trial .............................................................................. 39 
8 
Study Assessments and Procedures ....................................................................................... 39 
8.1 
Efficacy Assessments ..................................................................................................... 39 
8.1.1 
Seizure Burden ........................................................................................................ 39 
8.1.2 
Seizure Recurrence ................................................................................................. 40 
8.1.3 
Seizure Period ......................................................................................................... 40 
8.1.4 
Seizure Documentation ........................................................................................... 40 
8.2 
Safety and Other Assessments ....................................................................................... 40 
8.2.1 
Demographics and Medical History ....................................................................... 40 
8.2.2 
Pregnancy and Delivery History ............................................................................. 40 
8.2.3 
Medical History of Mother ..................................................................................... 41 
8.2.4 
Apgar Scores ........................................................................................................... 41 
8.2.5 
Physical Examination.............................................................................................. 41 
8.2.6 
Vital Signs ............................................................................................................... 42 
8.2.7 
Clinical Laboratory Determinations ....................................................................... 42 
8.2.8 
Continuous Video EEG Monitoring ....................................................................... 43 
8.2.9 
Clinical Seizure Assessment ................................................................................... 44 
8.2.10 
Assessment of Adverse Events ............................................................................... 44 
8.3 
Adverse Events and Serious Adverse Events ................................................................. 44 
8.3.1 
Definition of Adverse Events (AE)......................................................................... 44 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................... 45 
8.3.3 
Classification of an Adverse Event ......................................................................... 45 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-up ........................ 47 
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8.3.5 
Adverse Event Reporting ........................................................................................ 48 
8.3.6 
Serious Adverse Event Reporting ........................................................................... 48 
8.3.7 
Reporting Events to Parents/Legal Guardians ........................................................ 48 
8.3.8 
Events of Special Interest........................................................................................ 49 
8.3.9 
Reporting of Pregnancy .......................................................................................... 49 
8.4 
Unanticipated Problems ................................................................................................. 49 
8.4.1 
Definition of Unanticipated Problems (UP) ........................................................... 49 
8.4.2 
Unanticipated Problem Reporting........................................................................... 50 
8.4.3 
Reporting Unanticipated Problems to Parents/Legal Guardians ............................ 50 
9 
Statistical Considerations ...................................................................................................... 50 
9.1 
Statistical Hypothesis ..................................................................................................... 50 
9.2 
Sample Size Determination ............................................................................................ 51 
9.3 
Populations For Analyses ............................................................................................... 51 
9.4 
Statistical Analyses ........................................................................................................ 51 
9.4.1 
General Approach ................................................................................................... 51 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................ 51 
9.4.3 
Analysis of the Secondary Endpoint(s)................................................................... 52 
9.4.4 
Safety Analyses ....................................................................................................... 52 
9.4.5 
Baseline Descriptive Statistics ................................................................................ 52 
9.4.6 
Planned Interim Analyses ....................................................................................... 53 
9.4.7 
Subgroup Analyses ................................................................................................. 53 
9.4.8 
Tabulation of Individual Participant Data............................................................... 53 
9.4.9 
Exploratory Analyses .............................................................................................. 53 
10 Supporting Documentation and Operational Considerations ................................................ 53 
10.1 Regulatory, Ethical, and Study Oversight Considerations ............................................. 53 
10.1.1 
Informed Consent Process ...................................................................................... 53 
10.1.2 
Study Discontinuation and Closure ........................................................................ 54 
10.1.3 
Confidentiality and Privacy .................................................................................... 54 
10.1.4 
Future Use of Stored Specimens and Data ............................................................. 55 
10.1.5 
Key Roles and Study Governance .......................................................................... 55 
10.1.6 
Site Principal Investigators ..................................................................................... 56 
10.1.7 
Safety Oversight...................................................................................................... 56 
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10.1.8 
Clinical Monitoring ................................................................................................. 56 
10.1.9 
Quality Assurance and Quality Control .................................................................. 56 
10.1.10 
Data Handling and Record Keeping.................................................................... 57 
10.1.11 
Protocol Deviations ............................................................................................. 58 
10.1.12 
Publication and Data Sharing Policy ................................................................... 58 
10.1.13 
Conflict of Interest Policy ................................................................................... 58 
10.2 Additional Considerations .............................................................................................. 59 
10.3 Abbreviations ................................................................................................................. 59 
10.4 Protocol Amendment History......................................................................................... 60 
11 References ............................................................................................................................. 61 
12 APPENDICES ....................................................................................................................... 64 
12.1 APPENDIX I – Names of Study Personnel ................................................................... 64 
12.2 APPENDIX II – Declaration of Helsinki ....................................................................... 65 
12.3 APPENDIX III List of Medical Concepts for Consideration of Seriousness Stratified by 
System Organ Class (15-Sep-2009) .......................................................................................... 72 
12.4 APPENDIX IV Clinical Laboratory Tests ..................................................................... 76 
 
 
 
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Statement of Compliance 
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following: 
x United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
Investigators and clinical trial site staff who are responsible for the conduct, management, or 
oversight of clinical trials have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
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1 
Protocol Summary 
1.1 
Synopsis 
Title: 
A Randomized, Double-Blind, Controlled Study to Assess the 
Efficacy and Safety of Intravenous Phenobarbital in Neonatal 
Seizures 
Study Description: 
This is a multicenter, randomized, double-blinded, active-controlled, 
parallel study in neonates (≥34 - ≤44 gestational weeks).  
This study is designed to evaluate the efficacy, safety and tolerability 
of intravenous phenobarbital in treatment of neonatal seizures 
diagnosed by continuous video EEG (cvEEG). 
This study will consist of a Screening Period, Treatment Period, 
Follow-up Period and Open Label Extension Period. 
Objectives: 
Primary Objective: The primary objective is to evaluate a potential 
dose-response of two different doses of intravenous phenobarbital for 
safety and efficacy in a neonatal population at high risk for seizures. 
 
Secondary Objectives:  
x To assess the safety and tolerability of intravenous 
phenobarbital administration in neonates experiencing 
seizures. 
x To assess the requirement of a second dose of intravenous 
phenobarbital in neonates with ongoing seizures. 
x To assess the requirement of alternative anticonvulsive 
therapy in neonates with ongoing seizures after the second 
dose of intravenous phenobarbital. 
x To characterize the seizure burden following administration 
of intravenous phenobarbital. 
 
Endpoints 
Primary Endpoint: 
x Percent of neonates who do not require additional seizure 
treatment after the first dose of phenobarbital during the first 
24 hours after treatment. 
 
Secondary Endpoints:  
x Percent of neonates who do not require additional seizure 
treatment for 2 hours after the first dose of phenobarbital. 
x Percent of neonates who do not require additional seizure 
treatment after the second dose of phenobarbital within the 
first 24 hours of treatment. 
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x Seizure burden over 24 hours following initial administration 
of the phenobarbital injection. 
x Seizure burden over 48 hours following initial administration 
of the phenobarbital injection. 
x Percent of neonates requiring alternative anticonvulsive 
therapy for the management of seizures at 24 and 48 hours 
x Time period between the first dose and second dose of 
intravenous phenobarbital in neonates randomized. 
x Time period between the second dose of intravenous 
phenobarbital to alternative anticonvulsant treatment in 
neonates randomized. 
x Time period between the first dose of intravenous 
phenobarbital 
to 
administration 
of 
an 
alternative 
anticonvulsant treatment in neonates randomized. 
Study 
Participant 
Population 
Male or female neonates with a gestational age of ≥ 34 - ≤ 44 weeks 
admitted into the NICU with a high probability of developing seizures 
Phase: 
Phase III 
Description 
of 
Sites/Facilities 
Enrolling Participants 
Level III/IV NICU 
Description of Study 
Drug 
Phenobarbital 20 mg/kg (first/initial dose) followed by 20 mg/kg (if 
required) 
 
Phenobarbital 40 mg/kg (first/initial dose) followed by 10 mg/kg (if 
required) 
 
The doses will be administered intravenously over a 30-minute 
period. 
 
Study Duration: 
Estimated Study Start Date: Q4 2020 
Estimated Primary Completion Date: Q3 2023 
Estimated Study Completion Date: Q4 2023 
Participant Duration: 
Total study duration for a single neonate is up to 5 days. 
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1.2 
Schema 
 
Screening Period
(see Section 1.3, Schedule of Activities)
(N=490)
Randomization
Electrographic seizures lasting >= 30s/h 
during Screening Period
(N=196)
Double-Blind Treatment Period
Administration of study drug within 2hrs 
from end of last confirmed cvEEG seizure 
(see Section 1.3, Schedule of Activities)
24 hour Follow-up Period
(see Section 1.3, Schedule of Activities)
(N=186)
Open Label Extension Period
Administration of Phenobarbital 
Maintenance Dose
(See Section 1.3.1, Schedule of Activities)
Screen Failure
No Electrographic Seizures 
within 24hrs of entering 
Screening Period
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1.3 
Schedule of Events 
Study Procedure 
Screening 
Period 
Double-Blind Treatment 
Period 
Follow-Up Period / 
Early Discontinuation/ End 
of Study 
Study Day(s) 
-1-0 
0-1 
1-2 
NICU Admission 
X 
 
 
Informed Consent 
X 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
Delivery History 
X 
 
 
Medical History 
X 
 
 
Apgar Score 
X 
 
 
Physical Examination (includes neurological 
exam) 
X1 
 
X2 
Height/Length (include Head Circumference and 
Abdominal Circumference) 
X 
 
 
Body Weight 
X 
 
 
Vital Signs1,3 
X 
X 
X 
Laboratory Safety Tests (Hematology, 
Chemistry, Coagulation)1,4 
X 
X 
X 
Continuous Video EEG Assessment5 
X 
X 
X 
Clinical Seizure Assessment6 
 
X 
X 
Randomization 
 
X 
 
Phenobarbital Administration  
 
X 
 
Phenobarbital Maintenance Administration 
 
 
 
Phenobarbital PK Samples7 
 
X 
X 
Recording of Additional Anticonvulsant 
Medication 
 
X 
X 
Prior and Concomitant Medication Review  
X 
X 
X 
Adverse Events Evaluation 
X 
X 
X 
 
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1. All neonates will undergo a baseline physical exam (including a neurologic exam), baseline vital signs (blood pressure, pulse 
rate, respiration rate, oxygen saturation, and auxiliary or rectal temperature) and baseline laboratory safety tests. 
2. Physical examination and neurologic exam to be completed at end of Follow-up Period and/or prior to discharge. 
3. Vital signs will be monitored and recorded prior to each (loading dose and second dose) phenobarbital treatment administration 
and every 15±5 minutes up to 1 hour after the completion of each 30-minute dose infusion. Recording of vital signs will continue 
to be collected every 4-6 hours post phenobarbital administration through the Treatment Period and until completion of the 
Follow-up Period or at early study discontinuation. The 4-6 hours is calculated from initial loading dose start of infusion time.  
4. Laboratory safety tests will be collected at the completion of the Treatment Period, at end of Follow-up Period and every 24 
hours during the Open-Label Extension Period or at time of discharge/early study discontinuation. 
5. cvEEG monitoring will be recorded for the study from time of informed consent or start of cvEEG (which ever comes last) and 
up to 48 hours after first loading dose of phenobarbital. 
6. Clinical seizure assessment will be monitored and recorded prior to each phenobarbital treatment dose and at 30 and 60 minutes 
after the completion of each 30-minute dose infusion. At the end of Treatment and Follow-up Period, whether seizures were 
observed clinically will be documented in the eCRFs. 
7. Collection of plasma samples for phenobarbital analysis will be obtained:  
o PK Group 1: 30 minutes, 4-6 hours post initial dose, 
o PK Group 2: 30 minutes, 10-12 hours post initial dose, 
o PK Group 3: 30 minutes, 16-18 hours post initial dose, 
o PK Group 4: 30 minutes, 22-24 hours post initial dose, 
o A sample will be collected after second dose infusion is complete (if applicable) 
o A sample will be collected at end of Follow-up Period or at time of discharge/discontinuation. 
o During the Open Label Extension Period, phenobarbital plasma concentrations will be obtained every 24 hours post 
initial dose up to 120 hours and or at time of discharge/discontinuation. 
 
 
 
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1.3.1 Schedule of Events (Open Label Extension Period) 
Study Procedure 
Open Label Extension 
Open Label Discharge/End of 
Open Label 
Study Day(s) 
2-4 
2-4 
NICU Admission 
 
 
Informed Consent 
 
 
Inclusion/Exclusion Criteria 
 
 
Delivery History 
 
 
Medical History 
 
 
Apgar Score 
 
 
Physical Examination (includes neurological exam) 
 
X1 
Height/Length (include Head Circumference and 
Abdominal Circumference) 
 
 
Body Weight 
X 
 
Vital Signs 
X2 
X2 
Laboratory Safety Tests (Hematology, Chemistry, 
Coagulation) 
X3 
X3 
Continuous Video EEG Assessment 4 
 
 
Clinical Seizure Assessment 
X5 
X5 
Randomization 
 
 
Phenobarbital Administration  
 
 
Phenobarbital Maintenance Administration 
X 
 
Phenobarbital PK Samples6 
X 
X 
Recording of Additional Anticonvulsant Medication 
X 
X 
Prior and Concomitant Medication Review  
 
X 
Adverse Events Evaluation 
X 
X 
1. Physical examination and neurologic exam to be completed prior to discharge. 
2. Vital signs will be monitored and recorded prior to each phenobarbital maintenance treatment administration and every 15±5 
minutes up to 1 hour after the completion of each 30-minute dose infusion. Recording of vital signs will continue to be collected 
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every 4-6 hours hour post phenobarbital administration until the completion of the Open Label Extension Period or at study 
discharge. The 4-6 hours is calculated from initial loading dose start of infusion time. 
3. Laboratory safety tests will continue to be collected every 24 hours during Open-Label Extension Period or at time of 
discharge/early study discontinuation. 
4. cvEEG monitoring will be recorded from time of informed consent or start of cvEEG (which ever comes last) and up to 48 hours 
and up to 48 hours after first loading dose of phenobarbital. If study participant enters Open Label Extension before end of 
Follow-up Period, cvEEG recording and monitoring will continue until the 48 hours is complete. cvEEG recording and 
monitoring after 48 hours is not required per this protocol and will follow site’s standard of practice. 
5. Clinical seizure assessment will be recorded prior to each phenobarbital maintenance treatment administration and at 30- and 
60-minutes after the completion of each 30-minute dose infusion. At the end of each 24-hour Open Label Maintenance Study, 
whether seizures were observed clinically will be documented in the eCRFs. 
6. Collection of plasma samples for phenobarbital analysis will be obtained every 24 hours post initial loading dose up to 120 hours 
and or at time of discharge/discontinuation. 
 
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2 
Introduction 
2.1 
Study Rationale 
This is a randomized, double-blind, parallel-group, phase 3 study to evaluate the efficacy of the 
administration of phenobarbital sodium injection in neonates who have suffered from 
electrographic or electroclinical seizure. As neonatal seizures can have long-term adverse effects, 
including death, placebo-controlled studies are not appropriate for this population. This study is 
designed to show intravenous phenobarbital is effective at preventing subsequent seizures by 
demonstrating greater efficacy at a higher dose compared to a lower dose. 
2.2 
Background 
Phenobarbital is one of the first barbiturates synthesized and is one of the approximate 50 
barbiturates used clinically. Phenobarbital has an extensive history with nearly 100 years of use as 
a sedative, hypnotic and anticonvulsant drug. It is recommended by the World Health Organization 
(WHO) as a first-line agent for partial and generalized tonic-clonic seizures in developing 
countries.  
Currently, phenobarbital is one of the oldest and most utilized antiepileptic drugs worldwide. The 
drug is relatively safe, and provides a cost-effective alternative to other antiseizure medications 
(ASMs), making this drug a more popular choice. Despite other conventional ASMs including 
carbamazepine, sodium valproate and phenytoin replacing phenobarbital as a first-line agent and 
possible behavior and cognitive side effects as well as sedation from drug use, phenobarbital 
continues to be a second- or third-line agent in the developed world. 
Phenobarbital is commonly administered orally in tablet form for prophylactic purposes but can 
also be used parenterally when the oral route is impossible or impractical (i.e. emergency 
situations). Phenobarbital is administered parenterally as a slow intravenous (IV) injection or given 
as an intramuscular (IM) injection. Subcutaneous routes are not recommended. 
Phenobarbital sodium injection is no longer a first-line therapy for many types of acute epileptic 
seizures since it has been largely replaced by newer parenteral antiepileptic drugs such as 
lorazepam, “which is the most commonly administered benzodiazepine for status epilepticus when 
intravenous access is available”(1). Other intravenous antiepileptic drugs available in the USA 
include phenytoin, fosphenytoin, levetiracetam, sodium valproate, and lacosamide. 
However, phenobarbital remains the first-line therapy for acute seizures in neonates in the USA 
and international survey data indicate that it remains the most commonly used agent in this setting 
(2). Seizures occur more often during the newborn period (2-3.5 per 1000 live births) than at any 
later age. Neonatal seizures can lead to frequent and serious long-term consequences in survivors, 
such as later epilepsy and significant cognitive and motor disabilities. A National Hospital 
Discharge Survey indicates that the incidence of all types of neonatal seizures is 2.84 per 1,000 
live births in the United States; similar rates of neonatal seizures have been reported in population-
based studies in California (0.95/1000 live births) and Texas (1.8/1000 live births) (3-5). For 
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hypoxic-ischemic encephalopathy specifically, similar incidence rates of 1-3 per 1000 live births 
have been reported in the United States and other high-income countries (6, 7). In a recent Task 
Force Report for the ILAE Commission of Pediatrics, phenobarbital, carbamazepine, and valproate 
were recommended choices for benign infantile convulsions, but the committee indicated that each 
was “possibly effective” and that the published data were “weak” with overall recommendations 
of “C” (possibly effective, ineffective, or harmful, or as useful/predictive or not useful/predictive) 
for all three drugs according to the American Academy of Neurology (AAN) grading system (8). 
2.2.1 Clinical  
In infants with seizures, phenobarbital 15−20 mg loading dose with additional 5−10 mg/kg doses 
to maximal plasma concentration of 40 mg/L (172 micromol/L) resulted in a plateau of the 
response rate. Plasma concentrations >50 mg/L (215 micromol/L) were associated with sedation 
and feeding difficulty (9). 
The clearance of phenobarbital increases with birth weight and postnatal age, but is reduced at a 
concentration >50 mg/L (215 micromol/L) (10). Bioavailability is 50% after oral administration. 
Simulations recommend a loading dose 20 mg/kg and maintenance 2.5 − 5 mg/kg/day for 
intravenous administration and; loading dose 40 mg/kg and maintenance 5 − 11 mg/kg/day for oral 
administration to meet a target phenobarbital concentration between 15 and 30 mg/L (64.5 and 
129.1 micromol/L) (11). The clinical management of neonatal seizures and the doses (both partial 
and cumulative) of phenobarbital administered as first line therapy have generally varied among 
clinicians and institutions.  A total dose of  50 mg/kg can be given if required (12). 
The clearance may also be reduced in infants with perinatal asphyxia undergoing therapeutic 
hypothermia (13-15). In term infants treated with hypothermia, an initial phenobarbital loading 
dose of 20 mg/kg with an additional 10−20 mg/kg if needed is recommended (15). 
2.2.2 Importance of Clinical Trial 
This clinical trial represents a national and international, therapeutic confirmatory study to further 
demonstrate the tolerability, safety and efficacy of phenobarbital use in neonatal seizures. 
2.3 
Risk/Benefit Assessment 
2.3.1 Known Potential Risks 
2.3.1.1 Contraindications 
Hypersensitivity to phenobarbital or any ingredients. Any forms of acute porphyria. 
2.3.1.2 Precautions 
Use with caution in renal or hepatic impairment. Dependence may develop with prolonged use – 
consider weaning instead of abrupt withdrawal. Therapeutic hypothermia may increase the serum 
concentrations of phenobarbital – monitor serum concentrations closely. 
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Additional precautions in preterm infants, especially those with extreme immaturity and neonates 
with respiratory failure. 
2.3.1.3 Drug Interactions 
Phenobarbital is known as an inducer of microsomal liver enzymes. Morphine, fentanyl, 
midazolam and other CNS depressants may cause reduced blood levels when co-administered with 
phenobarbital, resulting in ineffective treatment (16-18). If phenobarbital is substituted by non-
CYP3A inducers, lower doses of other drugs might be appropriate to avoid excessive exposure.  
Acceleration of elimination of digoxin, metronidazole, corticosteroids (e.g. betamethasone, 
dexamethasone), vitamin D, and beta-blockers (e.g. propranolol, sotalol), resulting in reduced 
plasma levels may occur if administered concurrently with phenobarbital. Concurrent 
administration of phenytoin with phenobarbital has variable effects on serum concentrations of 
either drug. Serum concentrations should be monitored for both drugs. 
2.3.1.4 Adverse Reactions 
Expected phenobarbital adverse reactions include drowsiness, lethargy, impaired sucking reflex 
and poor feeding. If administration is too rapid, expected adverse reactions include respiratory 
depression, apnea, hypotension, laryngospasm and bronchospasm. Other expected adverse 
reactions include phlebitis, tissue necrosis if extravasation occurs, GI intolerance, physical 
dependence and tolerance, folate deficiency, hepatitis and hypocalcaemia. 
Stevens-Johnson syndrome and Toxic Epidermal Necrolysis: Serious and sometimes fatal 
dermatologic reactions, including Stevens-Johnson syndrome (SJS) and Toxic Epidermal 
Necrolysis (TEN) have been reported with phenobarbital. Post-marketing reporting rate is 
generally accepted to be an underestimate due to under-reporting. Recurrence of serious skin 
reactions following re- challenge with phenobarbital has also been reported. Therefore, if a study 
participant develops a skin reaction during phenobarbital treatment, consideration should be given 
to permanent discontinuation and replacement of the drug with alternative treatment. 
2.3.2 Known Potential Benefits 
Phenobarbital has been recommended as first-line treatment for neonatal seizures (19). In RCTs, 
phenobarbital (target plasma concentration 25 mg/L) was reported to be similarly as effective as 
phenytoin (target plasma concentration 3 mg/L) for control of electrical seizures (43% versus 45%) 
(20); and phenobarbital 20 mg/kg was reported to be more effective than phenytoin 20 mg/kg at 
controlling clinical seizures (72% versus 15%) (21). 
2.3.3 Assessment of Potential Risks and Benefits 
Overall, this is a carefully designed trial targeting to meet its objectives of providing effective 
neonatal seizure treatment without exposing study participants to any unnecessary risk. 
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2.3.3.1 Physical Harms 
The study is designed to measure the effects of therapeutic doses of phenobarbital for treating 
neonatal seizures. The risks associated with the drug is assumed not to beyond those presented 
during standard of care treatment or described in the literature (12). The doses tested in this study 
are within the dosing guidelines available in the literature (12). The increased number of blood 
draws required for the study can be considered beyond that of standard of care. There is risk 
associated with multiple blood draws during a prespecified time period. 
2.3.3.2 Psychological Harms 
The risks associated with the drug are assumed not to be beyond those presented during standard 
of care treatment or presented in the literature (12). The doses tested in this study are within the 
dosing guidelines available in the literature (12). It is not expected for the study participant to 
experience any psychological harm during the study. Undesired changes in thought process and 
emotion may occur for the parents/legal guardians during the study. These changes are only 
expected to be transitory and not, recurrent or permanent. 
2.3.3.3 Invasion of Privacy 
 The study does not involve any type of observation that would be seen as covert or intrusion. 
2.3.3.4 Social and Economic Harms 
 The study does not involve any type of outcome that would be seen to affect the social or economic 
status of the parents/legal guardians or study participant. 
2.3.3.5 Minimization of Risk 
Minimization of risk will be achieved by following the listed guidelines: 
x Study staff will receive complete information in the protocol regarding the experimental 
design and the scientific rationale underlying the proposed research, including the results 
of previous animal and human studies. 
x A research team with sufficient expertise and experience to conduct the research will be 
assembled. 
x Statisticians will ensure that the projected sample size is sufficient to yield useful results. 
x As much data will be collected from standard-of-care procedures to avoid unnecessary risk, 
particularly for invasive or risky procedures (e.g., spinal taps, cardiac catheterization). 
x Appropriate safeguards will be incorporated into the research design such as an appropriate 
data safety monitoring plan, the presence of trained personnel who can respond to 
emergencies, and procedures to protect the confidentiality of the data (e.g., encryption, 
codes, and passwords). 
x The protocol has also been designed in order to meet the requirements of Part 46.205 
(Protection of Human Subjects, Research involving neonates) which include: 
x Neonates of uncertain viability will not be included in the study 
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x Preclinical and clinical studies have been conducted and provide data for assessing 
potential risks to neonates 
x Parents/Legal Guardians providing consent (in-person or remote) will be fully 
informed regarding the impact of the research on the neonate 
x Study staff engaged in the protocol will have no part in determining the viability of a 
neonate 
3 
Objectives and Endpoints 
3.1 
Objectives 
3.1.1 Primary Objective 
The primary objective is to evaluate a potential dose-response of two different doses of intravenous 
phenobarbital for safety and efficacy in a neonatal population at high risk for seizures. 
3.1.2 Secondary Objectives 
x To assess the safety and tolerability of intravenous phenobarbital administration in 
neonates experiencing seizures. 
x To assess the requirement of a second dose of intravenous phenobarbital in neonates with 
ongoing seizures. 
x To assess the requirement of alternative anticonvulsive therapy in neonates with ongoing 
seizures. 
x To characterize the seizure burden following administration of intravenous phenobarbital. 
3.1.3 Exploratory Objectives 
x To characterize the population pharmacokinetics of intravenous phenobarbital in neonates 
with seizures. 
x To evaluate a potential dose-response of two different doses of intravenous phenobarbital 
for safety and efficacy in neonatal populations with different seizure etiologies. 
3.2 
Endpoints 
3.2.1 Primary Endpoint  
Percent of neonates who do not require additional seizure treatment after the first dose of 
phenobarbital during the first 24 hours after treatment. 
Time zero (T0) will be defined as the start of the first loading dose 30-minute infusion. 
3.2.1.1 Justification for Primary Endpoint 
Primary endpoint is in line with recommendations provided by the US Food and Drug 
Administration. This measure should provide a clear delineation between the efficacy of the low 
and high loading doses of intravenous phenobarbital. 
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3.2.2 Secondary Endpoints 
x Percent of neonates who do not require additional seizure treatment after 2 hours of the 
first dose of phenobarbital. 
x Percent of neonates who do not require additional seizure treatment after the second dose 
of phenobarbital within the first 24 hours of treatment. 
x Seizure burden over 24 hours following initial administration of the phenobarbital 
injection. 
x Seizure burden over 48 hours following initial administration of the phenobarbital 
injection. 
x Percent of neonates requiring alternative anticonvulsive therapy for the management of 
seizures at 24 and 48 hours. 
x Time period between the first dose and second dose of intravenous phenobarbital in 
neonates randomized.  
x Time period between the second dose of intravenous phenobarbital and alternative 
anticonvulsant treatment in neonates  
x Time period between the first dose of intravenous phenobarbital and administration of an 
alternative anticonvulsant treatment in neonates randomized. 
3.2.2.1 Justification for Secondary Endpoints 
Reduction in seizure burden, seizure recurrence and administration of rescue ASDs have been 
identified as reliable outcomes to assess efficacy of antiepileptic drugs in late stage drug trials (22). 
3.2.3 Exploratory Endpoints  
3.2.3.1 Pharmacokinetic Endpoints 
A population PK analysis approach utilizing sparse plasma sampling will be implemented to assess 
the pharmacokinetics of intravenous phenobarbital in neonatal seizures. The following 
phenobarbital pharmacokinetic parameters may be explored during the study:  
x Observed time to reach maximum drug concentration (Tmax)  
x Observed peak drug concentration (Cmax)  
x Area under the plasma concentration-time curve (AUC0- t), the percent AUC extrapolated 
from AUC0-t to infinity AUCextrap and infinity (AUC0-inf)  
x Apparent terminal elimination rate constant (Kel)  
x Apparent terminal drug elimination half-life (t1/2)  
x Clearance adjusted by absorption, calculated as dose/AUC0-inf (Cl/F)  
x Volume of distribution adjusted by absorption, calculated as Dose/Kel•AUC0-inf (Vd/F) 
 
Both free and total phenobarbital will be attempted to be measured in order to assess the variability 
in protein binding of phenobarbital. 
 
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Relationship between potential covariates including co-medication, cooling therapy, renal 
function, liver function, gestational age and protein binding will be explored. Specific analyses 
will be detailed in the final pharmacokinetic analysis plan. 
 
3.2.3.2 Other Exploratory Endpoints 
The endpoints described in Section 3.2.1 and Section 3.2.2 will also be evaluated for different 
neonatal seizure etiologies. The subpopulations to be evaluated include HIE, stroke and 
intracerebral hemorrhage. 
3.2.3.3 Justification for Exploratory Endpoints 
Gestational age less than 44 weeks has different seizure etiologies, seizure pathogenesis, and 
hepatic/renal function, potentially affecting drug efficacy, safety, and/or drug metabolism and 
elimination. Pharmacokinetic data and analysis are necessary to understand these potential study 
participant differences (22). The data collected is also part of the overall safety assessment for the 
study participants. 
3.2.4 Safety Endpoints 
The following safety assessments will be performed during the study:  
x Type, incidence, and severity of adverse events  
x Physical examination (including neurologic exam) 
x Vital signs (blood pressure [arterial line], respiration rate, pulse rate, oxygen saturation, 
and temperature)  
x Clinical laboratory tests (hematology, serum chemistry) 
 
3.2.4.1 Justification for Safety Endpoints 
Safety monitoring is a standard, yet critical component of any clinical trial. The safety assessments 
in this study are not beyond that of standard safety assessments performed in many clinical studies. 
4 
Study Design 
4.1 
Overall Design 
This is a multicenter, randomized, double-blinded, active-controlled, parallel study in neonates 
(defined as ≥34 - ≤44 gestational weeks). The study will consist of a Screening Period, Double-
Blind Treatment Period, Follow-up Period and an Open-Label Extension Period. The study 
participant population is neonates being admitted to the NICU and requiring continuous video 
electroencephalography (cvEEG) for seizure detection. One or two parents and/or legal guardians 
must provide written approval of informed consent, before the neonate can be assessed, monitored 
and managed in accordance with the study protocol and before any study data can be collected and 
recorded as study data. The reviewing IRB, based on its standard operating procedures, will 
determine number of parents/legal guardians who will be required to sign the informed consent.  
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Upon NICU admission and after parents or legal guardians provide informed consent, neonates 
will be monitored for electrographic seizures. 
Seizures requiring study drug treatment will be defined as cumulative electrographic seizure of at 
least 30 sec/h (22). Confirmation of electrographic seizures by principal investigator or site 
designees (recommended to be a pediatric neurologist and/or neurophysiologist) is required. 
Randomization and study drug administration should start as soon as possible after the 30 sec/h of 
seizure activity criteria is met ideally within 30 min (maximum two hours) (22). If study drug cannot 
be administered within two hours of recognition of qualifying seizure burden (≥ 30 sec/h), then 
study drug should not be administered and the neonate will be discontinued from the study and 
will be a screen failure. 
Following confirmation of seizure criteria, neonates will be randomized in a 1:1 allocation to 
receive a phenobarbital treatment loading dose of 20mg/kg or 40mg/kg, infused over 30 minutes. 
If seizures persist (≥30 sec/h of seizure activity) 60 minutes following the start of the initial dose 
of phenobarbital, neonates receiving an initial dose of 20 mg/kg will receive an additional 20 
mg/kg dose. Neonates receiving an initial dose of 40 mg/kg will receive an additional 10 mg/kg 
dose. Administration of this second loading dose is required to be within 2 hours of recognition of 
qualifying seizure burden (≥ 30 sec/h). The time period between the first and second dose of study 
treatment will be determined by the principal investigator or site designee (recommended to be a 
pediatric neurologist and/or neurophysiologist) review of the cvEEG, but must be at least 30 
minutes after infusion is completed and no more than 24 hours after the first dose of study 
treatment (22).  
If the seizure activity continues (≥30 sec/h) is still not resolved, study participants may receive a 
second-line alternative anticonvulsant therapy per institutional protocol. In each treatment arm, the 
second-line anticonvulsant therapy will be confirmed by the principal investigator or site designee 
(recommended to be a pediatric neurologist and/or neurophysiologist) and recorded in the study 
documentation as a concomitant medication. 
All phenobarbital treatment doses will be prepared by the unblinded investigational pharmacist. 
The investigational pharmacist will be unblinded (have access to the treatment arm labels) and will 
not be involved in the assessment or medical management of the neonate. All other study personnel 
will be blinded to the first and second phenobarbital dose treatment. Each study treatment arm will 
be prepared in the same total volume of administration and administered over a 30-minute 
infusion in order to maintain the study blind.  
Throughout the Treatment Period the neonate will be continuously monitored by cvEEG, vital 
signs will be recorded, clinical seizure assessment will be recorded, and blood samples will be 
collected for laboratory safety monitoring and phenobarbital plasma concentrations according to 
the schedule of activities (Section 1.3). cvEEG monitoring will continue throughout the Treatment 
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Period and will be discontinued at end of Follow-up Period or upon entering Open Label Extension 
Period. 
A population pharmacokinetic approach will be implemented using sparse sampling collection. 
Collection of plasma samples for phenobarbital analysis will be obtained after each loading dose 
and will follow the sampling guidelines in the schedule of activities (Section 1.3). Additional 
plasma samples will be obtained at the completion of the treatment period or at early study 
discontinuation. In order to maintain the study blind, the phenobarbital plasma concentrations will 
not be made available to the study personnel.  
Seizure management in the treatment period will be determined by cvEEG monitoring. Recording 
of all vital signs and collection of laboratory safety monitoring and collection of phenobarbital 
plasma samples will be dependent on the clinical management and status of the neonate. The 
principal investigator will be allowed to discontinue the neonate from the study protocol at any 
time throughout the study protocol and allowed to administer alternative anticonvulsant therapy as 
medically required or following standard of care guidelines.  
The study treatment period for the primary study analysis will end 24 hours after the neonate meets 
the seizure criteria and receives the initial phenobarbital study dose (i.e. T0-24 hr). Prior to 
completing the Treatment Period or early study discontinuation, cvEEG assessment, clinical 
seizure assessment, and vital signs will be recorded, clinical laboratory tests will be performed, 
and a phenobarbital plasma sample will be collected. The neonate will be monitored for an 
additional 24 hours (Follow-up Period) after the Treatment Period is completed. During the 24-
hour Follow-up Period general seizure activity, administration of additional non-study 
anticonvulsant medication, and adverse events will be recorded. Neonates requiring 
ongoing/maintenance intravenous phenobarbital therapy following study treatment completion 
will enter an Open Label Extension Period (up to 3 days) and will be monitored for safety and 
additional phenobarbital plasma samples will be obtained while they are on therapy and until 
hospital discharge. All study related assessments and work related to the study will be compensated 
by the funding Sponsor. 
4.1.1 Definitions 
4.1.2 Screening Period 
Parental/Legal Guardian consent must be provided prior to study participant enrollment and prior 
to any study-related procedures being done. All screening evaluations must be completed before 
the study participant enters the Treatment Period. Screening Period is from time of consent or start 
of cvEEG (which ever comes last) and up to 24 hours (T(-)24-0 hrs). 
The following procedures will be completed during the Screening Period (prior to dosing): 
x Informed Consent 
x NICU Admission 
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x Review of Inclusion/Exclusion Criteria 
x Delivery History 
x Medical History (includes Family History of Seizures and Delivery Complications) 
x Physical Examination (including neurologic exam) 
x Vital Signs (baseline assessment) 
x Height/Length 
x Head Circumference 
x Abdominal Circumference 
x Apgar Score 
x Body Weight 
x Collection and review of Laboratory Safety Tests (Hematology, Chemistry and 
Coagulation) (baseline assessment) 
x cvEEG recording and monitoring 
x Prior and Concomitant Medication Review  
x Adverse Events Evaluation 
Gestational age can be calculated using either ultrasound, last menstrual period, or neonatal 
assessment. 
4.1.3 Treatment Period 
Treatment Period is from time of first drug administration and up to 24 hours (T0-24 hrs). 
The following procedures will be performed during the Treatment Period: 
x Review of Inclusion/Exclusion Criteria 
x Vital Signs 
x Collection and review of Laboratory Tests (Hematology, Chemistry and Coagulation) 
x Randomization 
x cvEEG recording and monitoring 
x Clinical Seizure Assessment 
x Initial Phenobarbital Administration  
x Additional Phenobarbital Administration  
x Phenobarbital Plasma Samples 
x Recording of Additional Anticonvulsant Medication 
x Concomitant Medication Review  
x Adverse Events Evaluation 
4.1.4 24 Hour Follow-Up Period /Early Discontinuation/End of Study  
Follow-Up Period is from end of Treatment Period and up to 24 hours (T24-48 hrs). 
The following procedures will be performed during the Follow-up Period: 
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x Physical Examination (including neurologic examination) 
x Vital Signs 
x Collection and review of Laboratory Tests (Hematology, Chemistry and Coagulation) 
x cvEEG recording and monitoring  
x Clinical Seizure Assessment 
x Phenobarbital Plasma Samples 
x Recording of Additional non-study Anticonvulsant Medication 
x Concomitant Medication Review 
x Adverse Events Evaluation 
4.1.5 Open-Label Extension Period  
Open-Label Extension Period is from start of first phenobarbital maintenance dose and up to 72 
hours. Maintenance cannot be started <24 hours after T0 (e.g., not during Treatment Period). If it 
is determined that maintenance phenobarbital is no longer needed, study participant will be 
discontinued from the Open-Label Extension Period and final study assessments will be completed 
based on schedule of activities (Section 1.3). 
The following procedures will be performed during the Open-Label Extension Period: 
x Vital Signs 
x Physical Examination (including neurologic examination) 
x Collection and review of Laboratory Tests (Hematology, Chemistry and Coagulation)  
x Clinical Seizure Assessment 
x Phenobarbital Administration  
x Phenobarbital Plasma Samples every 24 hours 
x Recording of Additional Anticonvulsant Medication 
x Concomitant Medication Review 
x Adverse Events Evaluation  
4.2 
Scientific Rationale for Study Design 
4.3 
Justification for Dose 
The clinical management of neonatal seizures and the doses (both partial and cumulative) of 
phenobarbital administered as first line therapy have generally varied among clinicians and 
institutions. A total daily dose up to 50 mg/kg have been recommended for the treatment of 
neonatal seizures (12). Based on the published literature and current standard practices, the most 
frequently used initial doses of phenobarbital to treat neonatal HIE are 20 to 30 mg/kg i.v. followed 
by maintenance dose of 4 to 6 mg/kg per day (2). If seizures do not resolve with the initial dose, 
repeat boluses of 10 to 20 mg/kg may be administered with a goal of approximately 50 μg/mL 
phenobarbital serum level or a total 24 hour total dose of 50 mg/kg (2). 
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The Sponsor proposes evaluating two double-blind intravenous dose regimens of phenobarbital: 
Phenobarbital 20 mg/kg (initial dose) followed by 20 mg/kg (second dose, if required) [total daily 
dose 40 mg/kg] or phenobarbital 40 mg/kg (initial dose) followed by 10 mg/kg (second dose, if 
required)[total daily dose of 50 mg/kg]. 
If seizures do not resolve following the initial or second dose of phenobarbital, the PI or site 
designee will choose an alternate drug for additional dosing. The PI or site designee will be 
permitted to choose an alternate drug of choice if the neonate does not achieve appropriate seizure 
control at any time during the study. 
For ethical concerns, there will not be a placebo control group. 
4.4 
End of Study Definition 
A study participant is considered to have completed the study if he or she has completed all phases 
of the study including the last scheduled procedure prior to discharge shown in the Schedule of 
Activities (SoA). 
The end of the study is defined as completion of the last procedure shown in the SoA in the trial 
for the last enrolled study participant. 
5 
Study Population 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Male or female neonates with a gestational age of ≥ 34 - ≤44 weeks admitted into the NICU 
with a high probability of developing seizures (e.g., HIE, stroke, intracerebral hemorrhage, 
central nervous system infection)  
2. Parental/Legal Guardian informed consent (in-person or remote consent) 
3. Undergoing continuous video electroencephalogram (cvEEG) monitoring 
4. Has evidence of electrographic seizure burden of at least 30 seconds/h 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Received anticonvulsant treatment, including phenobarbital, prior to randomization (with 
exception of lorazepam and midazolam administered ≥ 8 hours before enrollment) 
2. Strong suspicion or confirmed diagnosis of brain malformation, inborn error of metabolism 
genetic syndrome, or major congenial malformation prior to randomization 
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3. Seizures responding to correction of hypoglycemia, hypocalcemia or any other metabolic 
disorder 
4. Death appears to be imminent as assessed by the NICU attending physician 
5. Is currently enrolled in another study assessing the same and/or similar primary/secondary 
endpoints with/without drug treatment. 
Study participants who may be already participating in another neonatal clinical trial (e.g., registry 
or observational) that meet all MI-5780 inclusion criteria and none of the MI-5780 exclusion 
criteria as well as can meet study assessment requirements, can be enrolled into this study. In 
addition, study participants enrolled in this trial can enroll in other neonatal trials as long as 1) the 
inclusion criteria for study MI-5780 continue to be met 2) none of the exclusion criteria for study 
MI-5780 are met 3) the other study will not result in minor or major MI-5780 protocol deviations. 
5.3 
Lifestyle Considerations 
Not applicable 
5.4 
Screen Failures 
Screen failures are defined as study participants whom parent/legal guardian consented to 
participate in the clinical trial but are not subsequently randomly assigned to the study drug. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) MAY NOT 
be rescreened. 
5.5 
Strategies for Recruitment and Retention 
5.5.1 Target Study Sample Size 
Literature supports that lower loading doses of phenobarbital achieve seizure control in 
approximately 30 to 60% of treated neonates, with higher loading doses achieving seizure control 
up to 85% (19, 20, 23, 24). Based on 70% and 50% of study participants would achieve seizure 
control in high dose and low, respectively, an effect size of 20%, an alpha of 0.05 and 80% power, 
it is estimated that the number of completed study participants required will be 93 study 
participants in each group (total 186). With approximately, 5% dropout and or non-evaluable study 
participants, the minimum required for randomization will be 196. A screen failure rate of 
approximately 60% is anticipated. A total of 490 study participants would be enrolled. 
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5.5.2 Anticipated Accrual Rate 
It is estimated that investigator sites will enroll approximately 1-2 neonates a month. This rate 
would achieve the necessary 490 screened over the course of approximately one year. 
5.5.3 Anticipated Number of Sites 
Total number of sites/institutions expected to enroll study participants is up to 30 sites. 
5.5.4 Source of Study Participants 
Study participants are expected to come from sites/institutions that are level 3/level 4 NICUs. 
5.5.5 Recruitment Venues 
Not applicable 
5.5.6 Identification of Potential Study Participants 
Maternity ward and hospital transfer staff will, at minimum, be informed about the study being 
performed at their associated NICU. The ward or transfer staff will alert the PI or delegated study 
staff of the transfer of the potential study participant after their birth. The ward staff should inform 
the study staff of the potential seizure risk, any suspected seizure activity and who identified the 
seizure risk/activity. At that time, it will be the responsibility of the PI or designated study staff to 
begin the informed consent process with the parents/legal guardians as well as ensure ward or 
transfer staff do not administer any prohibited anticonvulsants. 
Potential study participants who are at increased risk of seizure activity are listed below. The list 
is not all inclusive and can be used as a guide when determining study participant eligibility. 
Study participants with the following characteristics may be high risk for experiencing seizures: 
x Hypoxic-ischemic encephalopathy 
x Ischemic stroke 
x Intracranial hemorrhage 
x Epileptic encephalopathy 
x Intracranial infection 
Those with the following characteristics are recommended to not be included, but ultimately at the 
discretion of the investigator and are within the study participant eligibility requirements. 
x Brain malformation 
x Transient metabolic (e.g. hypoglycemia, hypocalcemia) 
x Benign familial epilepsy 
5.5.7 Recruitment Strategies 
Specific recruitment strategies are detailed in a separate Recruitment Plan. 
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5.5.8 Long-term Recruitment/Enrollment Strategies 
Specific recruitment strategies are detailed in a separate Recruitment Plan. 
5.5.9 Justification for Vulnerable Population Recruitment 
Phenobarbital is the first line therapy for neonatal seizures. In order to evaluate the efficacy of 
phenobarbital in a randomized, double-blind clinical trial, neonates must be included as the study 
population. The risks associated with enrollment are discussed in Section 2.3. 
5.5.10 Compensation for Study Participation 
Study participants’ parents/legal guardians will not be receiving compensation for participating in 
the study. This information will be clearly out lined and described in the informed consent form 
and approved by an institutional review board (IRB). 
6 
Study Drug 
6.1 
Study Drug(s) Administration 
6.1.1 Study Drug Description 
Phenobarbital sodium injection is part of the class of drugs known as barbiturates. The barbiturates 
are nonselective central nervous system (CNS) depressants which are primarily used as sedative 
hypnotics and anticonvulsants in subhypnotic doses. The barbiturates and their sodium salts are 
subject to control under the Federal Controlled Substances Act as scheduled IV controlled 
substances. 
Barbiturates are substituted pyrimidine derivatives in which the basic structure common to these 
drugs is barbituric acid, a substance which has no central nervous system activity. CNS activity is 
obtained by substituting alkyl, alkenyl or aryl groups on the pyrimidine ring. 
6.1.2 Dosing and Administration 
Following confirmation of seizure criteria, neonates will receive 1 of 2 different phenobarbital 
treatment dose regimens.  
x Phenobarbital 20 mg/kg (first/initial dose) followed by 20 mg/kg (if required)[dose to be 
prepared from 90 mg/ml vials], or 
x Phenobarbital 40 mg/kg (first/initial dose) followed by 10 mg/kg (if required)[dose to be 
prepared from 90 mg/ml vials] 
The initial dose will be administered intravenously over a 30-minute period. If seizures persist and 
the criteria for a second dose is achieved, a second dose of phenobarbital will be administered.  
The time period between the first and second dose of phenobarbital cannot occur within 30 minutes 
of the end of the first dose. Note: the second loading dose can only be administered while study 
participant is in the Treatment Period and cannot be administered during the Follow-up Period. 
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Any additional treatment required must be a second line anticonvulsant and be based on 
site/institutional protocol/standard operating procedures. 
If seizures persist following the second dose of phenobarbital, additional treatment will be based 
on site/institutional protocol/standard operating procedures or site has the option to administer the 
phenobarbital maintenance dose. Note, the optional maintenance dose cannot be administered 
during the Treatment Period. Study participant must enter the Follow-up Period before 
phenobarbital maintenance dose can be administered. 
If study participant qualifies for the optional phenobarbital maintenance dose, the study participant 
can enter the Open-Label Extension Period. 
x Optional Maintenance Dose: 5 mg/kg/day administered intravenously as a single dose over 
a 30-minute period, no earlier than 24 hours after completion of initial loading dose (dose 
to be prepared from 55 mg/ml vials) 
Treatment administration information should be reported to the study participants treating pediatric 
physician and entered into their medical records at time of study completion and unblinding of the 
study participant. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 Acquisition and Accountability 
For detailed instructions regarding study drug acquisition and accountability, refer to the IP 
Instructions for Handling. 
The PI is responsible for ensuring accountability of all study medication supplied and appropriate 
storage and allocation of these supplies. 
The PI is responsible for ensuring that all study medication received at the site are inventoried and 
accountability performed, and that dispensed study medication is recorded in both the eCRF and 
the Study Medication Accountability Logs. The PI, or designee, will verify study medication 
accountability with the CRA during site visits. Any discrepancies should be investigated. The PI 
will not supply study medication or rescue medication to any person except those named as Sub-
Is on Form FDA 1572, designated staff, and study participants in this study and will not dispense 
study medication or rescue medication from any sites other than those listed on Form FDA 1572. 
Study medication and rescue medication may not be relabeled or reassigned for use by other study 
participants. 
All unused or damaged study medication and/or rescue medication will be returned, and unit 
counts will be performed whenever medication is returned. The site must account for all study 
medication received. The site will retain and store all study medication and rescue medication until 
inventoried by the monitor. 
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All unused or damaged (e.g., films that were torn during opening of the foil package) study 
medication and/or rescue medication will be returned to the CRO’s return vendor along with copies 
of the Study Medication Accountability Logs. 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
Phenobarbital Sodium Injection, USP is a sterile solution for intramuscular or slow intravenous 
administration as a long-acting barbiturate. Each mL contains phenobarbital sodium either 55 mg 
or 90 mg, alcohol 140 mg/mL, propylene glycol ~779mg/mL or 754mg/mL, respectively, and no 
benzyl alcohol in water for Injection; hydrochloric acid and sodium hydroxide added, if needed, 
for pH adjustment. Chemically, phenobarbital sodium is 2,4,6(1H,3H,5H)-Pyrimidinetrione,5-
ethyl-5-phenyl-, monosodium salt. 
The packaging and labeling will be detailed in the IP Supply Plan. 
6.2.3 Product Storage and Stability 
Phenobarbital vials can be stored at 15°-25°C (68°-77°F), excursions permitted between 15°-30°C 
(59°-86°F) are allowed provided that the mean kinetic temperature (MKT) does not exceed 25C. 
Transient spikes up to 40C are allowed only if they do not exceed 24 hours. 
Do not use if solution is discolored or contains a precipitate. 
Detailed storage conditions of phenobarbital prepared in syringes is described in the study 
provided pharmacy manual. 
6.2.4 Preparation 
All phenobarbital treatment doses will be prepared by the unblinded investigational pharmacist. 
The investigational pharmacist will be unblinded (have access to the randomization code) and will 
not be involved in the assessment or medical management of the neonate. All other study personnel 
will be blinded to the phenobarbital dose treatment administered. Each study treatment arm will 
be prepared in the same total volume of administration in order to maintain the study blind. 
Further details are provided in the IP Instructions for Handling (also known as Pharmacy Manual). 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
Study participants will be assigned unique study participant numbers upon completion of the 
Screening Period and upon achieving the seizure criteria. 
A unique randomization number will be assigned by an interactive web response system (IWRS) 
once eligibility for the Treatment Period of the study has been determined. Randomization codes 
will be prepared by an external-to-study, unblinded biostatistician.  
Detailed instructions for contacting the IWRS will be provided in the Study Manual. The PI or 
designee will use the IWRS to determine which investigational medicinal product (IMP) will be 
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dispensed to a given study participant for the Treatment Period of the study. The unblinded 
investigational pharmacist will prepare the IMP (both first and second loading dose for each 
treatment arm [labeled A and B in IWRS for unblinded pharmacist]) after the informed consent is 
signed and provide to the PI or designee for storage in the NICU’s pyxis machine, if possible. At 
time of randomization, the PI or designee will contact the IWRS for the randomization code and 
syringe code prior to first dose administration. The IWRS will be contacted again if second loading 
dose administration is needed. 
6.3.1 Unblinding 
The Investigator may unblind an individual study participant’s treatment in an emergency when 
knowledge of such treatment may have an impact on further treatment decisions or aid in the 
emergency treatment of the study participant. Every effort must be made to contact the Medical 
Monitor prior to any unblinding of the study drug. The circumstances that lead to unblinding will 
be promptly communicated via telephone and in writing to the Medical Monitor.  
6.4 
Study Drug Compliance 
The PI, or designee, will verify study medication accountability with study participants during 
site visits. 
6.5 
Concomitant Therapy 
6.5.1 Allowed Concomitant Medication  
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, over-the-counter medications (if applicable) and 
supplements (if applicable). 
Only the short acting benzodiazepine lorazepam and midazolam administered ≥8 hours before 
enrollment will be permitted prior to study entry. 
6.5.2 Second-line Anticonvulsants 
Non-phenobarbital second line anticonvulsants/antiseizure medications are allowed and include: 
x Fosphenytoin  
x Levetiracetam 
x Topiramate 
x Clonazepam 
x Lidocaine 
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7 
Study Drug Discontinuation and Participant Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Drug 
Discontinuation from intravenous phenobarbital does not mean discontinuation from the study, 
and remaining study procedures should be completed as indicated by the study protocol. If a 
clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. 
The data to be collected at the time of study drug discontinuation will include the following: 
x Vital Signs 
x Collection and review of Laboratory Tests (Hematology, Chemistry and Coagulation) 
x cvEEG Assessment  
x Clinical Seizure Assessment 
x Phenobarbital PK Samples 
x Recording of Additional Anticonvulsant Medication 
x Concomitant Medication Review  
x Adverse Events Evaluation 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Parents/Legal Guardians are free to withdraw their study participants in the study at any time upon 
request. 
An investigator may discontinue or withdraw a study participant from the study for the following 
reasons: 
x If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the study participant 
x If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
x Participant unable to receive study drug 
The reason for study participant discontinuation or withdrawal from the study will be recorded on 
the Study Participant Disposition Case Report Form (CRF). Study participants who sign the 
informed consent form and are randomized but do not receive the study drug may be replaced. 
Study participants whose parent/legal guardian sign the informed consent form, and are 
randomized and receive the study drug, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
7.3 
Lost to Follow-up 
Not applicable 
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7.4 
Study Stopping Rules 
The trial DSMB will decide on terminating the trial based on stopping rules defined under Section 
7.4.2. Stopping rules will be reviewed along with information regarding conduct and progress of 
the study, study participant accrual, protocol compliance and other study issues. After each 
meeting, a recommendation to continue or terminate the study will be provided. DSMB 
responsibilities, board process, communications and meeting format details are defined in the 
DSMB Charter. 
The study may be prematurely terminated at any time by the Sponsor, IRB and or Investigator in 
the interest of the study participant safety and welfare. The Sponsor reserves the right to 
discontinue the trial at any time for any reason. 
7.4.1 Stopping rules for study participants 
7.4.1.1 Efficacy 
Study participants will not be stopped in the trial if seizure cessation is not achieved with one or 
two doses of phenobarbital. Study participants will be placed on second-line treatments per 
institutional protocol/standard operating procedures and will continue to be observed. Sponsor is 
not providing sites with second-line anticonvulsant treatments. 
7.4.1.2 Safety 
Newborns who will be enrolled in this study are at high risk for several serious medical 
complications and death related to underlying etiology of their seizures. It is very unlikely that 
phenobarbital will result in death or any serious adverse event. The following adverse events not 
described in the investigator brochure for phenobarbital will be considered expected adverse 
events in this population: 
x Clinical or electrographic seizures 
x Multiorgan Failure 
x Abnormal lab values associated with organ failure 
x Death 
x Any other adverse events associated with systemic asphyxia and hypoxic-ischemic 
encephalopathy in newborns 
Any adverse events that are expected, not related to phenobarbital, and not severe in nature will 
be recorded in the database and reviewed at regular meetings of the DSMB. The DSMB will be 
able to review significant trends of adverse events at their meetings, since the DSMB will be the 
only party not blinded in this trial. After review of the data, the DSMB will report to NEMA 
regarding the risks of the study and whether the risks are consistent with what is described in the 
informed consent form. These reports will be provided by NEMA to the local IRBs for determining 
continuing review, and to the FDA for annual IND safety reports. 
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7.4.2 Stopping rules for Overall Trial 
The DSMB may recommend stopping the study for the following reasons: 
x The data show a clinically important risk of serious adverse effects in one or both of the 
treatment arms. 
x It becomes clear that successful completion of the study is not feasible (e.g. there is an 
excess of study participant dropout, missing data, lack of recruitment etc). 
7.4.2.1 Safety-Continuous Monitoring 
Adverse Events will be continuously monitored by the investigator, clinical research associate, 
CRO Medical Monitor and Sponsor.  
If while continuous monitoring the investigator deems an adverse event to be severe, unexpected 
and possibly related to phenobarbital, the investigator will report the event to NEMA within 24 
hours of the event. These unanticipated adverse events will events will also be reported by the PI 
to the local IRB in accordance with the local IRB policies. NEMA will be responsible for reporting 
the unanticipated adverse events to all DSMB members within 24 hours of receiving the report, 
and to the FDA in an IND safety report in accordance with FDA regulations. The DSMB will 
determine if the adverse event changes the known risk to study participants. If the information 
changes the known risk to study participants, the DSMB’s report regarding the change in risk will 
be released to all participating investigators by NEMA. The DSMB may request changes to the 
DSMB Charter and or potentially halt the trial. 
7.4.2.2 Safety-Interim Monitoring 
The DSMB will evaluate the study after the first 10% and 50% of randomized study participants.  
Criteria to be evaluated are outlined in detail in the committee charter. 
8 
Study Assessments and Procedures 
8.1 
Efficacy Assessments 
8.1.1 Seizure Burden 
8.1.1.1 Total Seizure Burden 
Total Seizure Burden summarizes the duration of all seizures on the cvEEG recording for each 
study participant individually and is measured in minutes. 
At minimum, the start and end time of each seizure will be recorded in the case report forms.  
8.1.1.2 Maximum Seizure Burden 
The Maximum Seizure Burden is defined as the maximum hourly seizure burden with the cvEEG 
recording and is measured in minutes per hour. 
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8.1.2 Seizure Recurrence 
The recurrence of seizures is measured by total seizure burden from the end of the defined response 
period until 24 h after study drug administration. If the study participant continues in the open-
label period, seizure recurrence will be evaluated every 24 hours until discharge. This is contingent 
on maintenance of therapeutic levels of study drug. 
8.1.3 Seizure Period 
Seizure period is calculated as the time from the onset of the first electrographic seizure to the 
offset of the last electrographic seizure. 
8.1.4 Seizure Documentation 
The start and end time of seizures will be recorded in the case report forms based on the following 
guidelines: 
x All seizures within the first 2 hours from the start of the first dose of study drug. 
x If a second dose of study drug is given, start time of seizure that prompted a second dose 
will be recorded as well as the stop time of the seizure. 
x If need to give a second line seizure medication, document start time for the seizure that 
prompted giving the second line seizure medication as well as the stop time of the seizure. 
x If seizures continue, for each additional seizure medication administered, document start 
time for the seizure that prompted giving the seizure medication as well as the seizure stop 
times. 
8.2 
Safety and Other Assessments 
8.2.1 Demographics and Medical History 
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race. 
Medical history to be obtained will include determining whether the study participant has any 
significant conditions or diseases relevant to the disease under study. If available, family history 
of seizures and delivery complications should be recorded under medical history. Ongoing 
conditions are considered concurrent medical conditions. Concurrent medical conditions are those 
significant ongoing conditions or diseases that are present at signing of informed consent. This 
includes clinically relevant laboratory or physical examination abnormalities noted at Screening. 
The condition (i.e., diagnosis) must be described. 
8.2.2 Pregnancy and Delivery History 
Current delivery information will be recorded for the following:  
x Date of delivery 
x Delivery presentation 
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o Occiput posterior 
o Occiput anterior 
o Brow 
o Face 
o Compound 
o Transverse 
o Breech 
o Other (please specify) 
o Unknown 
8.2.3 Medical History of Mother 
The medical history of the mother will not be recorded. 
8.2.4 Apgar Scores 
Apgar is a point system routinely used at birth to assess a neonate's vitality at one, five and ten 
minutes after birth. The scale ranges between 0 and 10, where a score of 10 indicates a baby in full 
health. Retrospective apgar assessment scores may be used if assessment can’t be performed after 
time of consent. 
8.2.5 Physical Examination 
A complete physical examination will be done that is limited to the following body systems: 
general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, skin, and neurological. A neurologic exam will also be 
performed as part of safety evaluation. 
Neurological exam to include the examination of the following: 
x General Exam 
o Newborn reflexes 
o Posture 
o Alertness 
o Level of activity 
o Jitteriness 
o Benign neonatal sleep myoclonus 
o Saccadic Intrusions 
o Periodic breathing 
x Cranial Nerve Exam 
o Pupil reflex 
o Doll’s Eyes 
o Corneal, sucking and rooting reflexes 
o Response to noise 
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o Gag reflex 
8.2.6 Vital Signs 
Temperature, blood pressure, pulse, respiratory rate and O2 saturation will be recorded. Vital signs 
will continue to be recorded based on schedule of assessments (Section 1.3). 
8.2.7 Clinical Laboratory Determinations  
Clinical laboratory tests will be conducted according to the SoA. Clinical laboratory tests to be 
conducted include complete blood count with differentials, liver panel, basic metabolic panel and 
coagulation tests (See Appendix 12.4 for list of tests). Clinical laboratory tests will be performed 
by a designated local or institutional laboratory. PK blood testing will be performed by a 
Bioanalytical Laboratory. Each site will be provided with instructions on PK specimen collection, 
preparation, packaging and transport. Refer to the Bioanalytical Laboratory’s manual for further 
information regarding sample collection, handling, and labeling.  
Clinical laboratory test data will be reviewed by the PI, or designee, and additional clinical 
laboratory tests may be ordered at his/her discretion (e.g., if the results of any clinical laboratory 
test falls outside the reference range or clinical symptoms necessitate additional testing to ensure 
safety). Any additional testing will be performed by the designated central laboratory. 
The PI will review the lab results for clinical significance. Any clinical laboratory test result 
meeting the PI’s or Sponsor’s criteria for clinical significance (refer to laboratory manual) will be 
recorded as an AE or SAE as appropriate. 
8.2.7.1 Blood Sampling for Pharmacokinetic Analysis 
Phenobarbital in neonates (1-10 days old) have been reported to have a half-life of approximately 
114±43 hours. 
Collection of plasma samples for phenobarbital analysis will be obtained using a population 
pharmacokinetic approach at the following time points: 
o PK Group 1: 30 minutes, 4-6 hours post initial dose, 
o PK Group 2: 30 minutes, 10-12 hours post initial dose, 
o PK Group 3: 30 minutes, 16-18 hours post initial dose, 
o PK Group 4: 30 minutes, 22-24 hours post initial dose, 
At the time of randomization to treatment, the IWRS system will also randomize study participants 
to the 4 PK groups with a 1:1:1:1 allocation. Collection of blood will also occur after the second 
dose (if applicable). During the Open Label Extension Period, phenobarbital plasma 
concentrations will be obtained every 24 hours post initial dose up to 120 hours or at time of early 
discontinuation. 
Total blood volume drawn for each PK time point will be approximately 1 mL. 
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Total blood volume withdrawn per day for clinical labs and PK should be within institution 
standard of care. If total maximum daily blood volume will be exceeded, the following priority list 
should be followed: 
1. Standard of Care/Institution’s Standard of Care Clinical Labs 
2. Study related/requested Clinical Labs 
3. PK Blood Samples 
If study related blood draws are missed, this will be captured as “minor” protocol deviations. 
8.2.8 Continuous Video EEG Monitoring 
Continuous video-EEG (cvEEG) monitoring is the gold standard for neonatal seizure detection 
and quantification and should be used whenever available for seizure detection and differential 
diagnosis of abnormal appearing, paroxysmal clinical events (25). It is the ideal tool to measure 
the exact number and duration of seizures, their site(s) of onset and spatial patterns of migration. 
Multichannel (minimum 8-20 channels) cvEEG monitoring is required for accurate detection of 
seizures to determine drug response (26).  
The following are cvEEG reading recommendations during the Screening and Treatment Period 
for the site neurophysiologist or site designee: 
x Review first hour of cvEEG recording as soon as possible. 
x If not sure if a pattern is a seizure or study participant does not have 30 seconds/hour seizure 
burden, review every hour for up to 6 hours followed by every 2 hours for up to 4 hours 
and then every 4 hours. 
x If runs of spike/sharp wave discharges or focal discharges, review every 2 hours for up to 
6 hours and then review every 4 hours. 
x For any other EEG background/pattern- every 4 hour (if normal not to have to wake up 
midnight to 6 AM). 
x Shortly after reports of suspicious clinical event or 1 hour after start of a therapeutic 
intervention to evaluate for treatment response (assumes 30-minute infusion). 
The following are cvEEG reading recommendations during the Follow-up Period and Open Label 
Maintenance Period: 
x Site is to follow their cvEEG reading standard of practice. 
It is also recommended that the cvEEG technologist or site designee should remain at the monitor 
for the first hour of recording to ensure a high-quality recording and to make note of relevant 
clinical signs. Thereafter, the cvEEG technologist or site designee should re-evaluate the quality 
of the cvEEG recording frequently and adjust recording leads as required by site’s standard of 
practice. It is also recommended that the bedside research staff evaluate the quality of the 
recording periodically and should contact the technologist or designee if the tracing is suboptimal. 
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cvEEG recording and monitoring will start at time of informed consent or when study participant 
is hooked up (whichever is latest) and continue up to 48 hours from start time of first phenobarbital 
dose. cvEEG recording and monitoring after 48 hours is not required per this protocol and will 
follow site’s standard of practice. 
Skin assessments as required by institutional standard operating procedures will be allowed. It is 
recommended that the amount of time the leads are off the study participant are minimized. 
 
At minimum, the entire EEG recording will need to be backed up and archived for the study. 
Details regarding data transfer for the cvEEG recordings and video clippings are described in the 
Operational Procedure Manual. 
8.2.9 Clinical Seizure Assessment 
Clinical manifestations of seizures will be assessed and reported based on the SoA. Research staff 
will observe the study participants for abnormal behaviors or movements. Research staff should 
observe for the following (27): 
x Ocular, oral-buccal-lingual, autonomic, apnea, limb posturing and movements 
x Repetitive jerking, distinct from jittering (can be unifocal or multifocal) 
x Rapid isolated jerks (focal, multifocal or generalized) 
x Stiffening and/or decerebrate posturing (focal or generalized) 
Seizures should also be categorized as either clonic, tonic, myoclonic or subtle.  
8.2.10 Assessment of Adverse Events 
Adverse Events that are ongoing at the end of the study will be followed until resolution or for 30 
days, whichever is shorter. 
8.3 
Adverse Events and Serious Adverse Events 
8.3.1 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related (21 CFR 312.32 (a)). 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, and does not imply any judgment about causality. An adverse event can 
arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with 
any route of administration, formulation, or dose, including an overdose. 
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8.3.1.1 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug (21 CFR 312.32 (a)). 
8.3.2 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or Sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
8.3.3 Classification of an Adverse Event 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity.  
x Mild: Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
x Moderate: Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
x Severe: Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.1 Relationship to Study Drug 
All adverse events (AEs) must have their relationship to study drug assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a 
clinical trial, the study product must always be suspect.  
x Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
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laboratory test result, occurs in a plausible time relationship to study drug administration 
and cannot be explained by concurrent disease or other drugs or chemicals. The response 
to withdrawal of the study drug (dechallenge) should be clinically plausible. The event 
must be pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary. 
x Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required 
to fulfill this definition. 
x Potentially Related: There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be upgraded 
to “probably related” or “definitely related”, as appropriate. 
x Unlikely to be related: A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the study drug) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
x Not Related: The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
As a guide, some questions to ask/think about when addressing drug-related causality may include: 
x Is the AE a known reaction of the drug? 
x Is the AE similar to other adverse events listed the investigator’s brochure or consent 
documents? 
x Has the AE occurred before in this study? 
x Is the AE reasonably temporally related to the drug? 
x Does the AE improve or disappear when the drug is discontinued? What happens on re-
test? 
x Was the AE present at the baseline assessment of the study participant or in the study 
participant’s recent medical history? 
x Can the AE be reasonably explained by the study participant’s clinical disease status? 
x Are there any other potential causes for the AE? 
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8.3.3.2 Expectedness 
An unexpected adverse event is one where the nature or intensity is not consistent with the 
information in the Investigator´s Brochure (for compounds in development) or the USPI (for 
compounds marketed in the US). 
Furthermore, reports which add significant information on specificity or so far unexpected 
severity of a known, already documented adverse reaction constitute unexpected events. For 
example, an event more specific or more severe than described in the USPI or Investigator´s 
Brochure would be considered ‘unexpected’.  
Expectedness will be assessed by the CRO Medical Monitor and Sponsor. 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention 
of study personnel during study visits and interviews of a study participant presenting for medical 
care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. A follow-up call at day 7 or day 30 will be conducted to confirm resolution or 
stabilization of adverse events. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. 
Any adverse event or abnormal laboratory result considered clinically relevant will be followed 
until it reaches a satisfactory resolution, becomes stable, or can be explained by other causes 
(e.g., concurrent condition or medication), and clinical judgment indicates that further evaluation 
is not warranted. All findings must be reported in the study participant’s file. 
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8.3.5 Adverse Event Reporting 
Adverse events reported spontaneously by site staff outside the above indicated time points will 
also be documented. 
The occurrence of all adverse events will be documented in the electronic Case Report Form with 
the following information where appropriate: 
• Nature of adverse event (reported adverse event term) 
• When the adverse event first occurred (onset) 
• When the adverse event ended and/or how long it persisted 
• Whether the adverse event was serious 
• Intensity of the adverse event 
• Concomitant medications 
• Concomitant procedures 
• Definite or last observed outcome 
• Relationship to IMPs 
8.3.6 Serious Adverse Event Reporting 
The study clinician will immediately report (within 24 hours) to the CRO any serious adverse 
event, whether or not considered study drug related, including those listed in the protocol or 
investigator brochure and must include an assessment of whether there is a reasonable possibility 
that the study drug caused the event. Study endpoints that are serious adverse events (e.g., all-
cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study drug and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the CRO. 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the Data Coordinating Center (DCC)/study 
Sponsor and should be provided as soon as possible. 
The CRO will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the CRO’s initial receipt of the information. In addition, the Sponsor 
must notify FDA and all participating investigators in an Investigational New Drug (IND) safety 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but in 
no case later than 15 calendar days after the CRO determines that the information qualifies for 
reporting. 
8.3.7 Reporting Events to Parents/Legal Guardians 
Not applicable. 
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8.3.8 Events of Special Interest 
8.3.8.1 Cardiovascular Events 
The following events will be considered serious adverse events: 
x Systemic Hypertension (must require treatment) 
x Major venous or arterial thrombosis (clot) 
x Disseminated Intravascular Coagulation (DIC) 
x Pulmonary Hypertension 
x Intracranial Hemorrhage 
x Cardiopulmonary Arrest 
8.3.8.2 Laboratory Investigations 
The following events will be considered serious adverse events: 
x Polycythemia 
8.3.8.3 Serious Dermatological Reactions 
Serious and sometimes fatal post-marketing cases of dermatologic reactions, including Stevens- 
Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported in patients 
treated with phenobarbital. Post-marketing reporting rate is generally accepted to be an 
underestimate due to under-reporting. Recurrence of serious skin reactions following rechallenge 
with phenobarbital has also been reported. Therefore, if a study participant develops a skin reaction 
during phenobarbital treatment, consideration should be given to permanent discontinuation and 
replacement of the drug with alternative treatment. 
8.3.9 Reporting of Pregnancy 
Not Applicable 
8.4 
Unanticipated Problems 
8.4.1 Definition of Unanticipated Problems (UP) 
Sponsor considers unanticipated problems involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria: 
x Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review Board 
(IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
x Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
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x Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.4.2 Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Data Management/lead principal investigator (PI). The UP report will 
include the following information: 
x Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number. 
x A detailed description of the event, incident, experience, or outcome.  
x An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP.  
x A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
x UPs that are serious adverse events (SAEs) will be reported to CRO study team within 24 
hours 
x CRO study team will review and request additional information immediately and report 
the information to the IRB and to the DSMB/study Sponsor within 24 hours of the CRO 
study team becoming aware of the event.  
x Any other UP will be reported to the IRB and to the DSMB/study Sponsor within 48 hours 
of the investigator becoming aware of the problem.  
x All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), after 
the IRB’s receipt of the report of the problem from the investigator.  
8.4.3 Reporting Unanticipated Problems to Parents/Legal Guardians 
Not applicable. 
9 
Statistical Considerations 
9.1 
Statistical Hypothesis 
This study was designed to show that high dose phenobarbital (40 mg/kg) is more effective than 
low dose phenobarbital (20 mg/kg) following single dose administration in terms of study’s 
primary endpoint (Section 3.2.1). Specifically, the following primary statistical hypotheses will be 
tested. 
Null hypothesis H0: there is no difference between treatments in the proportion of participants having 
a primary efficacy endpoint.  
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Alternative hypothesis Ha: The proportions of participants having a primary efficacy endpoint are 
different between the two treatment groups. 
9.2 
Sample Size Determination 
Literature supports that lower loading doses of phenobarbital achieve seizure control in 
approximately 30 to 60% of treated neonates, with higher loading doses achieving seizure control 
up to 85% (19, 20, 23, 24). Based on 70% and 50% of study participants achieving seizure control 
in high dose and low, respectively, an effect size of 20%, an alpha of 0.05 and 80% power, it is 
estimated that the number of completed study participants required will be 93 study participants 
in each group (total 186). With approximately, 5% dropout or unevaluable study participant, the 
minimum required for randomization will be 196. 
9.3 
Populations For Analyses 
1. Intention-to-treat (ITT) population: Study participant population consists of all randomized 
study participants with valid informed consent. 
2. Per-protocol (PP) population: A Subset of the ITT population. Study participants with 
major protocol deviations will be excluded from PP population. Major protocol deviations 
will be defined in the Statistical Analysis Plan (SAP). 
3. Safety population: A subset of the ITT population, consisting of all randomized study 
participants who receive at least one dose or partial dose of study drug. 
4. Pharmacokinetic (PK) population: Study participants that received at least 1 dose from the 
same study arm (as per randomization or per error) are included in this population group. 
9.4 
Statistical Analyses 
9.4.1 General Approach 
Please refer to the SAP for specific details. 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) 
The primary endpoint will be summarized by number and percent of participants with events and 
compared by a log binomial model (a generalized linear model [GLM]) that includes treatment as 
a study variable, which will generate risk ratio (RR) together with their 95% CIs of having a 
primary outcome between high dose and low dose groups. A study participant who is withdrawn 
from the study within the first 24 hours after treatment will be considered not to have achieved the 
primary endpoint. Treatment of such dropouts with respect to other endpoints will be specified in 
the SAP. 
In addition, covariate adjustment will be performed by GLM model with treatment as a study 
variable and, gender, gestational age, birth weight, apgar scores, liver function tests, seizure 
etiology, therapeutic hypothermia and pre-treatment seizure burden as covariates. From this 
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model, adjusted RR together with their 95% confidence interval will be derived. Imputation for 
these baseline missing covariates will be carried out for adjusted analysis. 
9.4.3 Analysis of the Secondary Endpoint(s) 
The secondary outcomes will be analyzed similarly as the primary endpoint analysis using a GLM. 
For GLM analysis of a continuous endpoint such as quality of life, normal distribution and identity 
link functions will be used; for GLM analysis of a binary outcome (such as having a primary 
endpoint), binomial distribution and log link functions will be used.  
For the analysis of time-to-event outcome, the Kaplan-Meier curves will be presented and 
compared by the log rank test by treatment group and hazard ratio and its 95% confidence interval 
will be calculated using Cox regression model with the treatment arm as the study variable.  
The secondary binary outcomes with repeated measurements at different time points will be 
summarized using number (%) of events at each time point and analyzed using a generalized linear 
mixed model (GLMMIX) model, in which treatment, time, interaction between treatment and time 
as fixed effects and participant as cluster effect. Exchangeable covariance structure will be used. 
The odds ratio together with their 95%CIs at each time point will be derived. 
9.4.4 Safety Analyses 
Safety analysis will be based on the safety population. Assessment of safety will be based on the 
incidence of TEAE, TEAEs resulting in discontinuation, and serious TEAEs (SAEs). TEAE 
summaries will be provided showing the number and percentage of study participants who 
experienced at least 1 AE. These summaries will be presented by body system (system organ class) 
and preferred term (Medical Dictionary for Regulatory Activities). SAEs, TEAEs, ADRs, and 
SADRs resulting in discontinuation will be summarized separately. Laboratory data and their 
change from Baseline will be summarized using descriptive statistics. Vital signs data and any 
changes from Baseline will be summarized using descriptive statistics. Changes in physical 
examination will be summarized. 
Serious adverse events and serious adverse drug reactions (SADR, serious adverse events at least 
possibly related to IMP) will be followed up and specifically analyzed (details in protocol/SAP). 
In case of an ongoing SADR at time of discharge, the follow-up visit should take place at the site. 
9.4.5 Baseline Descriptive Statistics 
Continuous variables will be summarized according to number of study participants with non-
missing data (n), mean, standard deviation (SD), median, minimum, and maximum.  
Categorical variables will be summarized according to the absolute frequency and percentage of 
study participants (%) in each category level. The denominator for the percentages is the number 
of study participants in the treatment arm with data available, unless noted otherwise. 
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9.4.6 Planned Interim Analyses 
Due to the small sample size of the study population, an interim analysis for efficacy will not be 
performed. 
9.4.7 Subgroup Analyses 
Subgroup analysis for the primary outcome will be performed in a series of predefined strata, 
which will include gender, gestational age, birth weight, Apgar scores, liver function tests, seizure 
etiology, therapeutic hypothermia, pre-informed consent seizure burden and pre-treatment seizure 
burden. Assessment of the homogeneity of treatment effect by a subgroup variable will be 
conducted by a GLM with the treatment, subgroup variable, and their interaction term as 
predictors, and the P-value presented for the interaction term. 
9.4.8 Tabulation of Individual Participant Data 
Data collected from all randomized study participants will be presented in data listings. Both absolute 
values and change from baseline values for each study participant will be given where applicable. Data 
listings will be sorted by treatment, study participant number, and time point. 
9.4.9 Exploratory Analyses 
Plasma concentrations will be summarized descriptively and graphically by nominal time. 
Pharmacokinetic parameters will be assessed for calculation. Individual plasma phenobarbital 
concentrations will be listed and plotted by neonate.  
10 Supporting Documentation and Operational Considerations 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Informed Consent Process 
10.1.1.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study drug, study procedures, and risks are given to the 
parents / legal guardians and written documentation of informed consent is required prior to 
starting screening and administering study drug. Electronic consent, if approved by local or central 
IRBs, will also be acceptable. Verbal consent, if approved by local or central IRBs, can be used to 
initiate screening process; however, written consent must be obtained prior to drug administration. 
The following consent materials are submitted with this protocol: 
• Informed Consent Form 
10.1.1.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the parent/legal guardian will be asked to read and 
review the document. The investigator will explain the research study to the parent/legal guardian 
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and answer any questions that may arise. A verbal explanation will be provided in terms suited to 
the parent/legal guardian’s comprehension of the purposes, procedures, and potential risks of the 
study and of their rights. Parent/legal guardian will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The parent/legal guardians should have 
the opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate. The parent/legal guardian will sign the informed consent document prior 
to any procedures being done specifically for the study. Parent/legal guardians must be informed 
that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the parent/legal guardians 
for their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the study participant undergoes any 
study-specific procedures. The rights and welfare of the study participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
10.1.2 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) Sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants’ parent/legal guardian, the Institutional Review Board (IRB), 
and Sponsor and will provide the reason(s) for the termination or suspension. Study participants’ 
parent/legal guardian will be contacted, as applicable, and be informed of changes to study visit 
schedule.  
Circumstances that may warrant termination or suspension include, but are not limited to: 
x Determination of unexpected, significant, or unacceptable risk to participants 
x Demonstration of efficacy that would warrant stopping 
x Insufficient compliance to protocol requirements 
x Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB and/or Food and Drug Administration (FDA). 
10.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the Sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor.  
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All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the Data Management Center. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by NEMA research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived 
at NEMA Research. 
10.1.4 Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored at Data Management Facility. After the 
study is completed, the de-identified, archived data will be transmitted to and stored at the 
Sponsor’s approved location. Information will be included in the informed consent.  
With the parents / legal guardians approval and as approved by local Institutional Review Boards 
(IRBs), de-identified biological samples will be stored at the Bioanalytical Lab. These samples 
could be used to research the causes of special events of interest, its complications and other 
conditions for which individuals with special events of interest are at increased risk, and to improve 
treatment. 
During the conduct of the study, an individual parent / guardian can choose to withdraw consent 
to have biological specimens stored for future research. However, withdrawal of consent with 
regard to biosample storage may not be possible after the study is completed. 
When the study is completed, access to study data and/or samples will be provided through the 
Sponsor. 
10.1.5 Key Roles and Study Governance 
Principal Investigator and Medical Monitor information is available in the Operational Procedure 
Manual and on the Trial Team Details sheet located in the eTMF.  
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10.1.6 Site Principal Investigators 
Site Principal Investigators will have expertise in treating neonatal seizures and can be a trained 
neonatologist, pediatric neurologist, pediatric neurophysiologist and/or pediatric epileptologist. 
Confirmation of training will be based on their current curriculum vitae.  
10.1.7 Safety Oversight 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise. Members of the DSMB should be 
independent from the study conduct and free of conflict of interest, or measures should be in place 
to minimize perceived conflict of interest. The DSMB will meet at least semiannually to assess 
safety and efficacy data on each arm of the study, unless noted otherwise in the charter. The DMSB 
will operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. The DSMB will provide its input to the CRO and Sponsor. The 
CRO will report the results to the respective IRB(s).  
10.1.8 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial study 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
Clinical Monitoring Plan (CMP), with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s).  
 
x Monitoring for this study will be performed by trained NEMA Clinical Research 
Associates.  
x Monitoring will be done on-site and remotely. Frequency of visits will be based on 
guidelines set forth in the CMP. 100% Source Document Verification will be performed. 
x Sponsor will be provided copies of monitoring reports within 30 days of visit. 
x Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
x Independent audits will be conducted by NEMA Quality Manager or Designee to ensure 
monitoring practices are performed consistently across all participating sites and that 
monitors are following the CMP. 
10.1.9 Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management. 
 
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Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by local and 
regulatory authorities. 
10.1.10 Data Handling and Record Keeping 
10.1.10.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into Medidata Rave, a 21 CFR Part 11-
compliant data capture system. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
Details regarding data transfer for the cvEEG recordings and video clippings are described in the 
Operational Procedure Manual. 
10.1.10.2 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonization (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the study drug. These 
documents should be retained for a longer period, however, if required by local regulations. No 
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records will be destroyed without the written consent of the Sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the investigator when these documents no longer need to 
be retained. 
10.1.11 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly. 
These practices are consistent with ICH GCP:  
x 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
x 5.1 Quality Assurance and Quality Control, section 5.1.1  
x 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the PIs and delegated SubIs to use continuous vigilance to identify and 
report deviations within 2 working days of identification of the protocol deviation, or within 2 
working days of the scheduled protocol-required activity. All deviations must be addressed in 
study source documents, reported to Clinical Monitor. Protocol deviations must be sent to the 
reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible 
for knowing and adhering to the reviewing IRB requirements. Further details about the handling 
of protocol deviations will be included in the MOP. 
10.1.12 Publication and Data Sharing Policy 
This study will be conducted in accordance with the Sponsor’s publication and data sharing 
policies and regulations. 
10.1.13 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the Sponsor has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
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10.2 Additional Considerations 
10.3 Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
cvEEG 
Continuous Video Electroencephalography 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation 
GLM 
Generalized Linear Model 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIE 
Hypoxic-Ischemic Encephalopathy 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
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NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PP 
Per-Protocol 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
eTMF 
Electronic Trial Master File 
UP 
Unanticipated Problem 
US 
United States 
 
10.4 Protocol Amendment History 
The table below is intended to capture changes of IRB-approved versions of the protocol, including 
a description of the change and rationale. A Summary of Changes table for the current amendment 
is located in the Protocol Title Page. 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
28-Aug-
2020 
Initial Protocol 
 
2.0 
07-Dec-
2021 
See Summary of Changes in 
Protocol Title Page 
Administrative changes and 
changes to assessments to 
align protocol more with 
standard of care at individual 
sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11 References 
1. 
Ochoa JG, Kilgo WA. The Role of Benzodiazepines in the Treatment of Epilepsy. Curr 
Treat Options Neurol. 2016;18(4):18. Epub 2016/03/01. doi: 10.1007/s11940-016-0401-x. 
PubMed PMID: 26923608. 
2. 
Shellhaas R. Treatment of Neonatal Seizures. Up to Date. 2015. 
3. 
Lanska MJ, Lanska DJ. Neonatal seizures in the United States: results of the National 
Hospital Discharge Survey, 1980-1991. Neuroepidemiology. 1996;15(3):117-25. Epub 
1996/01/01. doi: 10.1159/000109898. PubMed PMID: 8700303. 
4. 
Glass HC, Pham TN, Danielsen B, Towner D, Glidden D, Wu YW. Antenatal and 
intrapartum risk factors for seizures in term newborns: a population-based study, California 1998-
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PubMed PMID: 18760807; PubMed Central PMCID: PMCPMC2635430. 
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Saliba RM, Annegers FJ, Waller DK, Tyson JE, Mizrahi EM. Risk factors for neonatal 
seizures: a population-based study, Harris County, Texas, 1992-1994. Am J Epidemiol. 
2001;154(1):14-20. Epub 2001/06/28. doi: 10.1093/aje/154.1.14. PubMed PMID: 11427400. 
6. 
Selway LD. State of the science: hypoxic ischemic encephalopathy and hypothermic 
intervention for neonates. Adv Neonatal Care. 2010;10(2):60-6; quiz 7-8. Epub 2010/04/14. doi: 
10.1097/ANC.0b013e3181d54b30. PubMed PMID: 20386369. 
7. 
Glass HC, Rowitch DH. The Role of the Neurointensive Care Nursery for Neonatal 
Encephalopathy. 
Clin 
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PubMed 
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27524453; 
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Central 
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Wilmshurst JM, Gaillard WD, Vinayan KP, Tsuchida TN, Plouin P, Van Bogaert P, et al. 
Summary of recommendations for the management of infantile seizures: Task Force Report for 
the ILAE Commission of Pediatrics. Epilepsia. 2015;56(8):1185-97. Epub 2015/07/01. doi: 
10.1111/epi.13057. PubMed PMID: 26122601. 
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Gilman JT, Gal P, Duchowny MS, Weaver RL, Ransom JL. Rapid sequential phenobarbital 
treatment of neonatal seizures. Pediatrics. 1989;83(5):674-8. Epub 1989/05/01. PubMed PMID: 
2717283. 
10. 
Yukawa M, Yukawa E, Suematsu F, Takiguchi T, Ikeda H, Aki H, et al. Population 
pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical 
pharmacokinetic data in Japanese neonates and infants: an update. J Clin Pharm Ther. 
2011;36(6):704-10. Epub 2011/10/26. doi: 10.1111/j.1365-2710.2010.01220.x. PubMed PMID: 
22023343. 
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11. 
Marsot A, Brevaut-Malaty V, Vialet R, Boulamery A, Bruguerolle B, Simon N. 
Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a 
population pharmacokinetic modelling approach. Fundam Clin Pharmacol. 2014;28(4):465-71. 
Epub 2013/07/17. doi: 10.1111/fcp.12042. PubMed PMID: 23855753. 
12. 
Shellhaas R. Treatment of neonatal seizures. Up To Date. 2019. 
13. 
Filippi L, la Marca G, Cavallaro G, Fiorini P, Favelli F, Malvagia S, et al. Phenobarbital 
for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole 
body hypothermia. Epilepsia. 2011;52(4):794-801. Epub 2011/03/05. doi: 10.1111/j.1528-
1167.2011.02978.x. PubMed PMID: 21371018. 
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Shellhaas RA, Ng CM, Dillon CH, Barks JD, Bhatt-Mehta V. Population pharmacokinetics 
of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. 
Pediatr 
Crit 
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10.1097/PCC.0b013e31825bbbc2. PubMed PMID: 23254984; PubMed Central PMCID: 
PMCPMC3717607. 
15. 
van den Broek MP, Groenendaal F, Toet MC, van Straaten HL, van Hasselt JG, Huitema 
AD, et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated 
with hypothermia: a thermopharmacological approach. Clin Pharmacokinet. 2012;51(10):671-9. 
Epub 2012/09/29. doi: 10.1007/s40262-012-0004-y. PubMed PMID: 23018530. 
16. 
Lingamchetty TN, Hosseini SA, Saadabadi A. Midazolam.  StatPearls. Treasure Island 
(FL)2020. 
17. 
Favie LMA, Groenendaal F, van den Broek MPH, Rademaker CMA, de Haan TR, van 
Straaten HLM, et al. Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug 
Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia. Neonatology. 
2019;116(2):154-62. Epub 2019/07/01. doi: 10.1159/000499330. PubMed PMID: 31256150; 
PubMed Central PMCID: PMCPMC6878731. 
18. 
Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin 
Pharmacol. 2006;61(3):246-55. Epub 2006/02/21. doi: 10.1111/j.1365-2125.2005.02529.x. 
PubMed PMID: 16487217; PubMed Central PMCID: PMCPMC1885026. 
19. 
Slaughter LA, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a 
systematic 
review. 
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2013;28(3):351-64. 
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doi: 
10.1177/0883073812470734. 
PubMed 
PMID: 
23318696; 
PubMed 
Central 
PMCID: 
PMCPMC3805825. 
20. 
Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital 
compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485-
9. Epub 1999/08/12. doi: 10.1056/NEJM199908123410704. PubMed PMID: 10441604. 
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21. 
Pathak G, Upadhyay A, Pathak U, Chawla D, Goel SP. Phenobarbitone versus phenytoin 
for treatment of neonatal seizures: an open-label randomized controlled trial. Indian Pediatr. 
2013;50(8):753-7. Epub 2013/03/19. PubMed PMID: 23502660. 
22. 
Soul JS, Pressler R, Allen M, Boylan G, Rabe H, Portman R, et al. Recommendations for 
the design of therapeutic trials for neonatal seizures. Pediatr Res. 2018. Epub 2018/12/26. doi: 
10.1038/s41390-018-0242-2. PubMed PMID: 30584262. 
23. 
Gal P, Toback J, Boer HR, Erkan NV, Wells TJ. Efficacy of phenobarbital monotherapy 
in treatment of neonatal seizures -- relationship to blood levels. Neurology. 1982;32(12):1401-4. 
Epub 1982/12/01. doi: 10.1212/wnl.32.12.1401. PubMed PMID: 6890650. 
24. 
Boylan GB, Rennie JM, Chorley G, Pressler RM, Fox GF, Farrer K, et al. Second-line 
anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. 
2004;62(3):486-8. Epub 2004/02/12. PubMed PMID: 14872039. 
25. 
Shah DK, Boylan GB, Rennie JM. Monitoring of seizures in the newborn. Arch Dis Child 
Fetal Neonatal Ed. 2012;97(1):F65-9. Epub 2010/08/07. doi: 10.1136/adc.2009.169508. PubMed 
PMID: 20688863. 
26. 
McCoy B, Hahn CD. Continuous EEG monitoring in the neonatal intensive care unit. J 
Clin 
Neurophysiol. 
2013;30(2):106-14. 
Epub 
2013/04/03. 
doi: 
10.1097/WNP.0b013e3182872919. PubMed PMID: 23545760. 
27. 
Berg AT, Jallon P, Preux PM. The epidemiology of seizure disorders in infancy and 
childhood: definitions and classifications. Handb Clin Neurol. 2013;111:391-8. Epub 2013/04/30. 
doi: 10.1016/B978-0-444-52891-9.00043-9. PubMed PMID: 23622188. 
 
 
 
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12 APPENDICES 
12.1 APPENDIX I – Names of Study Personnel 
 
Sponsor: 
Hikma Pharmaceuticals. 
 
Medical Monitor: 
Sumedha Labhsetwar, MD 
NEMA Research Inc. 
 
Clinical Research Organizations: 
 
NEMA Research Inc. 
Bioanalytical Laboratory: 
Axis Bioanalytical 
 
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12.2 APPENDIX II – Declaration of Helsinki 
 https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects/WORLD 
MEDICAL 
ASSOCIATION 
DECLARATION OF HELSINKI 
 
Ethical Principles 
for 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
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PREAMBLE 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to 
adopt these principles. 
GENERAL PRINCIPLES 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient’s best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician’s knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
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standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will 
not adversely affect the health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
RISKS, BURDENS AND BENEFITS 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
VULNERABLE GROUPS AND INDIVIDUALS 
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19. Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable 
group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research. 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, Sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
RESEARCH ETHICS COMMITTEES 
23. The research protocol must be submitted for consideration, comment, guidance and approval 
to the concerned research ethics committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the researcher, the Sponsor and any other 
undue influence and must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing 
a summary of the study’s findings and conclusions. 
PRIVACY AND CONFIDENTIALITY 
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24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
INFORMED CONSENT 
25. Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community 
leaders, no individual capable of giving informed consent may be enrolled in a research study 
unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative. These individuals must not 
be included in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the group represented by the potential subject, the research cannot instead 
be performed with persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
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30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances 
the physician must seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent for 
its collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be 
done only after consideration and approval of a research ethics committee. 
USE OF PLACEBO 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of 
not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
POST-TRIAL PROVISIONS 
34. In advance of a clinical trial, Sponsors, researchers and host country governments should make 
provisions for post-trial access for all subjects who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to subjects during the informed 
consent process. 
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RESEARCH REGISTRATION AND PUBLICATION AND DISSEMINATION OF 
RESULTS 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, Sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
 
 
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12.3 APPENDIX III List of Medical Concepts for Consideration of Seriousness Stratified 
by System Organ Class (15-Sep-2009) 
Blood and lymphatic system disorders 
Agranulocytosis 
Aplastic anaemia 
Blast cell proliferation 
(myeloproliferative and 
lymphoprolipherative 
disorders) 
Bone marrow depression 
Disseminated intravascular 
coagulation (DIC) 
Haemolytic anaemia  
Histiocytosis 
Loss of anticoagulation 
control  
Pancytopenia  
Splenic haemorrhage, 
infarction or thrombosis 
Thrombocytopenia (<30000) 
Thrombotic 
thrombocytopenic purpura 
Cardiac disorders 
Angina unstable 
Atrial flutter 
Atrioventricular block 
complete 
Cardiac arrest 
Cardiac failure 
Cardiac fibrillation 
Cardiac tamponade  
Cardiogenic shock  
Cardiomyopathy acute  
Coronary artery spasm 
Cor pulmonale 
Myocardial infarction 
Torsade de pointes 
Ventricular fibrillation 
Ventricular tachycardia  
Ear and labyrinth disorder 
Deafness 
Vestibular ataxia 
 
Endocrine disorders 
Adrenocortical insufficiency 
acute 
 
 
Eye disorders 
Cataract/lens opacity 
Glaucoma 
Keratitis/corneal 
opacification 
Macular degeneration  
Optic neuropathy, atrophy  
Papilloedema  
Ptosis  
Retinal artery/vein occlusion  Retinitis  
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Blood and lymphatic system disorders 
Scotoma 
Sudden visual loss 
Uveitis 
Vitreous detachment 
 
 
Gastrointestinal disorders 
Colitis haemorrhagic 
Gastric ulcer haemorrhage 
Gastric ulcer perforation 
Haematemesis 
Haemoperitoneum 
Ileus  
Intestinal ischaemia  
Intestinal perforation  
Melaena  
Mesenteric occlusion  
Mesenteric vein thrombosis 
Pancreatitis 
Peritonitis 
 
 
General disorders 
Malignant hyperthermia 
Drug withdrawal syndrome 
 
Hepatobiliary disorders 
Hepatic failure 
Hepatitis fulminant 
Hepatic necrosis 
Hepatorenal syndrome 
Portal hypertension 
Reye's syndrome 
Immune system disorders 
Amyloidosis 
Anaphylactic reaction 
Anaphylactic shock 
Graft versus host disease 
 
 
Infections and infestations 
Endotoxic shock 
Sepsis 
Toxic shock syndrome 
Transmission of an infectious 
agent via a medicinal product 
 
 
Injury, poisoning and procedural complications  
Transplant failure 
Wound dehiscence 
 
Metabolism and nutrition disorders 
Diabetic coma 
Failure to thrive (CTC IV) 
Hypercalcaemia (CTC IV) 
Hyperkalaemia (CTC IV) 
Hypocalcaemia (CTC IV) 
Hypokalaemia (CTC IV) 
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Blood and lymphatic system disorders 
Lactic acidosis 
Porphyria 
Shock hypoglycaemic  
Tetany 
 
 
Musculoskeletal, connective tissue and bone disorders 
Aseptic necrosis bone 
Fracture pathological  
Muscle necrosis  
Osteomalacia  
Rhabdomyolysis 
Systemic lupus erythematous 
Systemic sclerosis 
 
 
Nervous system disorders 
Amnesia 
Anticholinergic syndrome 
Aphasia 
Cerebral oedema 
Chorea 
Coma 
Convulsions 
Demyelination 
Encephalitis 
Encephalopathy  
Epilepsy 
Guillain Barré syndrome 
Hydrocephalus 
Intracranial haemorrhage 
Meningitis  
Multiple sclerosis 
Myasthenia gravis 
Myelitis 
Neuroleptic malignant 
syndrome 
Opisthotonus 
Paralysis 
Paresis 
Parkinson syndrome 
Serotonin syndrome 
Stroke 
Tunnel vision 
 
Pregnancy, puerperium and perinatal conditions 
Abortion 
Eclampsia 
Intra-uterine death 
Psychiatric disorders 
Anorexia nervosa 
Delirium 
Drug abuse 
Drug dependence 
Homicidal ideation 
Intentional misuse 
Self-injurious 
ideation/attempt 
Suicidal ideation/attempt 
Suicide completed 
Renal and urinary disorders 
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Blood and lymphatic system disorders 
Anuria 
Goodpasture's syndrome 
Haemolytic uraemic 
syndrome 
Nephritis/nephritic syndrome Nephrotic syndrome 
Oliguria 
Renal failure acute 
Renal tubular necrosis 
Urinary obstruction/retention 
Reproductive system and breast disorders 
Metrorrhagia/uterine 
haemorrhage 
Priapism 
 
Respiratory, thoracic and mediastinal disorders 
Acute respiratory failure 
Adult respiratory distress 
syndrome  
Alveolitis allergic 
Asphyxia 
Bronchospasm 
Laryngeal oedema 
Pulmonary fibrosis 
Pulmonary haemorrhage 
Pulmonary infarction 
Pulmonary vasculitis 
Respiratory arrest 
Status asthmaticus 
Pulmonary oedema 
 
 
Skin and subcutaneous tissue disorders 
Angioneurotic oedema 
Erythema nodosum  
Pemphigus 
Stevens Johnson syndrome 
Toxic epidermal necrolysis 
Vascular purpura 
Vascular disorders 
Acute circulatory failure  
Embolism 
Malignant hypertension 
Necrosis ischaemic 
Thrombosis 
 
 
 
 
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12.4 APPENDIX IV Clinical Laboratory Tests 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit should remain within the following guidelines. 
The following chart outlines the guidelines for blood drawing and the max volume which can be 
safely drawn per day: 
Conversions: 
lbs/2.2 = kg 
kg X 1.7 = mL 
Kilograms 
(mLs) Volume which can be safely drawn per 
day 
2.7 – 3.6 
4.6 – 6.1 
4.1-4.6 
7.0-7.8 
5.0-6.4 
8.5-10.8 
 
The following is a list of lab tests collected for each study participant. 
Blood 
Comprehensive Metabolic Panel 
Complete Blood Count w/ Differential 
Glucose 
WBC Count 
Calcium 
RBC Count 
Sodium 
Hemoglobin 
Potassium 
Hematocrit 
CO2/Bicarbonate 
RBC indices (MCV, MCH, MCHC, RDW) 
Chloride 
Reticulocyte count 
BUN 
Platelet count 
Creatinine 
 
Total Protein 
 
Albumin 
 
Bilirubin (total and direct) 
 
ALP 
 
AST 
 
ALT 
 
 
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