Clinical trial NCT03336450
Conditions: Nervous System Diseases
Sponsor: Shire
Start date: 2018-04-23; Completion date: 2020-10-13
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if the investigational treatment, MHOS/SHP615, is safe and effective in children with status epilepticus (SE) (convulsive) in the community setting. This study is open-label extension for patients who completed the SHP615-301 study and who tolerated and responded to MHOS/SHP615 treatment in the hospital setting.

Detailed description:

Arms: arm 1: Participants will receive a single age-specific dose (approximately 0.25 to 0.5 milligram per kilogram \[mg/kg\] as midazolam) of SHP615 oromucosal solution through buccal route upon onset of seizures.
Interventions: intervention 1: SHP615 intervention 2: MHOS/SHP615
Intervention descriptions: intervention 1: SHP615 oromucosal solution will be administered as a single age-specific dose (2.5, 5, 7.5 and 10 mg). intervention 2: MHOS/SHP615

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:  
NCT03336450 
 
Study Title: 
A Phase 3, Multicenter, Open-label Extension Study of Buccally 
Administered MHOS/SHP615 in Pediatric Patients with Status 
Epilepticus (Convulsive) in Community Settings 
 
Study Number: 
SHP615-302 
 
Protocol Version and Date: 
Original Protocol: 
23 Mar 2017 
Amendment 1: 
08 Jul 2017 
Amendment 2: 
28 Aug 2017 
Amendment 3: 
18 Dec 2017 
 
For non-commercial use only


PROTOCOL: SHP615-302
TITLE:
A Phase 3, Multicenter, Open-label Extension Study of Buccally 
Administered MHOS/SHP615 in Pediatric Patients with Status 
Epilepticus (Convulsive) in Community Settings
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
, MD
PROTOCOL 
HISTORY:
Original Protocol: Final 23 Mar 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP615-302 Protocol
SHP615
23 Mar 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to Quintiles Transnational Japan K.K., the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor.
Applicable fax numbers and e-mail address can be found on the form (sent under separate cover). 
A copy of this form must also be sent to the CRO/Shire medical monitor by fax or e-mail using 
the details below.
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor email address: 
For protocol- or safety-related issues during normal business hours, the investigator must 
contact the Quintiles medical monitor:
Quintiles Medical Advisor name, title: 
, 
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor mobile number: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the:
Quintiles Medical Advisor mobile number: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP615-302 Protocol
SHP615
23 Mar 2017
PRODUCT QUALITY COMPLAINTS
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to PMDA as a device 
malfunction report, regardless of whether or not the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP615-302 Protocol
SHP615
23 Mar 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
LIST OF TABLES...........................................................................................................................9
LIST OF APPENDICES..................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................12
1.
BACKGROUND INFORMATION.......................................................................................19
1.1
Status Epilepticus .....................................................................................................19
1.2
Current Treatment Options.......................................................................................20
1.3
Unmet Medical Need for Buccal Midazolam...........................................................21
1.4
Product Background and Clinical Information ........................................................21
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Study.............................................................................................23
2.2
Study Objectives ......................................................................................................23
2.2.1
Primary Objectives.................................................................................................23
2.2.2
Secondary Objectives.............................................................................................23
2.2.3
Exploratory Objectives ..........................................................................................24
3.
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................25
3.3
Sites and Regions .....................................................................................................26
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................28
4.3
Restrictions...............................................................................................................28
4.3.1
Medical Intervention..............................................................................................28
4.4
Reproductive Potential .............................................................................................29
4.4.1
Female Contraception............................................................................................29
4.4.2
Male Contraception................................................................................................29
4.5
Discontinuation of Subjects .....................................................................................29
4.5.1
Subject Withdrawal Criteria ..................................................................................29
4.5.2
Reasons for Discontinuation..................................................................................30
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................31
4.5.4
Stopping Rules.......................................................................................................31
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP615-302 Protocol
SHP615
23 Mar 2017
4.5.4.1
Study Level Stopping Rules...................................................................31
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria................................31
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ........................................................................................................32
5.2
Concomitant Treatment............................................................................................32
6.
INVESTIGATIONAL PRODUCT ........................................................................................33
6.1
Identity of Investigational Product...........................................................................33
6.1.1
Blinding the Treatment Assignment......................................................................33
6.2
Administration of Investigational Product(s)...........................................................33
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dose Regimen and Dose Administration...............................................................34
6.2.2.1
Dosing Regimen.....................................................................................34
6.2.2.2
Dose Administration ..............................................................................34
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................36
6.3.3
Storage ...................................................................................................................36
6.3.4
Special Handling....................................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
6.6
Destruction of Investigational Product.....................................................................38
7.
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening Period....................................................................................................39
7.1.2
Baseline Visit.........................................................................................................39
7.1.3
Treatment Period....................................................................................................39
7.1.3.1
Treatment of Seizure in the Community Setting....................................39
7.1.4
Clinic or Hospital Visit..........................................................................................40
7.1.5
Follow-up Period ...................................................................................................41
7.1.6
Additional Care of Subjects after the Study ..........................................................41
7.2
Study Evaluations and Procedures ...........................................................................42
7.2.1
Informed Consent...................................................................................................42
7.2.2
Demographic and Other Baseline Characteristics .................................................42
7.2.3
Efficacy..................................................................................................................42
7.2.4
Safety .....................................................................................................................42
7.2.4.1
Medical and Medication History............................................................43
7.2.4.2
Adverse Event Collection.......................................................................43
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP615-302 Protocol
SHP615
23 Mar 2017
7.2.4.3
Vital Signs..............................................................................................43
7.2.4.4
Clinical Laboratory Evaluations.............................................................44
7.2.4.5
Pregnancy Test .......................................................................................45
7.2.4.6
Electrocardiogram ..................................................................................45
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................45
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................47
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................47
8.1.1
Severity Categorization..........................................................................................47
8.1.2
Relationship Categorization...................................................................................48
8.1.3
Outcome Categorization ........................................................................................48
8.1.4
Symptoms of the Disease Under Study .................................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................49
8.1.6
Pregnancy...............................................................................................................49
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................50
8.2
Serious Adverse Event Procedures ..........................................................................50
8.2.1
Reference Safety Information................................................................................50
8.2.2
Reporting Procedures.............................................................................................50
8.2.3
Serious Adverse Event Definition .........................................................................51
8.2.4
Serious Adverse Event Collection Time Frame.....................................................52
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................53
8.2.6
Fatal Outcome........................................................................................................53
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................53
8.3
Product Quality Complaints.....................................................................................53
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................55
9.1
Data Collection.........................................................................................................55
9.2
Clinical Data Management.......................................................................................55
9.3
Data Handling Considerations..................................................................................55
9.4
Statistical Analysis Process......................................................................................55
9.4.1
Appropriateness of Measurements.........................................................................56
9.4.2
General Considerations..........................................................................................56
9.5
Planned Interim Analysis .........................................................................................56
9.6
Sample Size Calculation and Power Considerations................................................56
9.7
Study Population ......................................................................................................56
9.8
Efficacy Analyses.....................................................................................................57
9.8.1
Primary Efficacy Endpoint ....................................................................................57
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP615-302 Protocol
SHP615
23 Mar 2017
9.8.2
Secondary Efficacy Endpoints...............................................................................57
9.8.3
Exploratory Efficacy Endpoints.............................................................................58
9.9
Safety Analyses........................................................................................................58
9.9.1
Primary Safety Endpoints ......................................................................................58
9.9.2
Secondary Safety Endpoints ..................................................................................58
9.9.3
Clinical Laboratory Tests.......................................................................................58
9.9.4
Vital Signs..............................................................................................................59
9.9.5
Electrocardiography...............................................................................................59
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................60
10.1
Sponsor’s Responsibilities .......................................................................................60
10.1.1 Good Clinical Practice Compliance.......................................................................60
10.1.2 Public Posting of Study Information......................................................................60
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards............................60
10.1.4 Study Suspension, Termination, and Completion..................................................60
10.2
Investigator’s Responsibilities .................................................................................61
10.2.1 Good Clinical Practice Compliance.......................................................................61
10.2.2 Protocol Adherence and Investigator Agreement..................................................61
10.2.3 Documentation and Retention of Records.............................................................62
10.2.3.1
Case Report Forms.................................................................................62
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................62
10.2.3.3
Audit/Inspection.....................................................................................63
10.2.3.4
Financial Disclosure...............................................................................63
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................63
10.3
Ethical Considerations..............................................................................................63
10.3.1 Informed Consent...................................................................................................63
10.3.2 Institutional Review Board ....................................................................................64
10.4
Privacy and Confidentiality......................................................................................64
10.5
Study Results/Publication Policy .............................................................................65
11. REFERENCES .......................................................................................................................67
12. APPENDICES ........................................................................................................................69
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP615-302 Protocol
SHP615
23 Mar 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................17
Table 2
Volume of Blood to Be Drawn from Each Subject.......................................45
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................70
Appendix 2
Scales and Assessments .........................................................................71
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP615-302 Protocol
SHP615
23 Mar 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
ESE
early status epilepticus
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ILAE
International League Against Epilepsy
IM
intramuscular
IRB
institutional review board
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
MHOS/SHP615
midazolam hydrochloride oromucosal solution
PIP
pediatric investigation plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PQCROW
Product Quality Complaint Rest of World
PUMA
pediatric-use marketing authorisation
SAE
serious adverse event
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP615-302 Protocol
SHP615
23 Mar 2017
SAP
statistical analysis plan
SE
status epilepticus
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP615-302 Protocol
SHP615
23 Mar 2017
STUDY SYNOPSIS
Protocol number: SHP615-302
Drug: Midazolam hydrochloride oromucosal solution MHOS/SHP615
Title of the study: A Phase 3, Multicenter, Open-label Extension Study of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in Community Settings
Number of subjects (total): ≥6 subjects
Investigator(s): Multicenter study (in community settings)
Site(s) and Region(s): Approximately 25 sites in Japan
Study period (planned):
August 2017 to July 2019
Clinical phase:
3
Objectives:
Primary:  The primary objective of this study is to assess the efficacy of buccally administered MHOS/SHP615 in 
pediatric subjects with status epilepticus (SE) (convulsive) in the community setting.
Secondary:  The secondary objective of this study is to assess the safety of buccally administered MHOS/SHP615 
in pediatric patients with status epilepticus (SE) (convulsive) in the community setting.
Rationale:  MHOS/SHP615 is expected to be used in both the hospital and community settings. While the efficacy 
and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric subjects with SE in the hospital 
setting in the antecedent pivotal Phase 3 study (SHP615-301), this study is an open-label extension (OLE) study in 
subjects who completed the SHP615-301 study and who tolerated and responded to MHOS/SHP615 treatment. 
The rationale for this interventional OLE study is to determine the safety and efficacy of MHOS/SHP615 
administered buccally by caregivers in subjects whose corrected gestational age is >64 weeks (gestational weeks 
plus the number of weeks after birth) and weight >5kg with convulsive SE in community settings.
Investigational product, dose, and mode of administration:
Midazolam hydrochloride oromucosal solution (MHOS/SHP615) is a clear, colorless, ready-to-use solution 
(containing 5 mg midazolam [as hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a 
single, age-specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:
MHOS Dose
Subject Age
2.5 mg
>6 months (>64 weeks of corrected gestational age) to <1 year
5 mg
1 to <5 years
7.5 mg
5 to <10 years
10 mg
≥10 years
Methodology:  SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label extension (OLE) 
study of MHOS/SHP615 administered buccally by caregivers to subjects who present with SE (convulsive) in 
community settings. Children whose corrected gestational age is >64 weeks (and weight >5kg) who completed the 
antecedent Phase 3 pivotal SHP615-301 study, tolerated and responded to treatment with MHOS/SHP615, and
subsequently experience full seizure in the community setting, are eligible to participate in this study providing all 
eligibility criteria are met. The seizure event(s) must be accompanied by loss of consciousness and can be either 
generalized tonic clonic or start focally and then generalize.
Other procedures/instructions include the following:

Single dose only.
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP615-302 Protocol
SHP615
23 Mar 2017

The investigator will provide training/education to caregivers, which will include instructions on how to 
buccally administer MHOS/SHP615 and record timing and characteristics of seizures and safety measures. 
Caregivers will be qualified by the investigator to ensure understanding of all the necessary
procedures/materials.

Prior to dosing, the caregiver will organize emergency transport, and all subjects will be brought to the 
study site (hospital or emergency treatment center) as soon as possible, even if the seizure has stopped. A 
follow-up visit will take place for medical evaluation, review of adverse events and collection of study 
materials.

In the event of a medical emergency (including slowing of breathing and other adverse events that may 
require treatment) and it is not possible to bring the subject to the study site, the caregiver will be instructed 
to bring the subject to the closest emergency medical center so that the subject can receive treatment as 
quickly as possible. If this occurs, the caregiver will report the incident and relevant information, including
any rescue treatment received, to the investigator/study site within 7 days after the incident.

The caregiver will be instructed to administer MHOS/SHP615 after confirming that the seizure activity is 
appropriate for MHOS/SHP615 treatment, eg, the seizure lasts at least 5 minutes, a second seizure occurs 
before recovery of consciousness from the first seizure, or 3 seizures have occurred within 1 hour.

The caregiver will record observations on the seizure activity and timing of the seizure(s) in a study diary 
before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, review of adverse 
events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and bring it to the study 
site. Any dosing relating error, such as leaking liquid, etc., are to be recorded in the study diary.
The ability of MHOS/SHP615 to stop prolonged convulsive seizures will be assessed by measuring the percentage 
of subjects whose initial seizure stopped within 10 minutes with a sustained absence of visible seizure activity for 30 
minutes following a single, age-based dose of MHOS/SHP615. If the seizures have not stopped within 10 minutes 
after the administration of MHOS/SHP615 the subject should be treated according to the participating hospital 
protocol or guideline. The safety of MHOS/SHP615 will also be assessed.
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP615-302 Protocol
SHP615
23 Mar 2017
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Subjects who completed the SHP615-301 study and who tolerated and responded to treatment with 
MHOS/SHP615 in the hospital and/or emergency room, and are considered stable for discharge from the 
hospital.
2.
Parent, guardian, or legally authorized representative of the child who provides informed consent and assent 
(when applicable) to participate in the study after initial stabilization of the subject with SE in hospital or 
emergency room during the SHP615-301 study. The subject also provides informed consent prior to 
participation, where applicable.
3.
Subjects with parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including time of seizure 
onset, type of seizure, time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.), and

Follow the necessary instructions to secure the safety of the subject.
4.
Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of consciousness with 
any of the following characteristics persistent at the time of study drug administration:

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the preceding 
hour.

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without recovery of 
consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
Exclusion Criteria:
1.
Female subjects who are pregnant, suspected to be pregnant, or nursing.
2.
Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
4.
Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5.
Subjects with seizures of psychogenic origin.
6.
Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to benzodiazepines 
(ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia gravis, syndrome of 
sleep apnea, glaucoma with closed angle, or use of CYP3A inhibitors or inducers).
7.
Subjects with a known history of benzodiazepine abuse.
8.
Subjects who have not responded to previous administrations of midazolam systemic therapies, including 
MIDAFRESA and/or DORMICUM.
9.
Subjects who need emergent surgical intervention and general anesthesia/intubation.
10. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 
transcriptase inhibitors.
11. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
12. Have used an investigational product or been enrolled in a clinical study (including vaccine studies) that, in the 
investigator's opinion, may impact this Shire-sponsored study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP615-302 Protocol
SHP615
23 Mar 2017
13. Subject has prior placement of a vagus nerve stimulator.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 1 day

Planned duration of treatment period: 1 day (a minimum of 6 hours observation and up to 24 hours)

Planned duration of follow-up period: 7 days
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects with therapeutic 
success:

Therapeutic success will be defined as: 
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE according to the 
participating hospital protocol or guideline, 10 minutes after administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment. 
o
Treatment failure/Nonresponder is defined as continuing seizure activity and/or the need for any 
additional rescue medication in the study site (or another emergency medical institution), 10 
minutes after administration of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures after 
MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 1, 4, 6, and 24 hours post dose (ie, <92% on 
room air for 2 minutes or more after dosing while monitoring [per healthcare setting protocol and/or the 
clinical judgment of the physician]).

Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or 
endotracheal intubation).
The secondary safety endpoints include the following:

Aspiration pneumonia.

Sedation or agitation as measured by the Riker Sedation-Agitation Scale.
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP615-302 Protocol
SHP615
23 Mar 2017

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign measurements, laboratory 
tests, oxygen saturation, and electrocardiogram (ECG).

Occurrence of buccal irritation.
Statistical methods: 
Efficacy and safety data will be summarized using descriptive statistics.
Sample size*:  Maximum sample size: approximately 25 subjects
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% expected drop-out 
rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of MHOS/SHP615 in the 
Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response rate in hospital 
settings is conservatively estimated to be 58.5%. This is close to the lowest response rate reported in worldwide 
clinical studies.
Efficacy analysis
Efficacy data of the full analysis set (FAS) will be summarized using descriptive statistics. The FAS will include the 
population of subjects with SE who received a single dose of MHOS/SHP615 and have at least 1 assessment of 
therapeutic success performed after the administration of MHOS/SHP615.

Therapeutic success will be defined as:
o
The cessation of visible seizure activity within 10 minutes, with
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
Safety analysis
Safety data will be summarized using descriptive statistics on the safety set. The safety set will include subjects who 
receive a single dose of MHOS/SHP615. Treatment-emergent adverse events will be summarized and will include 
treatment, seriousness, and severity. Other TEAE data that will be reported in the listings include treatment, 
relationship to MHOS/SHP615, and the time of event onset.
Other safety data (including vital signs, laboratory tests, ECG findings, aspiration pneumonia, Riker Sedation-
Agitation Scale, and oxygen saturation) will be summarized.
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP615-302 Protocol
SHP615
23 Mar 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 mina
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Informed consent/assent 
X
Inclusion/exclusion criteria
X
Demographics
X
Medical/procedural history
X
Provide study diary and educational 
materials to caregiver
X
Provide training/education to 
caregivers
X
Dispense age-based dose of SHP615 
with administration instructions
X
Evaluate seizure symptoms/record 
diary information
X
X
X
X
X
X
X
X
SHP615 administration in 
community setting
X
Riker Sedation-Agitation Scale
Xc
X
X
X
X
Vital signsd
Xc
Xc
X
X
X
X
Oxygen saturatione
Xc
X
X
X
X
12-Lead ECGf
Xc
X
X
X
X
Laboratory evaluationsg
X
Physical examination
Xh
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP615-302 Protocol
SHP615
23 Mar 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 mina
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Supportive care
X
Xh
X
X
Concomitant medications/recording
X
X
Xh
X
X
Adverse event monitoring/recording
X
X
Xh
X
X
AE=adverse event; ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute.
a Minimum 6-hour observation period after dosing for safety monitoring and blood sampling. Otherwise monitored per standard medical healthcare setting 
procedure.
b Assessments at the 24-hour post dose time point will be made if the subject has not been discharged from the hospital; or a telephone follow-up call will be 
made to assess AEs and concomitant medications. Patients will be asked to return for additional assessment of ongoing AEs, as needed.
c Performed if subject has arrived at study site.
d Vital signs will include single sitting blood pressure (if feasible), pulse rate, respiratory rate, body temperature; collection of vital signs information will begin 
as soon as possible in community setting or after transfer to healthcare setting.
e O2 saturation should be measured from time of arrival in hospital.
f Electrocardiogram should be performed upon arrival at the hospital.
g Laboratory evaluations include hematology, serum biochemistry, and urinalysis. A urine pregnancy test should be administered to female patients of 
childbearing age.
h Upon arrival at hospital and across all time periods, as appropriate.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP615-302 Protocol
SHP615
23 Mar 2017
1.
BACKGROUND INFORMATION
1.1
Status Epilepticus
A seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal, 
excessive, and synchronous neuronal activity in the brain. Several seizure types can be described, 
but they all fall into 1 of 2 classifications:  primary generalized seizures (eg, grand mal, petit mal, 
or absence seizures) and partial (focal) onset seizures (ie, localized). Regardless of seizure type, 
most seizures (>90%) last less than a few minutes (<2 minutes) (Theodore et al. 1983). If 
seizures are prolonged or occur in a series, there is an increased risk of status epilepticus (SE), 
which literally means a continuous state of seizure (Epilepsy Foundation 2015). 
Status epilepticus (SE), a condition resulting either from the failure of the mechanisms 
responsible for seizure termination or from the initiation of mechanisms that lead to abnormally 
prolonged seizures, is a life-threatening neurologic emergency with significant morbidity and 
mortality. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute 
complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and 
cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), 
encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Prompt cessation and 
rapid control of SE is critical to prevent this neurological and systemic pathology (Fountain 
2000). 
Convulsive SE (CSE), the most common childhood neurological emergency in developed 
countries, can lead to neurocognitive sequelae and death. History with epilepsy is the strongest 
single risk factor for generalized CSE:  15% to 27% of patients with epilepsy will experience at 
least 1 episode of SE; 25% to 40% of SE occurs in patients with epilepsy.
The term SE includes not only epilepsy, but also status of serial convulsive seizures associated 
with febrile convulsion, encephalitis, and encephalopathy. The International League Against 
Epilepsy (ILE) defines SE as a seizure lasting longer than a defined period of time or more than 
1 seizure occurring within a shorter timeframe without return to normalcy between seizures 
(ILAE 1989). More recently, the minimum seizure duration had been defined as 30 minutes 
(Riviello et al. 2006); however, because epileptic discharge longer than 30 minutes has been 
reported to damage the brain, the diagnosis of SE was subsequently updated to a seizure lasting 
longer than 10 minutes (Treiman et al. 1998) and then more recently, 5 minutes (Alldredge et al. 
2001), at which time treatment should be promptly initiated. The urgency to treat this condition, 
supported by evidence that seizures rarely last more than a few minutes, led to implementation of 
an operational definition of early status epilepticus (ESE), or seizures lasting more than 5 
minutes (Dham et al. 2014; Lowenstein 1999). This definition of SE (ie, seizures lasting more 
than 5 minutes) will be used throughout this study. 
Incidence, cause, and prognosis of pediatric SE vary geographically, as well as by different 
socioeconomic conditions, environments, and genetic susceptibility. The incidence of SE is 
bimodally distributed, occurring most frequently during the first year of life and after age 60 
years. Amongst children (<15 years of age), infants <12 months have the highest incidence and 
frequency of the disease. In Japan, annual incidence in children younger than 17 years is 42 cases 
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP615-302 Protocol
SHP615
23 Mar 2017
per 100,000 persons with SE. In addition to young age, other risk factors include genetic 
predisposition and acquired brain insults (Fountain NB, 2000; Shinnar et al. 1996; Berg et al. 
1999).
Depending on the type and duration of seizures, if left untreated (or undertreated) SE can cause 
permanent neurological injury (including neuronal death, neuronal injury, and alteration of 
neuronal networks) or death (Trinka et al. 2015). Therefore, a rapid treatment must be initiated.
1.2
Current Treatment Options 
For an anti-epileptic drug to be effective in SE, it is usually administered intravenously (IV) by 
health professionals to provide quick access to the brain without the risk of serious systemic and 
neurological adverse effects (Sirven and Waterhouse 2003). Multiple drugs are available; the 
first line treatment is benzodiazepines (eg, diazepam and midazolam [midazolam is unauthorized 
for SE in the US]).
The first-choice medication in Japan for treating SE in pediatric patients without venous access is 
diazepam suppositories administered rectally. Rectal diazepam is the medication most commonly 
used throughout the European Union (EU) in the community setting, and is authorized for this 
indication. Diazepam is effective in 60% to 80% of patients but with a risk of early seizure 
recurrence of up to 30% and respiratory depression [McIntyre et al. 2005]. The increase of drug 
concentration in the blood is slow by this route; constipation and bowel movements can interfere 
with absorption of drug (Wilson et al. 2004). Rectal administration can be difficult during tonic-
clonic seizures. For wheelchair users, it can be challenging to remove clothing and to insert the 
suppository in a convulsing child. Therefore, the rectal route of administration is not always 
practical, socially acceptable, or convenient.
For resistant cases, phenytoin (or fosphenytoin), phenobarbital, and thiopentone are injectable, 
fast-acting drugs that have strong anti convulsant effects and a positive safety profile. Securing 
vascular access in children, however, is generally more difficult and prolongs stopping the 
convulsion by IV injection upon arrival at the hospital. In the community setting, a therapeutic 
agent that can be administered by a nonmedical expert, such as a parent or caregiver, would be 
more appropriate for emergency treatment. 
For pediatric patients in Japan, midazolam has been used off-label as a first or second choice 
medication for seizures intractable with diazepam treatment. However, since the approval of 
MIDAFRESA Injection 0.1% in 2014, midazolam IV injection is now positioned as first-choice 
medication in Japan for pediatric patients with SE; however, the IV formulation is too dilute to 
use for oromucosal delivery. DORMICUM (an injectable IV formulation of midazolam) is 
frequently administered oromucosally or intranasally, which is considered to be an off-label use 
of this drug.
Accordingly, it has been recognized that there is an unmet need for an effective, fast-acting 
treatment that can easily be administered by a more convenient route and by individuals other 
than medical experts and that is suitable for use in both the healthcare setting and community
(Scott et al. 1999a).
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP615-302 Protocol
SHP615
23 Mar 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs outlined above, it has been common practice to administer 
midazolam buccally (oromucosal administration of other midazolam formulations) off-label for 
the treatment of SE. Buccal administration does not cause pain or distress to the patient or 
require that the patient be in the prone position. 
Currently, the national average time in Japan for patients with SE to be transported to the 
healthcare setting is 39.6 minutes. In many cases as much as 50 minutes has been reported until 
medical treatment has been received at the healthcare setting. Buccal midazolam treatment in 
children with seizures could be started at home by trained clinical personnel, family members, or 
caregivers before securing vascular access, as well as after arriving at a medical institution, thus 
potentially reducing life-threatening risks of brain disorders (eg, encephalopathy) and other 
sequelae due to prolonged seizures and resulting from delays in getting the child to a healthcare 
setting.
1.4
Product Background and Clinical Information
The investigational product midazolam hydrochloride oromucosal solution (hereafter referred to 
as MHOS/SHP615) contains 5 mg/mL of the active substance midazolam and has been 
specifically developed for the buccal administration of midazolam in children with SE. 
Currently, there is extensive clinical experience with midazolam as it is authorized for use in 
children (including neonates <32 weeks gestational age in intensive care units) and adults as a 
sedative and in anesthesia and may be given by the intravenous (IV), intramuscular (IM), or 
rectal route of administration. As midazolam undergoes significant first pass metabolism in both 
the small intestine and the liver, a systemic drug delivery system was selected for 
MHOS/SHP615. In suspension, midazolam is water soluble and, therefore, readily absorbed via 
the buccal mucosa. At physiological pH the drug becomes lipid soluble, which enables it to cross 
the blood-brain barrier. In addition, its pharmacokinetic (PK) parameters such as the short 
elimination half-life (1.5-2.5 hours) and rapid plasma clearance (300-500 mL/min) are optimal 
for a rescue medication [Hypnovel SmPC 2008]. The buccal mucosa, with its expanse of smooth 
muscle and relative immobility, makes it a desirable region for retentive systems used for oral 
transmucosal drug delivery.
MHOS/SHP615 has a formulation essentially identical to its authorized originator product, a 
systemically administered midazolam hydrochloride (HYPNOVEL® Injection 10 mg/2 mL [EU], 
VERSED® Oral Syrup 2 mg/mL now marketed generically [US], and DORMICUM Injection 10 
mg [Japan]) used for sedation or anesthetic premedication. When approved in Japan, 
MHOS/SHP615) will provide major advantages over unauthorized/off-label buccal midazolam 
preparations and other formulations of authorized rescue medication (such as IV, IM, or rectal 
routes of administration) currently used for SE.
In the EU, MHOS is commercially known as BUCCOLAM®, a nonintravenous treatment to stop 
seizures (including convulsive seizures). An oromucosal solution, BUCCOLAM contains 5 
mg/mL of the active substance midazolam and was approved in the EU on 05 Sep 2011 for the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP615-302 Protocol
SHP615
23 Mar 2017
treatment of prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents 
(from 3 months to ≤18 years). Parents and/or caregivers are allowed to administer BUCCOLAM 
only to patients older than 6 months who have been diagnosed with epilepsy. For infants between 
3 and 6 months of age, treatment should be in a hospital setting, where close medical supervision 
and resuscitation equipment are available.
Efficacy
The age range proposed for the SHP615-301 study is >52 weeks corrected gestational age 
(gestational weeks plus the number of weeks after birth) to <18 years. The efficacy and safety of 
buccal midazolam in this age range have been established in 4 pivotal, rectal-diazepam-
controlled clinical studies. These studies all used the HYPNOVEL 10 mg/2 mL formulation 
delivered buccally. All 4 studies demonstrated that buccal midazolam was either more effective 
than or as effective as rectal diazepam for the treatment of acute seizures in children (licensed 
indication and dosage of diazepam). However, the meta-analysis of the 3 (standard randomized) 
pivotal studies [Mpimbaza et al. 2008; McIntyre et al. 2005; Scott et al. 1999b; Baysun et al. 
2005] (comprising a total of 628 seizure events [525 patients]) demonstrated that buccal 
midazolam is significantly more effective than rectal diazepam in stopping seizures within 
10 minutes (Mantel-Haenszel Weighted Risk Ratio [buccal midazolam/rectal diazepam] of 1.24 
[95% CI: 1.11 - 1.39] p = 0.0002). 
In a study vs IV diazepam [Talukdar and Chakrabarty 2009], the buccal midazolam dose was 
slightly lower than that used in the pivotal rectal diazepam studies (0.2 mg/kg vs ~0.25-
0.5 mg/kg in the pivotal studies). Nevertheless, this study supported the results of the pivotal 
studies and meta-analysis. It demonstrated that buccal midazolam is an effective treatment for 
acute seizures with no statistically significant difference compared with IV diazepam for overall 
control of convulsive episodes within 5 minutes (85% vs 93.3% in buccal midazolam vs IV 
diazepam groups, respectively; p = 0.142). 
Safety
The clinical safety profile of midazolam (and other benzodiazepines) for the authorized uses are
well established (and summarized in the EU and US labeling [HYPNOVEL SMPC 2008; 
Midazolam HCl Injection US Prescribing Information 2009; Midazolam HCl Syrup US 
Prescribing Information 2009]). The main adverse effects (reported to occur rarely for 
HYPNOVEL) and precautions applicable to the buccal route of administration in children include 
cardiorespiratory adverse events (respiratory depression, apnea, respiratory arrest, and/or cardiac 
arrest), anterograde amnesia, and paradoxical reactions. Precautions are required for patients 
with impaired respiratory function or cardiovascular instability. Pediatric patients less than 
6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Always refer to the latest version of the (MHOS)/SHP615 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of (MHOS)/SHP615. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP615-302 Protocol
SHP615
23 Mar 2017
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the hospital or community settings. The rectal route 
of administration, however, is not always practical, socially acceptable, or convenient. 
The need to remove clothing and the difficulty with rectal administration during seizures, 
particularly for wheelchairs users, is socially embarrassing or unacceptable by some individuals, 
parents, or caregivers. 
MHOS/SHP615 is expected to be used in both the hospital and community settings. While the 
efficacy and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric 
subjects with SE in the hospital setting in the antecedent pivotal Phase 3 study (SHP615-301), 
this study is an open-label extension study in subjects who completed the SHP615-301 study and 
who tolerated and responded to MHOS/SHP615 treatment.
MHOS/SHP615 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg midazolam) presentation for children. The 4 different, age-
specific, fixed-dose presentations were selected as a convenient oromucosal administration of 
midazolam injectable solution to enable rapid treatment in the emergency and community 
settings where individual dosing by body weight is not feasible (except for infants aged from 3 
months to <6 months: this age population should be treated in a healthcare setting only). This 
dosing regimen was evaluated extensively by the European Medicines Agency (EMA) Pediatric
Committee as part of the pediatric investigation plan (PIP) application and by the EMA 
Committee for Medicinal Products for Human Use (CHMP) as part of the review and approval 
of the pediatric-use marketing authorisation (PUMA).
The rationale for this interventional OLE study is to determine the safety and efficacy of 
MHOS/SHP615 administered buccally by caregivers in pediatric subjects with CSE in 
community settings.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of buccally administered 
MHOS/SHP615 in pediatric subjects with status epilepticus (SE) (convulsive) in the community 
setting.
2.2.2
Secondary Objectives
The secondary objective of this study is to assess the safety of buccally administered 
MHOS/SHP615 in pediatric patients with status epilepticus (SE) (convulsive) in the community 
setting.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP615-302 Protocol
SHP615
23 Mar 2017
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
Study SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label 
extension (OLE) study of MHOS/SHP615 administered buccally by caregivers to pediatric 
subjects who present with SE (convulsive) in community settings. Children whose corrected 
gestational age is >64 weeks (gestational weeks plus the number of weeks after birth) (and 
weight >5kg) who completed the antecedent Phase 3 pivotal SHP615-301 study, tolerated and 
responded to treatment with MHOS/SHP615, subsequently experience full seizure in the 
community setting, have not received immediate treatment, and have parent, guardian, or legal 
representative consent/assent, are eligible to participate in this extension study providing all 
eligibility criteria are met. The seizure event(s) must be accompanied by loss of consciousness 
and can be either generalized tonic clonic or start focally and then generalize.
This study consists of a 24-hour, open-label treatment period followed by a 1-week safety 
follow-up period. After completing Study SHP615-301, the subject’s parent, guardian, or legal 
representative will be dispensed a single oral, prefilled syringe of MHOS/SHP615 stratified by 
age (2.5, 5, 7.5, 10 mg buccally) along with a diary and training on how to administer the drug 
and record details associated with the seizure. Upon the onset of the next seizure in the home, 
school, or community setting, the parent, guardian, or legal representative will administer the
single MHOS/SHP615 treatment as trained.
The efficacy of MHOS/SHP615 in treating SE will be assessed by measuring the percentage of 
subjects whose seizure stopped within 10 minutes, with a sustained absence of visible seizure 
activity for 30 minutes following a single, age-based dose of MHOS/SHP615. If the seizures 
have not stopped within 10 minutes, and/or if a serious AE (SAE) emerges, the subject should be 
treated according to the participating hospital protocol or guideline. The caregiver/parent and 
subject must visit the study site for examination as soon as possible following MHOS/SHP615
administration, even if the seizure has stopped. All subjects will be followed up at study sites 
even if the seizure resolves. The safety of MHOS will also be assessed. 
Subjects will be monitored by vital signs, laboratory tests, and electrocardiograms (ECGs) for 
safety evaluations. All subjects treated in this study will be followed for 1 week after the 
administration of MHOS/SHP615 for safety evaluations. The caregiver will record observations 
on seizure activity, timing of the seizure(s), and dosing relating errors in a study diary.
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 1 week. The 
study will be completed in approximately 2 years. 
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment, or is discontinued early. Please note that this includes the 
follow-up visit or contact, whichever is later. The study completion date is used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP615-302 Protocol
SHP615
23 Mar 2017
3.3
Sites and Regions
This study will be conducted in approximately 25 study sites in Japan.
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP615-302 Protocol
SHP615
23 Mar 2017
4.
STUDY POPULATION
The total enrollment for the SHP615-302 study is expected to be ≥6 subjects with active 
generalized tonic-clonic SE with seizures. Diagnosis of SE will be confirmed through an
evaluation of seizure symptoms conducted and documented by the caregiver at the time of the 
event.
Each parent, guardian, or legal representative (and/or the subject, where necessary) must 
participate in the informed consent process and provide written informed consent/assent before 
any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator
before subjects are included in the study.
The subjects will not be considered eligible for the study without meeting all of the criteria 
below.
1. Subjects who completed the SHP615-301 study and who tolerated and responded to
treatment with MHOS/SHP615 in the hospital and/or emergency room, and are considered 
stable for discharge from the hospital.
2. Parent, guardian, or legally authorized representative of the child who provides informed 
consent and assent (when applicable) to participate in the study after initial stabilization of 
the subject with SE in hospital or emergency room during the SHP615-301 study. The 
subject also provides informed consent prior to participation, where applicable.
3. Parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, time necessary to administer MHOS/SHP615, time 
between MHOS/SHP615 administration to seizure cessation, etc.), and

Follow the necessary instructions to secure the safety of the subject.
4. Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of 
consciousness with any of the following characteristics persistent at the time of study drug 
administration:

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within 
the preceding hour
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP615-302 Protocol
SHP615
23 Mar 2017

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession 
without recovery of consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Female subjects who are pregnant, suspected to be pregnant, or nursing.
2. Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
4. Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5. Subjects with seizures of psychogenic origin.
6. Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, or use of CYP3A 
inhibitors or inducers).
7. Subjects with a known history of benzodiazepine abuse.
8. Subjects who have not responded to previous administrations of midazolam systemic 
therapies, including MIDAFRESA and/or DORMICUM.
9. Subjects who need emergent surgical intervention and general anesthesia/intubation.
10. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors 
or HIV reverse transcriptase inhibitors.
11. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
12. Have used an investigational product or been enrolled in a clinical study (including vaccine 
studies) that, in the investigator’s opinion, may impact this Shire-sponsored study.
13. Subject has prior placement of a vagus nerve stimulator.
4.3
Restrictions
4.3.1
Medical Intervention
There will be no special restrictions on medical interventions deemed necessary by the 
investigator for the health and wellbeing of the subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP615-302 Protocol
SHP615
23 Mar 2017
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at 
screening/baseline. Females of childbearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use medically acceptable methods of 
contraception.
Medically acceptable methods of contraception are:

Double-barrier methods (eg, condoms with spermicidal agent)

Oral hormonal contraceptives, stabilized for at least 30 days prior to the administration of 
investigational product, plus condoms. 
4.4.2
Male Contraception
Males should use condoms if they are sexually active for 7 days of the study and must not donate 
or use sperm for the purposes of making a woman pregnant until 7 days after the administration 
of study drug.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Subjects may withdraw from active treatment within the treatment period at any time at their 
own request, or they may be withdrawn at any time at the discretion of the investigator or 
sponsor for safety, behavioral, or administrative reasons. Additional reasons a subject may be 
withdrawn from active treatment include but are not limited to, adverse event (AE), SAE, 
protocol violations, and failure to return for visits. 
If a subject is withdrawn for whatever reason within a week following administration of study 
drug, the evaluations listed for the 1-week follow-up visit are to be performed as completely as 
possible. Whenever possible, all discontinued subjects should also undergo the protocol-
specified follow-up. The reason for termination and date of stopping the study must be recorded 
in the case report form (CRF) and source documents.
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP615-302 Protocol
SHP615
23 Mar 2017
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. In any circumstance, every effort should be made to document subject outcome, if 
possible. The investigator should inquire about the reason for withdrawal, request the subjects to 
return for a final visit, if applicable, and follow-up with the subject regarding unresolved adverse 
events. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluation should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse events

Protocol deviation

Withdrawal by subject

Lost to follow-up

The sponsor or investigator terminates the study.
Withdrawal/discontinuation due to AEs should be distinguished from withdrawal due to other 
causes, according to the definition of AE noted earlier, and recorded on the appropriate AE 
electronic case report form (eCRF) page. When a subject withdraws because of an SAE, the SAE 
must be reported in accordance with the reporting requirements defined in Section 8.2.
Sponsor Discontinuation Criteria
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the institutional review board (IRB)/EC, investigational product safety problems, or 
at the discretion of the sponsor.  In addition, the sponsor retains the right to discontinue 
development of MHOS/SHP615 at any time.
If a study is prematurely terminated or discontinued, the sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects, subject’s 
parents, guardians, or legally authorized representatives, and the hospital pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all eCRFs completed to the greatest extent possible.
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP615-302 Protocol
SHP615
23 Mar 2017
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent, guardian, or legally 
authorized representative of any subject lost to follow-up at any time point prior to the last 
scheduled contact (office visit or telephone contact). At least 1 of these documented attempts 
must include a written communication sent to the parents, guardians, or legally authorized 
representatives at subject’s last known address via courier or mail (with an acknowledgement of 
receipt request) asking that they return to the site for final safety evaluations.
4.5.4
Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if 1 or more of the 
following criteria are met:

Death that is considered related to the study drug.

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities [MedDRA] higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety lead physician and the Global Drug Safety therapeutic area head. Following 
the sponsor’s review of safety data, 1 of the following actions will be taken with respect to study 
status:

Continue study with protocol unchanged;

Continue study with modifications to the protocol; or

Terminate study.
Subject safety will be monitored on a continuous basis during this study until the last subject
completes his or her last scheduled study visit/assessment, or has discontinued from the study.
4.5.4.1
Study Level Stopping Rules
Safety data, including SAEs and adverse events of special interest (AESIs), will be monitored 
regularly throughout the duration of the study and submitted to Regulatory Authority(ies), as 
appropriate. If any potential safety signal is identified during safety monitoring in this study by 
the sponsor and/or following a safety data review, a comprehensive analysis of the issue will be 
undertaken by the sponsor. As a result of this assessment, the sponsor may take actions as 
deemed appropriate (which may include changing or suspending dosing in the study).
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or toxicity considered clinically relevant (AE, laboratory, 
physical examination, vital sign, or ECG finding) will be carefully monitored until resolution, 
which may include the following:

Additional clinical laboratory tests and/or other clinical investigations,

Additional visits or extended duration of follow-up, and/or

Obtaining a specialist consultation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP615-302 Protocol
SHP615
23 Mar 2017
5.
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) received within 
30 days prior to the administration of investigational product and through the final study contact 
(including protocol defined follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) 
received within 30 days of the date of investigational product administration. Prior treatment 
information must be recorded on the appropriate CRF page.
Medications taken during screening, before administration of the MHOS/SHP615 dose, will be 
documented as prior medications.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the time of the investigational 
product administration and the end of the follow-up period, inclusive. All concomitant 
medication(s) and treatment(s) during the study must be recorded on the appropriate CRF page, 
with indication, daily dose, start and stop dates of administration. All subjects (or 
parents/caregivers) will be questioned about concomitant medication during their follow-up visit.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP615-302 Protocol
SHP615
23 Mar 2017
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
MHOS/SHP615 is a clear, colorless, ready-to-use solution (containing 5 mg midazolam [as 
hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a single, age-
specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:

2.5 mg (yellow label) ages >6 months (>64 weeks corrected gestational age) to <1 year 
(and weight >5 kg)

5 mg (blue label) ages 1 year to <5 years

7.5 mg (purple label) ages 5 years to <10 years

10 mg (orange label) ages ≥10 years 
The investigational product MHOS/SHP615 will be provided in prefilled single-use, ready-to-
use, amber, age-specific, and color-coded oral dosing syringes, and is to be administered by the 
buccal (oromucosal) route. The full amount of solution will be delivered slowly into the space 
between the inside of the cheek and the lower gum. 
If at some point after entering the study, and prior to having a seizure, the subject ages from 1 
age category to the next, the parent/caregiver must return to the study site in order to exchange 
study drug supply for the appropriate dose.
Buccal (oromucosal) administration was considered to be an appropriate route to be progressed 
to address the unmet need for a convenient, fast–acting product suitable for use in both the 
community and hospital setting. Additional information is provided in the current version of the 
SHP615 midazolam investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment 
This is an open-label, nonrandomized study; therefore, assignment to MHOS/SHP615 will be 
unblinded to the investigators, subjects, caregivers, and the sponsor study team. Study treatment 
will only be administered by caregivers to subjects who have a signed and dated IRB-approved 
informed consent form (ICF) and who have met all eligibility criteria. 
All subjects enrolled in the study will receive treatment with the investigational product based on 
their age (Section 6.2.2.1).
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP615-302 Protocol
SHP615
23 Mar 2017
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. This identifying number will be retained 
throughout the study.
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If an identifier is allocated incorrectly, the clinical research 
associate (CRA)/study monitor must be notified as soon as the error is discovered. 
6.2.2
Dose Regimen and Dose Administration
MHOS/SHP615 will be administered buccally by caregivers as a single, fixed dose product, 
banded by age to subjects with SE (convulsive) in community settings. For buccal 
administration, midazolam is administered into the space between the lower gum and the inside 
of the cheek.
6.2.2.1
Dosing Regimen
Details of subject dosing and follow-up are outlined in Section 3.1 and included in the Schedule 
of Assessments (Table 1).
There are 4 single, fixed, banded by age, dose regimens of the MHOS/SHP615 formulation for 
the treatment of SE; 1 dosage per buccal administration for each of the following age groups:

2.5 mg
>6 months (>64 weeks corrected gestational age) to <1 year (and weight 
>5kg)

5 mg
1 to <5 years

7.5 mg
5 to <10 years

10 mg
≥10 years
6.2.2.2
Dose Administration
Before dosing:

The airway should be secured and respiratory and cardiac function assessed.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.

The caregiver will organize emergency transport, and all subjects will be brought to the 
study site as soon as possible (hospital or healthcare center), even if the seizure has 
stopped.
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP615-302 Protocol
SHP615
23 Mar 2017
Single-dose administration:

The caregiver will be instructed to administer a single dose of MHOS/SHP615 after 
confirming that the seizure activity is appropriate for MHOS/SHP615 treatment (eg, the 
seizures last at least 5 minutes or a second seizure occurs before recovery of 
consciousness from the first seizure, or 3 seizures occur within 1 hour).

Only 1 oral syringe with the specified dose must be given. The full amount of the 
MHOS/SHP615 prefilled oral dosing syringe is administered slowly into the buccal 
mucosa. In some cases, it might be necessary to divide the dose so that half of the 
solution is administered into each side of mouth.  
After dosing

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.

If the seizure has not stopped within 10 minutes of administration, and/or if a serious AE 
(SAE) emerges, then emergency medical assistance must be sought. 
Note:  A second or repeat dose of MHOS/SHP615 should not be given even if the seizure 
recurs after an initial response.

In the event of a medical emergency, and it is not possible to bring the subject to the 
study site, the caregiver will be instructed to bring the subject to the closest emergency 
medical institution so that the subject can receive treatment as quickly as possible. If this 
occurs, then the caregiver will report the incident and relevant information, including any 
rescue treatment received, to the investigator/study site within 1 week after the incident.

The caregiver/parent and subject must visit the study site for examination after 
MHOS/SHP615 administration, even if the seizure stops. All subjects will be followed up
at study sites even if the seizure resolves.
Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and
bring it to the study site. Any dosing relating errors (such as leaking liquid, etc.) are to be 
recorded in the study diary.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
A computer-generated label is applied to the investigational product. All investigational product 
is labeled with a minimum of the protocol number, pack number (if applicable), dosage form 
(including product name and quantity in pack), directions for use, storage conditions, expiry date 
(if applicable), batch number and/or packaging reference, the statements “For clinical trial use 
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP615-302 Protocol
SHP615
23 Mar 2017
only” and the name and country of the sponsor and contract research organization (CRO) name 
and address. Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
A single dose of the investigational product MHOS/SHP615 will be provided in an individual, 
labeled, single-dose, prefilled plastic, oral dosing syringe available in 4 different, age-specific, 
color-coded doses (2.5, 5, 7.5, and 10 mg dose packs) in a protective plastic tube which is
packaged and dispensed in cartons with tamper-evident seals. The cartons should not be opened 
until the investigational product is to be administered.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
Keep the oral dosing syringe containing the investigational product in the protective plastic tube. 
Keep at or below 25°C (77°F). Do not refrigerate or freeze.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The subinvestigator/designated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP615-302 Protocol
SHP615
23 Mar 2017
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling 
Investigational product for the sponsor’s studies must be stored according to all applicable local, 
state, and/or national laws. 
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
The investigator will provide or supervise the training of investigational product administration 
to the designated caregivers. Where permissible, tasks may be delegated to a qualified designee 
(eg, a pharmacist) who is adequately trained in the protocol and who works under the direct 
supervision of the investigator. This delegation must be documented in the applicable study 
delegation of authority form.
The caregiver will administer the investigational product only to subjects included in this study 
following the training provided by the investigator or his/her designee as set out in the study 
protocol. Each subject will be given only the investigational product corresponding to his/her 
treatment assignment. All administered investigational product will be documented on the CRFs 
and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor (or designated CRO). For unused
supplies where the original supplied tamper-evident feature is verified as intact, the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP615-302 Protocol
SHP615
23 Mar 2017
tamper-evident feature must not be broken and the labeled amount is to be documented in lieu of 
counting. Shipment return forms, when used, must be signed prior to shipment from the site. 
Returned investigational products must be packed in a tamper-evident manner to ensure product 
integrity. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws.
The investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product supplies.
6.5
Subject Compliance
Subjects/caregivers must be instructed to bring unused investigational product and empty/used 
investigational product packaging to the follow-up visit. Drug accountability must be assessed at 
the container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container or at the individual count level for opened 
containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.   
6.6
Destruction of Investigational Product 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by the sponsor, and all 
destruction must be adequately documented.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP615-302 Protocol
SHP615
23 Mar 2017
7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (Table 1).
7.1.1
Screening Period 
Screening for subject eligibility into this study occurs on the same day as baseline (Visit 1) for 
Study SHP615-301. This includes an assessment of inclusion/exclusion criteria.  
7.1.2
Baseline Visit 
Baseline Visit 1 will be conducted after the follow-up visit for study SHP615-301.
Written informed consent must be obtained prior to performing any protocol specific procedures. 
The following procedures will be performed:

Informed consent/assent 

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Provide study diary and educational materials to caregiver

Provide training/education to caregiver

Dispense study drug


Review concomitant medications/treatments
7.1.3
Treatment Period 
7.1.3.1
Treatment of Seizure in the Community Setting
At the onset of a seizure the caregiver will:

Confirm the seizure activity is appropriate for MHOS/SHP615 treatment, eg, the seizure 
lasts at least 5 minutes or a second seizure occurs before recovery of consciousness from 
the first seizure or 3 seizures occur within 1 hour.
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP615-302 Protocol
SHP615
23 Mar 2017

Before dosing, the caregiver will organize emergency transport, and all subjects will be 
brought to the study site right away (hospital or emergency treatment center), even if the 
seizure has stopped. A clinical visit will take place for medical evaluation, review of 
adverse events and collection of study materials.

Properly administer MHOS/SHP615 once SE is confirmed.

Follow the necessary instructions to secure the safety of the subject.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, characteristics of seizures and safety measures, 
time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.)

In the event of a medical emergency, the caregiver will be instructed to bring the subject
to the closest emergency medical institution if the subject is having a medical emergency 
(including slowing of breathing and other adverse events that may require treatment) and 
it is not possible to bring the subject to the study site so that the subject can receive 
treatment as quickly as possible. If this occurs, then the caregiver will report the incident 
and relevant information, including any rescue treatment received, to the 
investigator/study site within 1 week after the incident.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary, before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, 
review of adverse events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating error, such as leaking liquid, etc., are to be 
recorded in the study diary.
7.1.4
Clinic or Hospital Visit
Once the subject has been transported to the clinic or hospital, staff will conduct assessments and 
supportive care as outlined in Table 1. 
If the seizure continues or recurs, the subject should be treated according the procedures in use at 
the clinic or hospital.
The subjects should remain in the hospital under observation for at least 6 hours and up to 24 
hours after hospital arrival (as needed).
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP615-302 Protocol
SHP615
23 Mar 2017
The following procedures will be performed:

Evaluate seizure symptoms (by caregiver in the community or by PI once at the site) at 
10 and 30 (±5) minutes, and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min)
hours post dose.

Evaluate Riker Sedation Agitation Scale (once subject arrives at hospital or clinic) at 30 
(±5) minutes (if possible), and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min)
hours post dose.

6 hours (±30 min) post dose: Obtain blood and urine samples for safety laboratory tests 
for hematology, serum biochemistry, and urinalysis.

10 and 30 (±5) minutes, and 1, 4, 6, and 24 hours (±30 min) post dose (if subject has not 
been discharged from the healthcare setting):

Measure vital signs: single sitting blood pressure (BP) (if feasible), pulse rate, 
respiratory rate, temperature (°C or °F).

30 minutes*, 1 hour (±10 min) and 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours  
post dose if subject has not been discharged from the healthcare setting:

Measure oxygen saturation.

Perform standard 12-lead ECG.
*If possible, by EMT or at the site.

Administer supportive care.

Review and record concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
laboratory sampling).
7.1.5
Follow-up Period
The follow-up period for this protocol is 7 days (± 1 day). 
At the end of this period there will be a telephone call initiated by the site staff/follow-up visit to 
evaluate seizure symptoms, serious adverse events (SAEs), adverse events (AEs), and 
concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (see Section 8.1). In addition, caregivers will be asked to complete the 
.
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP615-302 Protocol
SHP615
23 Mar 2017
7.2
Study Evaluations and Procedures
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test. In these cases the investigator will take all steps necessary to ensure the safety and well-
being of the subject. When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions that he or she has taken to 
ensure that normal processes are adhered to as soon as possible. The study team will be informed 
of these incidents in a timely fashion.
7.2.1
Informed Consent
The ICF must be executed prior to performing any study-related activities and must be approved 
by the reviewing institutional review board (IRB). Subjects may withdraw consent at any time. 
Participation in the study may be terminated at any time without the subject’s consent as 
determined by the investigator. Due to the potential for long periods between initial consent and 
treatment, the investigator should, every 3 months, either have the subject/parent/caregiver resign 
and date the original consent form(s), or document phone contact with the 
subject/parent/caregiver confirming ongoing interest and willingness to participate in the study.
7.2.2
Demographic and Other Baseline Characteristics
Demographics: date of birth (alternately age or year of birth, if full date is not allowed to be 
collected for legal reasons), sex, race and ethnicity (where locally permitted) and medical history 
will be obtained at screening from subjects, parents, or caregivers and will be recorded on the 
source document and eCRF.
Medical history (including SE, smoking, and cardiovascular history) will capture the subject’s 
current medical status (current SE or CSE disease processes), past medical status (past disease 
processes), history of surgery, allergies, and concomitant medications/treatments.
7.2.3
Efficacy
Methods of measuring the efficacy of MHOS/SHP615 in SE that will be used throughout the
study are described in this section.
Information recorded in the subject diary by the caregiver along with evaluation by the 
investigator or subinvestigator will be used to evaluate the seizure and its duration, type (focal, 
generalized, convulsive or nonconvulsive), and recurrence. The other criteria are those set in the 
study protocol to define the treatment efficacy and include time of cessation and need for 
additional rescue medication.
7.2.4
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP615-302 Protocol
SHP615
23 Mar 2017
Any AE related to either efficacy or safety should be first recorded by the caregiver using a 
comprehensive study diary and other materials, and then finally verified by the investigator.
7.2.4.1
Medical and Medication History
Medical history is collected at the time points specified in the Schedule of Assessments (Table 
1).
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE or CSE (eg, dietary, medication, or other), must be 
recorded on the appropriate eCRF page.
7.2.4.2
Adverse Event Collection
At each assessment time point, subjects will be questioned/evaluated in a general way to 
ascertain if AEs have occurred since the previous time point. Adverse events are collected from 
the time informed consent is signed. (Please refer to Section 8, Adverse and Serious Adverse 
Events Assessment.)
7.2.4.3
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment include blood pressure (systolic and diastolic), pulse rate, respiration rate
(after 5 minutes of rest), and body temperature to be performed at the time points specified in the 
Schedule of Assessments (Table 1). Additional collection times or changes to collection times 
will be permitted, as necessary to ensure appropriate collection of safety data.
Sitting blood pressure (if feasible) will be measured with the subject’s arm supported at the level 
of the heart, and recorded to the nearest mm Hg. It is preferred that the same arm (preferably the 
dominant arm) will be used throughout the study. The same size BP cuff that has been properly 
sized and calibrated will be used to measure BP each time.
The use of automated devices for measuring BP and pulse rate are acceptable, although, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. 
When the timing of these measurements coincides with a blood collection, all vital signs should 
be obtained prior to the nominal time of the blood collection.
It is preferred that body temperature be collected using tympanic, oral, or axillary methods and 
that the same method be used consistently throughout the study.
Any clinically significant deviations from baseline vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP615-302 Protocol
SHP615
23 Mar 2017
7.2.4.4
Clinical Laboratory Evaluations
The following clinical laboratory assessments will be performed at times defined in the Schedule 
of Assessments (Table 1):
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
RBC morphology (if 
needed)
INR
BUN and Creatininea, b
Glucose (fasting if possible)
Calcium (total)
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Direct bilirubinb
Indirect bilirubin
Alkaline phosphatase
Gamma glutamyl transferase
Uric acid
Albumin
Total protein
Amylase
Lipase
Magnesium
Phosphorus
Bicarbonate
Cholesterol
Triglycerides
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Specific gravity
Microscopyc
Urine pregnancyd
ALT = alanine aminotransferase ; AST = aspartate aminotransferase; INR = international normalized ratio; RBC = red blood cell; 
WBC =white blood cell
a Creatinine clearance determination by central lab using Cockcroft & Gault method.
b Only if total bilirubin is elevated. 
c Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
d Complete for women of childbearing potential.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
Blood samples for laboratory assessments will be collected at the site by a trained phlebotomist 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
laboratory manual. 
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP615-302 Protocol
SHP615
23 Mar 2017
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 9 mL. When more than 1 blood assessment is to be done at the time
point/period, if they require the same type of tube, the assessments may be combined. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP615-302 Protocol
SHP615
23 Mar 2017
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP615-302 Protocol
SHP615
23 Mar 2017
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP615-302 Protocol
SHP615
23 Mar 2017
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
Quintiles Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor 
using the details specified in the emergency contact information section of the protocol. The 
pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP615-302 Protocol
SHP615
23 Mar 2017
beta-human chorionic gonadotropin (-hCG) test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of MHOS/SHP615

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the SHP615 midazolam HCl investigator’s 
brochure, which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K. and Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP615-302 Protocol
SHP615
23 Mar 2017
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to Quintiles Transnational Japan K.K. and 
the Shire Global Pharmacovigilance and Risk Management Department. A copy of the Shire 
Clinical Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form (and 
any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor using the 
details specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 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. 
Hospitalization
For this protocol, hospitalization is defined as any admission to a medical or equivalent 
healthcare facility or any prolongation of an existing admission lasting more than 24 hours.  
Admission also includes transfer within the hospital to an acute/intensive care unit (eg, from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to 
a tuberculosis unit). A healthcare setting visit does not necessarily constitute a hospitalization; 
however, the event leading to the healthcare setting visit should be assessed for medical 
importance.
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP615-302 Protocol
SHP615
23 Mar 2017
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include: 

Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for workup of 
persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4 and must be reported 
to Quintiles Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk 
Management Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP615-302 Protocol
SHP615
23 Mar 2017
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to Quintiles 
Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk Management 
Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and CRO are responsible for notifying the relevant regulatory authorities/and 
institutional IRBs or ECs of related, unexpected SAEs.
In addition the sponsor or Quintiles Transnational Japan K.K. is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the
SHP615 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Product Quality Complaints
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP615-302 Protocol
SHP615
23 Mar 2017
reporting of device defects. Quality complaints may be reportable to Pharmaceuticals and 
Medical Devices Agency (PMDA) as a device malfunction report, regardless of whether or not 
the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP615-302 Protocol
SHP615
23 Mar 2017
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate electronic case report form (eCRF).
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. 
Data collection procedures will be discussed with the site at the site initiation visit and/or at the 
investigator’s meeting. Once a subject is enrolled, it is expected that site personnel will complete 
the CRF entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the sponsor’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
All available data will be included in the analysis. No imputation of missing data will be 
performed.
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its designee. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP615-302 Protocol
SHP615
23 Mar 2017
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. All statistical analyses will be performed using SASVersion 
9.3 or higher (SAS Institute, Cary, NC, USA 27513). 
9.4.1
Appropriateness of Measurements
This is a Phase 3, open-label extension (OLE) study that is designed to evaluate the efficacy and 
safety of MHOS/SHP615 as therapy for subjects with SE or CSE. Measures employed in this 
protocol are standard measures routinely used for the evaluation of the efficacy, safety, and 
tolerability of an investigational product.
9.4.2
General Considerations
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. 
9.5
Planned Interim Analysis
There is no planned interim analysis.
9.6
Sample Size Calculation and Power Considerations
The target sample size (≥6 subjects) is estimated based on feasibility analysis rather than based 
on statistical rationale.
Maximum sample size*: approximately 25 subjects.
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% 
expected drop-out rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of 
MHOS/SHP615 in the Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response 
rate in hospital settings is conservatively estimated to be 58.5%. This is close to the lowest 
response rate reported in worldwide clinical studies.
9.7
Study Population
The screened set will consist of all subjects who have a signed informed consent.
The safety set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The full analysis set (FAS) will consist of all subjects who have received a single dose of 
MHOS/SHP615 and who have at least 1 assessment for therapeutic success (cessation of seizure 
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP615-302 Protocol
SHP615
23 Mar 2017
within 10 minutes with sustained absence of seizure for 30 minutes) performed after the 
administration of MHOS/SHP615.
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects 
with therapeutic success.

Therapeutic success will be defined as:
o
The cessation of visible seizure activity within 10 minutes, with
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615.
The response rate will be calculated with FAS and the 2-sided, 95% confidence interval (CI) will 
be constructed for the response rate.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE 
according to the participating hospital protocol or guideline, 10 minutes after 
administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment.

Treatment failure/Nonresponder is defined as continuing seizure activity and/or 
the need for any additional rescue medication in the study site (or another 
emergency medical institution), 10 minutes after administration of 
MHOS/SHP615.
For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP615-302 Protocol
SHP615
23 Mar 2017
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, the ethical principles in the Declaration of Helsinki, and local 
ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, and 
ICH Guidelines with Integrated Addendum E6(R2), Step 4 Version dated 09 Nov 2016, as well 
as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP615-302 Protocol
SHP615
23 Mar 2017
agencies and IRBs are notified as appropriate. Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, ICH Guidelines with Integrated Addendum E6(R2), Step 4 
Version dated 09 Nov 2016, the ethical principles in the Declaration of Helsinki, and applicable 
regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly
inform the sponsor and the IRB and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP615-302 Protocol
SHP615
23 Mar 2017
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
All data sent to the sponsor must be endorsed by the investigator.
Once the CRA/study monitor has verified the contents of the completed CRF pages against the 
source data, the duplicate pages are retrieved and forwarded to the study sponsor (or designee) 
for data entry. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB or regulatory inspectors) may check the CRF entries 
against the source documents. The ICF includes a statement by which the subject agrees to the 
monitor/auditor from the sponsor or its representatives, national or local regulatory authorities, or 
the IRB, having access to source data (eg, subject’s medical file, appointment books, original 
laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], EMA, PMDA) or an auditor.
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP615-302 Protocol
SHP615
23 Mar 2017
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the Japan Pharmaceuticals and 
Medical Devices Agency (PMDA), US FDA (as well as other US national and local regulatory 
authorities), the EMA, the Medicines and Healthcare products Regulatory Agency, other 
regulatory authorities, the sponsor or its representatives, and the IRB for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances the investigator must at all times comply with all local, state, 
and national laws pertaining to registration and reporting with the appropriate regulatory body 
and control and handling of such substances.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects (or parent, guardian, or legally authorized representative) prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
with applicable regulations and GCP. Each subject or the subject’s parent, guardian, or legally 
authorized representative, as applicable, is requested to sign and date the subject informed 
consent form or a certified translation if applicable, after the subject (and parent, guardian, or 
legally authorized representative) has received and read (or been read) the written subject
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent, guardian, or legally authorized representative, as applicable. This document 
may require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP615-302 Protocol
SHP615
23 Mar 2017
The principal investigator provides the sponsor with a copy of the blank informed consent form
that was reviewed by the IRB and received their favorable opinion/approval. A copy of the IRB’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB requires modification of the 
sample subject information and consent document provided by the sponsor, the documentation 
supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB for review, and all must 
be approved prior to site initiation.
The applicant for an IRB opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB must approve any revisions 
of all informed consent documents and amendments to the protocol unless there is a subject
safety issue.
Investigational product supplies will not be released until the sponsor has received written IRB
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects (and parent, guardian, or legally authorized representative) have consented to take 
part in the study, the sponsor and/or its representatives review their medical records and data 
collected during the study. These records and data may, in addition, be reviewed by others 
including the following: independent auditors who validate the data on behalf of the sponsor; 
third parties with whom the sponsor may develop, register, or market MHOS/SHP615; national 
or local regulatory authorities; and the IRB that gave approval for the study to proceed. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP615-302 Protocol
SHP615
23 Mar 2017
The sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP615-302 Protocol
SHP615
23 Mar 2017
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP615-302 Protocol
SHP615
23 Mar 2017
11.
REFERENCES 
Alldredge, BK, Gelb, AM, Isaacs, SM, Corry, MD, Allen, F, Ulrich, S, Gottwald, MD, O'neil, N, 
Neuhaus, JM, Segal, MR & Lowenstein, DH 2001. A comparison of lorazepam, 
diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J 
Med, 345, 631-7.
Baysun, S, Aydin, OF, Atmaca, E & Gurer, YK 2005. A comparison of buccal midazolam and 
rectal diazepam for the acute treatment of seizures. Clin Pediatr (Phila), 44, 771-6.
Berg, AT, Shinnar, S, Levy, SR & Testa, FM 1999. Status epilepticus in children with newly 
diagnosed epilepsy. Ann Neurol, 45, 618-23.
Dham, BS, Hunter, K & Rincon, F 2014. The epidemiology of status epilepticus in the United 
States. Neurocrit Care, 20, 476-83.
Epilepsy Foundation. 2015. Status Epilepticus [Online]. Available: 
http://www.epilepsy.com/learn/impact/seizure-emergencies/status-epilepticus.
Fountain, NB 2000. Status epilepticus: risk factors and complications. Epilepsia, 41 Suppl 2,
S23-30.
Hypnovel Smpc. 2008. Roche Products Ltd. Available: 
http://www.medicines.org.uk/EMC/medicine/1692/SPC/Hypnovel+10mg+2ml/.
Ilae 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Commission 
on Classification and Terminology of the International League Against Epilepsy. 
Epilepsia, 30, 389-99.
Lowenstein, DH 1999. Status epilepticus: an overview of the clinical problem. Epilepsia, 40, S3-
8, discussion S21-2.
Mcintyre, J, Robertson, S, Norris, E, Appleton, R, Whitehouse, WP, Phillips, B, Martland, T, 
Berry, K, Collier, J, Smith, S & Choonara, I 2005. Safety and efficacy of buccal 
midazolam versus rectal diazepam for emergency treatment of seizures in children: a 
randomised controlled trial. Lancet, 16-22, 205-10.
Midazolam Hcl Injection Us Prescribing Information. 2009. Roxane Laboratories Inc. Available: 
http://www.drugs.com/pro/midazolam-injection.html [Accessed 27 Apr 2010].
Midazolam Hcl Syrup Us Prescribing Information. 2009. Roxane Laboratories Inc. . Available: 
http://www.drugs.com/pro/midazolam-syrup.html [Accessed 27 Apr 2010].
Mpimbaza, A, Ndeezi, G, Staedke, S, Rosenthal, PJ & Byarugaba, J 2008. Comparison of buccal 
midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan 
children: a randomized clinical trial. Pediatrics, 121, e58-64.
Riviello, JJJ, Ashwal, S, Hirtz, D, Glauser, T, Ballaban-Gil, K, Kelley, K, Morton, LD, Phillips, 
S, Sloan, E, S., S, Subcommittee;, AaON & Society., PCOTCN 2006. Practice parameter: 
diagnostic assessment of the child with status epilepticus (an evidence-based review): 
report of the Quality Standards Subcommittee of the American Academy of Neurology 
and the Practice Committee of the Child Neurology Society. Neurology, 14, 1542-50.
Scott, RC, Besag, FM & Neville, BG 1999a. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Scott, RC, Besag, FM & Neville, BG 1999b. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
353, 623-6.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP615-302 Protocol
SHP615
23 Mar 2017
Shinnar, S, Berg, AT, Moshe, SL, O'dell, C, Alemany, M, Newstein, D, Kang, H, Goldensohn, 
ES & Hauser, WA 1996. The risk of seizure recurrence after a first unprovoked afebrile 
seizure in childhood: an extended follow-up. Pediatrics, 98, 216-25.
Sirven, JI & Waterhouse, E 2003. Management of status epilepticus. Am Fam Physician, 68,
469-76.
Talukdar, B & Chakrabarty, B 2009. Efficacy of buccal midazolam compared to intravenous 
diazepam in controlling convulsions in children: a randomized controlled trial. Brain 
Dev, 31, 744-9.
Theodore, WH, Porter, RJ & Penry, JK 1983. Complex partial seizures: clinical characteristics 
and differential diagnosis. Neurology, 33, 1115-21.
Treiman, DM, Meyers, PD, Walton, NY, Collins, JF, Colling, C, Rowan, AJ, Handforth, A, 
Faught, E, Calabrese, VP, Uthman, BM, Ramsay, RE & Mamdani, MB 1998. A 
comparison of four treatments for generalized convulsive status epilepticus. Veterans 
Affairs Status Epilepticus Cooperative Study Group. N Engl J Med, 17, 792-8.
Trinka, E, Höfler, J, Leitinger, M & Brigo, F 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, MT, Macleod, S & O'regan, ME 2004. Nasal/buccal midazolam use in the community. 
Arch Dis Child, 89, 50-1.
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP615-302 Protocol
SHP615
23 Mar 2017
12.
APPENDICES
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP615-302 Protocol
SHP615
23 Mar 2017
APPENDIX 2 SCALES AND ASSESSMENTS
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
Riker Sedation-Agitation Scale
1
1999
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
SHP615-302 Protocol
SHP615
23 Mar 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).
For non-commercial use only


PROTOCOL: SHP615-302
TITLE:
A Phase 3, Multicenter, Open-label Extension Study of Buccally 
Administered MHOS/SHP615 in Pediatric Patients with Status 
Epilepticus (Convulsive) in Community Settings
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
, MD
PROTOCOL 
HISTORY:
Original Protocol: 23 Mar 2017
Administrative changes made: 19 Jun 2017
Protocol Amendment 1: 8 Jul 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to Quintiles Transnational Japan K.K., the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor. 
Applicable fax numbers and e-mail address can be found on the form (sent under separate cover). 
A copy of this form must also be sent to the CRO/Shire medical monitor by fax or e-mail using 
the details below.
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor email address: 
For protocol- or safety-related issues during normal business hours, the investigator must 
contact the Quintiles medical monitor:
Quintiles Medical Advisor name, title: 
, 
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor mobile number: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the:
Quintiles Medical Advisor mobile number: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
PRODUCT QUALITY COMPLAINTS
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to PMDA as a device 
malfunction report, regardless of whether or not the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
LIST OF TABLES.........................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
1
BACKGROUND INFORMATION.......................................................................................21
1.1
Status Epilepticus .....................................................................................................21
1.2
Current Treatment Options.......................................................................................22
1.3
Unmet Medical Need for Buccal Midazolam ..........................................................23
1.4
Product Background and Clinical Information ........................................................23
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
2.2.1
Primary Objectives.................................................................................................25
2.2.2
Secondary Objectives.............................................................................................25
2.2.3
Exploratory Objectives ..........................................................................................26
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design and Flow Chart ..................................................................................26
3.2
Duration and Study Completion Definition .............................................................26
3.3
Sites and Regions .....................................................................................................27
4
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................28
4.3
Restrictions...............................................................................................................29
4.3.1
Medical Intervention..............................................................................................29
4.4
Reproductive Potential .............................................................................................29
4.4.1
Female Contraception............................................................................................29
4.4.2
Male Contraception................................................................................................29
4.5
Discontinuation of Subjects .....................................................................................29
4.5.1
Subject Withdrawal Criteria ..................................................................................29
4.5.2
Reasons for Discontinuation..................................................................................30
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................31
4.5.4
Stopping Rules.......................................................................................................31
4.5.4.1
Study Level Stopping Rules...................................................................31
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria................................32
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ........................................................................................................32
5.2
Concomitant Treatment............................................................................................32
6
INVESTIGATIONAL PRODUCT ........................................................................................32
6.1
Identity of Investigational Product...........................................................................32
6.1.1
Blinding the Treatment Assignment......................................................................33
6.2
Administration of Investigational Product(s)...........................................................33
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dose Regimen and Dose Administration...............................................................34
6.2.2.1
Dosing Regimen.....................................................................................34
6.2.2.2
Dose Administration ..............................................................................34
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................35
6.3.3
Storage ...................................................................................................................36
6.3.4
Special Handling....................................................................................................36
6.4
Drug Accountability.................................................................................................36
6.5
Subject Compliance..................................................................................................37
6.6
Destruction of Investigational Product.....................................................................38
7
STUDY PROCEDURES........................................................................................................38
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening Period....................................................................................................38
7.1.2
Baseline Visit.........................................................................................................38
7.1.3
Treatment Period....................................................................................................38
7.1.3.1
Treatment of Seizure in the Community Setting....................................38
7.1.4
Clinic or Hospital Visit..........................................................................................39
7.1.5
Follow-up Period ...................................................................................................40
7.1.6
Additional Care of Subjects after the Study ..........................................................40
7.2
Study Evaluations and Procedures ...........................................................................41
7.2.1
Informed Consent...................................................................................................41
7.2.2
Demographic and Other Baseline Characteristics .................................................41
7.2.3
Efficacy..................................................................................................................41
7.2.4
Safety .....................................................................................................................41
7.2.4.1
Medical and Medication History............................................................42
7.2.4.2
Adverse Event Collection.......................................................................42
7.2.4.3
Vital Signs..............................................................................................42
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
7.2.4.4
Clinical Laboratory Evaluations.............................................................43
7.2.4.5
Pregnancy Test .......................................................................................43
7.2.4.6
Electrocardiogram ..................................................................................44
7.2.4.7
Oxygen Saturation..................................................................................44
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................44
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease Under Study .................................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................48
8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................51
8.2.6
Fatal Outcome........................................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................51
8.3
Product Quality Complaints.....................................................................................51
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Data Handling Considerations .................................................................................53
9.4
Statistical Analysis Process......................................................................................53
9.4.1
Appropriateness of Measurements.........................................................................53
9.4.2
General Considerations..........................................................................................53
9.5
Planned Interim Analysis .........................................................................................53
9.6
Sample Size Calculation and Power Considerations................................................54
9.7
Study Population ......................................................................................................54
9.8
Efficacy Analyses.....................................................................................................54
9.8.1
Primary Efficacy Endpoint ....................................................................................54
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
9.8.2
Secondary Efficacy Endpoints...............................................................................54
9.8.3
Exploratory Efficacy Endpoints.............................................................................55
9.9
Safety Analyses........................................................................................................55
9.9.1
Primary Safety Endpoints ......................................................................................55
9.9.2
Secondary Safety Endpoints ..................................................................................55
9.9.3
Clinical Laboratory Tests.......................................................................................56
9.9.4
Vital Signs..............................................................................................................56
9.9.5
Electrocardiography...............................................................................................57
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................57
10.1
Sponsor’s Responsibilities .......................................................................................57
10.1.1 Good Clinical Practice Compliance.......................................................................57
10.1.2 Public Posting of Study Information......................................................................58
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards............................58
10.1.4 Study Suspension, Termination, and Completion..................................................58
10.2
Investigator’s Responsibilities .................................................................................58
10.2.1 Good Clinical Practice Compliance.......................................................................58
10.2.2 Protocol Adherence and Investigator Agreement..................................................59
10.2.3 Documentation and Retention of Records.............................................................59
10.2.3.1
Case Report Forms.................................................................................59
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................59
10.2.3.3
Audit/Inspection.....................................................................................60
10.2.3.4
Financial Disclosure...............................................................................60
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................60
10.3
Ethical Considerations..............................................................................................60
10.3.1 Informed Consent...................................................................................................60
10.3.2 Institutional Review Board ....................................................................................61
10.4
Privacy and Confidentiality......................................................................................62
10.5
Study Results/Publication Policy .............................................................................62
11 REFERENCES .......................................................................................................................64
12 APPENDICES ........................................................................................................................66
Appendix 1
Protocol History .....................................................................................67
Appendix 2
Scales and Assessments .........................................................................68
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................19
Table 2
Volume of Blood to Be Drawn from Each Subject.......................................44
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
ESE
early status epilepticus
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ILAE
International League Against Epilepsy
IM
intramuscular
IRB
institutional review board
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
MHOS/SHP615
midazolam hydrochloride oromucosal solution
PIP
pediatric investigation plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PQCROW
Product Quality Complaint Rest of World
PUMA
pediatric-use marketing authorisation
SAE
serious adverse event
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
SAP
statistical analysis plan
SE
status epilepticus
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
STUDY SYNOPSIS
Protocol number: SHP615-302
Drug: Midazolam hydrochloride oromucosal solution MHOS/SHP615
Title of the study: A Phase 3, Multicenter, Open-label Extension Study of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in Community Settings
Number of subjects (total): ≥6 subjects
Investigator(s): Multicenter study (in community settings)
Site(s) and Region(s): Approximately 25 sites in Japan
Study period (planned):
August 2017 to July 2019
Clinical phase:
3
Objectives:
Primary:  The primary objective of this study is to assess the efficacy of buccally administered MHOS/SHP615 in 
pediatric subjects with status epilepticus (SE) (convulsive) in the community setting.
Secondary:  The secondary objective of this study is to assess the safety of buccally administered MHOS/SHP615 
in pediatric patients with status epilepticus (SE) (convulsive) in the community setting.
Rationale:  MHOS/SHP615 is expected to be used in both the hospital and community settings. While the efficacy 
and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric subjects with SE in the hospital 
setting in the antecedent pivotal Phase 3 study (SHP615-301), this study is an open-label extension (OLE) study in 
subjects who completed the SHP615-301 study and who tolerated and responded to MHOS/SHP615 treatment. 
The rationale for this interventional OLE study is to determine the safety and efficacy of MHOS/SHP615 
administered buccally by caregivers in subjects who are >6 months and <18 years of age and weight >5kg with 
convulsive SE in community settings.
Investigational product, dose, and mode of administration:
Midazolam hydrochloride oromucosal solution (MHOS/SHP615) is a clear, colorless, ready-to-use solution 
(containing 5 mg midazolam [as hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a 
single, age-specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:
MHOS Dose
Subject Age
2.5 mg
>6 months to <1 year
5 mg
1 to <5 years
7.5 mg
5 to <10 years
10 mg
≥10 to <18 years
Methodology:  SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label extension (OLE) 
study of MHOS/SHP615 administered buccally by caregivers to subjects who present with SE (convulsive) in 
community settings. Children who are >6 months and <18 years of age and completed the antecedent Phase 3 
pivotal SHP615-301 study, tolerated and responded to treatment with MHOS/SHP615, and subsequently experience 
full seizure in the community setting, are eligible to participate in this study providing all eligibility criteria are met. 
The seizure event(s) must be accompanied by loss of consciousness and can be either generalized tonic clonic or 
start focally and then generalize.
Other procedures/instructions include the following:

Single dose only.
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017

The investigator will provide training/education to caregivers, which will include instructions on how to 
buccally administer MHOS/SHP615 and record timing and characteristics of seizures and safety measures. 
Caregivers will be qualified by the investigator to ensure understanding of all the necessary
procedures/materials.

Prior to dosing, the caregiver will organize emergency transport, and all subjects will be brought to the 
study site (hospital or emergency treatment center) immediately, even if the seizure has stopped. A follow-
up visit will take place for medical evaluation, review of adverse events and collection of study materials.

In the event of a medical emergency (including slowing of breathing and other adverse events that may 
require treatment) and it is not possible to bring the subject to the study site, the caregiver will be instructed 
to bring the subject to the closest emergency medical center so that the subject can receive treatment as 
quickly as possible. If this occurs, the caregiver will report the incident and relevant information, including
any rescue treatment received, to the investigator/study site within 7 days after the incident.

The caregiver will be instructed to administer MHOS/SHP615 after confirming that the seizure activity is 
appropriate for MHOS/SHP615 treatment, eg, the seizure lasts at least 5 minutes, a second seizure occurs 
before recovery of consciousness from the first seizure, or 3 seizures have occurred within 1 hour.

The caregiver will record observations on the seizure activity and timing of the seizure(s) in a study diary 
before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, review of adverse 
events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and bring it to the study 
site. Any dosing relating error, such as leaking liquid, etc., are to be recorded in the study diary.
The ability of MHOS/SHP615 to stop prolonged convulsive seizures will be assessed by measuring the percentage 
of subjects whose initial seizure stopped within 10 minutes with a sustained absence of visible seizure activity for 30 
minutes following a single, age-based dose of MHOS/SHP615. If the seizures have not stopped within 10 minutes 
after the administration of MHOS/SHP615 the subject should be treated according to the participating hospital 
protocol or guideline. The safety of MHOS/SHP615 will also be assessed.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Subjects who completed the SHP615-301 study and who tolerated and responded to treatment with 
MHOS/SHP615 in the hospital and/or emergency room, and are considered stable for discharge from the 
hospital.
2.
Subjects who are >6 months and <18 years of age at the time of investigational product administration. If the 
subject’s exact age is not known, the subject should be excluded.
3.
Parent, guardian, or legally authorized representative of the child who provides informed consent and assent 
(when applicable) to participate in the study after initial stabilization of the subject with SE in hospital or 
emergency room during the SHP615-301 study. The subject also provides informed consent prior to 
participation, where applicable.
4.
Subjects with parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including time of seizure 
onset, type of seizure, time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.) 

Follow the necessary instructions to secure the safety of the subject.
5.
Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of consciousness with 
any of the following characteristics persistent at the time of study drug administration:
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the preceding 
hour.

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without recovery of 
consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
Exclusion Criteria:
1.
Female subjects who are pregnant, suspected to be pregnant, or nursing.
2.
Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
4.
Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5.
Subjects with seizures of psychogenic origin.
6.
Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to benzodiazepines 
(ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia gravis, syndrome of 
sleep apnea, glaucoma with closed angle, or use of use of concomitant drugs determined by the investigator to 
have a contraindication to the use of benzodiazepines.  
7.
Subjects with a known history of benzodiazepine abuse.
8.
Subjects who have not responded to previous administrations of midazolam systemic therapies, including 
MIDAFRESA and/or DORMICUM.
9.
Subjects who need emergent surgical intervention and general anesthesia/intubation.
10. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 
transcriptase inhibitors.
11. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
12. Have used an investigational product or been enrolled in a clinical study (including vaccine studies) that, in the 
investigator's opinion, may impact this Shire-sponsored study.
13. Subject has prior placement of a vagus nerve stimulator.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 1 day

Planned duration of treatment period: 1 day (a minimum of 6 hours observation and up to 24 hours)

Planned duration of follow-up period: 7 days
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects with therapeutic 
success:

Therapeutic success will be defined as: 
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
The secondary efficacy endpoints will include:
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE according to the 
participating hospital protocol or guideline, 10 minutes after administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment. 
o
Treatment failure/Nonresponder is defined as continuing seizure activity and/or the need for any 
additional rescue medication in the study site (or another emergency medical institution), 10 
minutes after administration of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures after 
MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 1, 4, 6, and 24 hours post dose (ie, <92% on 
room air for 2 minutes or more after dosing while monitoring [per healthcare setting protocol and/or the 
clinical judgment of the physician]).

Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or 
endotracheal intubation).
The secondary safety endpoints include the following:

Aspiration pneumonia.

Sedation or agitation as measured by the Riker Sedation-Agitation Scale.

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign measurements, laboratory 
tests, oxygen saturation, and electrocardiogram (ECG).

Occurrence of buccal irritation.
Statistical methods: 
Efficacy and safety data will be summarized using descriptive statistics.
Sample size*:  Maximum sample size: approximately 25 subjects
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% expected drop-out 
rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of MHOS/SHP615 in the 
Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response rate in hospital 
settings is conservatively estimated to be 58.5%. This is close to the lowest response rate reported in worldwide 
clinical studies.
Efficacy analysis
Efficacy data of the full analysis set (FAS) will be summarized using descriptive statistics. The FAS will include the 
population of subjects with SE who received a single dose of MHOS/SHP615 and have at least 1 assessment of 
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
therapeutic success performed after the administration of MHOS/SHP615.

Therapeutic success will be defined as:
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
Safety analysis
Safety data will be summarized using descriptive statistics on the safety set. The safety set will include subjects who 
receive a single dose of MHOS/SHP615. Treatment-emergent adverse events will be summarized and will include 
treatment, seriousness, and severity. Other TEAE data that will be reported in the listings include treatment, 
relationship to MHOS/SHP615, and the time of event onset.
Other safety data (including vital signs, laboratory tests, ECG findings, aspiration pneumonia, Riker Sedation-
Agitation Scale, and oxygen saturation) will be summarized.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 mina
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Informed consent/assent 
X
Inclusion/exclusion criteria
X
Demographics
X
Medical/procedural history
X
Provide study diary and educational 
materials to caregiver
X
Provide training/education to 
caregivers
X
Dispense age-based dose of SHP615 
with administration instructions
X
Evaluate seizure symptoms/record 
diary information
X
X
X
X
X
X
X
X
SHP615 administration in 
community setting
X
Riker Sedation-Agitation Scale
Xc
X
X
X
X
Vital signsd
Xe
Xc
Xc
X
X
X
X
Oxygen saturationf
Xc
X
X
X
X
12-Lead ECGg
Xc
X
X
X
X
Laboratory evaluationsh
X
Buccal cavity assessmenti
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 mina
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Physical examination
Xj
X
X
Supportive care
X
Xj
X
X
Concomitant medications/recording
X
X
Xj
X
X
Adverse event monitoring/recording
X
X
Xj
X
X
AE=adverse event; ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute.
a Minimum 6-hour observation period after dosing for safety monitoring and blood sampling. Otherwise monitored per standard medical healthcare setting 
procedure.
b Assessments at the 24-hour post dose time point will be made if the subject has not been discharged from the hospital; or a telephone follow-up call will be 
made to assess AEs and concomitant medications. Patients will be asked to return for additional assessment of ongoing AEs, as needed.
c Performed if subject has arrived at study site.
d Vital signs will include single sitting blood pressure (if feasible), pulse rate, respiratory rate, body temperature; collection of vital signs information will begin 
as soon as possible in community setting or after transfer to healthcare setting.
e Parent, guardian, or legally authorized representative should count respiration rate prior to the administration of investigational product.
f Oxygen saturation should be measured from time of arrival in hospital. If it is not possible for the subject to have an oxygen saturation obtained on room air 
due to medical concerns, this will be recorded. The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of oxygen 
administered.
g Electrocardiogram should be performed upon arrival at the hospital.
h Laboratory evaluations include serum biochemistry and urinalysis. A urine pregnancy test should be administered to female patients of childbearing age.
i Buccal cavity where MHOS/SHP615 was administered between cheek and gum line will be examined for redness, inflammation, and ulceration and findings 
noted on physical examination CRF. 
j Upon arrival at hospital and across all time periods, as appropriate.
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
1
BACKGROUND INFORMATION
1.1
Status Epilepticus
A seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal, 
excessive, and synchronous neuronal activity in the brain. Several seizure types can be described, 
but they all fall into 1 of 2 classifications:  primary generalized seizures (eg, grand mal, petit mal, 
or absence seizures) and partial (focal) onset seizures (ie, localized). Regardless of seizure type, 
most seizures (>90%) last less than a few minutes (<2 minutes) (Theodore et al. 1983). If 
seizures are prolonged or occur in a series, there is an increased risk of status epilepticus (SE), 
which literally means a continuous state of seizure (Epilepsy Foundation 2015). 
Status epilepticus (SE), a condition resulting either from the failure of the mechanisms 
responsible for seizure termination or from the initiation of mechanisms that lead to abnormally 
prolonged seizures, is a life-threatening neurologic emergency with significant morbidity and 
mortality. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute 
complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and 
cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), 
encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Prompt cessation and 
rapid control of SE is critical to prevent this neurological and systemic pathology (Fountain 
2000). 
Convulsive SE (CSE), the most common childhood neurological emergency in developed 
countries, can lead to neurocognitive sequelae and death. History with epilepsy is the strongest 
single risk factor for generalized CSE:  15% to 27% of patients with epilepsy will experience at 
least 1 episode of SE; 25% to 40% of SE occurs in patients with epilepsy.
The term SE includes not only epilepsy, but also status of serial convulsive seizures associated 
with febrile convulsion, encephalitis, and encephalopathy. The International League Against 
Epilepsy (ILE) defines SE as a seizure lasting longer than a defined period of time or more than 
1 seizure occurring within a shorter timeframe without return to normalcy between seizures 
(ILAE 1989). More recently, the minimum seizure duration had been defined as 30 minutes 
(Riviello et al. 2006); however, because epileptic discharge longer than 30 minutes has been 
reported to damage the brain, the diagnosis of SE was subsequently updated to a seizure lasting 
longer than 10 minutes (Treiman et al. 1998) and then more recently, 5 minutes (Alldredge et al. 
2001), at which time treatment should be promptly initiated. The urgency to treat this condition, 
supported by evidence that seizures rarely last more than a few minutes, led to implementation of 
an operational definition of early status epilepticus (ESE), or seizures lasting more than 5 
minutes (Dham et al. 2014; Lowenstein 1999). This definition of SE (ie, seizures lasting more 
than 5 minutes) will be used throughout this study. 
Incidence, cause, and prognosis of pediatric SE vary geographically, as well as by different 
socioeconomic conditions, environments, and genetic susceptibility. The incidence of SE is 
bimodally distributed, occurring most frequently during the first year of life and after age 60 
years. Amongst children (<15 years of age), infants <12 months have the highest incidence and 
frequency of the disease. In Japan, annual incidence in children younger than 17 years is 42 cases 
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
per 100,000 persons. In addition to young age, other risk factors include genetic predisposition 
and acquired brain insults (Fountain 2000; Shinnar et al. 1996; Berg et al. 1999).
Depending on the type and duration of seizures, if left untreated (or undertreated) SE can cause 
permanent neurological injury (including neuronal death, neuronal injury, and alteration of 
neuronal networks) or death (Trinka et al. 2015). Therefore, a rapid treatment must be initiated.
1.2
Current Treatment Options 
For an anti-epileptic drug to be effective in SE, it is usually administered intravenously (IV) by 
health professionals to provide quick access to the brain without the risk of serious systemic and 
neurological adverse effects (Sirven and Waterhouse 2003). Multiple drugs are available; the 
first line treatment is benzodiazepines (eg, diazepam and midazolam [midazolam is unauthorized 
for SE in the US]).
The first-choice medication in Japan for treating SE in pediatric patients without venous access is 
diazepam suppositories administered rectally. Rectal diazepam is the medication most commonly 
used throughout the European Union (EU) in the community setting, and is authorized for this 
indication. Diazepam is effective in 60% to 80% of patients but with a risk of early seizure 
recurrence of up to 30% and respiratory depression (McIntyre et al. 2005). The increase of drug 
concentration in the blood is slow by this route; constipation and bowel movements can interfere 
with absorption of drug (Wilson et al. 2004). Rectal administration can be difficult during tonic-
clonic seizures. For wheelchair users, it can be challenging to remove clothing and to insert the 
suppository in a convulsing child. Therefore, the rectal route of administration is not always 
practical, socially acceptable, or convenient.
For resistant cases, phenytoin (or fosphenytoin), phenobarbital, and thiopentone are injectable, 
fast-acting drugs that have strong anti convulsant effects and a positive safety profile. Securing 
vascular access in children, however, is generally more difficult and prolongs stopping the 
convulsion by IV injection upon arrival at the hospital. In the community setting, a therapeutic 
agent that can be administered by a nonmedical expert, such as a parent or caregiver, would be 
more appropriate for emergency treatment. 
For pediatric patients in Japan, midazolam has been used off-label as a first or second choice 
medication for seizures intractable with diazepam treatment. However, since the approval of 
MIDAFRESA Injection 0.1% in 2014, midazolam IV injection is now positioned as first-choice 
medication in Japan for pediatric patients with SE; however, the IV formulation is too dilute to 
use for oromucosal delivery. DORMICUM (an injectable IV formulation of midazolam) is 
frequently administered oromucosally or intranasally, which is considered to be an off-label use 
of this drug.
Accordingly, it has been recognized that there is an unmet need for an effective, fast-acting 
treatment that can easily be administered by a more convenient route and by individuals other 
than medical experts and that is suitable for use in both the healthcare setting and community 
(Scott et al. 1999a).
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs outlined above, it has been common practice to administer 
midazolam buccally (oromucosal administration of other midazolam formulations) off-label for 
the treatment of SE. Buccal administration does not cause pain or distress to the patient or 
require that the patient be in the prone position. 
Currently, the national average time in Japan for patients with SE to be transported to the 
healthcare setting is 39.6 minutes. In many cases as much as 50 minutes has been reported until 
medical treatment has been received at the healthcare setting. Buccal midazolam treatment in 
children with seizures could be started at home by trained clinical personnel, family members, or 
caregivers before securing vascular access, as well as after arriving at a medical institution, thus 
potentially reducing life-threatening risks of brain disorders (eg, encephalopathy) and other 
sequelae due to prolonged seizures and resulting from delays in getting the child to a healthcare 
setting.
1.4
Product Background and Clinical Information
The investigational product midazolam hydrochloride oromucosal solution (hereafter referred to 
as MHOS/SHP615) contains 5 mg/mL of the active substance midazolam and has been 
specifically developed for the buccal administration of midazolam in children with SE. 
Currently, there is extensive clinical experience with midazolam as it is authorized for use in 
children (including neonates <32 weeks gestational age in intensive care units) and adults as a 
sedative and in anesthesia and may be given by the intravenous (IV), intramuscular (IM), or 
rectal route of administration. As midazolam undergoes significant first pass metabolism in both 
the small intestine and the liver, a systemic drug delivery system was selected for 
MHOS/SHP615. In suspension, midazolam is water soluble and, therefore, readily absorbed via 
the buccal mucosa. At physiological pH the drug becomes lipid soluble, which enables it to cross 
the blood-brain barrier. In addition, its pharmacokinetic (PK) parameters such as the short 
elimination half-life (1.5-2.5 hours) and rapid plasma clearance (300-500 mL/min) are optimal 
for a rescue medication (Hypnovel SmPC 2008). The buccal mucosa, with its expanse of smooth 
muscle and relative immobility, makes it a desirable region for retentive systems used for oral 
transmucosal drug delivery.
MHOS/SHP615 has a formulation essentially identical to its authorized originator product, a 
systemically administered midazolam hydrochloride (HYPNOVEL® Injection 10 mg/2 mL [EU], 
VERSED® Oral Syrup 2 mg/mL now marketed generically [US], and DORMICUM Injection 10 
mg [Japan]) used for sedation or anesthetic premedication. When approved in Japan, 
MHOS/SHP615) will provide major advantages over unauthorized/off-label buccal midazolam 
preparations and other formulations of authorized rescue medication (such as IV, IM, or rectal 
routes of administration) currently used for SE.
In the EU, MHOS is commercially known as BUCCOLAM®, a nonintravenous treatment to stop 
seizures (including convulsive seizures). An oromucosal solution, BUCCOLAM contains 5 
mg/mL of the active substance midazolam and was approved in the EU on 05 Sep 2011 for the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
treatment of prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents 
(from 3 months to ≤18 years). Parents and/or caregivers are allowed to administer BUCCOLAM 
only to patients older than 6 months who have been diagnosed with epilepsy. For infants between 
3 and 6 months of age, treatment should be in a hospital setting, where close medical supervision 
and resuscitation equipment are available.
Efficacy
The age range proposed for the SHP615-301 study is >52 weeks corrected gestational age 
(gestational weeks plus the number of weeks after birth) to <18 years. The efficacy and safety of 
buccal midazolam in this age range have been established in 4 pivotal, rectal-diazepam-
controlled clinical studies. These studies all used the HYPNOVEL 10 mg/2 mL formulation 
delivered buccally. All 4 studies demonstrated that buccal midazolam was either more effective 
than or as effective as rectal diazepam for the treatment of acute seizures in children (licensed 
indication and dosage of diazepam). However, the meta-analysis of the 3 (standard randomized) 
pivotal studies (Mpimbaza et al. 2008; McIntyre et al. 2005; Scott et al. 1999b) (comprising a 
total of 628 seizure events [525 patients]) demonstrated that buccal midazolam is significantly 
more effective than rectal diazepam in stopping seizures within 10 minutes (Mantel-Haenszel 
Weighted Risk Ratio [buccal midazolam/rectal diazepam] of 1.24 [95% CI: 1.11 - 1.39] p = 
0.0002). 
In a study vs IV diazepam (Talukdar and Chakrabarty 2009), the buccal midazolam dose was 
slightly lower than that used in the pivotal rectal diazepam studies (0.2 mg/kg vs ~0.25-
0.5 mg/kg in the pivotal studies). Nevertheless, this study supported the results of the pivotal 
studies and meta-analysis. It demonstrated that buccal midazolam is an effective treatment for 
acute seizures with no statistically significant difference compared with IV diazepam for overall 
control of convulsive episodes within 5 minutes (85% vs 93.3% in buccal midazolam vs IV 
diazepam groups, respectively; p = 0.142). 
Safety
The clinical safety profile of midazolam (and other benzodiazepines) for the authorized uses are
well established (and summarized in the EU and US labeling [HYPNOVEL SMPC 2008; 
Midazolam HCl Injection US Prescribing Information 2009; Midazolam HCl Syrup US 
Prescribing Information 2009]). The main adverse effects (reported to occur rarely for 
HYPNOVEL) and precautions applicable to the buccal route of administration in children include 
cardiorespiratory adverse events (respiratory depression, apnea, respiratory arrest, and/or cardiac 
arrest), anterograde amnesia, and paradoxical reactions. Precautions are required for patients 
with impaired respiratory function or cardiovascular instability. Pediatric patients less than 
6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Always refer to the latest version of the (MHOS)/SHP615 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of (MHOS)/SHP615. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the hospital or community settings. The rectal route 
of administration, however, is not always practical, socially acceptable, or convenient. 
The need to remove clothing and the difficulty with rectal administration during seizures, 
particularly for wheelchairs users, is socially embarrassing or unacceptable by some individuals, 
parents, or caregivers. 
MHOS/SHP615 is expected to be used in both the hospital and community settings. While the 
efficacy and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric 
subjects with SE in the hospital setting in the antecedent pivotal Phase 3 study (SHP615-301), 
this study is an open-label extension study in subjects who completed the SHP615-301 study and 
who tolerated and responded to MHOS/SHP615 treatment.
MHOS/SHP615 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg midazolam) presentation for children. The 4 different, age-
specific, fixed-dose presentations were selected as a convenient oromucosal administration of 
midazolam injectable solution to enable rapid treatment in the emergency and community 
settings where individual dosing by body weight is not feasible (except for infants aged from 3 
months to <6 months: this age population should be treated in a healthcare setting only). This 
dosing regimen was evaluated extensively by the European Medicines Agency (EMA) Pediatric
Committee as part of the pediatric investigation plan (PIP) application and by the EMA 
Committee for Medicinal Products for Human Use (CHMP) as part of the review and approval 
of the pediatric-use marketing authorisation (PUMA).
The rationale for this interventional OLE study is to determine the safety and efficacy of 
MHOS/SHP615 administered buccally by caregivers in pediatric subjects with CSE in 
community settings. 
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of buccally administered 
MHOS/SHP615 in pediatric subjects with status epilepticus (SE) (convulsive) in the community 
setting.
2.2.2
Secondary Objectives
The secondary objective of this study is to assess the safety of buccally administered 
MHOS/SHP615 in pediatric patients with status epilepticus (SE) (convulsive) in the community 
setting.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment, or is discontinued early. Please note that this includes the 
follow-up visit or contact, whichever is later. The study completion date is used to ascertain 
timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted in approximately 25 study sites in Japan.
4
STUDY POPULATION
The total enrollment for the SHP615-302 study is expected to be ≥6 subjects with active 
generalized tonic-clonic SE with seizures. Diagnosis of SE will be confirmed through an
evaluation of seizure symptoms conducted and documented by the caregiver at the time of the 
event.
Each parent, guardian, or legal representative (and/or the subject, where necessary) must 
participate in the informed consent process and provide written informed consent/assent before 
any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator
before subjects are included in the study.
The subjects will not be considered eligible for the study without meeting all of the criteria 
below.
1. Subjects who completed the SHP615-301 study and who tolerated and responded to
treatment with MHOS/SHP615 in the hospital and/or emergency room, and are considered 
stable for discharge from the hospital.
2. Subjects who are >6 months and <18 years of age at the time of investigational product 
administration. If the subject's exact age is not known, the subject should be excluded.
3. Parent, guardian, or legally authorized representative of the child who provides informed 
consent and assent (when applicable) to participate in the study after initial stabilization of 
the subject with SE in hospital or emergency room during the SHP615-301 study. The 
subject also provides informed consent prior to participation, where applicable.
4. Parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, time necessary to administer MHOS/SHP615, time 
between MHOS/SHP615 administration to seizure cessation, etc.)

Follow the necessary instructions to secure the safety of the subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
5. Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of 
consciousness with any of the following characteristics persistent at the time of study drug 
administration:

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within 
the preceding hour

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession 
without recovery of consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Female subjects who are pregnant, suspected to be pregnant, or nursing.
2. Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
4. Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5. Subjects with seizures of psychogenic origin.
6. Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, or use of 
concomitant drugs determined by the investigator to have a contraindication to the use of 
benzodiazepines.    
7. Subjects with a known history of benzodiazepine abuse.
8. Subjects who have not responded to previous administrations of midazolam systemic 
therapies, including MIDAFRESA and/or DORMICUM.
9. Subjects who need emergent surgical intervention and general anesthesia/intubation.
10. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors 
or HIV reverse transcriptase inhibitors.
11. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
12. Have used an investigational product or been enrolled in a clinical study (including vaccine 
studies) that, in the investigator’s opinion, may impact this Shire-sponsored study.
13. Subject has prior placement of a vagus nerve stimulator.
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
4.3
Restrictions
4.3.1
Medical Intervention
There will be no special restrictions on medical interventions deemed necessary by the 
investigator for the health and wellbeing of the subject.
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at 
screening/baseline. Females of childbearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use medically acceptable methods of 
contraception.
Medically acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms with spermicidal agent)

Oral hormonal contraceptives, stabilized for at least 30 days prior to the administration of 
investigational product, plus condoms. 
4.4.2
Male Contraception
Males should use condoms if they are sexually active for 7 days of the study and must not donate 
or use sperm for the purposes of making a woman pregnant until 7 days after the administration 
of study drug.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
A subject will be withdrawn from the study when they turn 18 years of age.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Subjects may withdraw from active treatment within the treatment period at any time at their 
own request, or they may be withdrawn at any time at the discretion of the investigator or 
sponsor for safety, behavioral, or administrative reasons. Additional reasons a subject may be 
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
withdrawn from active treatment include but are not limited to, adverse event (AE), SAE, 
protocol violations, and failure to return for visits. 
If a subject is withdrawn for whatever reason within a week following administration of study 
drug, the evaluations listed for the 1-week follow-up visit are to be performed as completely as 
possible. Whenever possible, all discontinued subjects should also undergo the protocol-
specified follow-up. The reason for termination and date of stopping the study must be recorded 
in the case report form (CRF) and source documents.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. In any circumstance, every effort should be made to document subject outcome, if 
possible. The investigator should inquire about the reason for withdrawal, request the subjects to 
return for a final visit, if applicable, and follow-up with the subject regarding unresolved adverse 
events. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluation should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse events

Protocol deviation

Withdrawal by subject

Lost to follow-up

The sponsor or investigator terminates the study.
Withdrawal/discontinuation due to AEs should be distinguished from withdrawal due to other 
causes, according to the definition of AE noted earlier, and recorded on the appropriate AE 
electronic case report form (eCRF) page. When a subject withdraws because of an SAE, the SAE 
must be reported in accordance with the reporting requirements defined in Section 8.2.
Sponsor Discontinuation Criteria
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the institutional review board (IRB)/EC, investigational product safety problems, or 
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
at the discretion of the sponsor.  In addition, the sponsor retains the right to discontinue 
development of MHOS/SHP615 at any time.
If a study is prematurely terminated or discontinued, the sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects, subject’s 
parents, guardians, or legally authorized representatives, and the hospital pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all eCRFs completed to the greatest extent possible.
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent, guardian, or legally 
authorized representative of any subject lost to follow-up at any time point prior to the last 
scheduled contact (office visit or telephone contact). At least 1 of these documented attempts 
must include a written communication sent to the parents, guardians, or legally authorized 
representatives at subject’s last known address via courier or mail (with an acknowledgement of 
receipt request) asking that they return to the site for final safety evaluations.
4.5.4
Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if 1 or more of the 
following criteria are met:

Death that is considered related to the study drug.

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities [MedDRA] higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety lead physician and the Global Drug Safety therapeutic area head. Following 
the sponsor’s review of safety data, 1 of the following actions will be taken with respect to study 
status:

Continue study with protocol unchanged;

Continue study with modifications to the protocol; or

Terminate study.
Subject safety will be monitored on a continuous basis during this study until the last subject
completes his or her last scheduled study visit/assessment, or has discontinued from the study.
4.5.4.1
Study Level Stopping Rules
Safety data, including SAEs and adverse events of special interest (AESIs), will be monitored 
regularly throughout the duration of the study and submitted to Regulatory Authority(ies), as 
appropriate. If any potential safety signal is identified during safety monitoring in this study by 
the sponsor and/or following a safety data review, a comprehensive analysis of the issue will be 
undertaken by the sponsor. As a result of this assessment, the sponsor may take actions as 
deemed appropriate (which may include changing or suspending dosing in the study).
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or toxicity considered clinically relevant (AE, laboratory, 
physical examination, vital sign, or ECG finding) will be carefully monitored until resolution, 
which may include the following:

Additional clinical laboratory tests and/or other clinical investigations,

Additional visits or extended duration of follow-up, 

Obtaining a specialist consultation.
5
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) received within 
30 days prior to the administration of investigational product and through the final study contact 
(including protocol defined follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) 
received within 30 days of the date of investigational product administration. Prior treatment 
information must be recorded on the appropriate CRF page.
Medications taken during screening, before administration of the MHOS/SHP615 dose, will be 
documented as prior medications.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the time of the investigational 
product administration and the end of the follow-up period, inclusive. All concomitant 
medication(s) and treatment(s) during the study must be recorded on the appropriate CRF page, 
with indication, daily dose, start and stop dates of administration. All subjects (or 
parents/caregivers) will be questioned about concomitant medication during their follow-up visit.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
MHOS/SHP615 is a clear, colorless, ready-to-use solution (containing 5 mg midazolam [as 
hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a single, age-
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:

2.5 mg (yellow label) ages >6 months to <1 year (and weight >5 kg)

5 mg (blue label) ages 1 year to <5 years

7.5 mg (purple label) ages 5 years to <10 years

10 mg (orange label) ages ≥10 to <18 years 
The investigational product MHOS/SHP615 will be provided in prefilled single-use, ready-to-
use, amber, age-specific, and color-coded oral dosing syringes, and is to be administered by the 
buccal (oromucosal) route. The full amount of solution will be delivered slowly into the space 
between the inside of the cheek and the lower gum. 
If at some point after entering the study, and prior to having a seizure, the subject ages from 1 
age category to the next, the parent/caregiver must return to the study site in order to exchange 
study drug supply for the appropriate dose.
Buccal (oromucosal) administration was considered to be an appropriate route to be progressed 
to address the unmet need for a convenient, fast–acting product suitable for use in both the 
community and hospital setting. Additional information is provided in the current version of the 
SHP615 midazolam investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment 
This is an open-label, nonrandomized study; therefore, assignment to MHOS/SHP615 will be 
unblinded to the investigators, subjects, caregivers, and the sponsor study team. Study treatment 
will only be administered by caregivers to subjects who have a signed and dated IRB-approved 
informed consent form (ICF) and who have met all eligibility criteria. 
All subjects enrolled in the study will receive treatment with the investigational product based on 
their age (Section 6.2.2.1).
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. This identifying number will be retained 
throughout the study.
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If an identifier is allocated incorrectly, the clinical research 
associate (CRA)/study monitor must be notified as soon as the error is discovered. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
6.2.2
Dose Regimen and Dose Administration
MHOS/SHP615 will be administered buccally by caregivers as a single, fixed dose product, 
banded by age to subjects with SE (convulsive) in community settings. For buccal 
administration, midazolam is administered into the space between the lower gum and the inside 
of the cheek.
6.2.2.1
Dosing Regimen
Details of subject dosing and follow-up are outlined in Section 3.1 and included in the Schedule 
of Assessments (Table 1).
There are 4 single, fixed, banded by age, dose regimens of the MHOS/SHP615 formulation for 
the treatment of SE; 1 dosage per buccal administration for each of the following age groups:

2.5 mg
>6 months to <1 year (and weight >5kg)

5 mg
1 to <5 years

7.5 mg
5 to <10 years

10 mg
≥10 to <18 years
6.2.2.2
Dose Administration
Before dosing:

The airway should be secured and respiratory and cardiac function assessed.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.

The caregiver will organize emergency transport, and all subjects will be brought to the 
study site immediately (hospital or healthcare center), even if the seizure has stopped.
Single-dose administration:

The caregiver will be instructed to administer a single dose of MHOS/SHP615 after 
confirming that the seizure activity is appropriate for MHOS/SHP615 treatment (eg, the 
seizures last at least 5 minutes or a second seizure occurs before recovery of 
consciousness from the first seizure, or 3 seizures occur within 1 hour).

Only 1 oral syringe with the specified dose must be given. The full amount of the 
MHOS/SHP615 prefilled oral dosing syringe is administered slowly into the buccal 
mucosa. In some cases, it might be necessary to divide the dose so that half of the 
solution is administered into each side of mouth.  
After dosing

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017

If the seizure has not stopped within 10 minutes of administration, and/or if a serious AE 
(SAE) emerges, then emergency medical assistance must be sought. 
Note:  A second or repeat dose of MHOS/SHP615 should not be given even if the seizure 
recurs after an initial response.

In the event of a medical emergency, and it is not possible to bring the subject to the 
study site, the caregiver will be instructed to bring the subject to the closest emergency 
medical institution so that the subject can receive treatment as quickly as possible. If this 
occurs, then the caregiver will report the incident and relevant information, including any 
rescue treatment received, to the investigator/study site within 1 week after the incident.

The caregiver/parent and subject must visit the study site for examination after 
MHOS/SHP615 administration, even if the seizure stops. All subjects will be followed up 
at study sites even if the seizure resolves.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating errors (such as leaking liquid, etc.) are to be 
recorded in the study diary.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
A computer-generated label is applied to the investigational product. All investigational product 
is labeled with a minimum of the protocol number, pack number (if applicable), dosage form 
(including product name and quantity in pack), directions for use, storage conditions, expiry date 
(if applicable), batch number and/or packaging reference, the statements “For clinical trial use 
only” and the name and country of the sponsor and contract research organization (CRO) name 
and address. Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
A single dose of the investigational product MHOS/SHP615 will be provided in an individual, 
labeled, single-dose, prefilled plastic, oral dosing syringe available in 4 different, age-specific, 
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
color-coded doses (2.5, 5, 7.5, and 10 mg dose packs) in a protective plastic tube which is
packaged and dispensed in cartons with tamper-evident seals. The cartons should not be opened 
until the investigational product is to be administered.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
Keep the oral dosing syringe containing the investigational product in the protective plastic tube. 
Keep at or below 25°C (77°F). Do not refrigerate or freeze.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The subinvestigator/designated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling 
Investigational product for the sponsor’s studies must be stored according to all applicable local, 
state, and/or national laws. 
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
The investigator will provide or supervise the training of investigational product administration 
to the designated caregivers. Where permissible, tasks may be delegated to a qualified designee 
(eg, a pharmacist) who is adequately trained in the protocol and who works under the direct 
supervision of the investigator. This delegation must be documented in the applicable study 
delegation of authority form.
The caregiver will administer the investigational product only to subjects included in this study 
following the training provided by the investigator or his/her designee as set out in the study 
protocol. Each subject will be given only the investigational product corresponding to his/her 
treatment assignment. All administered investigational product will be documented on the CRFs 
and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor (or designated CRO). For unused 
supplies where the original supplied tamper-evident feature is verified as intact, the 
tamper-evident feature must not be broken and the labeled amount is to be documented in lieu of 
counting. Shipment return forms, when used, must be signed prior to shipment from the site. 
Returned investigational products must be packed in a tamper-evident manner to ensure product 
integrity. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws.
The investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product supplies.
6.5
Subject Compliance
Subjects/caregivers must be instructed to bring unused investigational product and empty/used 
investigational product packaging to the follow-up visit. Drug accountability must be assessed at 
the container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container or at the individual count level for opened 
containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.   
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
6.6
Destruction of Investigational Product 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by the sponsor, and all 
destruction must be adequately documented.
7
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (Table 1).
7.1.1
Screening Period 
Screening for subject eligibility into this study occurs on the same day as baseline (Visit 1) for 
Study SHP615-301. This includes an assessment of inclusion/exclusion criteria.  
7.1.2
Baseline Visit 
Baseline Visit 1 will be conducted after the follow-up visit for study SHP615-301.
Written informed consent must be obtained prior to performing any protocol specific procedures. 
The following procedures will be performed:

Informed consent/assent 

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Provide study diary and educational materials to caregiver

Provide training/education to caregiver

Dispense study drug

Review concomitant medications/treatments
7.1.3
Treatment Period 
7.1.3.1
Treatment of Seizure in the Community Setting
At the onset of a seizure the caregiver will:

Confirm the seizure activity is appropriate for MHOS/SHP615 treatment, eg, the seizure 
lasts at least 5 minutes or a second seizure occurs before recovery of consciousness from 
the first seizure or 3 seizures occur within 1 hour.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017

Before dosing, the caregiver will organize emergency transport, and all subjects will be 
brought to the study site immediately (hospital or emergency treatment center), even if 
the seizure has stopped. A clinical visit will take place for medical evaluation, review of 
adverse events and collection of study materials.

If possible, count and record respiratory rate; collection of vital signs information will 
begin as soon as possible in community setting or after transfer to healthcare setting.

Properly administer MHOS/SHP615 once SE is confirmed.

Follow the necessary instructions to secure the safety of the subject. 

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, characteristics of seizures and safety measures, 
time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.)

In the event of a medical emergency, the caregiver will be instructed to bring the subject
to the closest emergency medical institution if the subject is having a medical emergency 
(including slowing of breathing and other adverse events that may require treatment) and 
it is not possible to bring the subject to the study site so that the subject can receive 
treatment as quickly as possible. If this occurs, then the caregiver will report the incident 
and relevant information, including any rescue treatment received, to the 
investigator/study site within 1 week after the incident.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary, before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, 
review of adverse events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating error, such as leaking liquid, etc., are to be 
recorded in the study diary.
7.1.4
Clinic or Hospital Visit
Once the subject has been transported to the clinic or hospital, staff will conduct assessments and 
supportive care as outlined in Table 1. 
The investigator or subinvestigator should obtain seizure information and dosing of 
MHOS/SHP615 from the subject diary or the subject’s parent, guardian, or legally authorized 
representative.
If the seizure continues or recurs, the subject should be treated according the procedures in use at 
the clinic or hospital.
The subjects should remain in the hospital under observation for at least 6 hours and up to 24 
hours after hospital arrival (as needed).
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
The following procedures will be performed:

Evaluate seizure symptoms (by caregiver in the community or by PI once at the site) at 
10 and 30 (±5) minutes, and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) 
hours post dose.

Evaluate Riker Sedation Agitation Scale (once subject arrives at hospital or clinic) at 30 
(±5) minutes (if possible), and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) 
hours post dose.

Assess buccal cavity where MHOS/SHP615 was administered between cheek and gum 
line for redness, inflammation, and ulceration at 1 (±10 min), 4 (±30 min), and 6 (±30 
min) hours postdose.

6 hours (±30 min) post dose: Obtain blood and urine samples for safety laboratory tests 
for serum biochemistry and urinalysis.

10 and 30 (±5) minutes, and 1, 4, 6, and 24 hours (±30 min) post dose (if subject has not 
been discharged from the healthcare setting):

Measure vital signs: single sitting blood pressure (BP) (if feasible), pulse rate, 
respiratory rate, temperature (°C or °F).

30 minutes*, 1 hour (±10 min) and 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours  
post dose if subject has not been discharged from the healthcare setting: 

Measure oxygen saturation on room air.

Perform standard 12-lead ECG.
*If possible, by EMT or at the site.

Administer supportive care.

Review and record concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
laboratory sampling).
7.1.5
Follow-up Period
The follow-up period for this protocol is 7 days (± 1 day). 
At the end of this period there will be a telephone call initiated by the site staff/follow-up visit to 
evaluate seizure symptoms, serious adverse events (SAEs), adverse events (AEs), and 
concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (see Section 8.1). In addition, caregivers will be asked to complete the 
.
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
7.2
Study Evaluations and Procedures
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test. In these cases the investigator will take all steps necessary to ensure the safety and well-
being of the subject. When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions that he or she has taken to 
ensure that normal processes are adhered to as soon as possible. The study team will be informed 
of these incidents in a timely fashion.
7.2.1
Informed Consent
The ICF must be executed prior to performing any study-related activities and must be approved 
by the reviewing institutional review board (IRB). Subjects may withdraw consent at any time. 
Participation in the study may be terminated at any time without the subject’s consent as 
determined by the investigator. Due to the potential for long periods between initial consent and 
treatment, the investigator should, every 3 months, either have the subject/parent/caregiver resign 
and date the original consent form(s), or document phone contact with the 
subject/parent/caregiver confirming ongoing interest and willingness to participate in the study.
7.2.2
Demographic and Other Baseline Characteristics
Demographics: date of birth, sex, race and ethnicity (where locally permitted) and medical 
history will be obtained at screening from subjects, parents, or caregivers and will be recorded on 
the source document and eCRF.
Medical history (including SE, smoking, and cardiovascular history) will capture the subject’s 
current medical status (current SE or CSE disease processes), past medical status (past disease 
processes), history of surgery, allergies, and concomitant medications/treatments.
7.2.3
Efficacy
Methods of measuring the efficacy of MHOS/SHP615 in SE that will be used throughout the 
study are described in this section. 
Information recorded in the subject diary by the caregiver along with evaluation by the 
investigator or subinvestigator will be used to evaluate the seizure and its duration, type (focal, 
generalized, convulsive or nonconvulsive), and recurrence. The other criteria are those set in the 
study protocol to define the treatment efficacy and include time of cessation and need for 
additional rescue medication.
7.2.4
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Any AE related to either efficacy or safety should be first recorded by the caregiver using a 
comprehensive study diary and other materials, and then finally verified by the investigator.
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
7.2.4.1
Medical and Medication History
Medical history is collected at the time points specified in the Schedule of Assessments (Table 
1).
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE or CSE (eg, dietary, medication, or other), must be 
recorded on the appropriate eCRF page.
7.2.4.2
Adverse Event Collection
At each assessment time point, subjects will be questioned/evaluated in a general way to 
ascertain if AEs have occurred since the previous time point. Adverse events are collected from 
the time informed consent is signed. (Please refer to Section 8, Adverse and Serious Adverse 
Events Assessment.)
7.2.4.3
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment include blood pressure (systolic and diastolic), pulse rate, respiration rate
(after 5 minutes of rest), and body temperature to be performed at the time points specified in the 
Schedule of Assessments (Table 1). Additional collection times or changes to collection times 
will be permitted, as necessary to ensure appropriate collection of safety data.
Sitting blood pressure (if feasible) will be measured with the subject’s arm supported at the level 
of the heart, and recorded to the nearest mm Hg. It is preferred that the same arm (preferably the 
dominant arm) will be used throughout the study. The same size BP cuff that has been properly 
sized and calibrated will be used to measure BP each time.
The use of automated devices for measuring BP and pulse rate are acceptable, although, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. 
When the timing of these measurements coincides with a blood collection, all vital signs should 
be obtained prior to the nominal time of the blood collection.
It is preferred that body temperature be collected using tympanic, oral, or axillary methods and 
that the same method be used consistently throughout the study.
Any clinically significant deviations from baseline vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
7.2.4.4
Clinical Laboratory Evaluations
The following clinical laboratory assessments will be performed at times defined in the Schedule 
of Assessments (Table 1):
Chemistry
Urinalysis
Other
BUN and Creatininea, b
Glucose (fasting if possible)
Calcium (total)
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Direct bilirubinb
Indirect bilirubinb
Alkaline phosphatase
Albumin
Total protein
Bicarbonate
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Specific gravity
Microscopyc
Urine pregnancyd
ALT = alanine aminotransferase ; AST = aspartate aminotransferase.
a Creatinine clearance determination by central lab using Schwartz method.
b Only if total bilirubin is elevated. 
c Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
d Complete for women of childbearing potential.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
Blood samples for laboratory assessments will be collected at the site by a trained phlebotomist 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
laboratory manual. 
Biological material will be stored and secured in a manner that assures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed.
7.2.4.5
Pregnancy Test
A urine pregnancy test is performed on all females of child-bearing potential after the subject is 
transferred to the hospital, emergency room, or clinical site.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 3.5 mL.
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
Quintiles Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor 
using the details specified in the emergency contact information section of the protocol. The 
pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
beta-human chorionic gonadotropin (-hCG) test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of MHOS/SHP615

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the SHP615 midazolam HCl investigator’s 
brochure, which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K. and Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to Quintiles Transnational Japan K.K. and 
the Shire Global Pharmacovigilance and Risk Management Department. A copy of the Shire 
Clinical Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form (and 
any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor using the 
details specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 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. 
Hospitalization
For this protocol, hospitalization is defined as any admission to a medical or equivalent 
healthcare facility or any prolongation of an existing admission lasting more than 24 hours.  
Admission also includes transfer within the hospital to an acute/intensive care unit (eg, from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to 
a tuberculosis unit). A healthcare setting visit does not necessarily constitute a hospitalization; 
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
however, the event leading to the healthcare setting visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include: 

Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for workup of 
persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4 and must be reported 
to Quintiles Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk 
Management Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to Quintiles 
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk Management 
Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and CRO are responsible for notifying the relevant regulatory authorities/and 
institutional IRBs or ECs of related, unexpected SAEs.
In addition the sponsor or Quintiles Transnational Japan K.K. is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the 
SHP615 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Product Quality Complaints
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to Pharmaceuticals and 
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Medical Devices Agency (PMDA) as a device malfunction report, regardless of whether or not 
the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate electronic case report form (eCRF).
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. 
Data collection procedures will be discussed with the site at the site initiation visit and/or at the 
investigator’s meeting. Once a subject is enrolled, it is expected that site personnel will complete 
the CRF entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the sponsor’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
All available data will be included in the analysis. No imputation of missing data will be 
performed.
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its designee. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. All statistical analyses will be performed using SASVersion 
9.3 or higher (SAS Institute, Cary, NC, USA 27513). 
9.4.1
Appropriateness of Measurements
This is a Phase 3, open-label extension (OLE) study that is designed to evaluate the efficacy and 
safety of MHOS/SHP615 as therapy for subjects with SE or CSE. Measures employed in this 
protocol are standard measures routinely used for the evaluation of the efficacy, safety, and 
tolerability of an investigational product.
9.4.2
General Considerations
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. 
9.5
Planned Interim Analysis
There is no planned interim analysis.
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
9.6
Sample Size Calculation and Power Considerations
The target sample size (≥6 subjects) is estimated based on feasibility analysis rather than based 
on statistical rationale.
Maximum sample size*: approximately 25 subjects.
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% 
expected drop-out rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of 
MHOS/SHP615 in the Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response 
rate in hospital settings is conservatively estimated to be 58.5%. This is close to the lowest 
response rate reported in worldwide clinical studies.
9.7
Study Population
The screened set will consist of all subjects who have a signed informed consent.
The safety set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The full analysis set (FAS) will consist of all subjects who have received a single dose of 
MHOS/SHP615 and who have at least 1 assessment for therapeutic success (cessation of seizure 
within 10 minutes with sustained absence of seizure for 30 minutes) performed after the 
administration of MHOS/SHP615.
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects 
with therapeutic success.

Therapeutic success will be defined as:

The cessation of visible seizure activity within 10 minutes, with

A sustained absence of visible seizure activity for 30 minutes following a single 
dose of MHOS/SHP615.
The response rate will be calculated with FAS and the 2-sided, 95% confidence interval (CI) will
be constructed for the response rate.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017

Sedation or agitation as measured by the Riker Sedation-Agitation Scale (Appendix 2).

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign 
measurements, laboratory tests, oxygen saturation, and ECGs.

Occurrence of buccal irritation.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by SOC, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
9.9.3
Clinical Laboratory Tests
Clinical laboratory tests will be summarized using the safety set. 
Actual values of clinical laboratory tests will be summarized by study time point. If more than 1 
laboratory result is reported per study visit time point per parameter, the last nonmissing result 
will be selected for analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. The number of subjects with a nonmissing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, nonclinically significant result less than the lower limit of normal, within the 
normal range, nonclinically significant result more than the upper limit of normal (ULN), and 
clinically significant result more than the ULN will be summarized by study time point. If more 
than 1 laboratory result is reported per study time point per parameter, the result yielding the 
most severe classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study time 
point. If more than 1 laboratory result is reported per study time point per parameter, the result 
yielding the most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator.
9.9.4
Vital Signs
Vital signs will be summarized using the safety set.
Actual values in vital signs will be summarized by study time point. All vital sign data will be 
presented in subject listings.
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a nonmissing result, and the number and percentage of 
subjects with a nonclinically significant result and clinically significant result will be 
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs are notified as appropriate. Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and any updates, EU Directive 2001/20/EC, the ethical principles in the Declaration of 
Helsinki, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
All data sent to the sponsor must be endorsed by the investigator.
Once the CRA/study monitor has verified the contents of the completed CRF pages against the 
source data, the duplicate pages are retrieved and forwarded to the study sponsor (or designee) 
for data entry. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB or regulatory inspectors) may check the CRF entries 
against the source documents. The ICF includes a statement by which the subject agrees to the 
monitor/auditor from the sponsor or its representatives, national or local regulatory authorities, or 
the IRB, having access to source data (eg, subject’s medical file, appointment books, original 
laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], EMA, PMDA) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the Japan Pharmaceuticals and 
Medical Devices Agency (PMDA), US FDA (as well as other US national and local regulatory 
authorities), the EMA, the Medicines and Healthcare products Regulatory Agency, other 
regulatory authorities, the sponsor or its representatives, and the IRB for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances the investigator must at all times comply with all local, state, 
and national laws pertaining to registration and reporting with the appropriate regulatory body 
and control and handling of such substances.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects (or parent, guardian, or legally authorized representative) prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
with applicable regulations and GCP. Each subject or the subject’s parent, guardian, or legally 
authorized representative, as applicable, is requested to sign and date the subject informed 
consent form or a certified translation if applicable, after the subject (and parent, guardian, or 
legally authorized representative) has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent, guardian, or legally authorized representative, as applicable. This document 
may require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the blank informed consent form 
that was reviewed by the IRB and received their favorable opinion/approval. A copy of the IRB’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB requires modification of the 
sample subject information and consent document provided by the sponsor, the documentation 
supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB for review, and all must 
be approved prior to site initiation.
The applicant for an IRB opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB must approve any revisions 
of all informed consent documents and amendments to the protocol unless there is a subject 
safety issue.
Investigational product supplies will not be released until the sponsor has received written IRB 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB informed of any serious and significant 
AEs.
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects (and parent, guardian, or legally authorized representative) have consented to take 
part in the study, the sponsor and/or its representatives review their medical records and data 
collected during the study. These records and data may, in addition, be reviewed by others 
including the following: independent auditors who validate the data on behalf of the sponsor; 
third parties with whom the sponsor may develop, register, or market MHOS/SHP615; national
or local regulatory authorities; and the IRB that gave approval for the study to proceed. 
The sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
11
REFERENCES 
Alldredge, BK, Gelb, AM, Isaacs, SM, Corry, MD, Allen, F, Ulrich, S, Gottwald, MD, O'neil, N, 
Neuhaus, JM, Segal, MR & Lowenstein, DH 2001. A comparison of lorazepam, 
diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J 
Med, 345, 631-7.
Berg, AT, Shinnar, S, Levy, SR & Testa, FM 1999. Status epilepticus in children with newly 
diagnosed epilepsy. Ann Neurol, 45, 618-23.
Dham, BS, Hunter, K & Rincon, F 2014. The epidemiology of status epilepticus in the United 
States. Neurocrit Care, 20, 476-83.
Epilepsy Foundation. 2015. Status Epilepticus [Online]. Available: 
http://www.epilepsy.com/learn/impact/seizure-emergencies/status-epilepticus.
Fountain, NB 2000. Status epilepticus: risk factors and complications. Epilepsia, 41 Suppl 2,
S23-30.
Hypnovel Smpc. 2008. Roche Products Ltd. Available: 
http://www.medicines.org.uk/EMC/medicine/1692/SPC/Hypnovel+10mg+2ml/.
Ilae 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Commission 
on Classification and Terminology of the International League Against Epilepsy. 
Epilepsia, 30, 389-99.
Lowenstein, DH 1999. Status epilepticus: an overview of the clinical problem. Epilepsia, 40, S3-
8, discussion S21-2.
Mcintyre, J, Robertson, S, Norris, E, Appleton, R, Whitehouse, WP, Phillips, B, Martland, T, 
Berry, K, Collier, J, Smith, S & Choonara, I 2005. Safety and efficacy of buccal 
midazolam versus rectal diazepam for emergency treatment of seizures in children: a 
randomised controlled trial. Lancet, 16-22, 205-10.
Midazolam Hcl Injection Us Prescribing Information. 2009. Roxane Laboratories Inc. Available: 
http://www.drugs.com/pro/midazolam-injection.html [Accessed 27 Apr 2010].
Midazolam Hcl Syrup Us Prescribing Information. 2009. Roxane Laboratories Inc. . Available: 
http://www.drugs.com/pro/midazolam-syrup.html [Accessed 27 Apr 2010].
Mpimbaza, A, Ndeezi, G, Staedke, S, Rosenthal, PJ & Byarugaba, J 2008. Comparison of buccal 
midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan 
children: a randomized clinical trial. Pediatrics, 121, e58-64.
Riviello, JJJ, Ashwal, S, Hirtz, D, Glauser, T, Ballaban-Gil, K, Kelley, K, Morton, LD, Phillips, 
S, Sloan, E, S., S, Subcommittee;, AaON & Society., PCOTCN 2006. Practice parameter: 
diagnostic assessment of the child with status epilepticus (an evidence-based review): 
report of the Quality Standards Subcommittee of the American Academy of Neurology 
and the Practice Committee of the Child Neurology Society. Neurology, 14, 1542-50.
Scott, RC, Besag, FM & Neville, BG 1999a. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Scott, RC, Besag, FM & Neville, BG 1999b. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
353, 623-6.
Shinnar, S, Berg, AT, Moshe, SL, O'dell, C, Alemany, M, Newstein, D, Kang, H, Goldensohn, 
ES & Hauser, WA 1996. The risk of seizure recurrence after a first unprovoked afebrile 
seizure in childhood: an extended follow-up. Pediatrics, 98, 216-25.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Sirven, JI & Waterhouse, E 2003. Management of status epilepticus. Am Fam Physician, 68,
469-76.
Talukdar, B & Chakrabarty, B 2009. Efficacy of buccal midazolam compared to intravenous 
diazepam in controlling convulsions in children: a randomized controlled trial. Brain 
Dev, 31, 744-9.
Theodore, WH, Porter, RJ & Penry, JK 1983. Complex partial seizures: clinical characteristics 
and differential diagnosis. Neurology, 33, 1115-21.
Treiman, DM, Meyers, PD, Walton, NY, Collins, JF, Colling, C, Rowan, AJ, Handforth, A, 
Faught, E, Calabrese, VP, Uthman, BM, Ramsay, RE & Mamdani, MB 1998. A 
comparison of four treatments for generalized convulsive status epilepticus. Veterans 
Affairs Status Epilepticus Cooperative Study Group. N Engl J Med, 17, 792-8.
Trinka, E, Höfler, J, Leitinger, M & Brigo, F 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, MT, Macleod, S & O'regan, ME 2004. Nasal/buccal midazolam use in the community. 
Arch Dis Child, 89, 50-1.
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
12
APPENDICES
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
APPENDIX 2 SCALES AND ASSESSMENTS
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
Riker Sedation-Agitation Scale
1
1999
1
8 Jul 2017
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP615-302 Protocol Amendment 1
SHP615
8 Jul 2017
Version 1, 8 July 2017
For non-commercial use only


PROTOCOL: SHP615-302
TITLE:
A Phase 3, Multicenter, Open-label Extension Study of Buccally 
Administered MHOS/SHP615 in Pediatric Patients with Status 
Epilepticus (Convulsive) in Community Settings
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
, MD
PROTOCOL 
HISTORY:
Original Protocol: 23 Mar 2017
Protocol Amendment 1: 8 Jul 2017
Protocol Amendment 2: 28 Aug 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to Quintiles Transnational Japan K.K., the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor. 
Applicable fax numbers and e-mail address can be found on the form (sent under separate cover). 
A copy of this form must also be sent to the CRO/Shire medical monitor by fax or e-mail using 
the details below.
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor email address: 
For protocol- or safety-related issues during normal business hours, the investigator must 
contact the Quintiles medical monitor:
Quintiles Medical Advisor name, title: 
, 
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor mobile number: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the:
Quintiles Medical Advisor mobile number: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
PRODUCT QUALITY COMPLAINTS
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to PMDA as a device 
malfunction report, regardless of whether or not the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
European Union and Rest of World (ROW)
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................12
1
BACKGROUND INFORMATION.......................................................................................19
1.1
Status Epilepticus .....................................................................................................19
1.2
Current Treatment Options.......................................................................................20
1.3
Unmet Medical Need for Buccal Midazolam ..........................................................21
1.4
Product Background and Clinical Information ........................................................21
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Study.............................................................................................23
2.2
Study Objectives ......................................................................................................23
2.2.1
Primary Objectives.................................................................................................23
2.2.2
Secondary Objectives.............................................................................................23
2.2.3
Exploratory Objectives ..........................................................................................24
3
STUDY DESIGN ...................................................................................................................24
3.1
Study Design and Flow Chart ..................................................................................24
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................25
4
STUDY POPULATION.........................................................................................................25
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................26
4.3
Restrictions...............................................................................................................27
4.3.1
Medical Intervention..............................................................................................27
4.4
Reproductive Potential .............................................................................................27
4.4.1
Female Contraception............................................................................................27
4.4.2
Male Contraception................................................................................................27
4.5
Discontinuation of Subjects .....................................................................................27
4.5.1
Subject Withdrawal Criteria ..................................................................................27
4.5.2
Reasons for Discontinuation..................................................................................28
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
4.5.4
Stopping Rules.......................................................................................................29
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
4.5.4.1
Study Level Stopping Rules...................................................................29
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria................................30
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Treatment ........................................................................................................30
5.2
Concomitant Treatment............................................................................................30
6
INVESTIGATIONAL PRODUCT ........................................................................................30
6.1
Identity of Investigational Product...........................................................................30
6.1.1
Blinding the Treatment Assignment......................................................................31
6.2
Administration of Investigational Product(s)...........................................................31
6.2.1
Allocation of Subjects to Treatment ......................................................................31
6.2.2
Dose Regimen and Dose Administration...............................................................32
6.2.2.1
Dosing Regimen.....................................................................................32
6.2.2.2
Dose Administration ..............................................................................32
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Labeling .................................................................................................................33
6.3.2
Packaging...............................................................................................................33
6.3.3
Storage ...................................................................................................................34
6.3.4
Special Handling....................................................................................................34
6.4
Drug Accountability.................................................................................................34
6.5
Subject Compliance..................................................................................................35
6.6
Destruction of Investigational Product.....................................................................36
7
STUDY PROCEDURES........................................................................................................36
7.1
Study Schedule.........................................................................................................36
7.1.1
Screening Period....................................................................................................36
7.1.2
Baseline Visit.........................................................................................................36
7.1.3
Treatment Period....................................................................................................36
7.1.3.1
Treatment of Seizure in the Community Setting....................................36
7.1.4
Clinic or Hospital Visit..........................................................................................37
7.1.5
Follow-up Period ...................................................................................................38
7.1.6
Additional Care of Subjects after the Study ..........................................................38
7.2
Study Evaluations and Procedures ...........................................................................39
7.2.1
Informed Consent...................................................................................................39
7.2.2
Demographic and Other Baseline Characteristics .................................................39
7.2.3
Efficacy..................................................................................................................39
7.2.4
Safety .....................................................................................................................39
7.2.4.1
Medical and Medication History............................................................40
7.2.4.2
Adverse Event Collection.......................................................................40
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
7.2.4.3
Vital Signs..............................................................................................40
7.2.4.4
Clinical Laboratory Evaluations.............................................................41
7.2.4.5
Pregnancy Test .......................................................................................41
7.2.4.6
Electrocardiogram ..................................................................................42
7.2.4.7
Oxygen Saturation..................................................................................42
7.2.4.8
Physical Examination.............................................................................42
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................43
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................43
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................43
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................44
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease Under Study .................................................................45
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................45
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................47
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Product Quality Complaints.....................................................................................50
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................51
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Data Handling Considerations .................................................................................51
9.4
Statistical Analysis Process......................................................................................51
9.4.1
Appropriateness of Measurements.........................................................................52
9.4.2
General Considerations..........................................................................................52
9.5
Planned Interim Analysis .........................................................................................52
9.6
Sample Size Calculation and Power Considerations................................................52
9.7
Study Population ......................................................................................................52
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
9.8
Efficacy Analyses.....................................................................................................53
9.8.1
Primary Efficacy Endpoint ....................................................................................53
9.8.2
Secondary Efficacy Endpoints...............................................................................53
9.8.3
Exploratory Efficacy Endpoints.............................................................................54
9.9
Safety Analyses........................................................................................................54
9.9.1
Primary Safety Endpoints ......................................................................................54
9.9.2
Secondary Safety Endpoints ..................................................................................54
9.9.3
Clinical Laboratory Tests.......................................................................................54
9.9.4
Vital Signs..............................................................................................................55
9.9.5
Electrocardiography...............................................................................................55
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................56
10.1
Sponsor’s Responsibilities .......................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Public Posting of Study Information......................................................................56
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards............................56
10.1.4 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities .................................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement..................................................57
10.2.3 Documentation and Retention of Records.............................................................58
10.2.3.1
Case Report Forms.................................................................................58
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection.....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................59
10.3
Ethical Considerations..............................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board ....................................................................................60
10.4
Privacy and Confidentiality......................................................................................60
10.5
Study Results/Publication Policy .............................................................................61
11 REFERENCES .......................................................................................................................63
12 APPENDICES ........................................................................................................................65
Appendix 1
Protocol History .....................................................................................66
Appendix 2
Scales and Assessments .........................................................................67
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................17
Table 2
Volume of Blood to Be Drawn from Each Subject.......................................43
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
ESE
early status epilepticus
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ILAE
International League Against Epilepsy
IM
intramuscular
IRB
institutional review board
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
MHOS/SHP615
midazolam hydrochloride oromucosal solution
PIP
pediatric investigation plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PQC
Product Quality Complaint 
PUMA
pediatric-use marketing authorisation
ROW
rest of world
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
SAE
serious adverse event
SAP
statistical analysis plan
SE
status epilepticus
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
STUDY SYNOPSIS
Protocol number: SHP615-302
Drug: Midazolam hydrochloride oromucosal solution MHOS/SHP615
Title of the study: A Phase 3, Multicenter, Open-label Extension Study of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in Community Settings
Number of subjects (total): ≥6 subjects
Investigator(s): Multicenter study (in community settings)
Site(s) and Region(s): Approximately 25 sites in Japan
Study period (planned):
October 2017 to September 2019
Clinical phase:
3
Objectives:
Primary:  The primary objective of this study is to assess the efficacy of buccally administered MHOS/SHP615 in 
pediatric subjects with status epilepticus (SE) (convulsive) in the community setting.
Secondary:  The secondary objective of this study is to assess the safety of buccally administered MHOS/SHP615 
in pediatric patients with status epilepticus (SE) (convulsive) in the community setting.
Rationale:  MHOS/SHP615 is expected to be used in both the hospital and community settings. While the efficacy 
and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric subjects with SE in the hospital 
setting in the antecedent pivotal Phase 3 study (SHP615-301), this study is an open-label extension (OLE) study in 
subjects who completed the SHP615-301 study and who tolerated and responded to MHOS/SHP615 treatment. 
The rationale for this interventional OLE study is to determine the safety and efficacy of MHOS/SHP615 
administered buccally by caregivers in subjects who are >6 months and <18 years of age and weight >5kg with 
convulsive SE in community settings.
Investigational product, dose, and mode of administration:
Midazolam hydrochloride oromucosal solution (MHOS/SHP615) is a clear, colorless, ready-to-use solution 
(containing 5 mg midazolam [as hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a 
single, age-specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:
MHOS Dose
Subject Age
2.5 mg
>6 months to <1 year (and weight >5 kg)
5 mg
1 to <5 years
7.5 mg
5 to <10 years
10 mg
≥10 to <18 years
Methodology:  SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label extension (OLE) 
study of MHOS/SHP615 administered buccally by caregivers to subjects who present with SE (convulsive) in 
community settings. Children who are >6 months and <18 years of age and completed the antecedent Phase 3 
pivotal SHP615-301 study, tolerated and responded to treatment with MHOS/SHP615, and subsequently experience 
full seizure in the community setting, are eligible to participate in this study providing all eligibility criteria are met. 
The seizure event(s) must be accompanied by loss of consciousness and can be either generalized tonic clonic or 
start focally and then generalize.
Other procedures/instructions include the following:

Single dose only.
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

The investigator will provide training/education to caregivers, which will include instructions on how to 
buccally administer MHOS/SHP615 and record timing and characteristics of seizures and safety measures. 
Caregivers will be qualified by the investigator to ensure understanding of all the necessary
procedures/materials.

Prior to dosing, the caregiver will organize emergency transport, and all subjects will be brought to the 
study site (hospital or emergency treatment center) immediately, even if the seizure has stopped. A follow-
up visit will take place for medical evaluation, review of adverse events and collection of study materials.

In the event of a medical emergency (including slowing of breathing and other adverse events that may 
require treatment) and it is not possible to bring the subject to the study site, the caregiver will be instructed 
to bring the subject to the closest emergency medical center so that the subject can receive treatment as 
quickly as possible. If this occurs, the caregiver will report the incident and relevant information, including
any rescue treatment received, to the investigator/study site within 7 days after the incident.

The caregiver will be instructed to administer MHOS/SHP615 after confirming that the seizure activity is 
appropriate for MHOS/SHP615 treatment, eg, the seizure lasts at least 5 minutes, a second seizure occurs 
before recovery of consciousness from the first seizure, or 3 seizures have occurred within 1 hour.

The caregiver will record observations on the seizure activity and timing of the seizure(s) in a study diary 
before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, review of adverse 
events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and bring it to the study 
site. Any dosing relating error, such as leaking liquid, etc., are to be recorded in the study diary.
The ability of MHOS/SHP615 to stop prolonged convulsive seizures will be assessed by measuring the percentage 
of subjects whose initial seizure stopped within 10 minutes with a sustained absence of visible seizure activity for 30 
minutes following a single, age-based dose of MHOS/SHP615. If the seizures have not stopped within 10 minutes 
after the administration of MHOS/SHP615 the subject should be treated according to the participating hospital 
protocol or guideline. The safety of MHOS/SHP615 will also be assessed.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Subjects who completed the SHP615-301 study and who tolerated and responded to treatment with 
MHOS/SHP615 in the hospital and/or emergency room, and are considered stable for discharge from the 
hospital.
2.
Subjects who are >6 months and <18 years of age at the time of investigational product administration. If the 
subject’s exact age is not known, the subject should be excluded.
3.
Parent, guardian, or legally authorized representative of the child who provides informed consent and assent 
(when applicable) to participate in the study after initial stabilization of the subject with SE in hospital or 
emergency room during the SHP615-301 study. The subject also provides informed consent prior to 
participation, where applicable.
4.
Subjects with parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including time of seizure 
onset, type of seizure, time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.) 

Follow the necessary instructions to secure the safety of the subject.
5.
Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of consciousness with 
any of the following characteristics persistent at the time of study drug administration:
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the preceding 
hour.

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without recovery of 
consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
Exclusion Criteria:
1.
Female subjects who are pregnant, suspected to be pregnant, or nursing.
2.
Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
4.
Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5.
Subjects with seizures of psychogenic origin.
6.
Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to benzodiazepines 
(ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia gravis, syndrome of 
sleep apnea, glaucoma with closed angle, or use of use of concomitant drugs determined by the investigator to 
have a contraindication to the use of benzodiazepines.)  
7.
Subjects with a known history of benzodiazepine abuse.
8.
Subjects who have not responded to previous administrations of midazolam systemic therapies, including 
MIDAFRESA and/or DORMICUM.
9.
Subjects who need emergent surgical intervention and general anesthesia/intubation.
10. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 
transcriptase inhibitors.
11. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
12. Have used an investigational product or been enrolled in a clinical study (including vaccine studies) that, in the 
investigator's opinion, may impact this Shire-sponsored study.
13. Subject has prior placement of a vagus nerve stimulator.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 1 day

Planned duration of treatment period: 1 day (a minimum of 6 hours observation and up to 24 hours)

Planned duration of follow-up period: 7 days
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects with therapeutic 
success:

Therapeutic success will be defined as: 
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
The secondary efficacy endpoints will include:
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE according to the 
participating hospital protocol or guideline, 10 minutes after administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment. 
o
Treatment failure/Nonresponder is defined as continuing seizure activity and/or the need for any 
additional rescue medication in the study site (or another emergency medical institution), 10 
minutes after administration of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures after 
MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 1, 4, 6, and 24 hours post dose (ie, <92% on 
room air for 2 minutes or more after dosing while monitoring [per healthcare setting protocol and/or the 
clinical judgment of the physician]).

Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or 
endotracheal intubation).
The secondary safety endpoints include the following:

Aspiration pneumonia.

Sedation or agitation as measured by the Riker Sedation-Agitation Scale.

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign measurements, laboratory 
tests, oxygen saturation, and electrocardiogram (ECG).

Occurrence of buccal irritation.
Statistical methods: 
Efficacy and safety data will be summarized using descriptive statistics.
Sample size*:  Maximum sample size: approximately 25 subjects
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% expected drop-out 
rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of MHOS/SHP615 in the 
Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response rate in hospital 
settings is conservatively estimated to be 58.5%. This is close to the lowest response rate reported in worldwide 
clinical studies.
Efficacy analysis
Efficacy data of the full analysis set (FAS) will be summarized using descriptive statistics. The FAS will include the
population of subjects with SE who received a single dose of MHOS/SHP615 and have at least 1 assessment of 
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
therapeutic success performed after the administration of MHOS/SHP615.

Therapeutic success will be defined as:
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
Safety analysis
Safety data will be summarized using descriptive statistics on the safety set. The safety set will include subjects who 
receive a single dose of MHOS/SHP615. Treatment-emergent adverse events will be summarized and will include 
treatment, seriousness, and severity. Other TEAE data that will be reported in the listings include treatment, 
relationship to MHOS/SHP615, and the time of event onset.
Other safety data (including vital signs, laboratory tests, ECG findings, aspiration pneumonia, Riker Sedation-
Agitation Scale, and oxygen saturation) will be summarized.
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 min
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Informed consent/assent 
X
Inclusion/exclusion criteria
X
Demographics
X
Medical/procedural history
X
Provide study diary and educational 
materials to caregiver
X
Provide training/education to 
caregivers
X
Dispense age-based dose of SHP615 
with administration instructions
X
X
Evaluate seizure symptoms/record 
diary information
X
X
X
X
X
X
X
X
SHP615 administration in 
community setting
X
Riker Sedation-Agitation Scale
Xc
X
X
X
X
Vital signsd
Xe
Xc
Xc
X
X
X
X
Oxygen saturationf
Xc
X
X
X
X
12-Lead ECGg
Xc
X
X
X
X
Laboratory evaluationsh
X
Buccal cavity assessmenti
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 min
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Physical examination
Xj
X
Supportive care
X
Xk
X
Concomitant medications/recording
X
X
Xk
X
X
Adverse event monitoring/recording
X
X
Xk
X
X
AE=adverse event; ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute.
a Minimum 6-hour observation period after dosing for safety monitoring and blood sampling. Otherwise monitored per standard medical healthcare setting 
procedure.
b Assessments at the 24-hour post dose time point will be made if the subject has not been discharged from the hospital; or a telephone follow-up call will be 
made to assess AEs and concomitant medications. Patients will be asked to return for additional assessment of ongoing AEs, as needed.
c Performed if subject has arrived at study site.
d Vital signs will include single sitting blood pressure (if feasible), pulse rate, respiratory rate, body temperature; collection of vital signs information will begin 
as soon as possible in community setting or after transfer to healthcare setting.
e Parent, guardian, or legally authorized representative should count respiration rate prior to the administration of investigational product.
f Oxygen saturation should be measured from time of arrival in hospital. If it is not possible for the subject to have an oxygen saturation obtained on room air 
due to medical concerns, this will be recorded. The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of oxygen 
administered.
g Electrocardiogram should be performed upon arrival at the hospital.
h Laboratory evaluations include serum biochemistry and urinalysis. A urine pregnancy test should be administered to female patients of childbearing age.
i Buccal cavity where MHOS/SHP615 was administered between cheek and gum line will be examined for redness, inflammation, and ulceration and findings 
noted on physical examination CRF. 
j Physical examination will be performed at some point between arrival at the hospital and 6 hours postdose, when possible.
k Upon arrival at hospital and across all time periods, as appropriate.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
1
BACKGROUND INFORMATION
1.1
Status Epilepticus
A seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal, 
excessive, and synchronous neuronal activity in the brain. Several seizure types can be described, 
but they all fall into 1 of 2 classifications:  primary generalized seizures (eg, grand mal, petit mal, 
or absence seizures) and partial (focal) onset seizures (ie, localized). Regardless of seizure type, 
most seizures (>90%) last less than a few minutes (<2 minutes) (Theodore et al. 1983). If 
seizures are prolonged or occur in a series, there is an increased risk of status epilepticus (SE), 
which literally means a continuous state of seizure (Epilepsy Foundation 2015). 
Status epilepticus (SE), a condition resulting either from the failure of the mechanisms 
responsible for seizure termination or from the initiation of mechanisms that lead to abnormally 
prolonged seizures, is a life-threatening neurologic emergency with significant morbidity and 
mortality. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute 
complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and 
cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), 
encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Prompt cessation and 
rapid control of SE is critical to prevent this neurological and systemic pathology 
(Fountain 2000). 
Convulsive SE (CSE), the most common childhood neurological emergency in developed 
countries, can lead to neurocognitive sequelae and death. History with epilepsy is the strongest 
single risk factor for generalized CSE:  15% to 27% of patients with epilepsy will experience at 
least 1 episode of SE; 25% to 40% of SE occurs in patients with epilepsy.
The term SE includes not only epilepsy, but also status of serial convulsive seizures associated 
with febrile convulsion, encephalitis, and encephalopathy. The International League Against 
Epilepsy (ILE) defines SE as a seizure lasting longer than a defined period of time or more than 
1 seizure occurring within a shorter timeframe without return to normalcy between seizures 
(ILAE 1989). More recently, the minimum seizure duration had been defined as 30 minutes 
(Riviello et al. 2006); however, because epileptic discharge longer than 30 minutes has been 
reported to damage the brain, the diagnosis of SE was subsequently updated to a seizure lasting 
longer than 10 minutes (Treiman et al. 1998) and then more recently, 5 minutes 
(Alldredge et al. 2001), at which time treatment should be promptly initiated. The urgency to 
treat this condition, supported by evidence that seizures rarely last more than a few minutes, led 
to implementation of an operational definition of early status epilepticus (ESE), or seizures 
lasting more than 5 minutes (Dham et al. 2014; Lowenstein 1999). This definition of SE (ie, 
seizures lasting more than 5 minutes) will be used throughout this study. 
Incidence, cause, and prognosis of pediatric SE vary geographically, as well as by different 
socioeconomic conditions, environments, and genetic susceptibility. The incidence of SE is 
bimodally distributed, occurring most frequently during the first year of life and after age 60 
years. Amongst children (<15 years of age), infants <12 months have the highest incidence and 
frequency of the disease. In Japan, annual incidence in children younger than 17 years is 42 cases 
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
per 100,000 persons. In addition to young age, other risk factors include genetic predisposition 
and acquired brain insults (Fountain 2000; Shinnar et al. 1996; Berg et al. 1999).
Depending on the type and duration of seizures, if left untreated (or undertreated) SE can cause 
permanent neurological injury (including neuronal death, neuronal injury, and alteration of 
neuronal networks) or death (Trinka et al. 2015). Therefore, a rapid treatment must be initiated.
1.2
Current Treatment Options 
For an anti-epileptic drug to be effective in SE, it is usually administered intravenously (IV) by 
health professionals to provide quick access to the brain without the risk of serious systemic and 
neurological adverse effects (Sirven and Waterhouse 2003). Multiple drugs are available; the 
first line treatment is benzodiazepines (eg, diazepam and midazolam [midazolam is unauthorized 
for SE in the US]).
The first-choice medication in Japan for treating SE in pediatric patients without venous access is 
diazepam suppositories administered rectally. Rectal diazepam is the medication most commonly 
used throughout the European Union (EU) in the community setting, and is authorized for this 
indication. Diazepam is effective in 60% to 80% of patients but with a risk of early seizure 
recurrence of up to 30% and respiratory depression (McIntyre et al. 2005). The increase of drug 
concentration in the blood is slow by this route; constipation and bowel movements can interfere 
with absorption of drug (Wilson et al. 2004). Rectal administration can be difficult during tonic-
clonic seizures. For wheelchair users, it can be challenging to remove clothing and to insert the 
suppository in a convulsing child. Therefore, the rectal route of administration is not always 
practical, socially acceptable, or convenient.
For resistant cases, phenytoin (or fosphenytoin), phenobarbital, and thiopentone are injectable, 
fast-acting drugs that have strong anti convulsant effects and a positive safety profile. Securing 
vascular access in children, however, is generally more difficult and prolongs stopping the 
convulsion by IV injection upon arrival at the hospital. In the community setting, a therapeutic 
agent that can be administered by a nonmedical expert, such as a parent or caregiver, would be 
more appropriate for emergency treatment. 
For pediatric patients in Japan, midazolam has been used off-label as a first or second choice 
medication for seizures intractable with diazepam treatment. However, since the approval of 
MIDAFRESA Injection 0.1% in 2014, midazolam IV injection is now positioned as first-choice 
medication in Japan for pediatric patients with SE; however, the IV formulation is too dilute to 
use for oromucosal delivery. DORMICUM (an injectable IV formulation of midazolam) is 
frequently administered oromucosally or intranasally, which is considered to be an off-label use 
of this drug.
Accordingly, it has been recognized that there is an unmet need for an effective, fast-acting 
treatment that can easily be administered by a more convenient route and by individuals other 
than medical experts and that is suitable for use in both the healthcare setting and community 
(Scott et al. 1999a).
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs outlined above, it has been common practice to administer 
midazolam buccally (oromucosal administration of other midazolam formulations) off-label for 
the treatment of SE. Buccal administration does not cause pain or distress to the patient or 
require that the patient be in the prone position. 
Currently, the national average time in Japan for patients with SE to be transported to the 
healthcare setting is 39.6 minutes. In many cases as much as 50 minutes has been reported until 
medical treatment has been received at the healthcare setting. Buccal midazolam treatment in 
children with seizures could be started at home by trained clinical personnel, family members, or 
caregivers before securing vascular access, as well as after arriving at a medical institution, thus 
potentially reducing life-threatening risks of brain disorders (eg, encephalopathy) and other 
sequelae due to prolonged seizures and resulting from delays in getting the child to a healthcare 
setting.
1.4
Product Background and Clinical Information
The investigational product midazolam hydrochloride oromucosal solution (hereafter referred to 
as MHOS/SHP615) contains 5 mg/mL of the active substance midazolam and has been 
specifically developed for the buccal administration of midazolam in children with SE. 
Currently, there is extensive clinical experience with midazolam as it is authorized for use in 
children (including neonates <32 weeks gestational age in intensive care units) and adults as a 
sedative and in anesthesia and may be given by the intravenous (IV), intramuscular (IM), or 
rectal route of administration. As midazolam undergoes significant first pass metabolism in both 
the small intestine and the liver, a systemic drug delivery system was selected for 
MHOS/SHP615. In suspension, midazolam is water soluble and, therefore, readily absorbed via 
the buccal mucosa. At physiological pH the drug becomes lipid soluble, which enables it to cross 
the blood-brain barrier. In addition, its pharmacokinetic (PK) parameters such as the short 
elimination half-life (1.5-2.5 hours) and rapid plasma clearance (300-500 mL/min) are optimal 
for a rescue medication (Hypnovel SmPC 2008). The buccal mucosa, with its expanse of smooth 
muscle and relative immobility, makes it a desirable region for retentive systems used for oral 
transmucosal drug delivery.
MHOS/SHP615 has a formulation essentially identical to its authorized originator product, a 
systemically administered midazolam hydrochloride (HYPNOVEL® Injection 10 mg/2 mL [EU], 
VERSED® Oral Syrup 2 mg/mL now marketed generically [US], and DORMICUM Injection 10 
mg [Japan]) used for sedation or anesthetic premedication. When approved in Japan, 
MHOS/SHP615) will provide major advantages over unauthorized/off-label buccal midazolam 
preparations and other formulations of authorized rescue medication (such as IV, IM, or rectal 
routes of administration) currently used for SE.
In the EU, MHOS is commercially known as BUCCOLAM®, a nonintravenous treatment to stop 
seizures (including convulsive seizures). An oromucosal solution, BUCCOLAM contains 5 
mg/mL of the active substance midazolam and was approved in the EU on 05 Sep 2011 for the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
treatment of prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents 
(from 3 months to ≤18 years). Parents and/or caregivers are allowed to administer BUCCOLAM 
only to patients older than 6 months who have been diagnosed with epilepsy. For infants between 
3 and 6 months of age, treatment should be in a hospital setting, where close medical supervision 
and resuscitation equipment are available.
Efficacy
The age range proposed for the SHP615-301 study is >52 weeks corrected gestational age 
(gestational weeks plus the number of weeks after birth) to <18 years. The efficacy and safety of 
buccal midazolam in this age range have been established in 4 pivotal, rectal-diazepam-
controlled clinical studies. These studies all used the HYPNOVEL 10 mg/2 mL formulation 
delivered buccally. All 4 studies demonstrated that buccal midazolam was either more effective 
than or as effective as rectal diazepam for the treatment of acute seizures in children (licensed 
indication and dosage of diazepam). However, the meta-analysis of the 3 (standard randomized) 
pivotal studies (Mpimbaza et al. 2008; McIntyre et al. 2005; Scott et al. 1999b) (comprising a 
total of 628 seizure events [525 patients]) demonstrated that buccal midazolam is significantly 
more effective than rectal diazepam in stopping seizures within 10 minutes (Mantel-Haenszel 
Weighted Risk Ratio [buccal midazolam/rectal diazepam] of 1.24 [95% CI: 1.11 - 1.39] p = 
0.0002). 
In a study vs IV diazepam (Talukdar and Chakrabarty 2009), the buccal midazolam dose was 
slightly lower than that used in the pivotal rectal diazepam studies (0.2 mg/kg vs ~0.25-
0.5 mg/kg in the pivotal studies). Nevertheless, this study supported the results of the pivotal 
studies and meta-analysis. It demonstrated that buccal midazolam is an effective treatment for 
acute seizures with no statistically significant difference compared with IV diazepam for overall 
control of convulsive episodes within 5 minutes (85% vs 93.3% in buccal midazolam vs IV 
diazepam groups, respectively; p = 0.142). 
Safety
The clinical safety profile of midazolam (and other benzodiazepines) for the authorized uses are
well established (and summarized in the EU and US labeling [HYPNOVEL SMPC 2008; 
Midazolam HCl Injection US Prescribing Information 2009; Midazolam HCl Syrup US 
Prescribing Information 2009]). The main adverse effects (reported to occur rarely for 
HYPNOVEL) and precautions applicable to the buccal route of administration in children include 
cardiorespiratory adverse events (respiratory depression, apnea, respiratory arrest, and/or cardiac 
arrest), anterograde amnesia, and paradoxical reactions. Precautions are required for patients 
with impaired respiratory function or cardiovascular instability. Pediatric patients less than 
6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Always refer to the latest version of the (MHOS)/SHP615 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of (MHOS)/SHP615. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the hospital or community settings. The rectal route 
of administration, however, is not always practical, socially acceptable, or convenient. 
The need to remove clothing and the difficulty with rectal administration during seizures, 
particularly for wheelchairs users, is socially embarrassing or unacceptable by some individuals, 
parents, or caregivers. 
MHOS/SHP615 is expected to be used in both the hospital and community settings. While the 
efficacy and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric 
subjects with SE in the hospital setting in the antecedent pivotal Phase 3 study (SHP615-301), 
this study is an open-label extension study in subjects who completed the SHP615-301 study and 
who tolerated and responded to MHOS/SHP615 treatment.
MHOS/SHP615 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg midazolam) presentation for children. The 4 different, age-
specific, fixed-dose presentations were selected as a convenient oromucosal administration of 
midazolam injectable solution to enable rapid treatment in the emergency and community 
settings where individual dosing by body weight is not feasible (except for infants aged from 3 
months to <6 months: this age population should be treated in a healthcare setting only). This 
dosing regimen was evaluated extensively by the European Medicines Agency (EMA) Pediatric
Committee as part of the pediatric investigation plan (PIP) application and by the EMA 
Committee for Medicinal Products for Human Use (CHMP) as part of the review and approval 
of the pediatric-use marketing authorisation (PUMA).
The rationale for this interventional OLE study is to determine the safety and efficacy of 
MHOS/SHP615 administered buccally by caregivers in pediatric subjects with CSE in 
community settings. 
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of buccally administered 
MHOS/SHP615 in pediatric subjects with status epilepticus (SE) (convulsive) in the community 
setting.
2.2.2
Secondary Objectives
The secondary objective of this study is to assess the safety of buccally administered 
MHOS/SHP615 in pediatric patients with status epilepticus (SE) (convulsive) in the community 
setting.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment, or is discontinued early. Please note that this includes the 
follow-up visit or contact, whichever is later. The study completion date is used to ascertain 
timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted in approximately 25 study sites in Japan.
4
STUDY POPULATION
The total enrollment for the SHP615-302 study is expected to be ≥6 subjects with active 
generalized tonic-clonic SE with seizures. Diagnosis of SE will be confirmed through an
evaluation of seizure symptoms conducted and documented by the caregiver at the time of the 
event.
Each parent, guardian, or legal representative (and/or the subject, where necessary) must 
participate in the informed consent process and provide written informed consent/assent before 
any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator
before subjects are included in the study.
The subjects will not be considered eligible for the study without meeting all of the criteria 
below.
1. Subjects who completed the SHP615-301 study and who tolerated and responded to
treatment with MHOS/SHP615 in the hospital and/or emergency room, and are considered 
stable for discharge from the hospital.
2. Subjects who are >6 months and <18 years of age at the time of investigational product 
administration. If the subject's exact age is not known, the subject should be excluded.
3. Parent, guardian, or legally authorized representative of the child who provides informed 
consent and assent (when applicable) to participate in the study after initial stabilization of 
the subject with SE in hospital or emergency room during the SHP615-301 study. The 
subject also provides informed consent prior to participation, where applicable.
4. Parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, time necessary to administer MHOS/SHP615, time 
between MHOS/SHP615 administration to seizure cessation, etc.)

Follow the necessary instructions to secure the safety of the subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
5. Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of 
consciousness with any of the following characteristics persistent at the time of study drug 
administration:

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within 
the preceding hour

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession 
without recovery of consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Female subjects who are pregnant, suspected to be pregnant, or nursing.
2. Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
4. Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5. Subjects with seizures of psychogenic origin.
6. Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, or use of 
concomitant drugs determined by the investigator to have a contraindication to the use of 
benzodiazepines.)    
7. Subjects with a known history of benzodiazepine abuse.
8. Subjects who have not responded to previous administrations of midazolam systemic 
therapies, including MIDAFRESA and/or DORMICUM.
9. Subjects who need emergent surgical intervention and general anesthesia/intubation.
10. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors 
or HIV reverse transcriptase inhibitors.
11. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
12. Have used an investigational product or been enrolled in a clinical study (including vaccine 
studies) that, in the investigator’s opinion, may impact this Shire-sponsored study.
13. Subject has prior placement of a vagus nerve stimulator.
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
4.3
Restrictions
4.3.1
Medical Intervention
There will be no special restrictions on medical interventions deemed necessary by the 
investigator for the health and wellbeing of the subject.
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at screening/baseline. 
Females of childbearing potential must agree to abstain from sexual activity that could result 
in pregnancy or agree to use medically acceptable methods of contraception.
Medically acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms with spermicidal agent)

Oral hormonal contraceptives, stabilized for at least 30 days prior to the administration of 
investigational product, plus condoms. 
4.4.2
Male Contraception
Males should use condoms if they are sexually active for 7 days after administration of study 
drug and must not donate or use sperm for the purposes of making a woman pregnant until 7 
days after the administration of study drug.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
A subject will be withdrawn from the study when they turn 18 years of age.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Subjects may withdraw from active treatment within the treatment period at any time at their 
own request, or they may be withdrawn at any time at the discretion of the investigator or 
sponsor for safety, behavioral, or administrative reasons. Additional reasons a subject may be 
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
withdrawn from active treatment include but are not limited to, adverse event (AE), SAE, 
protocol violations, and failure to return for visits. 
If a subject is withdrawn for whatever reason within a week following administration of study 
drug, the evaluations listed for the 1-week follow-up visit are to be performed as completely as 
possible. The reason for termination and date of stopping the study must be recorded in the case 
report form (CRF) and source documents.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. In any circumstance, every effort should be made to document subject outcome, if 
possible. The investigator should inquire about the reason for withdrawal, request the subjects to 
return for a final visit, if applicable, and follow-up with the subject regarding unresolved adverse 
events. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluation should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse events

Protocol deviation

Withdrawal by subject

Lost to follow-up

The sponsor or investigator terminates the study.

Withdrawal/discontinuation due to AEs should be distinguished from withdrawal due to other 
causes, according to the definition of AE noted earlier, and recorded on the appropriate AE 
electronic case report form (eCRF) page. When a subject withdraws because of an SAE, the SAE 
must be reported in accordance with the reporting requirements defined in Section 8.2.
Sponsor Discontinuation Criteria
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the institutional review board (IRB)/EC, investigational product safety problems, or 
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
at the discretion of the sponsor.  In addition, the sponsor retains the right to discontinue 
development of MHOS/SHP615 at any time.
If a study is prematurely terminated or discontinued, the sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects, subject’s 
parents, guardians, or legally authorized representatives, and the hospital pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all eCRFs completed to the greatest extent possible.
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent, guardian, or legally 
authorized representative of any subject lost to follow-up at any time point prior to the last 
scheduled contact (office visit or telephone contact). At least 1 of these documented attempts 
must include a written communication sent to the parents, guardians, or legally authorized 
representatives at subject’s last known address via courier or mail (with an acknowledgement of 
receipt request) asking that they return to the site for final safety evaluations.
4.5.4
Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if 1 or more of the 
following criteria are met:

Death that is considered related to the study drug.

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities [MedDRA] higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety lead physician and the Global Drug Safety therapeutic area head. Following 
the sponsor’s review of safety data, 1 of the following actions will be taken with respect to study 
status:

Continue study with protocol unchanged;

Continue study with modifications to the protocol; or

Terminate study.
Subject safety will be monitored on a continuous basis during this study until the last subject
completes his or her last scheduled study visit/assessment, or has discontinued from the study.
4.5.4.1
Study Level Stopping Rules
Safety data, including SAEs and adverse events of special interest (AESIs), will be monitored 
regularly throughout the duration of the study and submitted to Regulatory Authority(ies), as 
appropriate. If any potential safety signal is identified during safety monitoring in this study by 
the sponsor and/or following a safety data review, a comprehensive analysis of the issue will be 
undertaken by the sponsor. As a result of this assessment, the sponsor may take actions as 
deemed appropriate (which may include changing or suspending dosing in the study).
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or toxicity considered clinically relevant (AE, laboratory, 
physical examination, vital sign, or ECG finding) will be carefully monitored until resolution, 
which may include the following:

Additional clinical laboratory tests and/or other clinical investigations,

Additional visits or extended duration of follow-up, 

Obtaining a specialist consultation.
5
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) received within 
30 days prior to the administration of investigational product and through the final study contact 
(including protocol defined follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) 
received within 30 days of the date of investigational product administration. Prior treatment 
information must be recorded on the appropriate CRF page.
Medications taken during screening, before administration of the MHOS/SHP615 dose, will be 
documented as prior medications.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the time of the investigational 
product administration and the end of the follow-up period, inclusive. All concomitant 
medication(s) and treatment(s) during the study must be recorded on the appropriate CRF page, 
with indication, daily dose, start and stop dates of administration. All subjects (or 
parents/caregivers) will be questioned about concomitant medication during their follow-up visit.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
MHOS/SHP615 is a clear, colorless, ready-to-use solution (containing 5 mg midazolam [as 
hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a single, age-
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:

2.5 mg (yellow label) ages >6 months to <1 year (and weight >5 kg)

5 mg (blue label) ages 1 year to <5 years

7.5 mg (purple label) ages 5 years to <10 years

10 mg (orange label) ages ≥10 to <18 years 
The investigational product MHOS/SHP615 will be provided in prefilled single-use, ready-to-
use, amber, age-specific, and color-coded oral dosing syringes, and is to be administered by the 
buccal (oromucosal) route. The full amount of solution will be delivered slowly into the space 
between the inside of the cheek and the lower gum. 
If at some point after entering the study, and prior to having a seizure, the subject ages from 1 
age category to the next, the parent/caregiver must return to the study site in order to exchange 
study drug supply for the appropriate dose.
Buccal (oromucosal) administration was considered to be an appropriate route to be progressed 
to address the unmet need for a convenient, fast–acting product suitable for use in both the 
community and hospital setting. Additional information is provided in the current version of the 
SHP615 midazolam investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment 
This is an open-label, nonrandomized study; therefore, assignment to MHOS/SHP615 will be 
unblinded to the investigators, subjects, caregivers, and the sponsor study team. Study treatment 
will only be administered by caregivers to subjects who have a signed and dated IRB-approved 
informed consent form (ICF) and who have met all eligibility criteria. 
All subjects enrolled in the study will receive treatment with the investigational product based on 
their age (Section 6.2.2.1).
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. This identifying number will be retained 
throughout the study.
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If an identifier is allocated incorrectly, the clinical research 
associate (CRA)/study monitor must be notified as soon as the error is discovered. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
6.2.2
Dose Regimen and Dose Administration
MHOS/SHP615 will be administered buccally by caregivers as a single, fixed dose product,
banded by age to subjects with SE (convulsive) in community settings. For buccal 
administration, midazolam is administered into the space between the lower gum and the inside 
of the cheek.
6.2.2.1
Dosing Regimen
Details of subject dosing and follow-up are outlined in Section 3.1 and included in the Schedule 
of Assessments (Table 1).
There are 4 single, fixed, banded by age, dose regimens of the MHOS/SHP615 formulation for 
the treatment of SE; 1 dosage per buccal administration for each of the following age groups:

2.5 mg
>6 months to <1 year (and weight >5kg)

5 mg
1 to <5 years

7.5 mg
5 to <10 years

10 mg
≥10 to <18 years
6.2.2.2
Dose Administration
Before dosing:

The airway should be secured and respiratory and cardiac function assessed.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.

The caregiver will organize emergency transport, and all subjects will be brought to the 
study site immediately (hospital or healthcare center), even if the seizure has stopped.
Single-dose administration:

The caregiver will be instructed to administer a single dose of MHOS/SHP615 after 
confirming that the seizure activity is appropriate for MHOS/SHP615 treatment (eg, the 
seizures last at least 5 minutes or a second seizure occurs before recovery of 
consciousness from the first seizure, or 3 seizures occur within 1 hour).

Only 1 oral syringe with the specified dose must be given. The full amount of the 
MHOS/SHP615 prefilled oral dosing syringe is administered slowly into the buccal 
mucosa. In some cases, it might be necessary to divide the dose so that half of the 
solution is administered into each side of mouth.  
After dosing

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

If the seizure has not stopped within 10 minutes of administration, and/or if a serious AE 
(SAE) emerges, then emergency medical assistance must be sought. 

Note:  A second or repeat dose of MHOS/SHP615 should not be given even if the seizure 
recurs after an initial response.

In the event of a medical emergency, and it is not possible to bring the subject to the 
study site, the caregiver will be instructed to bring the subject to the closest emergency 
medical institution so that the subject can receive treatment as quickly as possible. If this 
occurs, then the caregiver will report the incident and relevant information, including any 
rescue treatment received, to the investigator/study site within 1 week after the incident.

The caregiver/parent and subject must visit the study site for examination after 
MHOS/SHP615 administration, even if the seizure stops. All subjects will be followed up 
at study sites even if the seizure resolves.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating errors (such as leaking liquid, etc.) are to be 
recorded in the study diary.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
A computer-generated label is applied to the investigational product. All investigational product 
is labeled with a minimum of the protocol number, pack number (if applicable), dosage form 
(including product name and quantity in pack), directions for use, storage conditions, expiry date 
(if applicable), batch number and/or packaging reference, the statements “For clinical trial use 
only” and the name and country of the sponsor and contract research organization (CRO) name 
and address. Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
A single dose of the investigational product MHOS/SHP615 will be provided in an individual, 
labeled, single-dose, prefilled plastic, oral dosing syringe available in 4 different, age-specific, 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
color-coded doses (2.5, 5, 7.5, and 10 mg dose packs) in a protective plastic tube which is
packaged and dispensed in cartons with tamper-evident seals. The cartons should not be opened 
until the investigational product is to be administered.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
Keep the oral dosing syringe containing the investigational product in the protective plastic tube. 
Keep at or below 25°C (77°F). Do not refrigerate or freeze.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The subinvestigator/designated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling 
Investigational product for the sponsor’s studies must be stored according to all applicable local, 
state, and/or national laws. 
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
The investigator will provide or supervise the training of investigational product administration 
to the designated caregivers. Where permissible, tasks may be delegated to a qualified designee 
(eg, a pharmacist) who is adequately trained in the protocol and who works under the direct 
supervision of the investigator. This delegation must be documented in the applicable study 
delegation of authority form.
The caregiver will administer the investigational product only to subjects included in this study 
following the training provided by the investigator or his/her designee as set out in the study 
protocol. Each subject will be given only the investigational product corresponding to his/her 
treatment assignment. All administered investigational product will be documented on the CRFs 
and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor (or designated CRO). For unused 
supplies where the original supplied tamper-evident feature is verified as intact, the 
tamper-evident feature must not be broken and the labeled amount is to be documented in lieu of 
counting. Shipment return forms, when used, must be signed prior to shipment from the site. 
Returned investigational products must be packed in a tamper-evident manner to ensure product 
integrity. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws.
The investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product supplies.
6.5
Subject Compliance
Subjects/caregivers must be instructed to bring unused investigational product and empty/used 
investigational product packaging to the follow-up visit. Drug accountability must be assessed at 
the container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container or at the individual count level for opened 
containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.   
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
6.6
Destruction of Investigational Product 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by the sponsor, and all 
destruction must be adequately documented.
7
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (Table 1).
7.1.1
Screening Period 
Screening for subject eligibility into this study occurs on the same day as baseline (Visit 1) for 
Study SHP615-301. This includes an assessment of inclusion/exclusion criteria.  
7.1.2
Baseline Visit 
Baseline Visit 1 will be conducted after the follow-up visit for study SHP615-301.
Written informed consent must be obtained prior to performing any protocol specific procedures. 
The following procedures will be performed:

Informed consent/assent 

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Provide study diary and educational materials to caregiver

Provide training/education to caregiver

Dispense study drug

Review concomitant medications/treatments
7.1.3
Treatment Period 
7.1.3.1
Treatment of Seizure in the Community Setting
At the onset of a seizure the caregiver will:

Confirm the seizure activity is appropriate for MHOS/SHP615 treatment, eg, the seizure 
lasts at least 5 minutes or a second seizure occurs before recovery of consciousness from 
the first seizure or 3 seizures occur within 1 hour.
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

Before dosing, the caregiver will organize emergency transport, and all subjects will be 
brought to the study site immediately (hospital or emergency treatment center), even if 
the seizure has stopped. A clinical visit will take place for medical evaluation, review of 
adverse events and collection of study materials.

If possible, count and record respiratory rate; collection of vital signs information will 
begin as soon as possible in community setting or after transfer to healthcare setting.

Properly administer MHOS/SHP615 once SE is confirmed.

Follow the necessary instructions to secure the safety of the subject. 

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, characteristics of seizures and safety measures, 
time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.)

In the event of a medical emergency, the caregiver will be instructed to bring the subject
to the closest emergency medical institution if the subject is having a medical emergency 
(including slowing of breathing and other adverse events that may require treatment) and 
it is not possible to bring the subject to the study site so that the subject can receive 
treatment as quickly as possible. If this occurs, then the caregiver will report the incident 
and relevant information, including any rescue treatment received, to the 
investigator/study site within 1 week after the incident.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary, before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, 
review of adverse events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating error, such as leaking liquid, etc., are to be 
recorded in the study diary.
7.1.4
Clinic or Hospital Visit
Once the subject has been transported to the clinic or hospital, staff will conduct assessments and 
supportive care as outlined in Table 1. 
The investigator or subinvestigator should obtain seizure information and dosing of 
MHOS/SHP615 from the subject diary or the subject’s parent, guardian, or legally authorized 
representative.
If the seizure continues or recurs, the subject should be treated according the procedures in use at 
the clinic or hospital.
The subjects should remain in the hospital under observation for at least 6 hours and up to 24 
hours after hospital arrival (as needed).
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The following procedures will be performed:

Evaluate seizure symptoms (by caregiver in the community or by PI once at the site) at 
10 and 30 (±5) minutes, and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) 
hours post dose.

Evaluate Riker Sedation Agitation Scale (once subject arrives at hospital or clinic) at 30 
(±5) minutes (if possible), and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) 
hours post dose.

Assess buccal cavity where MHOS/SHP615 was administered between cheek and gum 
line for redness, inflammation, and ulceration at 1 (±10 min), 4 (±30 min), and 6 (±30 
min) hours postdose.

6 hours (±30 min) post dose: Obtain blood and urine samples for safety laboratory tests 
for serum biochemistry and urinalysis.

10 and 30 (±5) minutes, and 1, 4, 6, and 24 hours (±30 min) post dose (if subject has not 
been discharged from the healthcare setting): 

Measure vital signs: single sitting blood pressure (BP) (if feasible), pulse rate, 
respiratory rate, temperature (°C or °F).

30 minutes*, 1 hour (±10 min) and 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours  
post dose if subject has not been discharged from the healthcare setting: 

Measure oxygen saturation.

Perform standard 12-lead ECG.
*If possible, by EMT or at the site.

Administer supportive care.

Review and record concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
laboratory sampling).

Perform physical examination when possible during the 6 hour time period.
7.1.5
Follow-up Period
The follow-up period for this protocol is 7 days (± 1 day). 
At the end of this period there will be a telephone call initiated by the site staff/follow-up visit to 
evaluate seizure symptoms, serious adverse events (SAEs), adverse events (AEs), and 
concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (see Section 8.1). In addition, caregivers will be asked to complete the 
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
7.2
Study Evaluations and Procedures
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test. In these cases the investigator will take all steps necessary to ensure the safety and well-
being of the subject. When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions that he or she has taken to 
ensure that normal processes are adhered to as soon as possible. The study team will be informed 
of these incidents in a timely fashion.
7.2.1
Informed Consent
The ICF must be executed prior to performing any study-related activities and must be approved 
by the reviewing institutional review board (IRB). Subjects may withdraw consent at any time. 
Participation in the study may be terminated at any time without the subject’s consent as 
determined by the investigator. Due to the potential for long periods between initial consent and 
treatment, the investigator should, every 3 months, either have the subject/parent/caregiver resign 
and date the original consent form(s), or document phone contact with the 
subject/parent/caregiver confirming ongoing interest and willingness to participate in the study.
7.2.2
Demographic and Other Baseline Characteristics
Demographics: date of birth, sex, race and ethnicity (where locally permitted) and medical 
history will be obtained at screening from subjects, parents, or caregivers and will be recorded on 
the source document and eCRF.
Medical history (including SE, smoking, and cardiovascular history) will capture the subject’s 
current medical status (current SE or CSE disease processes), past medical status (past disease 
processes), history of surgery, allergies, and concomitant medications/treatments.
7.2.3
Efficacy
Methods of measuring the efficacy of MHOS/SHP615 in SE that will be used throughout the 
study are described in this section. 
Information recorded in the subject diary by the caregiver along with evaluation by the 
investigator or subinvestigator will be used to evaluate the seizure and its duration, type (focal, 
generalized, convulsive or nonconvulsive), and recurrence. The other criteria are those set in the 
study protocol to define the treatment efficacy and include time of cessation and need for 
additional rescue medication.
7.2.4
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Any AE related to either efficacy or safety should be first recorded by the caregiver using a 
comprehensive study diary and other materials, and then finally verified by the investigator.
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
7.2.4.1
Medical and Medication History
Medical history is collected at the time points specified in the Schedule of Assessments (Table 
1).
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE or CSE (eg, dietary, medication, or other), must be 
recorded on the appropriate eCRF page.
7.2.4.2
Adverse Event Collection
At each assessment time point, subjects will be questioned/evaluated in a general way to 
ascertain if AEs have occurred since the previous time point. Adverse events are collected from 
the time of the seizure event onset. (Please refer to Section 8, Adverse and Serious Adverse 
Events Assessment.)
7.2.4.3
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment include blood pressure (systolic and diastolic), pulse rate, respiration rate
(after 5 minutes of rest), and body temperature to be performed at the time points specified in the 
Schedule of Assessments (Table 1). Additional collection times or changes to collection times 
will be permitted, as necessary to ensure appropriate collection of safety data.
Sitting blood pressure (if feasible) will be measured with the subject’s arm supported at the level 
of the heart, and recorded to the nearest mm Hg. It is preferred that the same arm (preferably the 
dominant arm) will be used throughout the study. The same size BP cuff that has been properly 
sized and calibrated will be used to measure BP each time.
The use of automated devices for measuring BP and pulse rate are acceptable, although, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. 
When the timing of these measurements coincides with a blood collection, all vital signs should 
be obtained prior to the nominal time of the blood collection.
It is preferred that body temperature be collected using tympanic, oral, or axillary methods and 
that the same method be used consistently throughout the study.
Any clinically significant deviations from baseline vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
7.2.4.4
Clinical Laboratory Evaluations
The following clinical laboratory assessments will be performed at times defined in the Schedule 
of Assessments (Table 1):
Chemistry
Urinalysis
Other
BUN and Creatininea
Glucose (fasting if possible)
Calcium (total)
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Direct bilirubinb
Indirect bilirubinb
Alkaline phosphatase
Albumin
Total protein
Bicarbonate
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Specific gravity
Microscopyc
Urine pregnancyd
ALT = alanine aminotransferase ; AST = aspartate aminotransferase.
a Creatinine clearance determination by central lab using Schwartz method.
b Only if total bilirubin is elevated. 
c Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
d Complete for women of childbearing potential.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
Blood samples for laboratory assessments will be collected at the site by a trained phlebotomist 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
laboratory manual. 
Biological material will be stored and secured in a manner that assures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed.
7.2.4.5
Pregnancy Test
A urine pregnancy test is performed on all females of child-bearing potential after the subject is 
transferred to the hospital, emergency room, or clinical site.
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
7.2.4.6
Electrocardiogram 
A standard twelve (12)-lead electrocardiogram (ECG, single recording) will be performed after 
MHOS/SHP615 administration and subject is transferred to the hospital, emergency room, or 
clinical site.
All scheduled ECGs should be performed after the subject has rested quietly for at least 10 
minutes in a supine position (if feasible). When the timing of these measurements coincides with 
a blood collection, the ECG should be obtained prior to the nominal time of the blood collection, 
BP, and pulse rate.
To ensure safety of the subjects, the investigator or subinvestigator at the investigator site will 
make comparisons to baseline measurements taken at screening. A copy of the ECG should be 
available as source documents for review.  
7.2.4.7
Oxygen Saturation
Oxygen saturation will be measured at time points specified in the Schedule of Assessments 
(Table 1). Oxygen saturation at baseline will be measured and recorded on room air, if feasible, 
in the emergency room.
If it is not possible for the subject to have an oxygen saturation obtained on room air due to 
medical concerns, this will be recorded and the investigator will record the oxygen saturation of 
the patient while on oxygen therapy as well as the oxygen delivery system and amount of oxygen 
administered (eg, 2 L/min via nasal cannula).
7.2.4.8
Physical Examination
A complete physical examination will be performed at some time point between dosing (0 
minute) and 6 hours post-dose, and at the follow-up. Height (without shoes) and weight will be 
measured during the first exam.
Complete physical examinations must be performed by the investigator or subinvestigator in 
accordance with standards at the site and per local guidelines. Complete physical examinations 
consist of assessments of:

General appearance 

Skin

Head, eyes, ears, nose, and throat; buccal cavity where MHOS/SHP615 was administered 
between cheek and gum line will be examined for redness, inflammation, and ulceration 
and noted on physical examination CRF

Spine/neck/thyroid

Respiratory

Cardiovascular

Abdomen (including liver and kidneys)
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
Quintiles Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor 
using the details specified in the emergency contact information section of the protocol. The 
pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
beta-human chorionic gonadotropin (-hCG) test or ultrasound result will determine the 
pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of MHOS/SHP615

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the SHP615 midazolam HCl investigator’s 
brochure, which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K. and Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to Quintiles Transnational Japan K.K. and 
the Shire Global Pharmacovigilance and Risk Management Department. A copy of the Shire 
Clinical Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form (and 
any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor using the 
details specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death.
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 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. 
Hospitalization
For this protocol, hospitalization is defined as any admission to a medical or equivalent 
healthcare facility or any prolongation of an existing admission lasting more than 24 hours.  
Admission also includes transfer within the hospital to an acute/intensive care unit (eg, from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to 
a tuberculosis unit). A healthcare setting visit does not necessarily constitute a hospitalization; 
however, the event leading to the healthcare setting visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017

Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for workup of 
persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time of seizure onset until 
the defined follow-up period stated in Section 7.1.4 and must be reported to Quintiles 
Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to Quintiles 
Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk Management 
Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and CRO are responsible for notifying the relevant regulatory authorities/and 
institutional IRBs or ECs of related, unexpected SAEs.
In addition the sponsor or Quintiles Transnational Japan K.K. is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the 
SHP615 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Product Quality Complaints
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to Pharmaceuticals and 
Medical Devices Agency (PMDA) as a device malfunction report, regardless of whether or not 
the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
European Union and Rest of World (ROW)
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate electronic case report form (eCRF).
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. 
Data collection procedures will be discussed with the site at the site initiation visit and/or at the 
investigator’s meeting. Once a subject is enrolled, it is expected that site personnel will complete 
the CRF entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the sponsor’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
All available data will be included in the analysis. No imputation of missing data will be 
performed.
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its designee. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. All statistical analyses will be performed using SASVersion 
9.3 or higher (SAS Institute, Cary, NC, USA 27513). 
9.4.1
Appropriateness of Measurements
This is a Phase 3, open-label extension (OLE) study that is designed to evaluate the efficacy and 
safety of MHOS/SHP615 as therapy for subjects with SE or CSE. Measures employed in this 
protocol are standard measures routinely used for the evaluation of the efficacy, safety, and 
tolerability of an investigational product.
9.4.2
General Considerations
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. 
9.5
Planned Interim Analysis
There is no planned interim analysis.
9.6
Sample Size Calculation and Power Considerations
The target sample size (≥6 subjects) is estimated based on feasibility analysis rather than based 
on statistical rationale.
Maximum sample size*: approximately 25 subjects.
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% 
expected drop-out rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of 
MHOS/SHP615 in the Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response 
rate in hospital settings is conservatively estimated to be 58.5%. This is close to the lowest 
response rate reported in worldwide clinical studies.
9.7
Study Population
The screened set will consist of all subjects who have a signed informed consent.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The safety set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The full analysis set (FAS) will consist of all subjects who have received a single dose of 
MHOS/SHP615 and who have at least 1 assessment for therapeutic success (cessation of seizure 
within 10 minutes with sustained absence of seizure for 30 minutes) performed after the 
administration of MHOS/SHP615.
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects 
with therapeutic success.

Therapeutic success will be defined as:

The cessation of visible seizure activity within 10 minutes, with

A sustained absence of visible seizure activity for 30 minutes following a single 
dose of MHOS/SHP615.
The response rate will be calculated with FAS and the 2-sided, 95% confidence interval (CI) will 
be constructed for the response rate.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE 
according to the participating hospital protocol or guideline, 10 minutes after 
administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Actual values of clinical laboratory tests will be summarized by study time point. If more than 1 
laboratory result is reported per study visit time point per parameter, the last nonmissing result 
will be selected for analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. The number of subjects with a nonmissing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, nonclinically significant result less than the lower limit of normal, within the 
normal range, nonclinically significant result more than the upper limit of normal (ULN), and 
clinically significant result more than the ULN will be summarized by study time point. If more 
than 1 laboratory result is reported per study time point per parameter, the result yielding the 
most severe classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study time 
point. If more than 1 laboratory result is reported per study time point per parameter, the result 
yielding the most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator.
9.9.4
Vital Signs
Vital signs will be summarized using the safety set.
Actual values in vital signs will be summarized by study time point. All vital sign data will be 
presented in subject listings.
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a nonmissing result, and the number and percentage of 
subjects with a nonclinically significant result and clinically significant result will be 
summarized by study time point. If more than 1 vital sign result is reported per study time point 
per parameter, the result yielding the most severe classification will be selected for analysis. 
Subjects with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the investigator to be clinically 
significant for a subject across study time points to identify any trends.
9.9.5
Electrocardiography
Electrocardiography results will be summarized using the safety set.
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG no performed, will be summarized by study 
time point. Subjects with clinically significant ECG results will be listed. This listing will 
include all results for a subject across study time points to identify any trends.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs are notified as appropriate. Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and any updates, EU Directive 2001/20/EC, the ethical principles in the Declaration of 
Helsinki, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
All data sent to the sponsor must be endorsed by the investigator.
Once the CRA/study monitor has verified the contents of the completed CRF pages against the 
source data, the duplicate pages are retrieved and forwarded to the study sponsor (or designee) 
for data entry. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB or regulatory inspectors) may check the CRF entries 
against the source documents. The ICF includes a statement by which the subject agrees to the 
monitor/auditor from the sponsor or its representatives, national or local regulatory authorities, or 
the IRB, having access to source data (eg, subject’s medical file, appointment books, original 
laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], EMA, PMDA) or an auditor.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the Japan Pharmaceuticals and 
Medical Devices Agency (PMDA), US FDA (as well as other US national and local regulatory 
authorities), the EMA, the Medicines and Healthcare products Regulatory Agency, other 
regulatory authorities, the sponsor or its representatives, and the IRB for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances the investigator must at all times comply with all local, state, 
and national laws pertaining to registration and reporting with the appropriate regulatory body 
and control and handling of such substances.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects (or parent, guardian, or legally authorized representative) prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
with applicable regulations and GCP. Each subject or the subject’s parent, guardian, or legally 
authorized representative, as applicable, is requested to sign and date the subject informed 
consent form or a certified translation if applicable, after the subject (and parent, guardian, or 
legally authorized representative) has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent, guardian, or legally authorized representative, as applicable. This document 
may require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The principal investigator provides the sponsor with a copy of the blank informed consent form 
that was reviewed by the IRB and received their favorable opinion/approval. A copy of the IRB’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB requires modification of the 
sample subject information and consent document provided by the sponsor, the documentation 
supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB for review, and all must 
be approved prior to site initiation.
The applicant for an IRB opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB must approve any revisions 
of all informed consent documents and amendments to the protocol unless there is a subject 
safety issue.
Investigational product supplies will not be released until the sponsor has received written IRB 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects (and parent, guardian, or legally authorized representative) have consented to take 
part in the study, the sponsor and/or its representatives review their medical records and data 
collected during the study. These records and data may, in addition, be reviewed by others 
including the following: independent auditors who validate the data on behalf of the sponsor; 
third parties with whom the sponsor may develop, register, or market MHOS/SHP615; national 
or local regulatory authorities; and the IRB that gave approval for the study to proceed. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
The sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
11
REFERENCES 
Alldredge, BK, Gelb, AM, Isaacs, SM, Corry, MD, Allen, F, Ulrich, S, Gottwald, MD, O'neil, N, 
Neuhaus, JM, Segal, MR & Lowenstein, DH 2001. A comparison of lorazepam, 
diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J 
Med, 345, 631-7.
Berg, AT, Shinnar, S, Levy, SR & Testa, FM 1999. Status epilepticus in children with newly 
diagnosed epilepsy. Ann Neurol, 45, 618-23.
Dham, BS, Hunter, K & Rincon, F 2014. The epidemiology of status epilepticus in the United 
States. Neurocrit Care, 20, 476-83.
Epilepsy Foundation. 2015. Status Epilepticus [Online]. Available: 
http://www.epilepsy.com/learn/impact/seizure-emergencies/status-epilepticus.
Fountain, NB 2000. Status epilepticus: risk factors and complications. Epilepsia, 41 Suppl 2,
S23-30.
Hypnovel Smpc. 2008. Roche Products Ltd. Available: 
http://www.medicines.org.uk/EMC/medicine/1692/SPC/Hypnovel+10mg+2ml/.
Ilae 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Commission 
on Classification and Terminology of the International League Against Epilepsy. 
Epilepsia, 30, 389-99.
Lowenstein, DH 1999. Status epilepticus: an overview of the clinical problem. Epilepsia, 40, S3-
8, discussion S21-2.
Mcintyre, J, Robertson, S, Norris, E, Appleton, R, Whitehouse, WP, Phillips, B, Martland, T, 
Berry, K, Collier, J, Smith, S & Choonara, I 2005. Safety and efficacy of buccal 
midazolam versus rectal diazepam for emergency treatment of seizures in children: a 
randomised controlled trial. Lancet, 16-22, 205-10.
Midazolam Hcl Injection Us Prescribing Information. 2009. Roxane Laboratories Inc. Available: 
http://www.drugs.com/pro/midazolam-injection.html [Accessed 27 Apr 2010].
Midazolam Hcl Syrup Us Prescribing Information. 2009. Roxane Laboratories Inc. . Available: 
http://www.drugs.com/pro/midazolam-syrup.html [Accessed 27 Apr 2010].
Mpimbaza, A, Ndeezi, G, Staedke, S, Rosenthal, PJ & Byarugaba, J 2008. Comparison of buccal 
midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan 
children: a randomized clinical trial. Pediatrics, 121, e58-64.
Riviello, JJJ, Ashwal, S, Hirtz, D, Glauser, T, Ballaban-Gil, K, Kelley, K, Morton, LD, Phillips, 
S, Sloan, E, S., S, Subcommittee;, AaON & Society., PCOTCN 2006. Practice parameter: 
diagnostic assessment of the child with status epilepticus (an evidence-based review): 
report of the Quality Standards Subcommittee of the American Academy of Neurology 
and the Practice Committee of the Child Neurology Society. Neurology, 14, 1542-50.
Scott, RC, Besag, FM & Neville, BG 1999a. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Scott, RC, Besag, FM & Neville, BG 1999b. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
353, 623-6.
Shinnar, S, Berg, AT, Moshe, SL, O'dell, C, Alemany, M, Newstein, D, Kang, H, Goldensohn, 
ES & Hauser, WA 1996. The risk of seizure recurrence after a first unprovoked afebrile 
seizure in childhood: an extended follow-up. Pediatrics, 98, 216-25.
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Sirven, JI & Waterhouse, E 2003. Management of status epilepticus. Am Fam Physician, 68,
469-76.
Talukdar, B & Chakrabarty, B 2009. Efficacy of buccal midazolam compared to intravenous 
diazepam in controlling convulsions in children: a randomized controlled trial. Brain 
Dev, 31, 744-9.
Theodore, WH, Porter, RJ & Penry, JK 1983. Complex partial seizures: clinical characteristics 
and differential diagnosis. Neurology, 33, 1115-21.
Treiman, DM, Meyers, PD, Walton, NY, Collins, JF, Colling, C, Rowan, AJ, Handforth, A, 
Faught, E, Calabrese, VP, Uthman, BM, Ramsay, RE & Mamdani, MB 1998. A 
comparison of four treatments for generalized convulsive status epilepticus. Veterans 
Affairs Status Epilepticus Cooperative Study Group. N Engl J Med, 17, 792-8.
Trinka, E, Höfler, J, Leitinger, M & Brigo, F 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, MT, Macleod, S & O'regan, ME 2004. Nasal/buccal midazolam use in the community. 
Arch Dis Child, 89, 50-1.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
12
APPENDICES
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
APPENDIX 2 SCALES AND ASSESSMENTS
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
Riker Sedation-Agitation Scale
1
1999
1
8 Jul 2017
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
SHP615-302 Protocol Amendment 2
SHP615
28 Aug 2017
Version 1, 8 July 2017
For non-commercial use only


PROTOCOL: SHP615-302
TITLE:
A Phase 3, Multicenter, Open-label Extension Study of Buccally 
Administered MHOS/SHP615 in Pediatric Patients with Status 
Epilepticus (Convulsive) in Community Settings
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
, MD
PROTOCOL 
HISTORY:
Original Protocol: 23 Mar 2017
Protocol Amendment 1: 8 Jul 2017
Protocol Amendment 2: 28 Aug 2017
Protocol Amendment 3: 18 Dec 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to Quintiles Transnational Japan K.K., the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor. 
Applicable fax numbers and e-mail address can be found on the form (sent under separate cover). 
A copy of this form must also be sent to the CRO/Shire medical monitor by fax or e-mail using 
the details below.
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor email address: 
For protocol- or safety-related issues during normal business hours, the investigator must 
contact the Quintiles medical monitor:
Quintiles Medical Advisor name, title: 
, 
Quintiles Medical Advisor fax number: 
Quintiles Medical Advisor telephone number: 
Quintiles Medical Advisor mobile number: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the:
Quintiles Medical Advisor mobile number: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
PRODUCT QUALITY COMPLAINTS
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to PMDA as a device 
malfunction report, regardless of whether or not the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
European Union and Rest of World (ROW)
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................12
1
BACKGROUND INFORMATION.......................................................................................19
1.1
Status Epilepticus .....................................................................................................19
1.2
Current Treatment Options.......................................................................................20
1.3
Unmet Medical Need for Buccal Midazolam ..........................................................21
1.4
Product Background and Clinical Information ........................................................21
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Study.............................................................................................23
2.2
Study Objectives ......................................................................................................23
2.2.1
Primary Objectives.................................................................................................23
2.2.2
Secondary Objectives.............................................................................................23
2.2.3
Exploratory Objectives ..........................................................................................24
3
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................25
3.3
Sites and Regions .....................................................................................................26
4
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................28
4.3
Restrictions...............................................................................................................28
4.3.1
Medical Intervention..............................................................................................28
4.4
Reproductive Potential .............................................................................................29
4.4.1
Female Contraception............................................................................................29
4.4.2
Male Contraception................................................................................................29
4.5
Discontinuation of Subjects .....................................................................................29
4.5.1
Subject Withdrawal Criteria ..................................................................................29
4.5.2
Reasons for Discontinuation..................................................................................30
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................31
4.5.4
Stopping Rules.......................................................................................................31
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
4.5.4.1
Study Level Stopping Rules...................................................................31
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria................................31
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ........................................................................................................32
5.2
Concomitant Treatment............................................................................................32
6
INVESTIGATIONAL PRODUCT ........................................................................................33
6.1
Identity of Investigational Product...........................................................................33
6.1.1
Blinding the Treatment Assignment......................................................................33
6.2
Administration of Investigational Product(s)...........................................................33
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dose Regimen and Dose Administration...............................................................34
6.2.2.1
Dosing Regimen.....................................................................................34
6.2.2.2
Dose Administration ..............................................................................34
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................36
6.3.3
Storage ...................................................................................................................36
6.3.4
Special Handling....................................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
6.6
Destruction of Investigational Product.....................................................................38
7
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening Period....................................................................................................39
7.1.2
Baseline Visit.........................................................................................................39
7.1.3
Treatment Period....................................................................................................39
7.1.3.1
Treatment of Seizure in the Community Setting....................................39
7.1.4
Clinic or Hospital Visit..........................................................................................40
7.1.5
Follow-up Period ...................................................................................................41
7.1.6
Additional Care of Subjects after the Study ..........................................................42
7.2
Study Evaluations and Procedures ...........................................................................42
7.2.1
Informed Consent...................................................................................................42
7.2.2
Demographic and Other Baseline Characteristics .................................................42
7.2.3
Efficacy..................................................................................................................42
7.2.4
Safety .....................................................................................................................43
7.2.4.1
Medical and Medication History............................................................43
7.2.4.2
Adverse Event Collection.......................................................................43
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
7.2.4.3
Vital Signs..............................................................................................43
7.2.4.4
Clinical Laboratory Evaluations.............................................................44
7.2.4.5
Pregnancy Test .......................................................................................44
7.2.4.6
Electrocardiogram ..................................................................................45
7.2.4.7
Oxygen Saturation..................................................................................45
7.2.4.8
Physical Examination.............................................................................45
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................46
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................47
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................47
8.1.1
Severity Categorization..........................................................................................47
8.1.2
Relationship Categorization...................................................................................48
8.1.3
Outcome Categorization ........................................................................................48
8.1.4
Symptoms of the Disease Under Study .................................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................48
8.1.6
Pregnancy...............................................................................................................49
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................50
8.2
Serious Adverse Event Procedures ..........................................................................50
8.2.1
Reference Safety Information................................................................................50
8.2.2
Reporting Procedures.............................................................................................50
8.2.3
Serious Adverse Event Definition .........................................................................51
8.2.4
Serious Adverse Event Collection Time Frame.....................................................52
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................52
8.2.6
Fatal Outcome........................................................................................................53
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................53
8.3
Product Quality Complaints.....................................................................................53
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................55
9.1
Data Collection.........................................................................................................55
9.2
Clinical Data Management.......................................................................................55
9.3
Data Handling Considerations .................................................................................55
9.4
Statistical Analysis Process......................................................................................55
9.4.1
Appropriateness of Measurements.........................................................................56
9.4.2
General Considerations..........................................................................................56
9.5
Planned Interim Analysis .........................................................................................56
9.6
Sample Size Calculation and Power Considerations................................................56
9.7
Study Population ......................................................................................................56
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
9.8
Efficacy Analyses.....................................................................................................57
9.8.1
Primary Efficacy Endpoint ....................................................................................57
9.8.2
Secondary Efficacy Endpoints...............................................................................57
9.8.3
Exploratory Efficacy Endpoints.............................................................................58
9.9
Safety Analyses........................................................................................................58
9.9.1
Primary Safety Endpoints ......................................................................................58
9.9.2
Secondary Safety Endpoints ..................................................................................58
9.9.3
Clinical Laboratory Tests.......................................................................................58
9.9.4
Vital Signs..............................................................................................................59
9.9.5
Electrocardiography...............................................................................................59
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................60
10.1
Sponsor’s Responsibilities .......................................................................................60
10.1.1 Good Clinical Practice Compliance.......................................................................60
10.1.2 Public Posting of Study Information......................................................................60
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards............................60
10.1.4 Study Suspension, Termination, and Completion..................................................60
10.2
Investigator’s Responsibilities .................................................................................61
10.2.1 Good Clinical Practice Compliance.......................................................................61
10.2.2 Protocol Adherence and Investigator Agreement..................................................61
10.2.3 Documentation and Retention of Records.............................................................62
10.2.3.1
Case Report Forms.................................................................................62
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................62
10.2.3.3
Audit/Inspection.....................................................................................63
10.2.3.4
Financial Disclosure...............................................................................63
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................63
10.3
Ethical Considerations..............................................................................................63
10.3.1 Informed Consent...................................................................................................63
10.3.2 Institutional Review Board ....................................................................................64
10.4
Privacy and Confidentiality......................................................................................64
10.5
Study Results/Publication Policy .............................................................................65
11 REFERENCES .......................................................................................................................67
12 APPENDICES ........................................................................................................................69
Appendix 1
Protocol History .....................................................................................70
Appendix 2
Scales and Assessments .........................................................................71
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................17
Table 2
Volume of Blood to Be Drawn from Each Subject.......................................46
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
ESE
early status epilepticus
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ILAE
International League Against Epilepsy
IM
intramuscular
IRB
institutional review board
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
MHOS/SHP615
midazolam hydrochloride oromucosal solution
PIP
pediatric investigation plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PQC
Product Quality Complaint 
PUMA
pediatric-use marketing authorisation
ROW
rest of world
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
SAE
serious adverse event
SAP
statistical analysis plan
SE
status epilepticus
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
STUDY SYNOPSIS
Protocol number: SHP615-302
Drug: Midazolam hydrochloride oromucosal solution MHOS/SHP615
Title of the study: A Phase 3, Multicenter, Open-label Extension Study of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in Community Settings
Number of subjects (total): ≥6 subjects
Investigator(s): Multicenter study (in community settings)
Site(s) and Region(s): Approximately 25 sites in Japan
Study period (planned):
October 2017 to September 2019
Clinical phase:
3
Objectives:
Primary:  The primary objective of this study is to assess the efficacy of buccally administered MHOS/SHP615 in 
pediatric subjects with status epilepticus (SE) (convulsive) in the community setting.
Secondary:  The secondary objective of this study is to assess the safety of buccally administered MHOS/SHP615 
in pediatric patients with status epilepticus (SE) (convulsive) in the community setting.
Rationale:  MHOS/SHP615 is expected to be used in both the hospital and community settings. While the efficacy 
and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric subjects with SE in the hospital 
setting in the antecedent pivotal Phase 3 study (SHP615-301), this study is an open-label extension (OLE) study in 
subjects who completed the SHP615-301 study and who tolerated and responded to MHOS/SHP615 treatment. 
The rationale for this interventional OLE study is to determine the safety and efficacy of MHOS/SHP615 
administered buccally by caregivers in subjects who are >6 months and <18 years of age and weight >5kg with 
convulsive SE in community settings.
Investigational product, dose, and mode of administration:
Midazolam hydrochloride oromucosal solution (MHOS/SHP615) is a clear, colorless, ready-to-use solution 
(containing 5 mg midazolam [as hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a 
single, age-specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:
MHOS Dose
Subject Age
2.5 mg
>6 months to <1 year (and weight >5 kg)
5 mg
1 to <5 years
7.5 mg
5 to <10 years
10 mg
≥10 to <18 years
Methodology:  SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label extension (OLE) 
study of MHOS/SHP615 administered buccally by caregivers to subjects who present with SE (convulsive) in 
community settings. Children who are >6 months and <18 years of age and completed the antecedent Phase 3 
pivotal SHP615-301 study, tolerated and responded to treatment with MHOS/SHP615, and subsequently experience 
full seizure in the community setting, are eligible to participate in this study providing all eligibility criteria are met. 
The seizure event(s) must be accompanied by loss of consciousness and can be either generalized tonic clonic or 
start focally and then generalize.
Other procedures/instructions include the following:

Single dose only.
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

The investigator will provide training/education to caregivers, which will include instructions on how to 
buccally administer MHOS/SHP615 and record timing and characteristics of seizures and safety measures. 
Caregivers will be qualified by the investigator to ensure understanding of all the necessary
procedures/materials.

Prior to dosing, the caregiver will organize emergency transport, and all subjects will be brought to the 
study site (hospital or emergency treatment center) immediately, even if the seizure has stopped. A follow-
up visit will take place for medical evaluation, review of adverse events and collection of study materials.

In the event of a medical emergency (including slowing of breathing and other adverse events that may 
require treatment) and it is not possible to bring the subject to the study site, the caregiver will be instructed 
to bring the subject to the closest emergency medical center so that the subject can receive treatment as 
quickly as possible. If this occurs, the caregiver will report the incident and relevant information, including
any rescue treatment received, to the investigator/study site within 7 days after the incident.

The caregiver will be instructed to administer MHOS/SHP615 after confirming that the seizure activity is 
appropriate for MHOS/SHP615 treatment, eg, the seizure lasts at least 5 minutes, a second seizure occurs 
before recovery of consciousness from the first seizure, or 3 seizures have occurred within 1 hour.

The caregiver will record observations on the seizure activity and timing of the seizure(s) in a study diary 
before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, review of adverse 
events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and bring it to the study 
site. Any dosing relating error, such as leaking liquid, etc., are to be recorded in the study diary.
The ability of MHOS/SHP615 to stop prolonged convulsive seizures will be assessed by measuring the percentage 
of subjects whose initial seizure stopped within 10 minutes with a sustained absence of visible seizure activity for 30 
minutes following a single, age-based dose of MHOS/SHP615. If the seizures have not stopped within 10 minutes 
after the administration of MHOS/SHP615 the subject should be treated according to the participating hospital 
protocol or guideline. The safety of MHOS/SHP615 will also be assessed.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Subjects who completed the SHP615-301 study and who tolerated and responded to treatment with 
MHOS/SHP615 in the hospital and/or emergency room, and are considered stable for discharge from the 
hospital.
2.
Subjects who are >6 months and <18 years of age at the time of investigational product administration. If the 
subject’s exact age is not known, the subject should be excluded.
3.
Parent, guardian, or legally authorized representative of the child who provides informed consent and assent 
(when applicable) to participate in the study after initial stabilization of the subject with SE in hospital or 
emergency room during the SHP615-301 study. The subject also provides informed consent prior to 
participation, where applicable.
4.
Subjects with parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including time of seizure 
onset, type of seizure, time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.) 

Follow the necessary instructions to secure the safety of the subject.
5.
Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of consciousness with 
any of the following characteristics persistent at the time of study drug administration:
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the preceding 
hour.

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without recovery of 
consciousness.

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
Exclusion Criteria:
1.
Female subjects who are pregnant, suspected to be pregnant, or nursing.
2.
Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.
3.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
4.
Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5.
Subjects with seizures of psychogenic origin.
6.
Subjects with seizures due to severe cases of encephalitis or meningitis, as determined by the investigator.
7.
Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to benzodiazepines 
(ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia gravis, syndrome of 
sleep apnea, glaucoma with closed angle, or use of use of concomitant drugs determined by the investigator to 
have a contraindication to the use of benzodiazepines.)  
8.
Subjects with a known history of benzodiazepine abuse.
9.
Subjects who have not responded to previous administrations of midazolam systemic therapies, including 
MIDAFRESA and/or DORMICUM.
10. Subjects who need emergent surgical intervention and general anesthesia/intubation.
11. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 
transcriptase inhibitors.
12. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
13. Have used an investigational product or been enrolled in a clinical study (including vaccine studies) that, in the 
investigator's opinion, may impact this Shire-sponsored study.
14. Subject has prior placement of a vagus nerve stimulator.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 1 day

Planned duration of treatment period: 1 day (a minimum of 6 hours observation and up to 24 hours)

Planned duration of follow-up period: 7 days
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects with therapeutic 
success:

Therapeutic success will be defined as: 
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
The secondary efficacy endpoints will include:
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration of 
MHOS/SHP615 and who have sustained absence of seizure activity for the at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE according to the 
participating hospital protocol or guideline, 10 minutes after administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment. 
o
Treatment failure/Nonresponder is defined as continuing seizure activity and/or the need for any 
additional rescue medication in the study site (or another emergency medical institution), 10 
minutes after administration of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures after 
MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 1, 4, 6, and 24 hours post dose (ie, <92% on 
room air for 2 minutes or more after dosing while monitoring [per healthcare setting protocol and/or the 
clinical judgment of the physician]).

Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or 
endotracheal intubation).
The secondary safety endpoints include the following:

Aspiration pneumonia.

Sedation or agitation as measured by the Riker Sedation-Agitation Scale.

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign measurements, laboratory 
tests, oxygen saturation, and electrocardiogram (ECG).

Occurrence of buccal irritation.
Statistical methods: 
Efficacy and safety data will be summarized using descriptive statistics.
Sample size*:  Maximum sample size: approximately 25 subjects
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% expected drop-out 
rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of MHOS/SHP615 in the 
Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response rate in hospital 
settings is conservatively estimated to be 58.5%. This is close to the lowest response rate reported in worldwide 
clinical studies.
Efficacy analysis
Efficacy data of the full analysis set (FAS) will be summarized using descriptive statistics. The FAS will include the 
population of subjects with SE who received a single dose of MHOS/SHP615 and have at least 1 assessment of 
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
therapeutic success performed after the administration of MHOS/SHP615.

Therapeutic success will be defined as:
o
The cessation of visible seizure activity within 10 minutes, with 
o
A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615. 
Safety analysis
Safety data will be summarized using descriptive statistics on the safety set. The safety set will include subjects who 
receive a single dose of MHOS/SHP615. Treatment-emergent adverse events will be summarized and will include 
treatment, seriousness, and severity. Other TEAE data that will be reported in the listings include treatment, 
relationship to MHOS/SHP615, and the time of event onset.
Other safety data (including vital signs, laboratory tests, ECG findings, aspiration pneumonia, Riker Sedation-
Agitation Scale, and oxygen saturation) will be summarized.
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 min
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Informed consent/assent 
X
Inclusion/exclusion criteria
X
Demographics
X
Medical/procedural history
X
Provide study diary and educational 
materials to caregiver
X
Provide training/education to 
caregivers
X
Dispense age-based dose of SHP615 
with administration instructions
X
X
Evaluate seizure symptoms/record 
diary information
X
X
X
X
X
X
X
X
SHP615 administration in 
community setting
X
Riker Sedation-Agitation Scale
Xc
Xc
Xc
Xc
X
Vital signsd
Xe
Xc
Xc
Xc
Xc
Xc
X
Oxygen saturationf
Xc
Xc
Xc
Xc
X
12-Lead ECGg
Xc
Xc
Xc
Xc
X
Laboratory evaluationsh
Xc
Buccal cavity assessmenti
Xc
Xc
Xc
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Table 1
Schedule of Assessments
Assessment
Screening
Treatment Period - Time from SHP615 Administration
Follow-
up
Community Setting
In Hospital
1 week
(±1day)
Seizure 
event onset
5 min
after
Time after MHOS/SHP615 administration
10 
min
30 
(±5min)
1 h
(±10min)
4 h
(±30min)
6 ha
(±30min)
24hb
(±30min)
Physical examination
Xj
X
Supportive care
X
Xk
X
Concomitant medications/recording
X
X
Xk
X
X
Adverse event monitoring/recording
X
Xk
X
X
AE=adverse event; ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute.
a Minimum 6-hour observation period after dosing for safety monitoring and blood sampling. Otherwise monitored per standard medical healthcare setting 
procedure.
b Assessments at the 24-hour post dose time point will be made if the subject has not been discharged from the hospital; or a telephone follow-up call will be 
made to assess AEs and concomitant medications. Patients will be asked to return for additional assessment of ongoing AEs, as needed.
c Performed if subject has arrived at study site.
d Vital signs will include single supine blood pressure, pulse rate, respiratory rate, body temperature; collection of vital signs information will begin as soon as 
possible in community setting or after transfer to healthcare setting.
e Parent, guardian, or legally authorized representative should count respiration rate prior to the administration of investigational product.
f Oxygen saturation should be measured from time of arrival in hospital, (on room air, if feasible). If it is not possible for the subject to have an oxygen 
saturation obtained on room air due to medical concerns, this will be recorded. The investigator will record the oxygen saturation as well as the oxygen 
delivery system and amount of oxygen administered.
g Electrocardiogram should be performed upon arrival at the hospital.
h Laboratory evaluations include serum biochemistry and urinalysis. A urine pregnancy test should be administered to female patients of childbearing age.
i Buccal cavity where MHOS/SHP615 was administered between cheek and gum line will be examined for redness, inflammation, and ulceration and findings
noted on physical examination CRF. 
j Physical examination will be performed at some point between arrival at the hospital and 6 hours postdose, when possible.
k Upon arrival at hospital and across all time periods, as appropriate.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
1
BACKGROUND INFORMATION
1.1
Status Epilepticus
A seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal, 
excessive, and synchronous neuronal activity in the brain. Several seizure types can be described, 
but they all fall into 1 of 2 classifications:  primary generalized seizures (eg, grand mal, petit mal, 
or absence seizures) and partial (focal) onset seizures (ie, localized). Regardless of seizure type, 
most seizures (>90%) last less than a few minutes (<2 minutes) (Theodore et al., 1983). If 
seizures are prolonged or occur in a series, there is an increased risk of status epilepticus (SE), 
which literally means a continuous state of seizure (Epilepsy Foundation, 2015). 
Status epilepticus (SE), a condition resulting either from the failure of the mechanisms 
responsible for seizure termination or from the initiation of mechanisms that lead to abnormally 
prolonged seizures, is a life-threatening neurologic emergency with significant morbidity and 
mortality. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute 
complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and 
cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), 
encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Prompt cessation and 
rapid control of SE is critical to prevent this neurological and systemic pathology (Fountain, 
2000). 
Convulsive SE (CSE), the most common childhood neurological emergency in developed 
countries, can lead to neurocognitive sequelae and death. History with epilepsy is the strongest 
single risk factor for generalized CSE:  15% to 27% of patients with epilepsy will experience at 
least 1 episode of SE; 25% to 40% of SE occurs in patients with epilepsy.
The term SE includes not only epilepsy, but also status of serial convulsive seizures associated 
with febrile convulsion, encephalitis, and encephalopathy. The International League Against 
Epilepsy (ILE) defines SE as a seizure lasting longer than a defined period of time or more than 
1 seizure occurring within a shorter timeframe without return to normalcy between seizures 
(ILAE, 1989). More recently, the minimum seizure duration had been defined as 30 minutes 
(Riviello et al., 2006); however, because epileptic discharge longer than 30 minutes has been 
reported to damage the brain, the diagnosis of SE was subsequently updated to a seizure lasting 
longer than 10 minutes (Treiman et al., 1998) and then more recently, 5 minutes (Alldredge et 
al., 2001), at which time treatment should be promptly initiated. The urgency to treat this 
condition, supported by evidence that seizures rarely last more than a few minutes, led to 
implementation of an operational definition of early status epilepticus (ESE), or seizures lasting 
more than 5 minutes (Dham et al., 2014; Lowenstein, 1999). This definition of SE (ie, seizures 
lasting more than 5 minutes) will be used throughout this study. 
Incidence, cause, and prognosis of pediatric SE vary geographically, as well as by different 
socioeconomic conditions, environments, and genetic susceptibility. The incidence of SE is 
bimodally distributed, occurring most frequently during the first year of life and after age 60 
years. Amongst children (<15 years of age), infants <12 months have the highest incidence and 
frequency of the disease. In Japan, annual incidence in children younger than 17 years is 42 cases 
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
per 100,000 persons. In addition to young age, other risk factors include genetic predisposition 
and acquired brain insults (Fountain, 2000; Shinnar et al., 1996; Berg et al., 1999).
Depending on the type and duration of seizures, if left untreated (or undertreated) SE can cause 
permanent neurological injury (including neuronal death, neuronal injury, and alteration of 
neuronal networks) or death (Trinka et al., 2015). Therefore, a rapid treatment must be initiated.
1.2
Current Treatment Options 
For an anti-epileptic drug to be effective in SE, it is usually administered intravenously (IV) by 
health professionals to provide quick access to the brain without the risk of serious systemic and 
neurological adverse effects (Sirven and Waterhouse, 2003). Multiple drugs are available; the 
first line treatment is benzodiazepines (eg, diazepam and midazolam [midazolam is unauthorized 
for SE in the US]).
The first-choice medication in Japan for treating SE in pediatric patients without venous access is 
diazepam suppositories administered rectally. Rectal diazepam is the medication most commonly 
used throughout the European Union (EU) in the community setting, and is authorized for this 
indication. Diazepam is effective in 60% to 80% of patients but with a risk of early seizure 
recurrence of up to 30% and respiratory depression (McIntyre et al., 2005). The increase of drug 
concentration in the blood is slow by this route; constipation and bowel movements can interfere 
with absorption of drug (Wilson et al., 2004). Rectal administration can be difficult during tonic-
clonic seizures. For wheelchair users, it can be challenging to remove clothing and to insert the 
suppository in a convulsing child. Therefore, the rectal route of administration is not always 
practical, socially acceptable, or convenient.
For resistant cases, phenytoin (or fosphenytoin), phenobarbital, and thiopentone are injectable, 
fast-acting drugs that have strong anti convulsant effects and a positive safety profile. Securing 
vascular access in children, however, is generally more difficult and prolongs stopping the 
convulsion by IV injection upon arrival at the hospital. In the community setting, a therapeutic 
agent that can be administered by a nonmedical expert, such as a parent or caregiver, would be 
more appropriate for emergency treatment. 
For pediatric patients in Japan, midazolam has been used off-label as a first or second choice 
medication for seizures intractable with diazepam treatment. However, since the approval of 
MIDAFRESA Injection 0.1% in 2014, midazolam IV injection is now positioned as first-choice 
medication in Japan for pediatric patients with SE; however, the IV formulation is too dilute to 
use for oromucosal delivery. DORMICUM (an injectable IV formulation of midazolam) is 
frequently administered oromucosally or intranasally, which is considered to be an off-label use 
of this drug.
Accordingly, it has been recognized that there is an unmet need for an effective, fast-acting 
treatment that can easily be administered by a more convenient route and by individuals other 
than medical experts and that is suitable for use in both the healthcare setting and community 
(Scott et al., 1999).
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs outlined above, it has been common practice to administer 
midazolam buccally (oromucosal administration of other midazolam formulations) off-label for 
the treatment of SE. Buccal administration does not cause pain or distress to the patient or 
require that the patient be in the prone position. 
Currently, the national average time in Japan for patients with SE to be transported to the 
healthcare setting is 39.6 minutes. In many cases as much as 50 minutes has been reported until 
medical treatment has been received at the healthcare setting. Buccal midazolam treatment in 
children with seizures could be started at home by trained clinical personnel, family members, or 
caregivers before securing vascular access, as well as after arriving at a medical institution, thus 
potentially reducing life-threatening risks of brain disorders (eg, encephalopathy) and other 
sequelae due to prolonged seizures and resulting from delays in getting the child to a healthcare 
setting.
1.4
Product Background and Clinical Information
The investigational product midazolam hydrochloride oromucosal solution (hereafter referred to 
as MHOS/SHP615) contains 5 mg/mL of the active substance midazolam and has been 
specifically developed for the buccal administration of midazolam in children with SE. 
Currently, there is extensive clinical experience with midazolam as it is authorized for use in 
children (including neonates <32 weeks gestational age in intensive care units) and adults as a 
sedative and in anesthesia and may be given by the intravenous (IV), intramuscular (IM), or 
rectal route of administration. As midazolam undergoes significant first pass metabolism in both 
the small intestine and the liver, a systemic drug delivery system was selected for 
MHOS/SHP615. In suspension, midazolam is water soluble and, therefore, readily absorbed via 
the buccal mucosa. At physiological pH the drug becomes lipid soluble, which enables it to cross 
the blood-brain barrier. In addition, its pharmacokinetic (PK) parameters such as the short 
elimination half-life (1.5-2.5 hours) and rapid plasma clearance (300-500 mL/min) are optimal 
for a rescue medication (Hypnovel SmPC, 2008). The buccal mucosa, with its expanse of smooth 
muscle and relative immobility, makes it a desirable region for retentive systems used for oral 
transmucosal drug delivery.
MHOS/SHP615 has a formulation essentially identical to its authorized originator product, a 
systemically administered midazolam hydrochloride (HYPNOVEL® Injection 10 mg/2 mL [EU], 
VERSED® Oral Syrup 2 mg/mL now marketed generically [US], and DORMICUM Injection 10 
mg [Japan]) used for sedation or anesthetic premedication. When approved in Japan, 
MHOS/SHP615) will provide major advantages over unauthorized/off-label buccal midazolam 
preparations and other formulations of authorized rescue medication (such as IV, IM, or rectal 
routes of administration) currently used for SE.
In the EU, MHOS is commercially known as BUCCOLAM®, a nonintravenous treatment to stop 
seizures (including convulsive seizures). An oromucosal solution, BUCCOLAM contains 5 
mg/mL of the active substance midazolam and was approved in the EU on 05 Sep 2011 for the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
treatment of prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents 
(from 3 months to ≤18 years). Parents and/or caregivers are allowed to administer BUCCOLAM 
only to patients older than 6 months who have been diagnosed with epilepsy. For infants between 
3 and 6 months of age, treatment should be in a hospital setting, where close medical supervision 
and resuscitation equipment are available.
Efficacy
The age range proposed for the SHP615-301 study is >52 weeks corrected gestational age 
(gestational weeks plus the number of weeks after birth) to <18 years. The efficacy and safety of 
buccal midazolam in this age range have been established in 4 pivotal, rectal-diazepam-
controlled clinical studies. These studies all used the HYPNOVEL 10 mg/2 mL formulation 
delivered buccally. All 4 studies demonstrated that buccal midazolam was either more effective 
than or as effective as rectal diazepam for the treatment of acute seizures in children (licensed 
indication and dosage of diazepam). However, the meta-analysis of the 3 (standard randomized) 
pivotal studies (Mpimbaza et al., 2008; McIntyre et al., 2005; Scott et al., 1999) (comprising a 
total of 628 seizure events [525 patients]) demonstrated that buccal midazolam is significantly 
more effective than rectal diazepam in stopping seizures within 10 minutes (Mantel-Haenszel 
Weighted Risk Ratio [buccal midazolam/rectal diazepam] of 1.24 [95% CI: 1.11 - 1.39] p = 
0.0002). 
In a study vs IV diazepam (Talukdar and Chakrabarty, 2009), the buccal midazolam dose was 
slightly lower than that used in the pivotal rectal diazepam studies (0.2 mg/kg vs ~0.25-
0.5 mg/kg in the pivotal studies). Nevertheless, this study supported the results of the pivotal 
studies and meta-analysis. It demonstrated that buccal midazolam is an effective treatment for 
acute seizures with no statistically significant difference compared with IV diazepam for overall 
control of convulsive episodes within 5 minutes (85% vs 93.3% in buccal midazolam vs IV 
diazepam groups, respectively; p = 0.142). 
Safety
The clinical safety profile of midazolam (and other benzodiazepines) for the authorized uses are
well established (and summarized in the EU and US labeling [HYPNOVEL SMPC, 2008; 
Midazolam HCl Injection US Prescribing Information, 2009; Midazolam HCl Syrup US 
Prescribing Information, 2009]). The main adverse effects (reported to occur rarely for 
HYPNOVEL) and precautions applicable to the buccal route of administration in children include 
cardiorespiratory adverse events (respiratory depression, apnea, respiratory arrest, and/or cardiac 
arrest), anterograde amnesia, and paradoxical reactions. Precautions are required for patients 
with impaired respiratory function or cardiovascular instability. Pediatric patients less than 
6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Always refer to the latest version of the (MHOS)/SHP615 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of (MHOS)/SHP615. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the hospital or community settings. The rectal route 
of administration, however, is not always practical, socially acceptable, or convenient. 
The need to remove clothing and the difficulty with rectal administration during seizures, 
particularly for wheelchairs users, is socially embarrassing or unacceptable by some individuals, 
parents, or caregivers. 
MHOS/SHP615 is expected to be used in both the hospital and community settings. While the 
efficacy and safety of buccally administered MHOS/SHP615 will be evaluated in pediatric 
subjects with SE in the hospital setting in the antecedent pivotal Phase 3 study (SHP615-301), 
this study is an open-label extension study in subjects who completed the SHP615-301 study and 
who tolerated and responded to MHOS/SHP615 treatment.
MHOS/SHP615 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg midazolam) presentation for children. The 4 different, age-
specific, fixed-dose presentations were selected as a convenient oromucosal administration of 
midazolam injectable solution to enable rapid treatment in the emergency and community 
settings where individual dosing by body weight is not feasible (except for infants aged from 3 
months to <6 months: this age population should be treated in a healthcare setting only). This 
dosing regimen was evaluated extensively by the European Medicines Agency (EMA) Pediatric
Committee as part of the pediatric investigation plan (PIP) application and by the EMA 
Committee for Medicinal Products for Human Use (CHMP) as part of the review and approval 
of the pediatric-use marketing authorisation (PUMA).
The rationale for this interventional OLE study is to determine the safety and efficacy of 
MHOS/SHP615 administered buccally by caregivers in pediatric subjects with CSE in 
community settings. 
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of buccally administered 
MHOS/SHP615 in pediatric subjects with status epilepticus (SE) (convulsive) in the community 
setting.
2.2.2
Secondary Objectives
The secondary objective of this study is to assess the safety of buccally administered 
MHOS/SHP615 in pediatric patients with status epilepticus (SE) (convulsive) in the community 
setting.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
3
STUDY DESIGN
3.1
Study Design and Flow Chart
Study SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label 
extension (OLE) study of MHOS/SHP615 administered buccally by caregivers to pediatric 
subjects who present with SE (convulsive) in community settings. Children who are >6 months 
and <18 years of age and completed the antecedent Phase 3 pivotal SHP615-301 study, tolerated 
and responded to treatment with MHOS/SHP615, subsequently experience full seizure in the 
community setting, have not received immediate treatment, and have parent, guardian, or legal 
representative consent/assent, are eligible to participate in this extension study providing all 
eligibility criteria are met. The seizure event(s) must be accompanied by loss of consciousness 
and can be either generalized tonic clonic or start focally and then generalize.
This study consists of a 24-hour, open-label treatment period followed by a 1-week safety 
follow-up period. After completing Study SHP615-301, the subject’s parent, guardian, or legal 
representative will be dispensed a single oral, prefilled syringe of MHOS/SHP615 stratified by 
age (2.5, 5, 7.5, 10 mg buccally) along with a diary and training on how to administer the drug 
and record details associated with the seizure. Upon the onset of the next seizure in the home, 
school, or community setting, the parent, guardian, or legal representative will administer the
single MHOS/SHP615 treatment as trained.
The efficacy of MHOS/SHP615 in treating SE will be assessed by measuring the percentage of 
subjects whose seizure stopped within 10 minutes, with a sustained absence of visible seizure 
activity for 30 minutes following a single, age-based dose of MHOS/SHP615. If the seizures 
have not stopped within 10 minutes, and/or if a serious AE (SAE) emerges, the subject should be 
treated according to the participating hospital protocol or guideline. The caregiver/parent and 
subject must visit the study site for examination as soon as possible following MHOS/SHP615
administration, even if the seizure has stopped. All subjects will be followed up at study sites
even if the seizure resolves. The safety of MHOS will also be assessed. 
Subjects will be monitored by vital signs, laboratory tests, and electrocardiograms (ECGs) for 
safety evaluations. All subjects treated in this study will be followed for 1 week after the 
administration of MHOS/SHP615 for safety evaluations. The caregiver will record observations 
on seizure activity, timing of the seizure(s), and dosing relating errors in a study diary.
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 1 week. The 
study will be completed in approximately 2 years. 
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment, or is discontinued early. Please note that this includes the 
follow-up visit or contact, whichever is later. The study completion date is used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
3.3
Sites and Regions
This study will be conducted in approximately 25 study sites in Japan.
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
4
STUDY POPULATION
The total enrollment for the SHP615-302 study is expected to be ≥6 subjects with active 
generalized tonic-clonic SE with seizures. Diagnosis of SE will be confirmed through an
evaluation of seizure symptoms conducted and documented by the caregiver at the time of the 
event.
Each parent, guardian, or legal representative (and/or the subject, where necessary) must 
participate in the informed consent process and provide written informed consent/assent before 
any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator
before subjects are included in the study.
The subjects will not be considered eligible for the study without meeting all of the criteria 
below.
1. Subjects who completed the SHP615-301 study and who tolerated and responded to
treatment with MHOS/SHP615 in the hospital and/or emergency room, and are considered 
stable for discharge from the hospital.
2. Subjects who are >6 months and <18 years of age at the time of investigational product 
administration. If the subject's exact age is not known, the subject should be excluded.
3. Parent, guardian, or legally authorized representative of the child who provides informed 
consent and assent (when applicable) to participate in the study after initial stabilization of 
the subject with SE in hospital or emergency room during the SHP615-301 study. The 
subject also provides informed consent prior to participation, where applicable.
4. Parent, guardian, or legally authorized representative who have received appropriate 
training/education and are deemed qualified by the investigator and are willing to:

Properly administer MHOS/SHP615.

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, time necessary to administer MHOS/SHP615, time 
between MHOS/SHP615 administration to seizure cessation, etc.)

Follow the necessary instructions to secure the safety of the subject.
5. Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of 
consciousness with any of the following characteristics persistent at the time of study drug 
administration:

Currently presenting with seizure (convulsive) activity and 3 or more convulsions within 
the preceding hour

Currently presenting with seizure (convulsive) and 2 or more convulsions in succession 
without recovery of consciousness.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Currently presenting with a single seizure (convulsive) persisting ≥5 minutes.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Female subjects who are pregnant, suspected to be pregnant, or nursing.
2. Subjects with major trauma, not necessarily restricted to the head, as the cause of the 
seizure.
3. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
4. Subjects with seizures due to illegal drug or acute alcoholic intoxication.
5. Subjects with seizures of psychogenic origin.
6. Subjects with seizures due to severe cases of encephalitis or meningitis, as determined by 
the investigator.
7. Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic 
failure, myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, or use of
concomitant drugs determined by the investigator to have a contraindication to the use of 
benzodiazepines.)    
8. Subjects with a known history of benzodiazepine abuse.
9. Subjects who have not responded to previous administrations of midazolam systemic 
therapies, including MIDAFRESA and/or DORMICUM.
10. Subjects who need emergent surgical intervention and general anesthesia/intubation.
11. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors 
or HIV reverse transcriptase inhibitors.
12. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
13. Have used an investigational product or been enrolled in a clinical study (including vaccine 
studies) that, in the investigator’s opinion, may impact this Shire-sponsored study.
14. Subject has prior placement of a vagus nerve stimulator.
4.3
Restrictions
4.3.1
Medical Intervention
There will be no special restrictions on medical interventions deemed necessary by the 
investigator for the health and wellbeing of the subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine pregnancy test at screening/baseline. 
Females of childbearing potential must agree to abstain from sexual activity that could result 
in pregnancy or agree to use medically acceptable methods of contraception.
Medically acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms with spermicidal agent)

Oral hormonal contraceptives, stabilized for at least 30 days prior to the administration of 
investigational product, plus condoms. 
4.4.2
Male Contraception
Males should use condoms if they are sexually active for 7 days after administration of study 
drug and must not donate or use sperm for the purposes of making a woman pregnant until 7 
days after the administration of study drug.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
A subject will be withdrawn from the study when they turn 18 years of age.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Subjects may withdraw from active treatment within the treatment period at any time at their 
own request, or they may be withdrawn at any time at the discretion of the investigator or 
sponsor for safety, behavioral, or administrative reasons. Additional reasons a subject may be 
withdrawn from active treatment include but are not limited to, adverse event (AE), SAE, 
protocol violations, and failure to return for visits. 
If a subject is withdrawn for whatever reason within a week following administration of study 
drug, the evaluations listed for the 1-week follow-up visit are to be performed as completely as 
possible. The reason for termination and date of stopping the study must be recorded in the case 
report form (CRF) and source documents.
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. In any circumstance, every effort should be made to document subject outcome, if 
possible. The investigator should inquire about the reason for withdrawal, request the subjects to 
return for a final visit, if applicable, and follow-up with the subject regarding unresolved adverse 
events. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluation should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF. 
Reasons for discontinuation include but are not limited to:

Adverse events

Protocol deviation

Withdrawal by subject

Lost to follow-up

The sponsor or investigator terminates the study.

Withdrawal/discontinuation due to AEs should be distinguished from withdrawal due to other 
causes, according to the definition of AE noted earlier, and recorded on the appropriate AE 
electronic case report form (eCRF) page. When a subject withdraws because of an SAE, the SAE 
must be reported in accordance with the reporting requirements defined in Section 8.2.
Sponsor Discontinuation Criteria
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the institutional review board (IRB)/EC, investigational product safety problems, or 
at the discretion of the sponsor.  In addition, the sponsor retains the right to discontinue 
development of MHOS/SHP615 at any time.
If a study is prematurely terminated or discontinued, the sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects, subject’s 
parents, guardians, or legally authorized representatives, and the hospital pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all eCRFs completed to the greatest extent possible.
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent, guardian, or legally 
authorized representative of any subject lost to follow-up. At least 1 of these documented 
attempts must include a written communication sent to the parents, guardians, or legally 
authorized representatives at subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations.
4.5.4
Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if 1 or more of the 
following criteria are met:

Death that is considered related to the study drug.

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities [MedDRA] higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety lead physician and the Global Drug Safety therapeutic area head. Following 
the sponsor’s review of safety data, 1 of the following actions will be taken with respect to study 
status:

Continue study with protocol unchanged;

Continue study with modifications to the protocol; or

Terminate study.
Subject safety will be monitored on a continuous basis during this study until the last subject
completes his or her last scheduled study visit/assessment, or has discontinued from the study.
4.5.4.1
Study Level Stopping Rules
Safety data, including SAEs and adverse events of special interest (AESIs), will be monitored 
regularly throughout the duration of the study and submitted to Regulatory Authority(ies), as 
appropriate. If any potential safety signal is identified during safety monitoring in this study by 
the sponsor and/or following a safety data review, a comprehensive analysis of the issue will be 
undertaken by the sponsor. As a result of this assessment, the sponsor may take actions as 
deemed appropriate (which may include changing or suspending dosing in the study).
4.5.4.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or toxicity considered clinically relevant (AE, laboratory, 
physical examination, vital sign, or ECG finding) will be carefully monitored until resolution, 
which may include the following:

Additional clinical laboratory tests and/or other clinical investigations,

Additional visits or extended duration of follow-up, 

Obtaining a specialist consultation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
5
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) received within 
30 days prior to the administration of investigational product and through the final study contact 
(including protocol defined follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, nonpharmacological treatment, such as psychotherapy, as appropriate) 
received within 30 days of the date of investigational product administration. Prior treatment 
information must be recorded on the appropriate CRF page.
Medications taken during screening, before administration of the MHOS/SHP615 dose, will be 
documented as prior medications.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the time of the investigational 
product administration and the end of the follow-up period, inclusive. All concomitant 
medication(s) and treatment(s) during the study must be recorded on the appropriate CRF page, 
with indication, daily dose, start and stop dates of administration. All subjects (or 
parents/caregivers) will be questioned about concomitant medication during their follow-up visit.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
MHOS/SHP615 is a clear, colorless, ready-to-use solution (containing 5 mg midazolam [as 
hydrochloride] per mL). MHOS/SHP615 has been specifically developed as a single, age-
specific, fixed dose (approximately 0.25 to 0.5 mg/kg as midazolam) formulation for buccal 
administration in children, 1 dosage per each of the following age groups:

2.5 mg (yellow label) ages >6 months to <1 year (and weight >5 kg)

5 mg (blue label) ages 1 year to <5 years

7.5 mg (purple label) ages 5 years to <10 years

10 mg (orange label) ages ≥10 to <18 years 
The investigational product MHOS/SHP615 will be provided in prefilled single-use, ready-to-
use, amber, age-specific, and color-coded oral dosing syringes, and is to be administered by the 
buccal (oromucosal) route. The full amount of solution will be delivered slowly into the space 
between the inside of the cheek and the lower gum. 
If at some point after entering the study, and prior to having a seizure, the subject ages from 1 
age category to the next, the parent/caregiver must return to the study site in order to exchange 
study drug supply for the appropriate dose.
Buccal (oromucosal) administration was considered to be an appropriate route to be progressed 
to address the unmet need for a convenient, fast–acting product suitable for use in both the 
community and hospital setting. Additional information is provided in the current version of the 
SHP615 midazolam investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment 
This is an open-label, nonrandomized study; therefore, assignment to MHOS/SHP615 will be 
unblinded to the investigators, subjects, caregivers, and the sponsor study team. Study treatment 
will only be administered by caregivers to subjects who have a signed and dated IRB-approved 
informed consent form (ICF) and who have met all eligibility criteria. 
All subjects enrolled in the study will receive treatment with the investigational product based on 
their age (Section 6.2.2.1).
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
to the sequence of presentation for study participation. This identifying number will be retained 
throughout the study.
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If an identifier is allocated incorrectly, the clinical research
associate (CRA)/study monitor must be notified as soon as the error is discovered. 
6.2.2
Dose Regimen and Dose Administration
MHOS/SHP615 will be administered buccally by caregivers as a single, fixed dose product, 
banded by age to subjects with SE (convulsive) in community settings. For buccal 
administration, midazolam is administered into the space between the lower gum and the inside 
of the cheek.
6.2.2.1
Dosing Regimen
Details of subject dosing and follow-up are outlined in Section 3.1 and included in the Schedule 
of Assessments (Table 1).
There are 4 single, fixed, banded by age, dose regimens of the MHOS/SHP615 formulation for 
the treatment of SE; 1 dosage per buccal administration for each of the following age groups:

2.5 mg
>6 months to <1 year (and weight >5kg)

5 mg
1 to <5 years

7.5 mg
5 to <10 years

10 mg
≥10 to <18 years
6.2.2.2
Dose Administration
Before dosing:

The airway should be secured and respiratory and cardiac function assessed.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.

The caregiver will organize emergency transport, and all subjects will be brought to the 
study site immediately (hospital or healthcare center), even if the seizure has stopped.
Single-dose administration:

The caregiver will be instructed to administer a single dose of MHOS/SHP615 after 
confirming that the seizure activity is appropriate for MHOS/SHP615 treatment (eg, the 
seizures last at least 5 minutes or a second seizure occurs before recovery of 
consciousness from the first seizure, or 3 seizures occur within 1 hour).

Only 1 oral syringe with the specified dose must be given. The full amount of the 
MHOS/SHP615 prefilled oral dosing syringe is administered slowly into the buccal 
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
mucosa. In some cases, it might be necessary to divide the dose so that half of the 
solution is administered into each side of mouth.  
After dosing

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary.

If the seizure has not stopped within 10 minutes of administration, and/or if a serious AE 
(SAE) emerges, then emergency medical assistance must be sought. 

Note:  A second or repeat dose of MHOS/SHP615 should not be given even if the seizure 
recurs after an initial response.

In the event of a medical emergency, and it is not possible to bring the subject to the 
study site, the caregiver will be instructed to bring the subject to the closest emergency 
medical institution so that the subject can receive treatment as quickly as possible. If this 
occurs, then the caregiver will report the incident and relevant information, including any 
rescue treatment received, to the investigator/study site within 1 week after the incident.

The caregiver/parent and subject must visit the study site for examination after 
MHOS/SHP615 administration, even if the seizure stops. All subjects will be followed up 
at study sites even if the seizure resolves.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating errors (such as leaking liquid, etc.) are to be 
recorded in the study diary.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
A computer-generated label is applied to the investigational product. All investigational product 
is labeled with a minimum of the protocol number, pack number (if applicable), dosage form 
(including product name and quantity in pack), directions for use, storage conditions, expiry date 
(if applicable), batch number and/or packaging reference, the statements “For clinical trial use 
only” and the name and country of the sponsor and contract research organization (CRO) name 
and address. Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
A single dose of the investigational product MHOS/SHP615 will be provided in an individual, 
labeled, single-dose, prefilled plastic, oral dosing syringe available in 4 different, age-specific, 
color-coded doses (2.5, 5, 7.5, and 10 mg dose packs) in a protective plastic tube which is
packaged and dispensed in cartons with tamper-evident seals. The cartons should not be opened 
until the investigational product is to be administered.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
Keep the oral dosing syringe containing the investigational product in the protective plastic tube. 
Keep at or below 25°C (77°F). Do not refrigerate or freeze.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The subinvestigator/designated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
6.3.4
Special Handling 
Investigational product for the sponsor’s studies must be stored according to all applicable local, 
state, and/or national laws. 
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
The investigator will provide or supervise the training of investigational product administration 
to the designated caregivers. Where permissible, tasks may be delegated to a qualified designee 
(eg, a pharmacist) who is adequately trained in the protocol and who works under the direct 
supervision of the investigator. This delegation must be documented in the applicable study 
delegation of authority form.
The caregiver will administer the investigational product only to subjects included in this study 
following the training provided by the investigator or his/her designee as set out in the study 
protocol. Each subject will be given only the investigational product corresponding to his/her 
treatment assignment. All administered investigational product will be documented on the CRFs 
and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor (or designated CRO). For unused 
supplies where the original supplied tamper-evident feature is verified as intact, the 
tamper-evident feature must not be broken and the labeled amount is to be documented in lieu of 
counting. Shipment return forms, when used, must be signed prior to shipment from the site. 
Returned investigational products must be packed in a tamper-evident manner to ensure product 
integrity. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws.
The investigative site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product supplies.
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
6.5
Subject Compliance
Subjects/caregivers must be instructed to bring unused investigational product and empty/used 
investigational product packaging to the follow-up visit. Drug accountability must be assessed at 
the container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container or at the individual count level for opened 
containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.   
6.6
Destruction of Investigational Product 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by the sponsor, and all 
destruction must be adequately documented.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
7
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (Table 1).
7.1.1
Screening Period 
Screening for subject eligibility into this study occurs on the same day as baseline (Visit 1) for 
Study SHP615-301. This includes an assessment of inclusion/exclusion criteria.  
7.1.2
Baseline Visit 
Baseline Visit 1 will be conducted after the follow-up visit for study SHP615-301.
Written informed consent must be obtained prior to performing any protocol specific procedures. 
The following procedures will be performed:

Informed consent/assent 

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Provide study diary and educational materials to caregiver

Provide training/education to caregiver

Dispense study drug

Review concomitant medications/treatments
7.1.3
Treatment Period 
7.1.3.1
Treatment of Seizure in the Community Setting
At the onset of a seizure the caregiver will:

Confirm the seizure activity is appropriate for MHOS/SHP615 treatment, eg, the seizure 
lasts at least 5 minutes or a second seizure occurs before recovery of consciousness from 
the first seizure or 3 seizures occur within 1 hour.

Before dosing, the caregiver will organize emergency transport, and all subjects will be 
brought to the study site immediately (hospital or emergency treatment center), even if 
the seizure has stopped. A clinical visit will take place for medical evaluation, review of 
adverse events and collection of study materials.

If possible, count and record respiratory rate; collection of vital signs information will 
begin as soon as possible in community setting or after transfer to healthcare setting.

Properly administer MHOS/SHP615 once SE is confirmed.
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Follow the necessary instructions to secure the safety of the subject. 

Record seizure information and dosing of MHOS/SHP615 in a subject diary (including 
time of seizure onset, type of seizure, characteristics of seizures and safety measures, 
time necessary to administer MHOS/SHP615, time between MHOS/SHP615 
administration to seizure cessation, etc.)

In the event of a medical emergency, the caregiver will be instructed to bring the subject
to the closest emergency medical institution if the subject is having a medical emergency 
(including slowing of breathing and other adverse events that may require treatment) and 
it is not possible to bring the subject to the study site so that the subject can receive 
treatment as quickly as possible. If this occurs, then the caregiver will report the incident 
and relevant information, including any rescue treatment received, to the 
investigator/study site within 1 week after the incident.

The caregiver will record observations on the seizure activity and timing of the seizure(s) 
in a study diary, before and after administering MHOS/SHP615.

A follow-up visit will take place after approximately 7 days for medical evaluation, 
review of adverse events and collection of study materials.

Caregivers will be instructed to save the used MHOS/SHP615 oral dosing syringe and 
bring it to the study site. Any dosing relating error, such as leaking liquid, etc., are to be 
recorded in the study diary.
7.1.4
Clinic or Hospital Visit
Once the subject has been transported to the clinic or hospital, staff will conduct assessments and 
supportive care as outlined in Table 1. 
The investigator or subinvestigator should obtain seizure information and dosing of 
MHOS/SHP615 from the subject diary or the subject’s parent, guardian, or legally authorized 
representative.
If the seizure continues or recurs, the subject should be treated according the procedures in use at 
the clinic or hospital.
The subjects should remain in the hospital under observation for at least 6 hours and up to 24 
hours after hospital arrival (as needed).
The following procedures will be performed:

Evaluate seizure symptoms (by caregiver in the community or by PI once at the site) at 
10 and 30 (±5) minutes, and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) 
hours post dose.

Evaluate Riker Sedation Agitation Scale (once subject arrives at hospital or clinic) at 30 
(±5) minutes (if possible), and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) 
hours post dose.
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Assess buccal cavity where MHOS/SHP615 was administered between cheek and gum 
line for redness, inflammation, and ulceration at 1 (±10 min), 4 (±30 min), and 6 (±30 
min) hours postdose.

6 hours (±30 min) post dose: Obtain blood and urine samples for safety laboratory tests 
for serum biochemistry and urinalysis.

10 and 30 (±5) minutes, and 1, 4, 6, and 24 hours (±30 min) post dose (if subject has not 
been discharged from the healthcare setting): 

Measure vital signs: single supine blood pressure (BP), pulse rate, respiratory rate, 
temperature (°C or °F).

30 minutes*, 1 hour (±10 min) and 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours  
post dose if subject has not been discharged from the healthcare setting: 

Measure oxygen saturation (on room air, if feasible).

Perform standard 12-lead ECG.
*If possible, by EMT or at the site.

Administer supportive care.

Review and record concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
laboratory sampling).

Perform physical examination when possible during the 6 hour time period.
Note:  Evaluate by telephone if subject is discharged between 6 hours (±30 min) and 24 hours 
(±30 min) after SHP615 administration.

Telephone contact: The subject’s parent or caregiver should be contacted by telephone by 
the investigator or subinvestigator at the site to assess the status of the subject at 
approximately 24 hours after SHP615 administration, specifically to collect AE and SAE 
information. If the subject, parent, or caregiver reports significant AEs, the subject should 
be requested to return to the site for a more thorough evaluation as soon as possible. The 
telephone contact for all subjects should be clearly documented in the source documents.
7.1.5
Follow-up Period
The follow-up period for this protocol is 7 days (± 1 day). 
At the end of this period there will be a telephone call initiated by the site staff/follow-up visit to 
evaluate seizure symptoms, serious adverse events (SAEs), adverse events (AEs), and 
concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (see Section 8.1). In addition, caregivers will be asked to complete the 
.
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to perform 
the test. In these cases the investigator will take all steps necessary to ensure the safety and well-
being of the subject. When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions that he or she has taken to 
ensure that normal processes are adhered to as soon as possible. The study team will be informed 
of these incidents in a timely fashion.
7.2.1
Informed Consent
The ICF must be executed prior to performing any study-related activities and must be approved 
by the reviewing institutional review board (IRB). Subjects may withdraw consent at any time. 
Participation in the study may be terminated at any time without the subject’s consent as 
determined by the investigator. Due to the potential for long periods between initial consent and 
treatment, the investigator should, every 3 months, either have the parent, guardian, or legally 
authorized representative resign and date the latest consent form(s), or document phone contact 
with the parent, guardian, or legally authorized representative confirming ongoing interest and 
willingness to participate in the study.
7.2.2
Demographic and Other Baseline Characteristics
Demographics: date of birth, sex, race and ethnicity (where locally permitted) and medical 
history will be obtained at screening from subjects, parents, or caregivers and will be recorded on 
the source document and eCRF.
Medical history (including SE, smoking, and cardiovascular history) will capture the subject’s 
current medical status (current SE or CSE disease processes), past medical status (past disease 
processes), history of surgery, allergies, and concomitant medications/treatments.
7.2.3
Efficacy
Methods of measuring the efficacy of MHOS/SHP615 in SE that will be used throughout the 
study are described in this section. 
Information recorded in the subject diary by the caregiver along with evaluation by the 
investigator or subinvestigator will be used to evaluate the seizure and its duration, type (focal, 
generalized, convulsive or nonconvulsive), and recurrence. The other criteria are those set in the 
study protocol to define the treatment efficacy and include time of cessation and need for 
additional rescue medication.
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
7.2.4
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Any AE related to either efficacy or safety should be first recorded by the caregiver using a 
comprehensive study diary and other materials, and then finally verified by the investigator.
7.2.4.1
Medical and Medication History
Medical history is collected at the time points specified in the Schedule of Assessments (Table 
1).
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE or CSE (eg, dietary, medication, or other), must be 
recorded on the appropriate eCRF page.
7.2.4.2
Adverse Event Collection
At each assessment time point, subjects will be questioned/evaluated in a general way to 
ascertain if AEs have occurred since the previous time point. Adverse events are collected from 
the time of the seizure event onset. (Please refer to Section 8, Adverse and Serious Adverse 
Events Assessment.)
7.2.4.3
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment include blood pressure (systolic and diastolic), pulse rate, respiration rate, 
and body temperature to be performed at the time points specified in the Schedule of 
Assessments (Table 1). Additional collection times or changes to collection times will be 
permitted, as necessary to ensure appropriate collection of safety data.
Supine blood pressure will be measured with the subject’s arm supported at the level of the heart, 
and recorded to the nearest mm Hg. It is preferred that the same arm (preferably the dominant 
arm) will be used throughout the study. The same size BP cuff that has been properly sized and 
calibrated will be used to measure BP each time.
The use of automated devices for measuring BP and pulse rate are acceptable, although, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. 
When the timing of these measurements coincides with a blood collection, all vital signs should 
be obtained prior to the nominal time of the blood collection.
It is preferred that body temperature be collected using tympanic, oral, or axillary methods and 
that the same method be used consistently throughout the study.
Any clinically significant deviations from baseline vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
7.2.4.4
Clinical Laboratory Evaluations
The following clinical laboratory assessments will be performed at times defined in the Schedule 
of Assessments (Table 1):
Chemistry
Urinalysis
Other
BUN and Creatininea
Glucose (fasting if possible)
Calcium (total)
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Direct bilirubinb
Indirect bilirubinb
Alkaline phosphatase
Albumin
Total protein
Bicarbonate
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Specific gravity
Microscopyc
Urine pregnancyd
ALT = alanine aminotransferase ; AST = aspartate aminotransferase.
a Creatinine clearance determination by central lab using Schwartz method.
b Only if total bilirubin is elevated. 
c Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
d Complete for women of childbearing potential.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
Blood samples for laboratory assessments will be collected at the site by a trained phlebotomist 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
laboratory manual. 
Biological material will be stored and secured in a manner that assures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed.
7.2.4.5
Pregnancy Test
A urine pregnancy test is performed on all females of child-bearing potential after the subject is 
transferred to the hospital, emergency room, or clinical site.
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
7.2.4.6
Electrocardiogram 
A standard twelve (12)-lead electrocardiogram (ECG, single recording) will be performed after 
MHOS/SHP615 administration and subject is transferred to the hospital, emergency room, or 
clinical site.
All scheduled ECGs should be performed after the subject has rested quietly for at least 10 
minutes in a supine position (if feasible). When the timing of these measurements coincides with 
a blood collection, the ECG should be obtained prior to the nominal time of the blood collection, 
BP, and pulse rate.
To ensure safety of the subjects, the investigator or subinvestigator at the investigator site will 
make comparisons to baseline measurements taken at screening. A copy of the ECG should be 
available as source documents for review.  
7.2.4.7
Oxygen Saturation
Oxygen saturation will be measured at time points specified (on room air, if feasible), in the 
Schedule of Assessments (Table 1). Oxygen saturation at baseline will be measured and recorded 
(on room air, if feasible) in the emergency room.
If it is not possible for the subject to have an oxygen saturation obtained on room air due to 
medical concerns, this will be recorded and the investigator will record the oxygen saturation of 
the patient while on oxygen therapy as well as the oxygen delivery system and amount of oxygen 
administered (eg, 2 L/min via nasal cannula).
7.2.4.8
Physical Examination
A complete physical examination will be performed at some time point between dosing (0 
minute) and 6 hours post-dose, and at 24 hours post dose (if subject has not been discharged 
from the healthcare setting). 
Complete physical examinations must be performed by the investigator or subinvestigator in 
accordance with standards at the site and per local guidelines. Complete physical examinations 
consist of assessments of:

General appearance 

Skin

Head, eyes, ears, nose, and throat; buccal cavity where MHOS/SHP615 was administered 
between cheek and gum line will be examined for redness, inflammation, and ulceration 
and noted on physical examination CRF

Spine/neck/thyroid

Respiratory

Cardiovascular

Abdomen (including liver and kidneys)
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time of seizure onset until the defined follow-up period stated in
Section 7.1.4. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a 
diagnosis has not been made, then each symptom should be listed individually. All AEs should 
be captured on the appropriate AE pages in the CRF and in source documents. In addition to 
untoward AEs, unexpected benefits outside the investigational product indication should also be 
captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
Quintiles Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor 
using the details specified in the emergency contact information section of the protocol. The 
pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
beta-human chorionic gonadotropin (-hCG) test or ultrasound result will determine the 
pregnancy onset date.
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of MHOS/SHP615

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the parent, 
guardian, or legally authorized representative.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the SHP615 midazolam HCl investigator’s 
brochure, which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Quintiles 
Transnational Japan K.K. and Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to Quintiles Transnational Japan K.K. and 
the Shire Global Pharmacovigilance and Risk Management Department. A copy of the Shire 
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Clinical Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form (and 
any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor using the 
details specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 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. 
Hospitalization
For this protocol, hospitalization is defined as any admission to a medical or equivalent 
healthcare facility or any prolongation of an existing admission lasting more than 24 hours.  
Admission also includes transfer within the hospital to an acute/intensive care unit (eg, from the 
psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to 
a tuberculosis unit). A healthcare setting visit does not necessarily constitute a hospitalization; 
however, the event leading to the healthcare setting visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017

Hospice facilities;

Respite care (eg, caregiver relief);

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE. Examples include: 

Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for workup of 
persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time of seizure onset until 
the defined follow-up period stated in Section 7.1.4 and must be reported to Quintiles 
Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk Management 
Department and the CRO/Shire medical monitor within 24 hours of the first awareness of the 
event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to Quintiles 
Transnational Japan K.K. and the Shire Global Pharmacovigilance and Risk Management
Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and CRO are responsible for notifying the relevant regulatory authorities/and 
institutional IRBs or ECs of related, unexpected SAEs.
In addition the sponsor or Quintiles Transnational Japan K.K. is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies across the 
SHP615 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Product Quality Complaints
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects. Quality complaints may be reportable to Pharmaceuticals and 
Medical Devices Agency (PMDA) as a device malfunction report, regardless of whether or not 
the event relates to an AE.
Investigators are required to report investigational product quality complaints to Shire within 24
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
European Union and Rest of World (ROW)
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate electronic case report form (eCRF).
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. 
Data collection procedures will be discussed with the site at the site initiation visit and/or at the 
investigator’s meeting. Once a subject is enrolled, it is expected that site personnel will complete 
the CRF entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the sponsor’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
All available data will be included in the analysis. No imputation of missing data will be 
performed.
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its designee. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. All statistical analyses will be performed using SASVersion 
9.3 or higher (SAS Institute, Cary, NC, USA 27513). 
9.4.1
Appropriateness of Measurements
This is a Phase 3, open-label extension (OLE) study that is designed to evaluate the efficacy and 
safety of MHOS/SHP615 as therapy for subjects with SE or CSE. Measures employed in this 
protocol are standard measures routinely used for the evaluation of the efficacy, safety, and 
tolerability of an investigational product.
9.4.2
General Considerations
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. 
9.5
Planned Interim Analysis
There is no planned interim analysis.
9.6
Sample Size Calculation and Power Considerations
The target sample size (≥6 subjects) is estimated based on feasibility analysis rather than based 
on statistical rationale.
Maximum sample size*: approximately 25 subjects.
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% 
expected drop-out rate from screening) = approximately 6 subjects.
*Evaluable sample size in this extension study depends on the actual efficacy and safety of 
MHOS/SHP615 in the Study SHP615-301.
**Based on the reported global clinical studies study data outside of Japan, expected response 
rate in hospital settings is conservatively estimated to be 58.5%. This is close to the lowest 
response rate reported in worldwide clinical studies.
9.7
Study Population
The screened set will consist of all subjects who have a signed informed consent.
The safety set will consist of all subjects who have taken at least 1 dose of investigational 
product. 
The full analysis set (FAS) will consist of all subjects who have received a single dose of 
MHOS/SHP615 and who have at least 1 assessment for therapeutic success (cessation of seizure 
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
within 10 minutes with sustained absence of seizure for 30 minutes) performed after the 
administration of MHOS/SHP615.
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects 
with therapeutic success.

Therapeutic success will be defined as:

The cessation of visible seizure activity within 10 minutes, with

A sustained absence of visible seizure activity for 30 minutes following a single 
dose of MHOS/SHP615.
The response rate will be calculated with FAS and the 2-sided, 95% confidence interval (CI) will 
be constructed for the response rate.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 1 hour.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 4 hours.

Percentage of subjects whose seizure event(s) stopped within 10 minutes after 
administration of MHOS/SHP615 and who have sustained absence of seizure activity for
at least 6 hours.

Time to resolution of seizures (convulsions).

Time to recovery of consciousness/baseline mental status.

Percentage of subjects who require additional anticonvulsant medication for ongoing SE 
according to the participating hospital protocol or guideline, 10 minutes after 
administration of MHOS/SHP615. 

Percentage of subjects who fail to respond to treatment.

Treatment failure/Nonresponder is defined as continuing seizure activity and/or 
the need for any additional rescue medication in the study site (or another 
emergency medical institution), 10 minutes after administration of 
MHOS/SHP615.
For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, the ethical principles in the Declaration of Helsinki, and local 
ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and any updates, EU Directive 
2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
agencies and IRBs are notified as appropriate. Additionally, the discontinuation of a registered 
clinical study which has been posted to a designated public website will be updated accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and any updates, EU Directive 2001/20/EC, the ethical principles in the Declaration of 
Helsinki, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
All data sent to the sponsor must be endorsed by the investigator.
Once the CRA/study monitor has verified the contents of the completed CRF pages against the 
source data, the duplicate pages are retrieved and forwarded to the study sponsor (or designee) 
for data entry. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB or regulatory inspectors) may check the CRF entries 
against the source documents. The ICF includes a statement by which the subject agrees to the 
monitor/auditor from the sponsor or its representatives, national or local regulatory authorities, or 
the IRB, having access to source data (eg, subject’s medical file, appointment books, original 
laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], EMA, PMDA) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the Japan Pharmaceuticals and 
Medical Devices Agency (PMDA), US FDA (as well as other US national and local regulatory 
authorities), the EMA, the Medicines and Healthcare products Regulatory Agency, other 
regulatory authorities, the sponsor or its representatives, and the IRB for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances the investigator must at all times comply with all local, state, 
and national laws pertaining to registration and reporting with the appropriate regulatory body 
and control and handling of such substances.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects (or parent, guardian, or legally authorized representative) prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
with applicable regulations and GCP. Each subject or the subject’s parent, guardian, or legally 
authorized representative, as applicable, is requested to sign and date the subject informed 
consent form or a certified translation if applicable, after the subject (and parent, guardian, or 
legally authorized representative) has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s parent, guardian, or legally authorized representative, as applicable. This document 
may require translation into the local language. Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the blank informed consent form 
that was reviewed by the IRB and received their favorable opinion/approval. A copy of the IRB’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB requires modification of the 
sample subject information and consent document provided by the sponsor, the documentation 
supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB for review, and all must 
be approved prior to site initiation.
The applicant for an IRB opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB must approve any revisions 
of all informed consent documents and amendments to the protocol unless there is a subject 
safety issue.
Investigational product supplies will not be released until the sponsor has received written IRB 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects (and parent, guardian, or legally authorized representative) have consented to take 
part in the study, the sponsor and/or its representatives review their medical records and data 
collected during the study. These records and data may, in addition, be reviewed by others 
including the following: independent auditors who validate the data on behalf of the sponsor; 
third parties with whom the sponsor may develop, register, or market MHOS/SHP615; national 
or local regulatory authorities; and the IRB that gave approval for the study to proceed. 
The sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however,
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
11
REFERENCES 
Alldredge, B. K., Gelb, A. M., Isaacs, S. M., Corry, M. D., Allen, F., Ulrich, S., Gottwald, M. D., 
O'Neil, N., Neuhaus, J. M., Segal, M. R.and Lowenstein, D. H. 2001. A comparison of 
lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. 
N Engl J Med, 345, 631-7.
Berg, A. T., Shinnar, S., Levy, S. R.and Testa, F. M. 1999. Status epilepticus in children with 
newly diagnosed epilepsy. Ann Neurol, 45, 618-23.
Dham, B. S., Hunter, K.and Rincon, F. 2014. The epidemiology of status epilepticus in the 
United States. Neurocrit Care, 20, 476-83.
Epilepsy Foundation. 2015. Status Epilepticus [Online]. Available: 
http://www.epilepsy.com/learn/impact/seizure-emergencies/status-epilepticus [Accessed].
Fountain, N. B. 2000. Status epilepticus: risk factors and complications. Epilepsia, 41 Suppl 2, 
S23-30.
Hypnovel SmPC. 2008. Roche Products Ltd. Available: 
http://www.medicines.org.uk/EMC/medicine/1692/SPC/Hypnovel+10mg+2ml/ 
[Accessed].
ILAE 1989. Proposal for revised classification of epilepsies and epileptic syndromes. 
Commission on Classification and Terminology of the International League Against 
Epilepsy. Epilepsia, 30, 389-99.
Lowenstein, D. H. 1999. Status epilepticus: an overview of the clinical problem. Epilepsia, 40, 
S3-8, discussion S21-2.
McIntyre, J., Robertson, S., Norris, E., Appleton, R., Whitehouse, W. P., Phillips, B., Martland, 
T., Berry, K., Collier, J., Smith, S.and Choonara, I. 2005. Safety and efficacy of buccal 
midazolam versus rectal diazepam for emergency treatment of seizures in children: a 
randomised controlled trial. Lancet, 16-22, 205-10.
Midazolam HCl Injection US Prescribing Information. 2009. Roxane Laboratories Inc. 
Available: http://www.drugs.com/pro/midazolam-injection.html [Accessed 27 Apr 2010].
Midazolam HCl Syrup US Prescribing Information. 2009. Roxane Laboratories Inc. Available:
http://www.drugs.com/pro/midazolam-syrup.html [Accessed 27 Apr 2010].
Mpimbaza, A., Ndeezi, G., Staedke, S., Rosenthal, P. J.and Byarugaba, J. 2008. Comparison of 
buccal midazolam with rectal diazepam in the treatment of prolonged seizures in 
Ugandan children: a randomized clinical trial. Pediatrics, 121, e58-64.
Riviello, J. J. J., Ashwal, S., Hirtz, D., Glauser, T., Ballaban-Gil, K., Kelley, K., Morton, L. D., 
Phillips, S., Sloan, E., S., S., Subcommittee;, A. A. o. N.and Society., P. C. o. t. C. N. 
2006. Practice parameter: diagnostic assessment of the child with status epilepticus (an 
evidence-based review): report of the Quality Standards Subcommittee of the American 
Academy of Neurology and the Practice Committee of the Child Neurology Society. 
Neurology, 14, 1542-50.
Scott, R. C., Besag, F. M.and Neville, B. G. 1999. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
353, 623-6.
Shinnar, S., Berg, A. T., Moshe, S. L., O'Dell, C., Alemany, M., Newstein, D., Kang, H., 
Goldensohn, E. S.and Hauser, W. A. 1996. The risk of seizure recurrence after a first 
unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics, 98, 216-25.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Sirven, J. I.and Waterhouse, E. 2003. Management of status epilepticus. Am Fam Physician, 68, 
469-76.
Talukdar, B.and Chakrabarty, B. 2009. Efficacy of buccal midazolam compared to intravenous 
diazepam in controlling convulsions in children: a randomized controlled trial. Brain 
Dev, 31, 744-9.
Theodore, W. H., Porter, R. J.and Penry, J. K. 1983. Complex partial seizures: clinical 
characteristics and differential diagnosis. Neurology, 33, 1115-21.
Treiman, D. M., Meyers, P. D., Walton, N. Y., Collins, J. F., Colling, C., Rowan, A. J., 
Handforth, A., Faught, E., Calabrese, V. P., Uthman, B. M., Ramsay, R. E.and Mamdani, 
M. B. 1998. A comparison of four treatments for generalized convulsive status 
epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med,
17, 792-8.
Trinka, E., Höfler, J., Leitinger, M.and Brigo, F. 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, M. T., Macleod, S.and O'Regan, M. E. 2004. Nasal/buccal midazolam use in the 
community. Arch Dis Child, 89, 50-1.
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
12
APPENDICES
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
APPENDIX 2
SCALES AND ASSESSMENTS
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
Riker Sedation-Agitation Scale
1
1999
1
8 Jul 2017
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
SHP615-302 Protocol Amendment 3
SHP615
18 Dec 2017
Version 1, 8 July 2017
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
NCT03336450 
Study Title: 
A Phase 3, Multicenter, Open-label Extension Study of Buccally 
Administered MHOS/SHP615 in Pediatric Patients with Status 
Epilepticus (Convulsive) in Community Settings 
Study Number: 
SHP615-302 
SAP Version and Date: 
Version 1: 
12 Sep 2019 
For non-commercial use only


For non-commercial use only


Shire 
CONFIDENTIAL 
Page 2 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
ABBREVIATIONS .........................................................................................................................5 
1. 
INTRODUCTION ....................................................................................................................6 
2. 
STUDY DESIGN .....................................................................................................................7 
2.1 
General Study Design .................................................................................................7 
2.2 
Randomization ...........................................................................................................7 
2.3 
Blinding ......................................................................................................................7 
2.4 
Schedule of Assessments ...........................................................................................7 
2.5 
Determination of Sample Size ..................................................................................10 
2.6 
Multiplicity Adjustments for Type I Error Control ..................................................10 
3. 
OBJECTIVES ............................................................................ ............................................11 
3.1 
Primary Objective ................................................... ................................................11 
3.2 
Secondary Objectives ........................................ ......................................................11 
3.3 
Exploratory Objectives ................................ .. .........................................................11 
4. 
SUBJECT POPULATION SETS ....................... ... ...............................................................12 
4.1 
Screened Set ..................................... . .....................................................................12 
4.2 
Safety Set ..................................... ............................................................................12 
4.3 
Full Analysis Set ......................................................................................................12 
4.4 
Per Protocol Set .............. ........................................................................................12 
5. 
SUBJECT DISPOSITION ...... . . ...........................................................................................13 
6. 
PROTOCOL DEVIATIONS ..................................................................................................13 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................14 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .......................................15 
9. 
PRIOR AND CONCOMITANT MEDICATION ..................................................................16 
10. EFFICACY ANALYSES .......................................................................................................17 
10.1 
Primary Efficacy Endpoint and Analysis .................................................................17 
10.2 
Secondary Efficacy Endpoints and Analysis ...........................................................17 
10.2.1 Percentage of Subjects Whose Seizure Event(s) Stopped Within 10 Minutes 
After Administration of MHOS/SHP615 and who Have Sustained Absence 
of Seizure Activity for At Least 1 Hour/4 Hours/6 Hours .....................................18 
10.2.2 Time to Resolution of Seizures (Convulsions) ......................................................18 
10.2.3 Time to Recovery of Consciousness ......................................................................18 
10.2.4 Percentage of Subjects Who Require Additional Anticonvulsant Medication 
for Ongoing SE 10 Minutes After Administration of MHOS/SHP615 .................18 
10.2.5 Percentage of Subjects Who Fail to Respond to Treatment ..................................19 
10.3 
Exploratory Efficacy Endpoint(s) and Analyses ......................................................19 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 3 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
10.4 
Sensitivity Analyses .................................................................................................19 
11. SAFETY ANALYSES ...........................................................................................................20 
11.1 
Primary Safety Endpoint and Analysis ....................................................................20 
11.2 
Secondary Safety Endpoint and Analysis ................................................................20 
11.2.1 Adverse Events ......................................................................................................21 
11.2.2 Clinical Laboratory Variables ................................................................................21 
11.2.3 Vital Signs ..............................................................................................................22 
11.2.4 Electrocardiogram (ECG) ......................................................................................22 
11.2.5 Riker Sedation-Agitation Scale (SAS)...................................................................22 
11.2.6 Oxygen Saturation .................................................................................................22 
11.2.7 Buccal Irritation .....................................................................................................22 
11.3 
Other Safety Variables .............................................................................................22 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ............23 
13. OTHER ANALYSES ............................................................. .. ...........................................23 
 
 
14. INTERIM ANALYSIS ................................................ ... ......................................................23 
15. DATA MONITORING/REVIEW COMMITTEE . ...............................................................23 
16. COMPUTER METHODS ................................ .. .................................................................23 
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .................................................23 
18. DATA HANDLING CONVENTIONS . .. .............................................................................24 
18.1 
General Data Reporting Conventions ......................................................................24 
18.1.1 Descriptive Statistics Presentation .........................................................................24 
18.1.2 Decimal Places and Rounding Rules .....................................................................24 
18.1.3 Format of Listings ..................................................................................................24 
18.2 
Derived Efficacy Endpoints .....................................................................................24 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters .................................24 
18.4 
Missing Date of Investigational Product ..................................................................25 
18.5 
Missing Date Information for Prior or Concomitant Medications ...........................25 
18.5.1 Incomplete Start Date/Time ...................................................................................25 
18.5.2 Incomplete Stop Date .............................................................................................26 
18.6 
Missing Date Information for Adverse Events ........................................................26 
18.6.1 Incomplete Start Date ............................................................................................26 
18.6.2 Incomplete Stop Date .............................................................................................26 
18.7 
Missing Severity Assessment for Adverse Events ...................................................26 
18.8 
Missing Relationship to Investigation Product for Adverse Events ........................26 
18.9 
Character Values of Clinical Laboratory Variables .................................................26 
19. REFERENCES .......................................................................................................................27 
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS ..............................27 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 4 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments .................................................................................8 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 5 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CTMS 
clinical trial management system 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHOS/SHP615 midazolam hydrochloride oromucosal solution 
pH 
potential of hydrogen 
PT 
preferred term 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Riker SAS 
Riker sedation-agitation scale 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SE 
status epilepticus 
SI 
international system of units 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 6 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the final study protocol version (amendment 
#3) dated 18Dec2017. In addition, the administrative letter #3 noted subject enrollment to the 
study continues after the Japan New Drug Application (JNDA) and supporting analysis for 
JNDA. 
Currently, only 2 subjects have been enrolled in this study. With the limit of the enrolment to 
subjects from its parent study, SHP615-301, Shire anticipates that the enrollment of 6 patients 
may not be possible or may only be possible with an extended study duration.  
Shire also intends to provide a clinical study report for SHP615-302, that will include the 
analysis results from all study data up to the approximately same data lock date as study 
SHP615-301 (data cut-off date for this analysis is 31 August 2019). Due to the expected small 
number of subjects, only subject data listings will be produced to support the JNDA for this 
study. Specifications for listings are included in a separate document. 
When study SHP615-302 is closed, all cumulative data including any additional data obtained 
during the study extension period will be analyzed, evaluated and reported as appropriate.  
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 7 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
2. 
STUDY DESIGN  
 
General Study Design 
Study SHP615-302 is a Phase 3, multicenter, interventional, nonrandomized, open-label 
extension study of MHOS/SHP615 administered buccally by caregivers to pediatric subjects who 
present with status epilepticus (SE) (convulsive) in community settings. Children who are >6 
months and <18 years of age and completed the antecedent Phase 3 pivotal SHP615-301 study, 
tolerated and responded to treatment with MHOS/SHP615, subsequently experience full seizure 
in the community setting, have not received immediate treatment, and have parent, guardian, or 
legal representative consent/assent, are eligible to participate in this extension study providing all 
eligibility criteria are met. The seizure event(s) must be accompanied by loss of consciousness 
and can be either generalized tonic clonic or start focally and then generalize. 
This study consists of a 24-hour, open-label treatment period followed by a 1-week safety 
follow-up period. After completing Study SHP615-301, the subject’s parent, guardian, or legal 
representative will be dispensed a single oral, prefilled syringe of MHOS/SHP615 stratified by 
age (2.5, 5, 7.5, 10 mg buccally) along with a diary and training on how to administer the drug 
and record details associated with the seizure. Upon the onset of the next seizure in the home, 
school, or community setting, the parent, guardian, or legal representative will administer the 
single MHOS/SHP615 treatment as trained. 
The efficacy of MHOS/SHP615 in treating SE will be assessed by measuring the percentage of 
subjects whose initial seizure stopped within 10 minutes, with a sustained absence of visible 
seizure activity for 30 minutes following a single, age-based dose of MHOS/SHP615. If the 
seizures have not stopped within 10 minutes, and/or if a serious adverse event emerges, the 
subject should be treated according to the participating hospital protocol or guideline. The 
caregiver/parent and subject must visit the study site for examination as soon as possible 
following MHOS/SHP615 administration, even if the seizure has stopped. All subjects will be 
followed up at study sites even if the seizure resolves. The safety of MHOS will also be assessed.  
Subjects will be monitored by vital signs, laboratory tests, and electrocardiograms (ECGs) for 
safety evaluations. All subjects treated in this study will be followed for 1 week after the 
administration of MHOS/SHP615 for safety evaluations. The caregiver will record observations 
on seizure activity, timing of the seizure(s), and dosing relating errors in a study diary. 
 
Randomization 
Not applicable. 
 
Blinding 
Not applicable. 
 
Schedule of Assessments  
Table 1 below presents the schedule of activities in the study. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 8 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
Table 1 
Schedule of Assessments 
Assessment 
Screening 
 
Treatment Period - Time from SHP615 Administration 
Follow-
up 
Community Setting 
In Hospital 
1 week 
(±1day) 
Seizure 
event onset 
5 min 
after 
Time after MHOS/SHP615 administration 
10 
min 
30  
(±5min) 
1 h 
(±10min) 
4 h 
(±30min) 
6 ha 
(±30min) 
24hb 
(±30min) 
Informed consent/assent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/procedural history 
X 
 
 
 
 
 
 
 
 
 
Provide study diary and educational 
materials to caregiver 
X 
 
 
 
 
 
 
 
 
 
Provide training/education to 
caregivers 
X 
 
 
 
 
 
 
 
 
 
Dispense age-based dose of 
SHP615 with administration 
instructions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Evaluate seizure symptoms/record 
diary information 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
SHP615 administration in 
community setting 
 
 
X 
 
 
 
 
 
 
 
Riker Sedation-Agitation Scale 
 
 
 
 
Xc 
Xc 
Xc 
Xc 
X 
 
Vital signsd 
 
Xe 
 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
 
Oxygen saturationf 
 
 
 
 
Xc 
Xc 
Xc 
Xc 
X 
 
12-Lead ECGg 
 
 
 
 
Xc 
Xc 
Xc 
Xc 
X 
 
Laboratory evaluationsh 
 
 
 
 
 
 
 
Xc 
 
 
Buccal cavity assessmenti 
 
 
 
 
 
Xc 
Xc 
Xc 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 9 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
Table 1 
Schedule of Assessments 
Assessment 
Screening 
 
Treatment Period - Time from SHP615 Administration 
Follow-
up 
Community Setting 
In Hospital 
1 week 
(±1day) 
Seizure 
event onset 
5 min 
after 
Time after MHOS/SHP615 administration 
10 
min 
30  
(±5min) 
1 h 
(±10min) 
4 h 
(±30min) 
6 ha 
(±30min) 
24hb 
(±30min) 
Physical examination 
 
 
Xj 
X 
 
Supportive care 
 
X 
Xk 
X 
 
Concomitant medications/recording 
X 
X 
Xk 
X 
X 
Adverse event 
monitoring/recording 
 
X 
Xk 
X 
X 
AE=adverse event; ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute. 
a  Minimum 6-hour observation period after dosing for safety monitoring and blood sampling. Otherwise monitored per standard medical healthcare setting procedure. 
b  Assessments at the 24-hour post dose time point will be made if the subject has not been discharged from the hospital; or a telephone follow-up call will be made to assess 
AEs and concomitant medications. Patients will be asked to return for additional assessment of ongoing AEs, as needed. 
c  Performed if subject has arrived at study site. 
d  Vital signs will include single supine blood pressure, pulse rate, respiratory rate, body temperature; collection of vital signs information will begin as soon as possible in 
community setting or after transfer to healthcare setting.  
e  Parent, guardian, or legally authorized representative should count respiration rate prior to the administration of investigational product.  
f  Oxygen saturation should be measured from time of arrival in hospital, (on room air, if feasible). If it is not possible for the subject to have an oxygen saturation obtained on 
room air due to medical concerns, this will be recorded. The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of oxygen 
administered. 
g  Electrocardiogram should be performed upon arrival at the hospital. 
h  Laboratory evaluations include serum biochemistry and urinalysis. A urine pregnancy test should be administered to female patients of childbearing age. 
i  Buccal cavity where MHOS/SHP615 was administered between cheek and gum line will be examined for redness, inflammation, and ulceration and findings noted on 
physical examination CRF.  
j  Physical examination will be performed at some point between arrival at the hospital and 6 hours postdose, when possible. 
k  Upon arrival at hospital and across all time periods, as appropriate. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 10 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
 
Determination of Sample Size 
The target sample size (≥6 subjects) is estimated based on feasibility analysis rather than based 
on statistical rationale. 
Maximum sample size*: approximately 25 subjects. 
Estimated minimum sample size: 25 x 0.585 (expected response rate in hospital**) x 0.4 (60% 
expected drop-out rate from screening) = approximately 6 subjects. 
*Evaluable sample size in this extension study depends on the actual efficacy and safety of 
MHOS/SHP615 in the Study SHP615-301. 
**Based on the reported global clinical studies data outside of Japan, expected response rate in 
hospital settings is conservatively estimated to be 58.5%. This is close to the lowest response rate 
reported in worldwide clinical studies. 
 
Multiplicity Adjustments for Type I Error Control 
Not applicable. 
For non-commercial use only


For non-commercial use only


Shire 
CONFIDENTIAL 
Page 12 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
4. 
SUBJECT POPULATION SETS 
 
Screened Set  
The Screened Set will consist of all subjects who have signed an informed consent/assent. 
 
Safety Set 
The Safety Set will consist of all subjects who have received a single dose of MHOS/SHP615, 
regardless of whether the study drug administration was documented to be complete or not on 
the study drug administration eCRF form. 
 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects in the Safety Set who have at least 1 
assessment for determination of therapeutic success (cessation of seizure within 10 minutes with 
sustained absence of seizure for 30 minutes) performed after the administration of 
MHOS/SHP615, i.e., provided that the following two conditions are met: 
1. For all subjects: Date and time of study drug administration and date and time of seizure 
cessation for the initial seizure are all recorded. 
2. For subjects who had initial seizure cessation within 10 minutes post-dose with no 
recurrence of seizure within 30 minutes but with the documentation of a recurrence of 
seizure post-dose: Date and time of the first recurrence during the first 6 hours post-dose is 
recorded.  
Refer to Section 10.1 for the definition of therapeutic success. 
 
Per Protocol Set 
The Per Protocol Set (PPS) will consist of subjects who meet all of the following criteria: 
• Subject is in the FAS  
• Subject met all eligibility criteria 
• Subject for whom the study drug administration is documented to be complete on the 
study drug administration eCRF form 
• Within 10 minutes of investigational product administration subject did not receive other 
anti-seizure rescue medication to treat the initial seizure  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 13 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
5. 
SUBJECT DISPOSITION 
A listing of all Screen Failures, i.e., subjects identified as Trial Screen Failure on the disposition 
page of the electronic case report form (eCRF), will be presented. 
The reason for exclusion from the FAS and PPS will be listed. 
All subjects who prematurely discontinued the study will be listed by discontinuation reason for 
the Safety Set. 
6. 
PROTOCOL DEVIATIONS 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. Protocol 
deviations from the CTMS will be coded to severity categories (minor and major) and provided 
as part of the CTMS transfer to Biostatistics. A listing of all protocol deviations by subject will 
be presented for the Safety Set. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 14 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
A listing of demographic and baseline characteristics will be presented for the Safety Set. The 
listing will include age group (age at the time of investigational product administration): 
- 
<1 year 
- 
1 to <5 years 
- 
5 to <10 years 
- 
10 to <18 years 
The following demographic characteristics will be listed:  
• 
Age (years) – calculated as [(number of months between date of birth and investigational 
product administration)/12] 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Weight (kg) measured during SHP615-301 study 
• 
Height (cm) measured during SHP615-301 study 
• 
BMI (kg/m2) – calculated as 10000*weight (kg)/ height (cm)2 
History of epilepsy and confirmation of SE pre-dose will also be listed as follows: 
• 
Duration of epilepsy history (years) – calculated as [(number of months between start 
date of epilepsy history and informed consent/assent)/12] 
• 
Years since epilepsy diagnosis (years) – calculated as [(number of months between date 
of epilepsy diagnosis and informed consent/assent)/12] 
• 
Major epilepsy etiology (genetic, metabolic, structural or idiopathic) 
• 
Confirmation of SE pre-dose: Loss of consciousness, seizure frequency/duration 
• 
Time between seizure onset pre-dose and investigational product administration 
(minutes) 
If the start date of epilepsy history or date of epilepsy diagnosis is incomplete with only month 
and year captured, the day will be imputed to the first day of the month for the purpose of 
calculating duration of epilepsy history and years since epilepsy diagnosis. The imputed dates 
will not be presented in the listings. 
In addition, the epilepsy diagnosis name will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 20.0 or higher. The listing of Epilepsy history will 
include System Organ Class (SOC) and Preferred Term (PT). 
Similarly, a listing including SOC and PT will be presented for medical history other than 
epilepsy. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 15 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Only one administration of the investigational product is planned in this study. All subjects 
enrolled in the study will receive treatment with the investigational product based on their age as 
follows: 
• 
2.5 mg: >6 months to <1 year (and weight >5 kg) 
• 
5 mg: 1 to <5 years 
• 
7.5 mg: 5 to <10 years 
• 
10 mg: 10 to <18 years 
A listing will be created by subject number giving the date and time of study drug 
administration, planned dose as well as drug accountability including study drug lot number. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 16 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
9. 
PRIOR AND CONCOMITANT MEDICATION  
Version 01Sep2017 or newer of the WHO Drug Dictionary will be used to classify prior and 
concomitant medications by therapeutic class and preferred name. Prior and concomitant 
therapies will be coded using MedDRA version 20.0 or newer. 
Prior medication (therapy) is defined as any medication (therapy) received within 30 days of and 
prior to the date of investigational product administration. In particular, medications (therapies) 
with an end date prior to 30 days before the date of investigational product administration are not 
considered prior medications (therapies). Concomitant medication (therapy) is defined as any 
medication (therapy) with a start date prior to the date of investigational product administration 
and continuing after the investigational product administration or with a start date on or after the 
date of investigational product administration and before the end of the follow-up period, 
inclusive. 
Considering the protocol allowed assessment window, the end of the follow-up period will be 
one week plus one day (i.e., 8 days) after the investigational product administration. Any 
medication (therapy) with a start date after the end of the follow-up period will not be considered 
a concomitant medication (therapy). 
Medications (therapies) can be counted both as prior and concomitant medication (therapy). 
For prior or concomitant medications (therapies), including rescue medications, incomplete 
start/stop dates will be imputed as specified in Section 18.5. Imputed dates will not be presented 
in the listings. 
A listing of prior and concomitant medication usage will be presented for the Safety Set and will 
include therapeutic class (level 3) and preferred name. 
Prior and concomitant therapies will be listed similarly except that MedDRA SOC and PT will 
be used instead of therapeutic class and preferred name. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 17 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
10. EFFICACY ANALYSES 
All efficacy analyses will be based on the FAS. 
 
Primary Efficacy Endpoint and Analysis  
The primary efficacy endpoint is response rate, which is defined as the percentage of subjects 
with therapeutic success. Therapeutic success will be declared for subjects who meet both of the 
following conditions: 
1. Cessation of visible seizure activity within 10 minutes, i.e., the time from investigational 
product administration to the end of the initial seizure is less than or equal to 10 minutes. 
The initial seizure refers to the seizure which triggered the use of the investigational product 
and which is captured on the “confirmation of status epilepticus” eCRF form. 
2. A sustained absence of visible seizure activity for 30 minutes following a single dose of 
MHOS/SHP615 without the need for additional rescue medication, i.e., subject has no 
recurrence of seizure within 30 minutes of investigational product administration as 
documented on the “subject seizure status (recurrence)” eCRF form, and no rescue 
medication has been administered within 30 minutes of investigational product 
administration. 
A listing will present therapeutic success status for subjects in the FAS. 
 
Secondary Efficacy Endpoints and Analysis  
The secondary efficacy endpoints will include: 
• 
Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration 
of MHOS/SHP615 and who have sustained absence of seizure activity for at least 1 hour. 
• 
Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration 
of MHOS/SHP615 and who have sustained absence of seizure activity for at least 4 hours. 
• 
Percentage of subjects whose seizure event(s) stopped within 10 minutes after administration 
of MHOS/SHP615 and who have sustained absence of seizure activity for at least 6 hours. 
• 
Time to resolution of seizures (convulsions)  
• 
Time to recovery of consciousness 
• 
Percentage of subjects who require additional anticonvulsant medication for ongoing SE 
according to the participating healthcare setting protocol or guideline, 10 minutes after 
administration of MHOS/SHP615.  
• 
Percentage of subjects who fail to respond to treatment: 
- 
Treatment failure/Non-responder is defined as continuing seizure activity and/or the 
need for any additional rescue medication in the study site (or another emergency 
medical institution), 10 minutes after administration of MHOS/SHP615. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 18 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
Details of the statistical analyses used for the secondary efficacy endpoints are provided in the 
subsections below. 
10.2.1 
Percentage of Subjects Whose Seizure Event(s) Stopped Within 10 Minutes After 
Administration of MHOS/SHP615 and who Have Sustained Absence of Seizure 
Activity for At Least 1 Hour/4 Hours/6 Hours 
The same definition of therapeutic success as given in Section 10.1 will be used except that the 
second condition will be modified to require sustained absence of visible seizure activity without 
the need for additional rescue medication for 1 hour, 4 hours or 6 hours, respectively, following 
administration of MHOS/SHP615. 
A listing will present the response status for subjects in the FAS. 
10.2.2 
Time to Resolution of Seizures (Convulsions) 
Time to resolution of seizures (convulsions) in minutes will be calculated as time from 
investigational product administration to the end of the initial seizure or administration of rescue 
anticonvulsant medication, whichever occurs first. The initial seizure refers to the seizure which 
triggered the use of the investigational product and which is captured on the “confirmation of 
status epilepticus” eCRF form. Note that, as per the definition of the FAS, there will be no 
censoring in this time to event analysis as all subjects will have a date and time captured for the 
initial seizure cessation. 
A listing will present the event type (end of the initial seizure or administration of rescue 
anticonvulsant medication) and time to resolution of seizures (convulsions). 
10.2.3 
Time to Recovery of Consciousness 
Time to recovery of consciousness in minutes will be calculated only for subjects who lose 
consciousness pre-dose as time from investigational product administration to recovery of 
consciousness post-dose or administration of rescue anticonvulsant medication, whichever 
occurs first. If the time of recovery of consciousness is missing and there is no administration of 
rescue anticonvulsant medication during the 24 hours treatment period, the time to recovery of 
consciousness will be censored at the latest time of any assessment captured in the eCRF up to 
hospital discharge during the 24 hours treatment period, i.e., vital signs, oxygen saturation, Riker 
SAS, buccal cavity assessment, laboratory, ECG or time the subject was discharged from the 
hospital.  
A listing will present the event type (recovery of consciousness, administration of rescue 
anticonvulsant medication or censored)) and time to recovery of consciousness. 
10.2.4 
Percentage of Subjects Who Require Additional Anticonvulsant Medication for 
Ongoing SE 10 Minutes After Administration of MHOS/SHP615 
Anticonvulsant medication for ongoing SE (rescue treatment) are captured on the “prior and 
concomitant medications” eCRF form. Subjects who require additional anticonvulsant 
medication for ongoing SE 10 minutes after investigational product administration and before the 
end of the initial seizure will be listed. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 19 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
10.2.5 
Percentage of Subjects Who Fail to Respond to Treatment 
Responder is defined as subject with cessation of visible seizure activity within 10 minutes after 
administration of MHOS/SHP615. A Treatment failure/Non-responder is defined as a subject 
with continuing seizure for more than 10 minutes after a single dose of MHOS/SHP615 or the 
need for any additional anticonvulsant rescue medication to treat the initial seizure any time after 
the single dose of MHOS/SHP615 according to the participating healthcare setting protocol or 
guideline. Any of the following events qualifies as a treatment failure: 
• 
The time from investigational product administration to the end of the initial seizure is more 
than 10 minutes. The initial seizure refers to the seizure which triggered the use of the 
investigational product and which is captured on the “confirmation of status epilepticus” 
eCRF form. 
• 
Rescue anticonvulsant medication is administered to treat the initial seizure anytime after 
MHOS/SHP615 administration. 
Subjects who fail to respond to treatment will be listed. 
 
Exploratory Efficacy Endpoint(s) and Analyses  
No exploratory efficacy endpoints are defined. 
 
Sensitivity Analyses 
Not applicable. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 20 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
11. SAFETY ANALYSES 
The safety analysis will be performed using the Safety Set. Safety variables include adverse 
events (AEs), clinical laboratory variables, vital signs, oxygen saturation, Riker SAS, buccal 
cavity assessment, and ECG variables. 
Section 18.3 provides the way unscheduled assessments will be handled in safety analyses. 
 
Primary Safety Endpoint and Analysis 
The primary safety endpoint will be respiratory depression, which will include the following 
measures after MHOS/SHP615 administration: 
• 
Persistent decrease in oxygen saturation to <92% measured at 30 minutes, 1, 4, 6, and 24 
hours post-dose (i.e., <92% on room air for 2 minutes or more after dosing while monitoring 
[per healthcare setting protocol and/or the clinical judgment of the physician]). 
• 
Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask 
ventilation or endotracheal intubation) 
In the primary safety analysis, any of the following events will qualify as a respiratory 
depression: 
• 
An oxygen saturation assessment (including unscheduled) within 24 hours (±30 minutes to 
account for the protocol allowed assessment window) after the investigational product 
administration indicates an oxygen saturation <92% on room air for 2 minutes or more after 
dosing while monitoring. 
• 
An AE with MedDRA preferred term "Respiratory depression" starts within 24 hours after 
the investigational product administration, i.e., the AE starts on the same day as 
investigational product administration and is identified as not occurring prior to 
investigational product administration on the eCRF or the AE starts on the day following 
investigational product administration. Such adverse event indicates an increase in 
respiratory effort requiring the use of assisted ventilation. 
Subjects with respiratory depression will be listed. 
 
Secondary Safety Endpoint and Analysis 
The secondary safety endpoints include the following: 
• 
Aspiration pneumonia 
• 
Sedation or agitation as measured by the Riker SAS 
• 
Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign 
measurements, laboratory tests, oxygen saturation, and ECGs 
• 
Occurrence of buccal irritation 
Details of the statistical analyses of secondary safety endpoints are provided in the subsections 
below. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 21 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
11.2.1 
Adverse Events  
Adverse events will be coded using Version 20.0 or newer of MedDRA. 
TEAEs are defined as AEs whose onset occurs, severity worsens or intensity increases on or 
after the date of investigational product administration. Events which occur more than one week 
(+1 day to account for the protocol allowed assessment window) after the investigational product 
administration will not be considered treatment emergent. 
For classifying AEs as TEAEs/non-TEAEs, incomplete start dates will be imputed as specified in 
Section 18.6. Imputed dates will not be presented in the listings. 
The following TEAEs of special interest will be listed: 
• 
Aspiration pneumonia 
• 
Respiratory depression 
• 
Buccal irritation 
The preferred terms corresponding to these TEAEs of special interest will be identified by Shire 
based on medical input and be provided to IQVIA for the analysis. 
A listing will be presented and will include both TEAEs and Non-TEAEs (unless specified 
otherwise). Serious AEs, AEs leading to death, and AEs leading to discontinuation from the 
study will be identified in the listing. Listings will indicate whether an AE is treatment emergent 
or not and whether it started before hospital admission, after hospital admission and before 
hospital discharge or after hospital discharge. Separate listings will be presented for AEs of 
special interest (aspiration pneumonia, respiratory depression, buccal irritation). 
11.2.2 
Clinical Laboratory Variables 
The following clinical laboratory variables are assessed in this study and will be presented in the 
listings:  
Chemistry 
BUN, serum creatinine, creatinine clearance determined by the Schwartz 
method, glucose (fasting if possible), calcium (total), sodium, potassium, 
chloride, AST, ALT, total bilirubin, direct and indirect bilirubin (if total 
bilirubin is elevated), alkaline phosphatase, albumin, total protein and 
bicarbonate. 
Urinalysis 
pH, glucose (qualitative), protein (qualitative), blood (qualitative), ketones, 
nitrites, leukocyte esterase, specific gravity and microscopy (if urine dipstick is 
positive for blood, protein, nitrites or leukocyte esterase). 
The summaries of laboratory variables will be based on central laboratory results. 
Clinical laboratory sample collection information and test results in SI units will be listed for all 
subjects in the Safety Set.  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 22 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator. 
11.2.3 
Vital Signs 
Vital signs actual values will be presented at each scheduled time point: 
Systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), respiratory rate 
(breaths/min) and body temperature (C). 
All vital sign data will be presented in a subject level listing. In addition, subjects with clinically 
significant vital sign values will be listed. This listing will include all results of the vital sign 
parameter that was determined by the investigator to be clinically significant for a subject across 
study time points to identify any trends.  
11.2.4 
Electrocardiogram (ECG) 
ECG variables will be presented at each scheduled assessment time point for the following 
parameters: 
Heart rate (bpm), RR interval (ms), PR interval (ms), QRS interval (ms), QT interval (ms), QTcB 
interval (ms) and QTcF interval (ms). 
QTcB and QTcF corrections will be summarized as provided by central laboratory, i.e., the 
corrections will not be recalculated for the analysis. 
All ECG data will be presented in a subject level listing. This listing will include all results for a 
subject across study time points to identify any trends. 
11.2.5 
Riker Sedation-Agitation Scale (SAS) 
Riker SAS score will be listed for all subjects in the Safety Set.  
11.2.6 
Oxygen Saturation 
Oxygen saturation results will be listed for all subjects in the Safety Set. 
11.2.7 
Buccal Irritation 
Details of the buccal cavity assessments for each subject, including the abnormalities, will be 
presented in the listings. 
 
Other Safety Variables 
Information on physical examination (whether performed, reason for not performing the 
examination and date of assessment) will be presented in the listings. 
Urine pregnancy test information and results will also be presented in the listings. 
For non-commercial use only


For non-commercial use only


Shire 
CONFIDENTIAL 
Page 24 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
18. DATA HANDLING CONVENTIONS 
 
General Data Reporting Conventions 
All available data will be included in the analysis. In general, no imputation of missing data will 
be performed except when specified in the subsections below. 
Data from all healthcare setting study sites that participate in this protocol will be combined so 
that an adequate number of subjects will be available for analysis. 
Outputs will be presented according to Shire TFLs Library V8.1. General considerations which 
are applicable to this study are summarized in the following subsections. 
18.1.1 
Descriptive Statistics Presentation 
No descriptive statistical summaries will be presented. 
18.1.2 
Decimal Places and Rounding Rules 
• 
BMI, age, duration of SE history and years since epilepsy diagnosis should be rounded to 1 
decimal place for reporting. 
18.1.3 
Format of Listings 
The compound name and study number shall appear in the top left corner of the page in the 
format of SHP615-302. Page numbering, in the format “Page X of Y”, shall be presented in all 
output in the upper right corner of the page for each table. 
Output shall be aligned so that the title of the table text is centrally aligned over the data; the 
body of the table, where applicable, text is left-justified. Column headers shall follow the 
alignment of their data. 
For cases in which there are no observations contributing to a listing, the listing shall be 
produced with all titles and footnotes as per its shell, but with the text “– No Observations –” in 
the body of the output. 
Footnotes shall be displayed under the table on each page. 
Final listings shall be combined into one bookmarked PDF file. 
 
Derived Efficacy Endpoints  
Derivations for efficacy endpoints are described in Section 10. 
 
Repeated or Unscheduled Assessments of Safety Parameters  
Listings will include all scheduled and unscheduled assessments. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 25 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
 
Missing Date of Investigational Product  
Not applicable in this single dose study. 
 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (i.e., partially 
missing) start date/time and/or stop date will be imputed. When the start date and the stop date 
are both incomplete for a subject, impute the start date first. 
18.5.1 
Incomplete Start Date/Time  
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing time 
• 
If the start time of another anti-seizure rescue medication is missing and the start date is 
equal to the date of study drug administration, then the time of study drug administration 
will be assigned to the missing time. 
• 
For any other cases, the missing time will not be imputed. 
Missing day and month 
• 
If the year of the incomplete start date is the same as the year of the date of investigational 
product administration, then the day and month of the date of investigational product 
administration will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the date of investigational 
product administration, then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of investigational 
product administration, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete start date are the same as the month and year of the 
date of investigational product administration, then the day of the date of investigational 
product administration will be assigned to the missing day 
• 
If either the year is before the year of the date of investigational product administration or 
if both years are the same but the month is before the month of the date of investigational 
product administration, then the last day of the month will be assigned to the missing day 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 26 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
• 
If either the year is after the year of the date of investigational product administration or if 
both years are the same but the month is after the month of the date of investigational 
product administration, then the first day of the month will be assigned to the missing day.  
18.5.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date will 
be equal to the start date. 
Missing day and month 
• 
31 December will be assigned to the missing fields 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
The last day of the month will be assigned to the missing day 
 
Missing Date Information for Adverse Events  
For AEs, only incomplete (i.e., partially missing) start dates will be imputed. 
18.6.1 
Incomplete Start Date  
Follow same rules as in Section 18.5.1. 
18.6.2 
Incomplete Stop Date  
Not applicable.  
 
Missing Severity Assessment for Adverse Events 
There will be no imputation, the actual values will be presented in data listings. 
 
Missing Relationship to Investigation Product for Adverse Events 
There will be no imputation, the actual values will be presented in data listings. 
 
Character Values of Clinical Laboratory Variables  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification, or “> X”, i.e. above the upper limit of quantification, will be presented as 
recorded, i.e. as “< X” or “> X” in the listings. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 27 
Statistical Analysis Plan 
SHP615-302 
 
12 Sep 2019 
 
 
19. REFERENCES 
Not applicable. 
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS 
See separate file with listings specifications. 
For non-commercial use only