Clinical trial NCT03336645
Conditions: Nervous System Diseases
Keywords: Seizure Midazolam hydrochloride Convulsive
Sponsor: Shire
Start date: 2017-10-23; Completion date: 2019-08-19
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the efficacy, safety and pharmacokinetics of MHOS/SHP615 administered buccally in children with status epilepticus (convulsive) in a healthcare 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 descriptions: intervention 1: SHP615 oromucosal solution will be administered as a single age-specific dose (2.5, 5, 7.5 and 10 mg).

Protocol documents:
Prot_003.pdf: 
PROTOCOL: SHP615-301
TITLE:
A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, 
Safety, and Pharmacokinetics of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in the Hospital 
or Emergency Room
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
PROTOCOL 
HISTORY:
Original Protocol: 20 Mar 2017
Protocol Amendment 1: 08 Jul 2017
Protocol Amendment 2: 28 Aug 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure 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.




Shire
CONFIDENTIAL
Page 3
SHP615-301 Protocol Amendment 2
Midazolam
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: 


Shire
CONFIDENTIAL
Page 4
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
PRODUCT QUALITY COMPLAINTS
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). 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. For instructions on reporting AEs related to product complaints, 
see Section 8.3.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
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)


Shire
CONFIDENTIAL
Page 5
SHP615-301 Protocol Amendment 2
Midazolam
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.......................................................................................18
1.1
Status Epilepticus .....................................................................................................18
1.2
Current Treatment Options.......................................................................................19
1.3
Unmet Medical Need for Buccal Midazolam...........................................................20
1.4
Product Background and Clinical Information ........................................................20
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Open-Label Study (SHP615-301) ................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objectives.................................................................................................22
2.2.2
Secondary Objectives.............................................................................................23
3.
STUDY DESIGN ...................................................................................................................23
3.1
Study Design ............................................................................................................23
3.2
Duration and Study Completion Definition .............................................................23
3.3
Sites and Regions .....................................................................................................24
4.
STUDY POPULATION.........................................................................................................24
4.1
Inclusion Criteria......................................................................................................24
4.2
Exclusion Criteria.....................................................................................................25
4.3
Restrictions...............................................................................................................26
4.3.1
Medical Intervention..............................................................................................26
4.4
Reproductive Potential .............................................................................................26
4.4.1
Female Contraception............................................................................................26
4.4.2
Male Contraception................................................................................................26
4.5
Discontinuation of Subjects .....................................................................................26
4.5.1
Reasons for Discontinuation..................................................................................27
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................27
4.5.3
Stopping Rules.......................................................................................................28
4.5.3.1
Study Level Stopping Rules...................................................................28
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria................................28


Shire
CONFIDENTIAL
Page 6
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................28
5.1
Prior Treatment ........................................................................................................29
5.2
Concomitant Treatment............................................................................................29
6.
INVESTIGATIONAL PRODUCT ........................................................................................29
6.1
Identity of Investigational Product...........................................................................29
6.1.1
Blinding the Treatment Assignment......................................................................30
6.2
Administration of Investigational Product(s)...........................................................30
6.2.1
Allocation of Subjects to Treatment ......................................................................30
6.2.2
Dose Regimen and Dose Administration...............................................................30
6.2.2.1
Dosing Regimen.....................................................................................30
6.2.2.2
Dose Administration ..............................................................................31
6.3
Labeling, Packaging, Storage, and Handling ...........................................................31
6.3.1
Labeling .................................................................................................................31
6.3.2
Packaging...............................................................................................................31
6.3.3
Storage ...................................................................................................................32
6.3.4
Special Handling....................................................................................................32
6.4
Drug Accountability.................................................................................................32
6.5
Subject Compliance..................................................................................................33
6.6
Destruction of Investigational Product.....................................................................33
7.
STUDY PROCEDURES........................................................................................................34
7.1
Study Schedule.........................................................................................................34
7.1.1
Screening/Baseline Assessments ...........................................................................34
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)........35
7.1.3
Treatment Period (0 minutes to 6 hours postdose) ................................................36
7.1.4
Treatment Period (10 minutes to 24 hours postdose) ............................................36
7.1.5
Follow-up Visit......................................................................................................36
7.1.6
Additional Care of Subjects after the Study ..........................................................37
7.2
Study Evaluations and Procedures ...........................................................................37
7.2.1
Informed Consent...................................................................................................37
7.2.2
Demographic and Other Baseline Characteristics .................................................37
7.2.3
Efficacy..................................................................................................................37
7.2.4
Safety .....................................................................................................................38
7.2.4.1
Medical and Medication History............................................................38
7.2.4.2
Physical Examination.............................................................................38
7.2.4.3
Adverse Event Collection.......................................................................39
7.2.4.4
Vital Signs..............................................................................................39
7.2.4.5
Clinical Laboratory Evaluations.............................................................39
7.2.4.6
Pregnancy Test .......................................................................................40


Shire
CONFIDENTIAL
Page 7
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
7.2.4.7
Electrocardiogram ..................................................................................41
7.2.4.8
Oxygen saturation ..................................................................................41
7.2.5
Others.....................................................................................................................41
7.2.5.1
Pharmacokinetic Assessments................................................................41
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................42
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................42
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................42
8.1.1
Severity Categorization..........................................................................................43
8.1.2
Relationship Categorization...................................................................................43
8.1.3
Outcome Categorization ........................................................................................44
8.1.4
Symptoms of the Disease Under Study .................................................................44
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................44
8.1.6
Pregnancy...............................................................................................................45
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................45
8.2
Serious Adverse Event Procedures ..........................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................46
8.2.3
Serious Adverse Event Definition .........................................................................46
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
8.2.6
Fatal Outcome........................................................................................................48
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting...................49
8.3
Product Quality Complaints.....................................................................................49
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................50
9.1
Data Collection.........................................................................................................50
9.2
Clinical Data Management.......................................................................................50
9.3
Data Handling Considerations..................................................................................50
9.4
Statistical Analysis Process......................................................................................50
9.4.1
Appropriateness of Measurements.........................................................................51
9.4.2
General Considerations..........................................................................................51
9.5
Planned Interim Analysis .........................................................................................51
9.6
Sample Size Calculation and Power Considerations................................................51
9.7
Study Population ......................................................................................................51
9.8
Efficacy Analyses.....................................................................................................52
9.8.1
Primary Efficacy Endpoint ....................................................................................52
9.8.2
Secondary Efficacy Endpoints...............................................................................52
9.8.3
Subgroup Analyses of Efficacy Endpoints ............................................................53


Shire
CONFIDENTIAL
Page 8
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
9.8.4
Exploratory Efficacy Endpoints.............................................................................53
9.9
Safety Analyses........................................................................................................53
9.9.1
Primary Safety Endpoints ......................................................................................53
9.9.2
Secondary Safety Endpoints ..................................................................................53
9.9.3
Clinical Laboratory Tests.......................................................................................54
9.9.4
Vital Signs..............................................................................................................54
9.9.5
Electrocardiography...............................................................................................55
9.10
Pharmacokinetic Analyses .......................................................................................55
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................55
10.1
Sponsor’s Responsibilities .......................................................................................55
10.1.1 Good Clinical Practice Compliance.......................................................................55
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..................................................56
10.2
Investigator’s Responsibilities .................................................................................56
10.2.1 Good Clinical Practice Compliance.......................................................................56
10.2.2 Protocol Adherence and Investigator Agreement..................................................57
10.2.3 Documentation and Retention of Records.............................................................57
10.2.3.1
Case Report Forms.................................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection.....................................................................................58
10.2.3.4
Financial Disclosure...............................................................................58
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................58
10.3
Ethical Considerations..............................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board ....................................................................................59
10.4
Privacy and Confidentiality......................................................................................60
10.5
Study Results/Publication Policy .............................................................................60
11. REFERENCES .......................................................................................................................62
12. APPENDICES ........................................................................................................................64
Appendix 1
Protocol History .....................................................................................65
Appendix 2
Scales and Assessments .........................................................................66
Appendix 3
Bioanalysis: Sample Handling ...............................................................68


Shire
CONFIDENTIAL
Page 9
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................16
Table 2
Recommended Prescreening Procedures and Assessments ..........................35
Table 3
Volume of Blood to Be Drawn from Each Subject.......................................42


Shire
CONFIDENTIAL
Page 10
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
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
Paediatric Investigation Plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PUMA
Paediatric-use marketing authorisation
ROW
rest of world


Shire
CONFIDENTIAL
Page 11
SHP615-301 Protocol Amendment 2
Midazolam
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
VT
ventricular tachycardia


Shire
CONFIDENTIAL
Page 12
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
STUDY SYNOPSIS
Protocol number: SHP615-301
Drug: Midazolam hydrochloride oromucosal solution (MHOS/SHP615) 
Title of the study: A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, Safety, and 
Pharmacokinetics of Buccally Administered MHOS/SHP615 in Pediatric Patients with Status Epilepticus 
(Convulsive) in the Hospital or Emergency Room
Number of subjects (total and for each treatment arm): Approximately 25 subjects (minimum 3 subjects per age 
group)
Investigator(s): Multicenter study (in hospital or healthcare settings)
Site(s) and Region(s): Approximately 25 hospitals in Japan
Study period (planned):
September 2017 to August 2019
Clinical phase:
3
Objectives:
Primary: To assess the efficacy of MHOS/SHP615 administered buccally in pediatric patients with status 
epilepticus (convulsive) in a healthcare setting.
Secondary: To assess the safety and pharmacokinetics of MHOS/SHP615 administered buccally to pediatric 
patients with status epilepticus (convulsive) in a healthcare setting.
Rationale: Under the proprietary name BUCCOLAM® MHOS/SHP615 is currently approved for treatment of 
pediatric patients presenting with status epilepticus (SE) in a hospital or emergency room in several European Union 
(EU) countries. The intravenous (IV) formulation of midazolam is currently administered buccally off label for the 
treatment of SE in a healthcare setting in Japan. This study will provide data to support approval and labeling of 
age-based dosing of MHOS/SHP615 for the treatment of SE in Japanese pediatric patients.
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.
Each pre-filled dosing syringe is individually packed in a protective plastic tube. 
The four available unit dose packs are:

2.5 mg (yellow label) for children aged 3 months (52 weeks corrected gestational age) to <1 year (and 
weight >5 kg)

5 mg (blue label) for children aged 1 year to <5 years

7.5 mg (purple label) for children aged 5 years to <10 years

10 mg (orange label) for children aged 10 years to <18 years
Methodology: SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
MHOS/SHP615 administered buccally to subjects <18 years who present with SE in the healthcare setting. Children 
whose corrected gestational age is 52 weeks (gestational weeks plus the number of weeks after birth) and <18
years, weight >5 kg ,who arrive at the healthcare setting in full seizure, and have not received immediate treatment, 
are eligible to participate in this study providing all inclusion/exclusion 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. Upon 
entry in the SHP615-301 study, subjects will receive a single open-label MHOS/SHP615 treatment, dosing stratified 
by age (2.5, 5, 7.5, 10 mg buccally).


Shire
CONFIDENTIAL
Page 13
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
The efficacy of MHOS/SHP615 in stopping prolonged convulsive seizures will be assessed by measuring the 
percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615 the subject will be treated according to participating 
healthcare setting protocol or guideline. The safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by vital signs, laboratory tests, and ECGs for safety evaluations. All subjects who 
withdraw early or who complete treatment in this study will be followed for 1 week after the dose of SHP615 for 
safety evaluations. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks plus the number 
of weeks after birth) and <18 years, and weight >5 kg, at the time of investigational product administration. 
If the subject’s exact age is not known, the subject should be excluded.
2.
Parent, guardian, or legally authorized representative of the child provides informed consent (and assent,
when applicable per Shire policy and country regulations) to participate in the study prior to participation 
in any protocol specific procedures. The subject may be prescreened by the investigator in their clinical 
practice and parent, guardian, or legally authorized representative may sign informed consent before the 
subject presents to the healthcare setting for treatment of the seizure.
3.
Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the 
preceding hour
b.
Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without 
recovery of consciousness
c.
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 seizures due to illegal drug or acute alcoholic intoxication.
4.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
5.
Subjects with history of seizures of psychogenic origin.
6.
Subjects with known history of hypersensitivities, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia 
gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] block of second 
or third degree, VT [ventricular tachycardia]).
11. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 
transcriptase inhibitors.


Shire
CONFIDENTIAL
Page 14
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
12. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or healthcare 
setting.
13. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
14. Subjects 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.
15. Subject has received antiseizure medication prior to arrival in the healthcare setting
16. 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: 1 week
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is the 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 of a single dose of 
MHOS/SHP615 and who have sustained absence of seizure activity for the following time periods after the 
single dose of MHOS/SHP615:
o
1 h
o
4 h
o
6 h

Time to resolution of seizures (convulsions) 

Time to recovery of consciousness

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 according to the participating healthcare setting protocol or 
guideline, 10 minutes after a single dose of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures within the 
4 hours after MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 6, and 
24 hours postdose (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


Shire
CONFIDENTIAL
Page 15
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign measurements, laboratory 
tests, oxygen saturation, and ECG

Occurrence of buccal irritation
Pharmacokinetics (population PK)

Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolite(s) will be evaluated. Exploratory evaluation of potential additional metabolite(s) may also be 
performed. PK samples will be collected at 1, 3, and 6 hours (or time of discharge, if earlier than 6 hours) after 
administration of MHOS/SHP615.
Statistical methods
Sample size:  The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is estimated 
based on the expected response rate which is assumed to be 58.5% compared with the threshold of 30% with at least 
80% of statistical power at the 2-sided 5% level.
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.
The primary efficacy analysis will be conducted on the FAS, by constructing the 2-sided, 95% confidence interval 
(CI) for the percentage of subjects reaching therapeutic success 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 lower limit of the 95% CI will be compared with the threshold of 30%, which is equivalent to comparing the 
percentage of success to the threshold at the 2-sided 5% level of significance.
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. TEAEs 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.
Population PK analysis
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolites will be evaluated using the Pharmacokinetic Set. The Pharmacokinetic Set will include subjects who 
receive a single dose of MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 
Pharmacokinetic parameters will be calculated using population PK modeling.


Shire
CONFIDENTIAL
Page 16
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-up
Screening/Baseline
0 min
10 min
30 
(± 5min)
1 h
(± 10min)
3h
(± 30min)
4 h
(± 30min)
6 ha
(± 30min)
24hb
(± 30min)
1 week
(± 1 day)
Informed consent/assent 
Xc
Inclusion/exclusion 
criteria
X
Demographics
X
Medical/procedural 
history
X
Confirmation of status 
epilepticus
X
Evaluation of seizure 
symptomsd
X
X
X
X
X
X
X
X
X
Riker Sedation-Agitation 
Scale
X
X
X
X
X
X
X
X
Laboratory evaluationse
Xf
X
X
SHP615 administration
X
PK collectiong
X
X
X
Buccal cavity assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Oxygen saturationj
X
X
X
X
X
X
12-Lead ECG
Xk
Xk
X
X
X
X
Supportive care
X
X
Physical examinationl
X
X
Concomitant medications
X
X
Xa
X
X
Adverse event monitoring
X
X
Xa
X
X
ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute; PK=pharmacokinetic.


Shire
CONFIDENTIAL
Page 17
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-up
Screening/Baseline
0 min
10 min
30 
(± 5min)
1 h
(± 10min)
3h
(± 30min)
4 h
(± 30min)
6 ha
(± 30min)
24hb
(± 30min)
1 week
(± 1 day)
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 postdose time point will be made if the subject has not been discharged from the healthcare setting; 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 If more than 3 months have elapsed between initial informed consent and seizure, parent, guardian, or legally authorized representative should re-sign at the time of admission 
prior to treatment.
d Seizure symptoms will be assessed based on physician’s clinical judgment and healthcare setting protocol.
e Laboratory evaluations include serum biochemistry and urinalysis (including a urine pregnancy test in women of childbearing potential at screening/baseline).
f
Blood glucose can be measured by local lab or testing kit.
g The PK samples will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
h 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. 
i
Vital signs will include single supine blood pressure, pulse rate, respiratory rate, and body temperature.
j
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. The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of 
oxygen administered.
k If subject is stable enough for ECG.
l
Physical examination will be performed at some point between 0 min (dosing) and 6 hours postdose, when possible.


Shire
CONFIDENTIAL
Page 18
SHP615-301 Protocol Amendment 2
Midazolam
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).
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 (ILAE) 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 either 10 minutes (Treiman et al., 1998) or 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; Brophy et al., 2012; Lowenstein et al., 1999; 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.


Shire
CONFIDENTIAL
Page 19
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
In Japan, annual incidence of SE in children younger than 17 years is 42 cases per 
100,000 persons. In addition to young age, other risk factors include genetic predisposition and 
acquired brain insults (Fountain, 2000; Working Group on Status Epilepticus, 1993; Shinnar et 
al., 1996; Berg et al., 1999).
Left untreated (or undertreated) SE, depending on the type and duration of seizures, 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 not 
authorized for SE in the United States [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 healthcare setting. 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 to diazepam treatment. 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).


Shire
CONFIDENTIAL
Page 20
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs as 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 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 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 non-IV 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 treatment of 


Shire
CONFIDENTIAL
Page 21
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 healthcare 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) and <18 years. The efficacy and safety 
of buccal midazolam 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; 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% 
confidence interval {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) from the authorized uses is 
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 (AEs) (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 
<6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Pharmacokinetics
Published PK studies in healthy adult volunteers have shown that buccal midazolam is quickly 
absorbed (producing peak concentrations at 30 minutes with a mean buccal midazolam 
bioavailability of 74.5% [Schwagmeier et al., 1998]) and has a rapid effect (≤5-10 minutes) on 
the central nervous system (CNS), shown on electroencephalography (Scott et al., 1998). The
rapid absorption of midazolam by the buccal route has also been demonstrated in a published 


Shire
CONFIDENTIAL
Page 22
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
study in children with severe malaria and convulsions (peak concentration at 10 [5–40] minutes 
with bioavailability estimated at 87%) (Muchohi et al., 2008).
For this open label SHP615-301 study, the MHOS/SHP615 formulation (the same as the 
HYPNOVEL 10 mg/2 mL formulation) and the proposed fixed doses will be the same as the 
4 pivotal, rectal-diazepam-controlled clinical studies. Thus, the PK/pharmacokinetics should not 
be different for MHOS compared to that in the pivotal efficacy/safety studies.
Always refer to the latest version of the SHP615 Midazolam HCl 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. 
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Open-Label Study (SHP615-301)
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the medical 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 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg as 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) Paediatric
Committee as part of the PIP application and by the EMA Committee for Medicinal Products for 
Human Use (CHMP) as part of the review and approval of the Paediatric-use marketing
authorisation (PUMA).
The rationale for this interventional open-label study is to determine the efficacy, safety, and 
pharmacokinetics of MHOS/SHP615 in pediatric patients with CSE.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of MHOS/SHP615 administered 
buccally in pediatric patients with status epilepticus (convulsive) in a healthcare setting.


Shire
CONFIDENTIAL
Page 23
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
2.2.2
Secondary Objectives
The secondary objectives of this study are to assess the safety and pharmacokinetics of 
MHOS/SHP615 administered buccally to pediatric patients with status epilepticus (convulsive) 
in a healthcare setting.
3
STUDY DESIGN
3.1
Study Design 
SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
buccally administered MHOS/SHP615 to pediatric subjects who present with SE in the 
healthcare setting. 
Approximately 25 subjects will be enrolled in this study. Children whose corrected gestational 
age is ≥52 weeks (gestational weeks plus the number of weeks after birth) and <18 years (and 
weight >5 kg) who arrive at the healthcare setting in full seizure, have not received immediate 
treatment, and have parent, guardian, or legally authorized representative informed 
consent/assent (when applicable, per Shire policy and country regulations), are eligible to 
participate 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. Upon entry in the SHP615-301 study, subjects will receive a single open-label 
MHOS/SHP615 treatment, dosing stratified by age (2.5, 5, 7.5, or 10 mg buccally).
The efficacy of MHOS/SHP615 in stopping convulsive seizures will be assessed by measuring 
the percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615, the 
subject will be treated according to the participating healthcare setting protocol or guideline. The 
safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by assessment of TEAEs, vital signs, laboratory tests, oxygen 
saturation, physical examination, and ECGs for safety evaluations. All subjects treated in this 
study will be followed for 1 week after dosing for safety evaluations.
3.2
Duration and Study Completion Definition
The duration of the treatment visit will be at least 6 hours and up to 24 hours, with a follow-up 
visit 1 week after the administration of MHOS/SHP615. It is anticipated that subjects will arrive 
at the healthcare setting while experiencing a seizure. Subjects will be screened and assessed at 
baseline immediately before administration of investigational product even if the informed 
consent and some prescreening assessments were completed at a previous clinical visit. 


Shire
CONFIDENTIAL
Page 24
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
Evaluation of seizure symptoms will be conducted up through 6 hours after the administration of 
the investigational product. After 6 hours, the subject may be discharged from the healthcare 
setting study site. 
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 the 
protocol-defined assessments, or discontinues the study. 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 healthcare setting study sites in Japan. 
4
STUDY POPULATION
Each subject (parent, guardian, or legally authorized representative) must participate in the 
informed consent process and provide written informed consent/assent (when applicable, per 
Shire policy and country regulations) before any procedures specified in the protocol are 
performed. The subject may be prescreened by the investigator in their clinical practice and the 
parent, guardian, or legally authorized representative may sign informed consent before the 
subject presents to the healthcare setting for treatment of the seizure.
The total enrollment for the SHP615-301 study is expected to be approximately 25 subjects
(minimum 3 subjects per age group) with active generalized tonic-clonic SE with seizures.
Diagnosis of SE will be confirmed through documented medical history and evaluation of 
seizure symptoms conducted either during the screening/baseline assessment period or during
treatment.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator 
before subjects are included in the study.
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks 
plus the number of weeks after birth) and <18 years (and weight >5 kg), at the time of 
investigational product administration. If the subject’s exact age is not known, the subject 
should be excluded.
2. Parent, guardian, or legally authorized representative of the child provides informed consent 
(and assent, when applicable per Shire policy and country regulations) to participate in the 
study prior to participation in any protocol specific procedures. The subject may be 
prescreened by the investigator in their clinical practice and the parent, guardian, or legally 


Shire
CONFIDENTIAL
Page 25
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
authorized representative may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure.
3. Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions 
within the preceding hour
b. Currently presenting with seizure (convulsive) and 2 or more convulsions in 
succession without recovery of consciousness
c.
Currently presenting with a single seizure (convulsive) lasting ≥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 seizures due to illegal drug or acute alcoholic intoxication.
4. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
5. Subjects with history of seizures of psychogenic origin.
6. Subjects with known history of hypersensitivities, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] 
block of second or third degree, VT [ventricular tachycardia]).
11. Subjects who have been receiving HIV protease inhibitors or HIV reverse transcriptase 
inhibitors.
12. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or 
healthcare setting.
13. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.


Shire
CONFIDENTIAL
Page 26
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
14. Subjects 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.
15. Subject has received antiseizure medication prior to arrival in the healthcare setting.
16. 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 during the study.
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Pre-menarchal 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 treatment visit, 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 with the medical monitor prior to withdrawal of a subject from the study, 
if possible.
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 


Shire
CONFIDENTIAL
Page 27
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
possible. The reason for termination and date of stopping the study must be recorded in the CRF 
and source documents. 
Subjects who discontinue will not be replaced. 
4.5.1
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:

AE

Protocol deviation

Withdrawal by subject, parent, guardian, or legally authorized representative

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 CRF 
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 reviewing institutional review board (IRB), or investigational product safety 
problems, or at the discretion of the sponsor. In addition, the sponsor retains the right to 
discontinue development of 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 subjects and subject’s parents, 
guardians, or legally authorized representatives and the healthcare setting pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
4.5.2
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.


Shire
CONFIDENTIAL
Page 28
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
4.5.3
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.

2 SAEs of similar type (defined as the 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 time point/assessment.
4.5.3.1
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).
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other 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 non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the treatment visit and through the final study contact (including 
protocol-defined follow-up period) must be recorded on the appropriate CRF page.


Shire
CONFIDENTIAL
Page 29
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, non-pharmacological 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 before investigational product administration 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 parent, 
guardian, or legally authorized representative) 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-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 3 months (52 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 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. 
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 


Shire
CONFIDENTIAL
Page 30
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
community and healthcare setting. Additional information is provided in the current version of 
the SHP615 Midazolam HCl 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, and the sponsor study team. Study treatment will only be 
administered by the healthcare setting study investigator or subinvestigator to subjects who have 
a signed and dated IRB-approved 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 present for enrollment. 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 the investigator or subinvestigator as a single, 
fixed dose product, banded by age to subjects with CSE in the healthcare setting. For buccal 
administration, MHOS/SHP615 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
3 months (52 weeks corrected gestational age) 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


Shire
CONFIDENTIAL
Page 31
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
6.2.2.2
Dose Administration
Only 1 syringe with the specified dose must be given. The full amount of the MHOS pre-filled 
dosing syringe is injected slowly into the buccal mucosa. In some cases, it might be necessary to 
divide the dose so that half of the solution is injected into each side of mouth.
All investigational product is dispensed by the investigator or subinvestigator.
Prior to administration of drug therapy, the airway should be secured and respiratory and cardiac 
function assessed (NICE Guidance National Institute for Health and Care Excellence, 2011). 
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 Quintiles 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
The investigational product MHOS/SHP615 will be provided in individual, labeled, single-dose, 
prefilled plastic, oral dosing syringes 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 are 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.


Shire
CONFIDENTIAL
Page 32
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 
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. 
Where permissible, tasks may be delegated to a subinvestigator who is adequately trained in the 


Shire
CONFIDENTIAL
Page 33
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying 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 product 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 product 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
All doses of open-label MHOS/SHP615 administered at the investigational site will be by the 
investigator or subinvestigator.
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, trays, 
vials) or at the individual count level for opened containers/packaging. The pharmacist or 
investigator-identified designee 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.


Shire
CONFIDENTIAL
Page 34
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 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/Baseline Assessments
Screening/Baseline assessments for subject eligibility into this study occur on the same day as 
the Treatment Period when subjects <18 years present with SE in the healthcare setting after 
informed consent has been obtained. Alternatively, the subject may be prescreened by the 
investigator for subjects at risk of SE in their clinical practice and parent, guardian, or legally 
authorized representative may sign informed consent before the subject presents to the healthcare 
setting for treatment of the seizure. However, confirmation of SE, evaluation of seizure 
symptoms, blood and urine samples, and AE monitoring must be completed in the healthcare 
setting.
Written informed consent must be obtained prior to performing any protocol-specific procedures. 
The complete list of assessments that will be performed in the study is listed below:

Informed consent/assent (when applicable, per Shire policy and country regulations)

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Confirmation of SE 

Evaluation of seizure symptoms (based on clinical judgment and healthcare setting 
procedures)

Riker Sedation Agitation Scale

Obtain blood and urine samples for the following laboratory tests:

Safety laboratory tests for serum biochemistry and urinalysis

Blood glucose can be measured by local lab or testing kit

Urine pregnancy test (females of childbearing potential only)

Vital signs

Review concomitant medications/treatments

Monitor AEs

Measure oxygen saturation on room air, if feasible


Shire
CONFIDENTIAL
Page 35
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
Table 2 lists recommend prescreening procedures and assessments that can be performed for 
subjects at risk of SE prior to presenting for treatment.
Table 2
Recommended Prescreening Procedures and Assessments
Obtain informed consenta
Collect demographic information
Review medical history 
Take blood and urine sample for laboratory analysisb
Review inclusion/exclusion criteria:
Inclusion Criteria
Exclusion Criteria
1. Age
1. Pregnancy
2. Informed consent
4. Known seizures due to drugs/alcohol
6. Contraindications to benzodiazepines
7. History of benzodiazepine abuse
8. Prior non-response to midazolam
11.Prior treatment for HIV
13.Severe cerebral anoxia (except cerebral palsy)
14.Prior study involvement impacting this study
16. Prior placement of a vagus nerve stimulator
Note: Procedures and assessments should be reviewed and reconfirmed when the subject arrives at the hospital or healthcare 
center for SE treatment.
a To be repeated every 3 months if no seizure resulting in study drug administration.
b  To be repeated every 6 months if no seizure resulting in study drug administration.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered investigational 
product(s). Subjects cannot be rescreened once they have been designated as a screen failure. 
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)
Healthcare setting study investigator or subinvestigator will administer investigational product 
MHOS/SHP615 (age-based dose of 2.5, 5, 7.5, or 10 mg) buccally.
The following procedures will be performed:

Evaluate seizure symptoms

Riker Sedation Agitation Scale

Provide supportive care per healthcare setting guidelines

Review concomitant medications/treatments

Monitor AEs

Measure oxygen saturation


Shire
CONFIDENTIAL
Page 36
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
7.1.3
Treatment Period (0 minutes to 6 hours postdose) 

Perform physical examination when possible during the 6 hour time period.
7.1.4
Treatment Period (10 minutes to 24 hours postdose) 
The following procedures will be performed throughout the Treatment Period at time points 
specified in the Schedule of Assessments (Table 1):

Evaluate seizure symptoms and Riker Sedation Agitation Scale at 10 and 30 (±5) minutes, 
and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours postdose

4 hours and 24 hours (±30 min) postdose (if subject has not been discharged from the 
healthcare setting): Obtain blood and urine samples for safety laboratory tests for serum 
biochemistry and urinalysis

1 (±10 min), 3 (±30 min), and 6 hours (±30 min) postdose:

Collect blood samples for PK analysis.

10 and 30 (±5) minutes, and 4, 6, and 24 hours (±30 min) postdose (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). 

Measure oxygen saturation.

Perform standard 12-lead ECG.

Administer supportive care throughout this time period.

Review concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
blood sampling).

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.
Note:  Evaluate by telephone if subject is discharged between 6 hours (±30 min) and 24 hours 
(±1 hour) 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 Visit
The follow-up period for this protocol is 1 week after the Treatment Period.


Shire
CONFIDENTIAL
Page 37
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
At the end of this period there will be a follow up visit to evaluate seizure symptoms, review 
concomitant medications, conduct a physical examination, and query for serious adverse events 
(SAEs), AEs. All AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure (see Section 8).
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study. It is the responsibility of the investigator to counsel 
subjects on their treatment alternatives when they exit the 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 informed consent form (ICF) must be executed prior to performing any study-related 
activities and the ICF must be approved by the reviewing IRB. The subject or the subject’s 
parents, guardians, or legally authorized representatives may withdraw consent at any time. The 
subject may be prescreened by the investigator in their clinical practice and the parent, guardian, 
or legally authorized representative may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure. If more than 3 months have elapsed between 
initial informed consent and seizure, the parent, guardian, or legally authorized representative 
should re-sign at the time of admission prior to treatment. Participation in the study may be 
terminated at any time without the consent of subjects or subject’s parents, guardians, or legally 
authorized representatives as determined by the investigator.
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 parents or caregivers and will be recorded on the 
source document and CRF.
Medical history (including SE) will capture the subject’s current medical status (current SE or 
CSE disease process), past medical status (past disease processes), history of surgery, allergies, 
and concomitant medications/treatments.
7.2.3
Efficacy
Evaluation of seizure activity will be conducted throughout the study to assess the therapeutic 
success.


Shire
CONFIDENTIAL
Page 38
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017

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.
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.
7.2.4.1
Medical and Medication History
The investigator will perform a complete medical history at Screening, including a medication 
history, and record all information gathered. The investigator must record all clinically or 
medically relevant information regardless of how much time has elapsed since the date of 
diagnosis.
With the consent of parents, guardians, or legally authorized representatives of participating 
subjects, medical records from other treatment providers should be requested. 
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE (eg, dietary, medication, or other), must be recorded on the 
appropriate CRF page.
7.2.4.2
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)

Musculoskeletal


Shire
CONFIDENTIAL
Page 39
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017

Neurological
Abnormalities identified at Screening will be documented in the subject’s source documents and 
on the medical history CRF. Changes after the Screening visit will be captured as AEs on the AE 
CRF page, as deemed by the investigator.
7.2.4.3
Adverse Event Collection
At each study time point, subjects (or parent, guardian, or legally authorized representative) will 
be questioned 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 when the subject with SE
arrives at the hospital or healthcare setting, or if the informed consent has been previously 
signed, from the time the subject begins evaluation and treatment in the hospital or healthcare 
setting for SE, to completion of the follow-up visit. (Please refer to Section 8, Adverse and 
Serious Adverse Events Assessment.)
7.2.4.4
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.
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 the initial vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Clinical Laboratory Evaluations
Clinical laboratory assessments will be performed at Screening, at 4 hours postdose, and at 
24 hours postdose if the subject is still at the healthcare setting. The following clinical laboratory 
assessments will be performed:


Shire
CONFIDENTIAL
Page 40
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 pregnancy testd
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 at screening for women of childbearing potential; may be repeated at the follow-up visit or withdrawal from study if 
pregnancy is suspected.
Aliquots from the PK samples may be retained as back-up for additional parameter testing if 
necessary. Subjects will be in a seated or supine position during blood collection. The total blood 
draw for each subject will be approximately 14.25 mL.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by Quintile’s central 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. 
Blood, serum, and urine samples 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.
7.2.4.6
Pregnancy Test
A urine pregnancy test is performed on all females of childbearing potential at Screening and at 
the follow up visit, if pregnancy is suspected, or upon withdrawal of the subject from the study.


Shire
CONFIDENTIAL
Page 41
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
7.2.4.7
Electrocardiogram 
A standard twelve (12)-lead electrocardiogram (ECG, single recording) will be performed at 
time points specified in the Schedule of Assessments (Table 1).
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.
The investigator or subinvestigator at the investigator site will make comparisons to baseline 
measurements taken at screening, if available. A copy of the ECG should be available as source 
documents for review.  
7.2.4.8
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).
7.2.5
Others 
7.2.5.1
Pharmacokinetic Assessments
Blood samples (~1.25 mL) to provide a minimum of 0.5 mL plasma for the assessment of plasma 
midazolam and 1-hydroxymidazolam concentrations will be collected (from all subjects who 
received investigational product) and analyzed at the specified time points for the duration of the 
study at the time points specified in the Schedule of Assessments (Table 1). The exact time of the 
sample collection should be noted on the source document and data collection tool (eg, CRF).
Samples will be analyzed for midazolam and 1-hydroxymidazolam using a validated assay. The 
methodologies will be appropriately validated in compliance with the CRO’s standard operating 
procedures. 
The address for shipment of serum samples and contact information for the laboratory analysis of 
midazolam and 1-hydroxymidazolam will be provided to the investigator site prior to initiation 
of the trial.


Shire
CONFIDENTIAL
Page 42
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
7.2.6
Volume of Blood to Be Drawn from Each Subject
Table 3
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
1.25
3
3.75
Safety
Biochemistry 
3.5
3
10.5
Total mL
14.25
a If a catheter is used, the first mL is to be discarded; then take 1.25 mL into appropriate tube for PK sample. A total of 
1.25 mL of blood drawn has been used in determination of sample volume.
During this study, it is expected that up to approximately 14.25 mL of blood will be drawn from 
each subject.
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 14.25 mL. Additional considerations may be made for small children 
and infants with sponsor review. 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.
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 when the subject with SE
arrives at the hospital or healthcare setting or if the informed consent has been previously signed, 
from the time the subject begins evaluation and treatment in the hospital or healthcare setting for 
SE, until the defined follow-up period stated in Section 7.1.5. 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 


Shire
CONFIDENTIAL
Page 43
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 change in severity. An event that changes in severity should be captured as a new event. 
Worsening of pre-treatment 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 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/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.


Shire
CONFIDENTIAL
Page 44
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 
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.


Shire
CONFIDENTIAL
Page 45
SHP615-301 Protocol Amendment 2
Midazolam
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 -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 
non-medical 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)


Shire
CONFIDENTIAL
Page 46
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of the product. 

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.
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 the Quintiles 
Transnational Japan K.K., the 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
An 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 


Shire
CONFIDENTIAL
Page 47
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 a hospital 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: 

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;


Shire
CONFIDENTIAL
Page 48
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017

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 informed consent is 
signed when the subject with SE arrives at the hospital or healthcare setting, or if the informed 
consent has been previously signed, from the time the subject begins evaluation and treatment in 
the hospital or healthcare setting for SE, until the defined follow-up period stated in Section 7.1.5
and must be reported to Quintiles Transnational Japan K.K., 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 ICF, 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 


Shire
CONFIDENTIAL
Page 49
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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, and Site Reporting
The sponsor and Quintiles Transnational Japan K.K. are responsible for notifying the relevant 
regulatory authorities/and institutional IRBs 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 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 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.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
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)


Shire
CONFIDENTIAL
Page 50
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate case report form (CRF).
The 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 the investigator or 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 healthcare setting 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 agent. 
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.


Shire
CONFIDENTIAL
Page 51
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 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 study that is designed to evaluate the efficacy and safety of 
MHOS/SHP615 in 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. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% CIs for least squares means will be provided. 
Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th (median), 
and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored 
observations. Plots of the Kaplan-Meier curves and supporting data listings detailing each 
subject’s contribution to the analysis will be provided. 
9.5
Planned Interim Analysis
There is no planned interim analysis for this study.
9.6
Sample Size Calculation and Power Considerations
The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is 
estimated based on the expected response rate which is assumed to be 58.5% compared with the 
threshold of 30% with at least 80% of statistical power at the 2-sided 5% level.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Set will consist of all subjects who have received a single dose of MHOS/SHP615.
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. 
The Pharmacokinetic Set will consist of all subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 


Shire
CONFIDENTIAL
Page 52
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
9.8
Efficacy Analyses
The primary efficacy analysis will be conducted on the FAS.
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 primary efficacy analysis will be conducted on FAS by constructing the 2-sided, 95% CI for 
the percentage of subjects reaching therapeutic success. The lower limit of the 95% CI will be 
compared with the threshold of 30%, which is equivalent to comparing the percentage of success 
to the threshold at the 2-sided 5% level of significance.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes of single 
dose 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 of single 
dose 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 of single 
dose 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

Percentage of subjects who require additional anticonvulsant medication for ongoing 
SE according to the participating healthcare setting protocol or guideline, 10 minutes after a 
single dose 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 according to the participating healthcare setting
protocol or guideline, 10 minutes after a single dose of MHOS/SHP615.


Shire
CONFIDENTIAL
Page 53
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
9.8.3
Subgroup Analyses of Efficacy Endpoints
Selected efficacy endpoints will be evaluated using descriptive statistics by the following 
subgroups, to the extent the data allow:

Age group: 

3 months (52 weeks corrected gestational age) to <1year (and weight >5 kg)

1 to <5 years

5 to <10 years

10 to <18 years

Gender: male and female

Epilepsy etiology (based on the underlying etiology of their epilepsy):

Genetic

Idiopathic

Metabolic 

Symptomatic (Structural)
9.8.4
Exploratory Efficacy Endpoints
A description of the analyses will be included in the SAP.
9.9
Safety Analyses
Safety data will be summarized using descriptive statistics for the Safety Set.
9.9.1
Primary Safety Endpoints
The primary safety endpoints will be respiratory depression, which will include the following 
measures within the 4 hours after MHOS/SHP615 administration:

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 
6, and 24 hours postdose (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)
9.9.2
Secondary Safety Endpoints
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 ECG

Occurrence of buccal irritation


Shire
CONFIDENTIAL
Page 54
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
Adverse events and medical history will be coded using MedDRA. The number of events, 
incidence, and percentage of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by age. 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.
Vital signs (systolic and diastolic blood pressure, pulse, and weight) including potentially 
clinically important vital signs will be summarized using the appropriate descriptive statistics.
The ECG results, including potentially clinically important results, will be summarized.   
9.9.3
Clinical Laboratory Tests 
Clinical laboratory tests will be summarized using the Safety Set. 
Actual values and change from baseline clinical laboratory tests will be summarized. If more 
than 1 laboratory result is reported per study time point per parameter, the last non-missing 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 non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, non-clinically significant result less than the lower limit of normal, within the 
normal range, non-clinically 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 for a subject across study time point to identify any trends.
9.9.4
Vital Signs
Vital signs will be summarized using the Safety Set.
Actual values and changes from baseline in vital signs will be summarized. 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 non-missing result, and the number and percentage 
of subjects with a non-clinically 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. 


Shire
CONFIDENTIAL
Page 55
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 not performed, will be summarized. 
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.
9.10
Pharmacokinetic Analyses
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any 
potential additional metabolite(s) will be evaluated using the Pharmacokinetic population.  
The Pharmacokinetic population will include subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. PK samples 
will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
PK parameters (eg, Cmax, Tmax, AUC and t1/2) will be calculated using population PK modeling.
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.


Shire
CONFIDENTIAL
Page 56
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 non-pediatric 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.


Shire
CONFIDENTIAL
Page 57
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 (July 1996). 
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.
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.
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.


Shire
CONFIDENTIAL
Page 58
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 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.


Shire
CONFIDENTIAL
Page 59
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 (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 (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.


Shire
CONFIDENTIAL
Page 60
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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 (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 non-commercial 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 


Shire
CONFIDENTIAL
Page 61
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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.
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.


Shire
CONFIDENTIAL
Page 62
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 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. & 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.
Baysun, S., Aydin, O. F., Atmaca, E. & Gurer, Y. K. 2005. A comparison of buccal midazolam 
and rectal diazepam for the acute treatment of seizures. Clin Pediatr (Phila), 44, 771-6.
Berg, A. T., Shinnar, S., Levy, S. R. & Testa, F. M. 1999. Status epilepticus in children with 
newly diagnosed epilepsy. Ann Neurol, 45, 618-23.
Brophy, G. M., Bell, R., Claassen, J., Alldredge, B., Bleck, T. P., Glauser, T., Laroche, S. M., 
Riviello, J. J. J., Shutter, L., Sperling, M. R., Treiman, D. M., Vespa, P. M. & Committee, 
N. C. S. S. E. G. W. 2012. Guidelines for the evaluation and management of status 
epilepticus. Neurocrit Care, 17, 3-23.
Dham, B. S., 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, 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/.
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.
Lowenstein, D. H., Bleck, T. & MacDonald, R. L. 1999. It's time to revise the definition of status 
epilepticus. Epilepsia, 40, 120-2.
McIntyre, J., Robertson, S., Norris, E., Appleton, R., Whitehouse, W. P., 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, P. J. & 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.
Muchohi, S. N., Kokwaro, G. O., Ogutu, B. R., Edwards, G., Ward, S. A. & Newton, C. R. 2008. 
Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and 
convulsions. Br J Clin Pharmacol, 66, 529-38.
NICE Guidance National Institute for Health and Care Excellence. 2011. Available: 
https://www.nice.org.uk/guidance/cg137/chapter/Appendix-F [Accessed 24 Jan 2017.


Shire
CONFIDENTIAL
Page 63
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
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. & 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.
Schwagmeier, R., Alincic, S. & Striebel, H. W. 1998. Midazolam pharmacokinetics following 
intravenous and buccal administration. Br J Clin Pharmacol, 46, 203-6.
Scott, R. C., Besag, F. M., Boyd, S. G., Berry, D. & Neville, B. G. 1998. Buccal absorption of 
midazolam: pharmacokinetics and EEG pharmacodynamics. Epilpesia, 39, 290-4.
Scott, R. C., Besag, F. M. & Neville, B. G. 1999. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Shinnar, S., Berg, A. T., Moshe, S. L., O'Dell, C., Alemany, M., Newstein, D., Kang, H., 
Goldensohn, E. S. & 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.
Sirven, J. I. & 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, W. H., Porter, R. J. & 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. & 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. & Brigo, F. 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, M. T., Macleod, S. & O'Regan, M. E. 2004. Nasal/buccal midazolam use in the 
community. Arch Dis Child, 89, 50-1.
Working Group on Status Epilepticus 1993. Treatment of convulsive status epilepticus. 
Recommendations of the Epilepsy Foundation of America's Working Group on Status 
Epilepticus. Jama, 270, 854-9.


Shire
CONFIDENTIAL
Page 64
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
12
APPENDICES




Shire
CONFIDENTIAL
Page 66
SHP615-301 Protocol Amendment 2
Midazolam
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
2016
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. 


Shire
CONFIDENTIAL
Page 67
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).


Shire
CONFIDENTIAL
Page 68
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
APPENDIX 3
BIOANALYSIS: SAMPLE HANDLING
1.1
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1 to measure plasma 
concentrations of midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s). 
Blood samples (~1.25 mL) for pharmacokinetic analysis will be drawn by in-dwelling catheters 
or direct venipuncture into K2EDTA tubes, capped, and chilled immediately on crushed ice. The 
actual time that the sample was obtained will be recorded in the subject’s source document and 
on the appropriate CRF page. After applying a tourniquet, venous blood will be drawn with a 
disposable needle. If a catheter is used, the first milliliter of blood on each sampling occasion 
will be discarded. Saline can be used to keep catheters patent.
1.2
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after
collection (within <15 minutes) by refrigerated centrifugation (4C, 1500 g, 15 minutes). The 
separated plasma will be transferred into appropriately labeled polypropylene tubes via a plastic 
pipette. Plasma to be split in two aliquots: first tube minimum 0.25 mL (primary sample), second 
tube remaining plasma volume (back-up sample).  Aliquots should be shipped separately to the 
bioanalytical laboratory. All samples will be stored at approximately -80C or colder and the 
freezer temperature will be controlled, monitored, and recorded during the storage period until 
they are transferred in the frozen state to a designated bioanalytical contract laboratory. Samples 
will remain frozen at -80C or colder until analysis. Note: For sites that do not have access 
to -80C storage, samples may be stored at -20C for a limited time (maximum 90 days) before
shipping to the bioanalytical CRO.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the clinical pharmacology unit. The labels will contain the following information:

Study number

Treatment 

Subject identifier 

Matrix identifier (plasma)

Nominal time
1.3
Shipment of Plasma Samples
Plasma samples should be double bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday to Wednesday only. 
Samples should be transported to ensure that they arrive at the bioanalytical laboratory between 


Shire
CONFIDENTIAL
Page 69
SHP615-301 Protocol Amendment 2
Midazolam
28 Aug 2017
the hours of 0900 and 1600. The recipient and primary Shire contact must be notified by phone, 
fax, and e-mail when the samples are shipped and must be provided with the shipment tracking 
number. 
Plasma samples, along with the corresponding documentation, will be shipped to:
Name of bioanalytical laboratory: York Bioanalytical Solutions (YBS)
Primary contact: 
Telephone DDI: 
E-mail:
Plasma samples will be stored nominally at -80C prior to and after analysis at York 
Bioanalytical Solutions Limited until their disposal is authorized by Shire.
1.4
Assay Methodology
Drug analysis will be performed at YBS under the guidance of the Department of Nonclinical 
Development, Shire Pharmaceuticals. Plasma sample analysis will be performed according to the 
bioanalytical study plans prepared for the study. 
Plasma samples (K2EDTA) will be analyzed at York Bioanalytical Solutions Limited for 
midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s) using the most 
current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at York Bioanalytical Solutions Limited.

Prot_002.pdf: 








Shire
CONFIDENTIAL
Page 5
SHP615-301 Protocol Amendment 1
Midazolam
08 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: 


Shire
CONFIDENTIAL
Page 6
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
PRODUCT QUALITY COMPLAINTS
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). 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. For instructions on reporting AEs related to product complaints, 
see Section 8.3.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
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)


Shire
CONFIDENTIAL
Page 7
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
1.
BACKGROUND INFORMATION.......................................................................................20
1.1
Status Epilepticus .....................................................................................................20
1.2
Current Treatment Options.......................................................................................21
1.3
Unmet Medical Need for Buccal Midazolam...........................................................22
1.4
Product Background and Clinical Information ........................................................22
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Open-Label Study (SHP615-301) ................................................25
2.2
Study Objectives ......................................................................................................25
2.2.1
Primary Objectives.................................................................................................25
2.2.2
Secondary Objectives.............................................................................................25
3.
STUDY DESIGN ...................................................................................................................26
3.1
Study Design ............................................................................................................26
3.2
Duration and Study Completion Definition .............................................................26
3.3
Sites and Regions .....................................................................................................27
4.
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
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................................................................................................30
4.5
Discontinuation of Subjects .....................................................................................30
4.5.1
Reasons for Discontinuation..................................................................................30
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................31
4.5.3
Stopping Rules.......................................................................................................31
4.5.3.1
Study Level Stopping Rules...................................................................32


Shire
CONFIDENTIAL
Page 8
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria................................32
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................33
5.1
Prior Treatment ........................................................................................................33
5.2
Concomitant Treatment............................................................................................33
6.
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Blinding the Treatment Assignment......................................................................34
6.2
Administration of Investigational Product(s)...........................................................34
6.2.1
Allocation of Subjects to Treatment ......................................................................34
6.2.2
Dose Regimen and Dose Administration...............................................................35
6.2.2.1
Dosing Regimen.....................................................................................35
6.2.2.2
Dose Administration ..............................................................................35
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/Baseline Assessments ...........................................................................39
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)........40
7.1.3
Treatment Period (0 minutes to 6 hours postdose) ................................................40
7.1.4
Treatment Period (10 minutes to 24 hours postdose) ............................................41
7.1.5
Follow-up Visit......................................................................................................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
Physical Examination.............................................................................43
7.2.4.3
Adverse Event Collection.......................................................................44
7.2.4.4
Vital Signs..............................................................................................44
7.2.4.5
Clinical Laboratory Evaluations.............................................................44


Shire
CONFIDENTIAL
Page 9
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
7.2.4.6
Pregnancy Test .......................................................................................45
7.2.4.7
Electrocardiogram ..................................................................................45
7.2.4.8
Oxygen saturation ..................................................................................46
7.2.5
Others.....................................................................................................................46
7.2.5.1
Pharmacokinetic Assessments................................................................46
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................46
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................48
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................48
8.1.1
Severity Categorization..........................................................................................48
8.1.2
Relationship Categorization...................................................................................49
8.1.3
Outcome Categorization ........................................................................................49
8.1.4
Symptoms of the Disease Under Study .................................................................50
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................50
8.1.6
Pregnancy...............................................................................................................50
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................51
8.2
Serious Adverse Event Procedures ..........................................................................51
8.2.1
Reference Safety Information................................................................................51
8.2.2
Reporting Procedures.............................................................................................51
8.2.3
Serious Adverse Event Definition .........................................................................52
8.2.4
Serious Adverse Event Collection Time Frame.....................................................53
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................54
8.2.6
Fatal Outcome........................................................................................................54
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting...................54
8.3
Product Quality Complaints.....................................................................................54
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................56
9.1
Data Collection.........................................................................................................56
9.2
Clinical Data Management.......................................................................................56
9.3
Data Handling Considerations..................................................................................56
9.4
Statistical Analysis Process......................................................................................56
9.4.1
Appropriateness of Measurements.........................................................................57
9.4.2
General Considerations..........................................................................................57
9.5
Planned Interim Analysis .........................................................................................57
9.6
Sample Size Calculation and Power Considerations................................................57
9.7
Study Population ......................................................................................................57
9.8
Efficacy Analyses.....................................................................................................58
9.8.1
Primary Efficacy Endpoint ....................................................................................58
9.8.2
Secondary Efficacy Endpoints...............................................................................58


Shire
CONFIDENTIAL
Page 10
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
9.8.3
Subgroup Analyses of Efficacy Endpoints ............................................................59
9.8.4
Exploratory Efficacy Endpoints.............................................................................59
9.9
Safety Analyses........................................................................................................59
9.9.1
Primary Safety Endpoints ......................................................................................59
9.9.2
Secondary Safety Endpoints ..................................................................................59
9.9.3
Clinical Laboratory Tests.......................................................................................60
9.9.4
Vital Signs..............................................................................................................60
9.9.5
Electrocardiography...............................................................................................61
9.10
Pharmacokinetic Analyses .......................................................................................61
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................62
10.1
Sponsor’s Responsibilities .......................................................................................62
10.1.1 Good Clinical Practice Compliance.......................................................................62
10.1.2 Public Posting of Study Information......................................................................62
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Institutional Review Boards............................62
10.1.4 Study Suspension, Termination, and Completion..................................................63
10.2
Investigator’s Responsibilities .................................................................................63
10.2.1 Good Clinical Practice Compliance.......................................................................63
10.2.2 Protocol Adherence and Investigator Agreement..................................................63
10.2.3 Documentation and Retention of Records.............................................................64
10.2.3.1
Case Report Forms.................................................................................64
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................64
10.2.3.3
Audit/Inspection.....................................................................................65
10.2.3.4
Financial Disclosure...............................................................................65
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................65
10.3
Ethical Considerations..............................................................................................65
10.3.1 Informed Consent...................................................................................................65
10.3.2 Institutional Review Board ....................................................................................66
10.4
Privacy and Confidentiality......................................................................................66
10.5
Study Results/Publication Policy .............................................................................67
11. REFERENCES .......................................................................................................................69
12. APPENDICES ........................................................................................................................71
Appendix 1
Protocol History .....................................................................................71
Appendix 2
Scales and Assessments .........................................................................72
Appendix 3
Bioanalysis: Sample Handling ...............................................................74


Shire
CONFIDENTIAL
Page 11
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................18
Table 2
Recommended Prescreening Procedures and Assessments ..........................40
Table 3
Volume of Blood to Be Drawn from Each Subject.......................................46


Shire
CONFIDENTIAL
Page 12
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
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
Paediatric Investigation Plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PQCROW
Product Quality Complaint Rest of World
PUMA
Paediatric-use marketing authorisation


Shire
CONFIDENTIAL
Page 13
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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
VT
ventricular tachycardia


Shire
CONFIDENTIAL
Page 14
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
STUDY SYNOPSIS
Protocol number: SHP615-301
Drug: Midazolam hydrochloride oromucosal solution (MHOS/SHP615) 
Title of the study: A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, Safety, and 
Pharmacokinetics of Buccally Administered MHOS/SHP615 in Pediatric Patients with Status Epilepticus 
(Convulsive) in the Hospital or Emergency Room
Number of subjects (total and for each treatment arm): Approximately 25 subjects (minimum 3 subjects per age 
group)
Investigator(s): Multicenter study (in hospital or healthcare settings)
Site(s) and Region(s): Approximately 25 hospitals in Japan
Study period (planned):
July 2017 to June 2019
Clinical phase:
3
Objectives:
Primary: To assess the efficacy of MHOS/SHP615 administered buccally in pediatric patients with status 
epilepticus (convulsive) in a healthcare setting.
Secondary: To assess the safety and pharmacokinetics of MHOS/SHP615 administered buccally to pediatric 
patients with status epilepticus (convulsive) in a healthcare setting.
Rationale: Under the proprietary name BUCCOLAM® MHOS/SHP615 is currently approved for treatment of 
pediatric patients presenting with status epilepticus (SE) in a hospital or emergency room in several European Union 
(EU) countries. The intravenous (IV) formulation of midazolam is currently administered buccally off label for the 
treatment of SE in a healthcare setting in Japan. This study will provide data to support approval and labeling of 
age-based dosing of MHOS/SHP615 for the treatment of SE in Japanese pediatric patients.
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.
Each pre-filled dosing syringe is individually packed in a protective plastic tube. 
The four available unit dose packs are:

2.5 mg (yellow label) for children aged 3 months (52 weeks corrected gestational age) to <1 year (and 
weight >5 kg)

5 mg (blue label) for children aged 1 year to <5 years

7.5 mg (purple label) for children aged 5 years to <10 years

10 mg (orange label) for children aged 10 years to <18 years
Methodology: SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
MHOS/SHP615 administered buccally to subjects <18 years who present with SE in the healthcare setting. Children 
whose corrected gestational age is 52 weeks (gestational weeks plus the number of weeks after birth) and <18
years, weight >5 kg ,who arrive at the healthcare setting in full seizure, and have not received immediate treatment, 
are eligible to participate in this study providing all inclusion/exclusion 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. Upon 
entry in the SHP615-301 study, subjects will receive a single open-label MHOS/SHP615 treatment, dosing stratified 
by age (2.5, 5, 7.5, 10 mg buccally).


Shire
CONFIDENTIAL
Page 15
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
The efficacy of MHOS/SHP615 in stopping prolonged convulsive seizures will be assessed by measuring the 
percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615 the subject will be treated according to participating 
healthcare setting protocol or guideline. The safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by vital signs, laboratory tests, and ECGs for safety evaluations. All subjects who 
withdraw early or who complete treatment in this study will be followed for 1 week after the dose of SHP615 for 
safety evaluations. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks plus the number 
of weeks after birth) and <18 years, and weight >5 kg, at the time of investigational product administration. 
If the subject’s exact age is not known, the subject should be excluded.
2.
Parent, guardian, or legally authorized representative of the child provides informed consent (and assent,
when applicable per Shire policy and country regulations) to participate in the study prior to participation 
in any protocol specific procedures. The subject may be prescreened by the investigator in their clinical 
practice and parents or legal guardians may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure.
3.
Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the 
preceding hour
b.
Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without 
recovery of consciousness
c.
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 seizures due to illegal drug or acute alcoholic intoxication.
4.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
5.
Subjects with history of seizures of psychogenic origin.
6.
Subjects with known history of hypersensitivities, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia 
gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] block of second 
or third degree, VT [ventricular tachycardia]).
11. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 
transcriptase inhibitors.


Shire
CONFIDENTIAL
Page 16
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
12. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or healthcare 
setting.
13. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
14. Subjects 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.
15. Subject has received antiseizure medication prior to arrival in the healthcare setting
16. 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: 1 week
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is the 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 of a single dose of 
MHOS/SHP615 and who have sustained absence of seizure activity for the following time periods after the 
single dose of MHOS/SHP615:
o
1 h
o
4 h
o
6 h

Time to resolution of seizures (convulsions) 

Time to recovery of consciousness

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 according to the participating healthcare setting protocol or 
guideline, 10 minutes after a single dose of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures within the 
4 hours after MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 6, and 
24 hours postdose (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


Shire
CONFIDENTIAL
Page 17
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017

Incidences/monitoring of treatment-emergent adverse events (TEAEs), vital sign measurements, laboratory 
tests, oxygen saturation, and ECG

Occurrence of buccal irritation
Pharmacokinetics (population PK)

Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolite(s) will be evaluated. Exploratory evaluation of potential additional metabolite(s) may also be 
performed. PK samples will be collected at 1, 3, and 6 hours (or time of discharge, if earlier than 6 hours) after 
administration of MHOS/SHP615.
Statistical methods
Sample size:  The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is estimated 
based on the expected response rate which is assumed to be 58.5% compared with the threshold of 30% with at least 
80% of statistical power at the 2-sided 5% level.
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.
The primary efficacy analysis will be conducted on the FAS, by constructing the 2-sided, 95% confidence interval 
(CI) for the percentage of subjects reaching therapeutic success 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 lower limit of the 95% CI will be compared with the threshold of 30%, which is equivalent to comparing the 
percentage of success to the threshold at the 2-sided 5% level of significance.
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. TEAEs 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.
Population PK analysis
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolites will be evaluated using the Pharmacokinetic Set. The Pharmacokinetic Set will include subjects who 
receive a single dose of MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 
Pharmacokinetic parameters will be calculated using population PK modeling.


Shire
CONFIDENTIAL
Page 18
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-
up
Screening/
Baseline
0 
min
10 
min
30 
(± 5min)
1 h
(± 
10min)
3h
(± 
30min)
4 h
(± 
30min)
6 ha
(± 
30min)
24hb
(± 
30min)
1 week
(± 1 day)
Informed 
consent/assent 
X
Inclusion/exclusion 
criteria
Xc
Demographics
X
Medical/procedural 
history
X
Confirmation of 
status epilepticus
X
Evaluation of 
seizure symptomsd
X
X
X
X
X
X
X
X
X
Riker Sedation-
Agitation Scale
X
X
X
X
X
X
X
X
Laboratory 
evaluationse
Xf
X
X
SHP615 
administration
X
PK collectiong
X
X
X
Buccal cavity 
assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Oxygen saturationj
X
X
X
X
X
X
12-Lead ECG
Xk
Xk
X
X
X
X
Supportive care
X
X
Physical 
examinationl
X
X
Concomitant 
medications
X
X
Xa
X
X
Adverse event 
monitoring
X
X
Xa
X
X
ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute; PK=pharmacokinetic.
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 postdose time point will be made if the subject has not been discharged from the healthcare 
setting; 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 If more than 3 months have elapsed between initial informed consent and seizure, parent or legal guardian should re-sign at 
the time of admission prior to treatment.
d Seizure symptoms will be assessed based on physician’s clinical judgment and healthcare setting protocol.


Shire
CONFIDENTIAL
Page 19
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-
up
Screening/
Baseline
0 
min
10 
min
30 
(± 5min)
1 h
(± 
10min)
3h
(± 
30min)
4 h
(± 
30min)
6 ha
(± 
30min)
24hb
(± 
30min)
1 week
(± 1 day)
e Laboratory evaluations include serum biochemistry and urinalysis (including a urine pregnancy test in women of 
childbearing potential at screening/baseline).
f
Blood glucose can be measured by local lab or testing kit.
g The PK samples will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
h 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. 
i
Vital signs will include single supine blood pressure, pulse rate, respiratory rate, and body temperature.
j
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. 
The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of oxygen 
administered.
k If subject is stable enough for ECG.
l
Physical examination will be performed at some point between 0 min (dosing) and 6 hours postdose, when possible.


Shire
CONFIDENTIAL
Page 20
SHP615-301 Protocol Amendment 1
Midazolam
08 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).
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 (ILAE) 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 either 10 minutes (Treiman et al., 1998) or 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; Brophy et al., 2012; Lowenstein et al., 1999; 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.


Shire
CONFIDENTIAL
Page 21
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
In Japan, annual incidence of SE in children younger than 17 years is 42 cases per 
100,000 persons. In addition to young age, other risk factors include genetic predisposition and 
acquired brain insults (Fountain, 2000; Working Group on Status Epilepticus, 1993; Shinnar et 
al., 1996; Berg et al., 1999).
Left untreated (or undertreated) SE, depending on the type and duration of seizures, 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 not 
authorized for SE in the United States {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 healthcare setting. 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 to diazepam treatment. 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).


Shire
CONFIDENTIAL
Page 22
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs as 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 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 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 non-IV 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 treatment of 
prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents (from 
3 months to ≤18 years).


Shire
CONFIDENTIAL
Page 23
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 healthcare 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) and <18 years. The efficacy and safety 
of buccal midazolam 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; 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% 
confidence interval {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) from the authorized uses is 
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 (AEs) (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 
<6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Pharmacokinetics
Published PK studies in healthy adult volunteers have shown that buccal midazolam is quickly 
absorbed (producing peak concentrations at 30 minutes with a mean buccal midazolam 
bioavailability of 74.5% [Schwagmeier et al., 1998]) and has a rapid effect (≤5-10 minutes) on 
the central nervous system (CNS), shown on electroencephalography (Scott et al., 1998). The 
rapid absorption of midazolam by the buccal route has also been demonstrated in a published 
study in children with severe malaria and convulsions (peak concentration at 10 [5–40] minutes 
with bioavailability estimated at 87%) (Muchohi et al., 2008).


Shire
CONFIDENTIAL
Page 24
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
For this open label SHP615-301 study, the MHOS/SHP615 formulation (the same as the 
HYPNOVEL 10 mg/2 mL formulation) and the proposed fixed doses will be the same as the 
4 pivotal, rectal-diazepam-controlled clinical studies. Thus, the PK/pharmacokinetics should not 
be different for MHOS compared to that in the pivotal efficacy/safety studies.
Always refer to the latest version of the SHP615 Midazolam HCl 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. 


Shire
CONFIDENTIAL
Page 25
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Open-Label Study (SHP615-301)
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the medical 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 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg as 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) Paediatric
Committee as part of the PIP application and by the EMA Committee for Medicinal Products for 
Human Use (CHMP) as part of the review and approval of the Paediatric-use marketing
authorisation (PUMA).
The rationale for this interventional open-label study is to determine the efficacy, safety, and 
pharmacokinetics of MHOS/SHP615 in pediatric patients with CSE.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of MHOS/SHP615 administered 
buccally in pediatric patients with status epilepticus (convulsive) in a healthcare setting.
2.2.2
Secondary Objectives
The secondary objectives of this study are to assess the safety and pharmacokinetics of 
MHOS/SHP615 administered buccally to pediatric patients with status epilepticus (convulsive) 
in a healthcare setting.


Shire
CONFIDENTIAL
Page 26
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
3.
STUDY DESIGN
3.1
Study Design 
SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
buccally administered MHOS/SHP615 to pediatric subjects who present with SE in the 
healthcare setting. 
Approximately 25 subjects will be enrolled in this study. Children whose corrected gestational 
age is ≥52 weeks (gestational weeks plus the number of weeks after birth) and <18 years (and 
weight >5 kg) who arrive at the healthcare setting in full seizure, have not received immediate 
treatment, and have parental/caregiver informed consent/assent (when applicable, per Shire 
policy and country regulations), are eligible to participate 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. Upon entry in the SHP615-301 study, subjects will receive a single open-label 
MHOS/SHP615 treatment, dosing stratified by age (2.5, 5, 7.5, or 10 mg buccally).
The efficacy of MHOS/SHP615 in stopping convulsive seizures will be assessed by measuring 
the percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615, the 
subject will be treated according to the participating healthcare setting protocol or guideline. The 
safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by assessment of TEAEs, vital signs, laboratory tests, oxygen 
saturation, physical examination, and ECGs for safety evaluations. All subjects treated in this 
study will be followed for 1 week after dosing for safety evaluations.
3.2
Duration and Study Completion Definition
The duration of the treatment visit will be at least 6 hours and up to 24 hours, with a follow-up 
visit 1 week after the administration of MHOS/SHP615. It is anticipated that subjects will arrive 
at the healthcare setting while experiencing a seizure. Subjects will be screened and assessed at 
baseline immediately before administration of investigational product even if the informed 
consent and some prescreening assessments were completed at a previous clinical visit. 
Evaluation of seizure symptoms will be conducted up through 6 hours after the administration of 
the investigational product. After 6 hours, the subject may be discharged from the healthcare 
setting study site. 
The subject’s maximum duration of participation is expected to be approximately 1 week. The 
study will be completed in approximately 2 years. 


Shire
CONFIDENTIAL
Page 27
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
The Study Completion Date is defined as the date the final subject, across all sites, completes the 
protocol-defined assessments, or discontinues the study. 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 healthcare setting study sites in Japan. 


Shire
CONFIDENTIAL
Page 28
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
4.
STUDY POPULATION
Each subject (parent or legal guardian) must participate in the informed consent process and 
provide written informed consent/assent (when applicable, per Shire policy and country 
regulations) before any procedures specified in the protocol are performed. The subject may be 
prescreened by the investigator in their clinical practice and the parent, guardian, or legally 
authorized representative may sign informed consent before the subject presents to the healthcare 
setting for treatment of the seizure.
The total enrollment for the SHP615-301 study is expected to be approximately 25 subjects
(minimum 3 subjects per age group) with active generalized tonic-clonic SE with seizures.
Diagnosis of SE will be confirmed through documented medical history and evaluation of 
seizure symptoms conducted either during the screening/baseline assessment period or during
treatment.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator 
before subjects are included in the study.
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks 
plus the number of weeks after birth) and <18 years (and weight >5 kg), at the time of 
investigational product administration. If the subject’s exact age is not known, the subject 
should be excluded.
2. Parent, guardian, or legally authorized representative of the child provides informed consent 
(and assent, when applicable per Shire policy and country regulations) to participate in the 
study prior to participation in any protocol specific procedures. The subject may be 
prescreened by the investigator in their clinical practice and the parent, guardian, or legally 
authorized representative may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure.
3. Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions 
within the preceding hour
b. Currently presenting with seizure (convulsive) and 2 or more convulsions in 
succession without recovery of consciousness
c.
Currently presenting with a single seizure (convulsive) lasting ≥5 minutes
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 


Shire
CONFIDENTIAL
Page 29
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 seizures due to illegal drug or acute alcoholic intoxication.
4. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
5. Subjects with history of seizures of psychogenic origin.
6. Subjects with known history of hypersensitivities, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] 
block of second or third degree, VT [ventricular tachycardia]).
11. Subjects who have been receiving HIV protease inhibitors or HIV reverse transcriptase 
inhibitors.
12. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or 
healthcare setting.
13. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
14. Subjects 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.
15. Subject has received antiseizure medication prior to arrival in the healthcare setting.
16. 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 during the study.
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:


Shire
CONFIDENTIAL
Page 30
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017

Pre-menarchal 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 treatment visit, 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 with the medical monitor prior to withdrawal of a subject from the study, 
if possible.
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 CRF and source documents. 
Subjects who discontinue will not be replaced. 
4.5.1
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:

AE

Protocol deviation

Withdrawal by subject, parent, guardian, or legally authorized representative


Shire
CONFIDENTIAL
Page 31
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017

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 CRF 
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 reviewing institutional review board (IRB), or investigational product safety 
problems, or at the discretion of the sponsor. In addition, the sponsor retains the right to 
discontinue development of 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 subjects and subject’s parents,
guardians, or legally authorized representatives and the healthcare setting pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
4.5.2
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.
4.5.3
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.

2 SAEs of similar type (defined as the 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.


Shire
CONFIDENTIAL
Page 32
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Subject safety will be monitored on a continuous basis during this study until the last subject
completes his or her last scheduled study time point/assessment.
4.5.3.1
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).
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other 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.


Shire
CONFIDENTIAL
Page 33
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the treatment visit 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, non-pharmacological 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 before investigational product administration 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.


Shire
CONFIDENTIAL
Page 34
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 3 months (52 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 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. 
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 healthcare setting. Additional information is provided in the current version of 
the SHP615 Midazolam HCl 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, and the sponsor study team. Study treatment will only be 
administered by the healthcare setting study investigator or subinvestigator to subjects who have 
a signed and dated IRB-approved 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 present for enrollment. 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.


Shire
CONFIDENTIAL
Page 35
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 the investigator or subinvestigator as a single, 
fixed dose product, banded by age to subjects with CSE in the healthcare setting. For buccal 
administration, MHOS/SHP615 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
3 months (52 weeks corrected gestational age) 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
6.2.2.2
Dose Administration
Only 1 syringe with the specified dose must be given. The full amount of the MHOS pre-filled 
dosing syringe is injected slowly into the buccal mucosa. In some cases, it might be necessary to 
divide the dose so that half of the solution is injected into each side of mouth.
All investigational product is dispensed by the investigator or subinvestigator.
Prior to administration of drug therapy, the airway should be secured and respiratory and cardiac 
function assessed (NICE Guidance National Institute for Health and Care Excellence, 2011). 
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 Quintiles name and address. 


Shire
CONFIDENTIAL
Page 36
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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
The investigational product MHOS/SHP615 will be provided in individual, labeled, single-dose, 
prefilled plastic, oral dosing syringes 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 are 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. 


Shire
CONFIDENTIAL
Page 37
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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. 
Where permissible, tasks may be delegated to a subinvestigator 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 investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying 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 product 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. 


Shire
CONFIDENTIAL
Page 38
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Returned investigational product 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
All doses of open-label MHOS/SHP615 administered at the investigational site will be by the 
investigator or subinvestigator.
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, trays, 
vials) or at the individual count level for opened containers/packaging. The pharmacist or 
investigator-identified designee 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.


Shire
CONFIDENTIAL
Page 39
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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/Baseline Assessments
Screening/Baseline assessments for subject eligibility into this study occur on the same day as 
the Treatment Period when subjects <18 years present with SE in the healthcare setting after 
informed consent has been obtained. Alternatively, the subject may be prescreened by the 
investigator for subjects at risk of SE in their clinical practice and parents or legal guardians may 
sign informed consent before the subject presents to the healthcare setting for treatment of the 
seizure. However, confirmation of SE, evaluation of seizure symptoms, blood and urine samples, 
and AE monitoring must be completed in the healthcare setting.
Written informed consent must be obtained prior to performing any protocol-specific procedures. 
The complete list of assessments that will be performed in the study is listed below:

Informed consent/assent (when applicable, per Shire policy and country regulations)

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Confirmation of SE 

Evaluation of seizure symptoms (based on clinical judgment and healthcare setting 
procedures)

Riker Sedation Agitation Scale

Obtain blood and urine samples for the following laboratory tests:

Safety laboratory tests for serum biochemistry and urinalysis

Blood glucose can be measured by local lab or testing kit

Urine pregnancy test (females of childbearing potential only)

Vital signs

Review concomitant medications/treatments

Monitor AEs

Measure oxygen saturation on room air, if feasible
Table 2 lists recommend prescreening procedures and assessments that can be performed for 
subjects at risk of SE prior to presenting for treatment.


Shire
CONFIDENTIAL
Page 40
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Table 2
Recommended Prescreening Procedures and Assessments
Obtain informed consent
Collect demographic information
Review medical history 
Take blood and urine sample for laboratory analysis*
Review inclusion/exclusion criteria:
Inclusion Criteria
Exclusion Criteria
1. Age
1. Pregnancy
2. Informed consent
4. Known seizures due to drugs/alcohol
6. Contraindications to benzodiazepines
7. History of benzodiazepine abuse
8. Prior non-response to midazolam
11.Prior treatment for HIV
13.Severe cerebral anoxia (except cerebral palsy)
14.Prior study involvement impacting this study
16. Prior placement of a vagus nerve stimulator
Note: Procedures and assessments should be reviewed and reconfirmed when the subject arrives at the hospital or healthcare 
center for SE treatment.
*To be repeated every 6 months if no seizure resulting in study drug administration.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered investigational 
product(s). Subjects cannot be rescreened once they have been designated as a screen failure. 
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)
Healthcare setting study investigator or subinvestigator will administer investigational product 
MHOS/SHP615 (age-based dose of 2.5, 5, 7.5, or 10 mg) buccally.
The following procedures will be performed:

Evaluate seizure symptoms

Riker Sedation Agitation Scale

Provide supportive care per healthcare setting guidelines

Review concomitant medications/treatments

Monitor AEs
7.1.3
Treatment Period (0 minutes to 6 hours postdose) 

Perform physical examination when possible during the 6 hour time period.


Shire
CONFIDENTIAL
Page 41
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
7.1.4
Treatment Period (10 minutes to 24 hours postdose) 
The following procedures will be performed throughout the Treatment Period at time points 
specified in the Schedule of Assessments (Table 1):

Evaluate seizure symptoms and Riker Sedation Agitation Scale at 10 and 30 (±5) minutes, 
and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours postdose

4 hours and 24 hours (±30 min) postdose (if subject has not been discharged from the 
healthcare setting): Obtain blood and urine samples for safety laboratory tests for serum 
biochemistry and urinalysis

1 (±10 min), 3 (±30 min), and 6 hours (±30 min) postdose:

Collect blood samples for PK analysis.

10 and 30 (±5) minutes, and 4, 6, and 24 hours (±30 min) postdose (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). 

Measure oxygen saturation on room air.

Perform standard 12-lead ECG.

Administer supportive care throughout this time period.

Review concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
blood sampling).

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.
Note:  Evaluate by telephone if subject is discharged between 6 hours (±30 min) and 24 hours 
(±1 hour) 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 Visit
The follow-up period for this protocol is 1 week after the Treatment Period.
At the end of this period there will be a follow up visit to evaluate seizure symptoms, review 
concomitant medications, conduct a physical examination, and query for serious adverse events 
(SAEs), AEs. All AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure (see Section 8).


Shire
CONFIDENTIAL
Page 42
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study. It is the responsibility of the investigator to counsel 
subjects on their treatment alternatives when they exit the 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 informed consent form (ICF) must be executed prior to performing any study-related 
activities and the ICF must be approved by the reviewing IRB. The subject or the subject’s 
parents, guardians, or legally authorized representatives may withdraw consent at any time. The 
subject may be prescreened by the investigator in their clinical practice and the parent, guardian, 
or legally authorized representative may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure. If more than 3 months have elapsed between 
initial informed consent and seizure, the parent, guardian, or legally authorized representative 
should re-sign at the time of admission prior to treatment. Participation in the study may be 
terminated at any time without the consent of subjects or subject’s parents, guardians, or legally 
authorized representatives as determined by the investigator.
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 parents or caregivers and will be recorded on the 
source document and CRF.
Medical history (including SE) will capture the subject’s current medical status (current SE or 
CSE disease process), past medical status (past disease processes), history of surgery, allergies, 
and concomitant medications/treatments.
7.2.3
Efficacy
Evaluation of seizure activity will be conducted throughout the study to assess the 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.


Shire
CONFIDENTIAL
Page 43
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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.
7.2.4.1
Medical and Medication History
The investigator will perform a complete medical history at Screening, including a medication 
history, and record all information gathered. The investigator must record all clinically or 
medically relevant information regardless of how much time has elapsed since the date of 
diagnosis.
With the consent of parents, guardians, or legally authorized representatives of participating 
subjects, medical records from other treatment providers should be requested. 
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE (eg, dietary, medication, or other), must be recorded on the 
appropriate CRF page.
7.2.4.2
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)

Musculoskeletal

Neurological
Abnormalities identified at Screening will be documented in the subject’s source documents and 
on the medical history CRF. Changes after the Screening visit will be captured as AEs on the AE 
CRF page, as deemed by the investigator.


Shire
CONFIDENTIAL
Page 44
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
7.2.4.3
Adverse Event Collection
At each study time point, subjects (or parent, guardian, or legally authorized representative) will 
be questioned 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 when the subject with SE
arrives at the hospital or healthcare setting, or if the informed consent has been previously 
signed, from the time the subject begins evaluation and treatment in the hospital or healthcare 
setting for SE, to completion of the follow-up visit. (Please refer to Section 8, Adverse and 
Serious Adverse Events Assessment.)
7.2.4.4
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.
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 the initial vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Clinical Laboratory Evaluations
Clinical laboratory assessments will be performed at Screening, at 4 hours postdose, and at 
24 hours postdose if the subject is still at the healthcare setting. The following clinical laboratory 
assessments will be performed:
Chemistry
Urinalysis
Other
BUN and Creatininea
Glucose (fasting if possible)
Calcium (total)
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Direct bilirubinb
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Specific gravity
Microscopyc
Urine pregnancy testd


Shire
CONFIDENTIAL
Page 45
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Chemistry
Urinalysis
Other
Indirect bilirubinb
Alkaline phosphatase
Albumin
Total protein
Amylase
Bicarbonate
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 at screening for women of childbearing potential; may be repeated at the follow-up visit or withdrawal from study if 
pregnancy is suspected.
Aliquots from the PK samples may be retained as back-up for additional parameter testing if 
necessary. Subjects will be in a seated or supine position during blood collection. The total blood 
draw for each subject will be approximately 14.25 mL.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by Quintile’s central 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. 
Blood, serum, and urine samples 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.
7.2.4.6
Pregnancy Test
A urine pregnancy test is performed on all females of childbearing potential at Screening and at 
the follow up visit, if pregnancy is suspected, or upon withdrawal of the subject from the study.
7.2.4.7
Electrocardiogram 
A standard twelve (12)-lead electrocardiogram (ECG, single recording) will be performed at 
time points specified in the Schedule of Assessments (Table 1).
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.


Shire
CONFIDENTIAL
Page 46
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
The investigator or subinvestigator at the investigator site will make comparisons to baseline 
measurements taken at screening, if available. A copy of the ECG should be available as source 
documents for review.  
7.2.4.8
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).
7.2.5
Others 
7.2.5.1
Pharmacokinetic Assessments
Blood samples (~1.25 mL) to provide a minimum of 0.5 mL plasma for the assessment of plasma 
midazolam and 1-hydroxymidazolam concentrations will be collected (from all subjects who 
received investigational product) and analyzed at the specified time points for the duration of the 
study at the time points specified in the Schedule of Assessments (Table 1). The exact time of the 
sample collection should be noted on the source document and data collection tool (eg, CRF).
Samples will be analyzed for midazolam and 1-hydroxymidazolam using a validated assay. The 
methodologies will be appropriately validated in compliance with the CRO’s standard operating 
procedures. 
The address for shipment of serum samples and contact information for the laboratory analysis of 
midazolam and 1-hydroxymidazolam will be provided to the investigator site prior to initiation 
of the trial.
7.2.6
Volume of Blood to Be Drawn from Each Subject
Table 3
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
1.25
3
3.75
Safety
Biochemistry 
3.5
3
10.5
Total mL
14.25
a If a catheter is used, the first mL is to be discarded; then take 1.25 mL into appropriate tube for PK sample. A total of 
1.25 mL of blood drawn has been used in determination of sample volume.
During this study, it is expected that up to approximately 14.25 mL of blood will be drawn from 
each subject.


Shire
CONFIDENTIAL
Page 47
SHP615-301 Protocol Amendment 1
Midazolam
08 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 14.25 mL. Additional considerations may be made for small children 
and infants with sponsor review. 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.


Shire
CONFIDENTIAL
Page 48
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 when the subject with SE
arrives at the hospital or healthcare setting or if the informed consent has been previously signed, 
from the time the subject begins evaluation and treatment in the hospital or healthcare setting for 
SE, until the defined follow-up period stated in Section 7.1.5. 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 change in severity. An event that changes in severity should be captured as a new event. 
Worsening of pre-treatment 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 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.


Shire
CONFIDENTIAL
Page 49
SHP615-301 Protocol Amendment 1
Midazolam
08 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/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


Shire
CONFIDENTIAL
Page 50
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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.
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.


Shire
CONFIDENTIAL
Page 51
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 -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 
non-medical 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 pre-specified total daily dose of the product. 

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.
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 the Quintiles 
Transnational Japan K.K., the 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. 


Shire
CONFIDENTIAL
Page 52
SHP615-301 Protocol Amendment 1
Midazolam
08 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
An 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 a hospital 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.


Shire
CONFIDENTIAL
Page 53
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 informed consent is 
signed when the subject with SE arrives at the hospital or healthcare setting, or if the informed 
consent has been previously signed, from the time the subject begins evaluation and treatment in 
the hospital or healthcare setting for SE, until the defined follow-up period stated in Section 7.1.5
and must be reported to Quintiles Transnational Japan K.K., 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.


Shire
CONFIDENTIAL
Page 54
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 ICF, 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, and Site Reporting
The sponsor and Quintiles Transnational Japan K.K. are responsible for notifying the relevant 
regulatory authorities/and institutional IRBs 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 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 PMDA as a 
device malfunction report, regardless of whether or not the event relates to an AE.


Shire
CONFIDENTIAL
Page 55
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
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)


Shire
CONFIDENTIAL
Page 56
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate case report form (CRF).
The 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 the investigator or 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 healthcare setting 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 agent. 
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.


Shire
CONFIDENTIAL
Page 57
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 study that is designed to evaluate the efficacy and safety of 
MHOS/SHP615 in 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. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% CIs for least squares means will be provided. 
Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th (median), 
and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored 
observations. Plots of the Kaplan-Meier curves and supporting data listings detailing each 
subject’s contribution to the analysis will be provided. 
9.5
Planned Interim Analysis
There is no planned interim analysis for this study.
9.6
Sample Size Calculation and Power Considerations
The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is 
estimated based on the expected response rate which is assumed to be 58.5% compared with the 
threshold of 30% with at least 80% of statistical power at the 2-sided 5% level.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Set will consist of all subjects who have received a single dose of MHOS/SHP615.
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. 
The Pharmacokinetic Set will consist of all subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 


Shire
CONFIDENTIAL
Page 58
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
9.8
Efficacy Analyses
The primary efficacy analysis will be conducted on the FAS.
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 primary efficacy analysis will be conducted on FAS by constructing the 2-sided, 95% CI for 
the percentage of subjects reaching therapeutic success. The lower limit of the 95% CI will be 
compared with the threshold of 30%, which is equivalent to comparing the percentage of success 
to the threshold at the 2-sided 5% level of significance.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes of single 
dose 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 of single 
dose 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 of single 
dose 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

Percentage of subjects who require additional anticonvulsant medication for ongoing 
SE according to the participating healthcare setting protocol or guideline, 10 minutes after a 
single dose 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 according to the participating healthcare setting
protocol or guideline, 10 minutes after a single dose of MHOS/SHP615.


Shire
CONFIDENTIAL
Page 59
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
9.8.3
Subgroup Analyses of Efficacy Endpoints
Selected efficacy endpoints will be evaluated using descriptive statistics by the following 
subgroups, to the extent the data allow:

Age group: 

3 months (52 weeks corrected gestational age) to <1year (and weight >5 kg)

1 to <5 years

5 to <10 years

10 to <18 years

Gender: male and female

Epilepsy etiology (based on the underlying etiology of their epilepsy):

Genetic

Idiopathic

Metabolic 

Symptomatic (Structural)
9.8.4
Exploratory Efficacy Endpoints
A description of the analyses will be included in the SAP.
9.9
Safety Analyses
Safety data will be summarized using descriptive statistics for the Safety Set.
9.9.1
Primary Safety Endpoints
The primary safety endpoints will be respiratory depression, which will include the following 
measures within the 4 hours after MHOS/SHP615 administration:

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 
6, and 24 hours postdose (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)
9.9.2
Secondary Safety Endpoints
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 ECG

Occurrence of buccal irritation


Shire
CONFIDENTIAL
Page 60
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Adverse events and medical history will be coded using MedDRA. The number of events, 
incidence, and percentage of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by age. 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.
Vital signs (systolic and diastolic blood pressure, pulse, and weight) including potentially 
clinically important vital signs will be summarized using the appropriate descriptive statistics.
The ECG results, including potentially clinically important results, will be summarized.   
9.9.3
Clinical Laboratory Tests 
Clinical laboratory tests will be summarized using the Safety Set. 
Actual values and change from baseline clinical laboratory tests will be summarized. If more 
than 1 laboratory result is reported per study time point per parameter, the last non-missing 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 non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, non-clinically significant result less than the lower limit of normal, within the 
normal range, non-clinically 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 for a subject across study time point to identify any trends.
9.9.4
Vital Signs
Vital signs will be summarized using the Safety Set.
Actual values and changes from baseline in vital signs will be summarized. 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 non-missing result, and the number and percentage 
of subjects with a non-clinically 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. 


Shire
CONFIDENTIAL
Page 61
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 not performed, will be summarized. 
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.
9.10
Pharmacokinetic Analyses
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any 
potential additional metabolite(s) will be evaluated using the Pharmacokinetic population.  
The Pharmacokinetic population will include subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. PK samples 
will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
PK parameters (eg, Cmax, Tmax, AUC and t1/2) will be calculated using population PK modeling.


Shire
CONFIDENTIAL
Page 62
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 non-pediatric studies as per 
guidance. 


Shire
CONFIDENTIAL
Page 63
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 (July 1996). 
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.


Shire
CONFIDENTIAL
Page 64
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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.
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 FDA, 
EMA, PMDA) or an auditor.


Shire
CONFIDENTIAL
Page 65
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 (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 (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. 


Shire
CONFIDENTIAL
Page 66
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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 (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.


Shire
CONFIDENTIAL
Page 67
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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 non-commercial 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.


Shire
CONFIDENTIAL
Page 68
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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.


Shire
CONFIDENTIAL
Page 69
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 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. & 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.
Baysun, S., Aydin, O. F., Atmaca, E. & Gurer, Y. K. 2005. A comparison of buccal midazolam 
and rectal diazepam for the acute treatment of seizures. Clin Pediatr (Phila), 44, 771-6.
Berg, A. T., Shinnar, S., Levy, S. R. & Testa, F. M. 1999. Status epilepticus in children with 
newly diagnosed epilepsy. Ann Neurol, 45, 618-23.
Brophy, G. M., Bell, R., Claassen, J., Alldredge, B., Bleck, T. P., Glauser, T., Laroche, S. M., 
Riviello, J. J. J., Shutter, L., Sperling, M. R., Treiman, D. M., Vespa, P. M. & Committee, 
N. C. S. S. E. G. W. 2012. Guidelines for the evaluation and management of status 
epilepticus. Neurocrit Care, 17, 3-23.
Dham, B. S., 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, 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/.
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.
Lowenstein, D. H., Bleck, T. & MacDonald, R. L. 1999. It's time to revise the definition of status 
epilepticus. Epilepsia, 40, 120-2.
McIntyre, J., Robertson, S., Norris, E., Appleton, R., Whitehouse, W. P., 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, P. J. & 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.
Muchohi, S. N., Kokwaro, G. O., Ogutu, B. R., Edwards, G., Ward, S. A. & Newton, C. R. 2008. 
Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and 
convulsions. Br J Clin Pharmacol, 66, 529-38.
NICE Guidance National Institute for Health and Care Excellence. 2011. Available: 
https://www.nice.org.uk/guidance/cg137/chapter/Appendix-F [Accessed 24 Jan 2017.


Shire
CONFIDENTIAL
Page 70
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
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. & 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.
Schwagmeier, R., Alincic, S. & Striebel, H. W. 1998. Midazolam pharmacokinetics following 
intravenous and buccal administration. Br J Clin Pharmacol, 46, 203-6.
Scott, R. C., Besag, F. M., Boyd, S. G., Berry, D. & Neville, B. G. 1998. Buccal absorption of 
midazolam: pharmacokinetics and EEG pharmacodynamics. Epilpesia, 39, 290-4.
Scott, R. C., Besag, F. M. & Neville, B. G. 1999. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Shinnar, S., Berg, A. T., Moshe, S. L., O'Dell, C., Alemany, M., Newstein, D., Kang, H., 
Goldensohn, E. S. & 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.
Sirven, J. I. & 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, W. H., Porter, R. J. & 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. & 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. & Brigo, F. 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, M. T., Macleod, S. & O'Regan, M. E. 2004. Nasal/buccal midazolam use in the 
community. Arch Dis Child, 89, 50-1.
Working Group on Status Epilepticus 1993. Treatment of convulsive status epilepticus. 
Recommendations of the Epilepsy Foundation of America's Working Group on Status 
Epilepticus. Jama, 270, 854-9.




Shire
CONFIDENTIAL
Page 72
SHP615-301 Protocol Amendment 1
Midazolam
08 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
2016
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. 


Shire
CONFIDENTIAL
Page 73
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).


Shire
CONFIDENTIAL
Page 74
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
APPENDIX 3
BIOANALYSIS: SAMPLE HANDLING
1.1
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1 to measure plasma 
concentrations of midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s). 
Blood samples (~1.25 mL) for pharmacokinetic analysis will be drawn by in-dwelling catheters 
or direct venipuncture into K2EDTA tubes, capped, and chilled immediately on crushed ice. The 
actual time that the sample was obtained will be recorded in the subject’s source document and 
on the appropriate CRF page. After applying a tourniquet, venous blood will be drawn with a 
disposable needle. If a catheter is used, the first milliliter of blood on each sampling occasion 
will be discarded. Saline can be used to keep catheters patent.
1.2
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after
collection (within <15 minutes) by refrigerated centrifugation (4C, 1500 g, 15 minutes). The 
separated plasma will be transferred into appropriately labeled polypropylene tubes via a plastic 
pipette. Plasma to be split in two aliquots: first tube minimum 0.25 mL (primary sample), second 
tube remaining plasma volume (back-up sample).  Aliquots should be shipped separately to the 
bioanalytical laboratory. All samples will be stored at approximately -80C or colder and the 
freezer temperature will be controlled, monitored, and recorded during the storage period until 
they are transferred in the frozen state to a designated bioanalytical contract laboratory. Samples 
will remain frozen at -80C or colder until analysis. Note: For sites that do not have access 
to -80C storage, samples may be stored at -20C for a limited time (maximum 90 days) before 
shipping to the bioanalytical CRO.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the clinical pharmacology unit. The labels will contain the following information:

Study number

Treatment 

Subject identifier 

Matrix identifier (plasma)

Nominal time
1.3
Shipment of Plasma Samples
Plasma samples should be double bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday to Wednesday only. 


Shire
CONFIDENTIAL
Page 75
SHP615-301 Protocol Amendment 1
Midazolam
08 Jul 2017
Samples should be transported to ensure that they arrive at the bioanalytical laboratory between 
the hours of 0900 and 1600. The recipient and primary Shire contact must be notified by phone, 
fax, and e-mail when the samples are shipped and must be provided with the shipment tracking 
number. 
Plasma samples, along with the corresponding documentation, will be shipped to:
Name of bioanalytical laboratory: York Bioanalytical Solutions (YBS)
Primary contact: 
Telephone DDI: 
E-mail:
Plasma samples will be stored nominally at -80C prior to and after analysis at York 
Bioanalytical Solutions Limited until their disposal is authorized by Shire.
1.4
Assay Methodology
Drug analysis will be performed at YBS under the guidance of the Department of Nonclinical 
Development, Shire Pharmaceuticals. Plasma sample analysis will be performed according to the 
bioanalytical study plans prepared for the study. 
Plasma samples (K2EDTA) will be analyzed at York Bioanalytical Solutions Limited for 
midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s) using the most 
current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at York Bioanalytical Solutions Limited.

Prot_004.pdf: 
PROTOCOL: SHP615-301
TITLE:
A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, 
Safety, and Pharmacokinetics of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in the Hospital 
or Emergency Room
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
PROTOCOL 
HISTORY:
Original Protocol: 20 Mar 2017
Protocol Amendment 1: 08 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 non-disclosure 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.




Shire
CONFIDENTIAL
Page 3
SHP615-301 Protocol Amendment 3
Midazolam
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: 


Shire
CONFIDENTIAL
Page 4
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
PRODUCT QUALITY COMPLAINTS
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). 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. For instructions on reporting AEs related to product complaints, 
see Section 8.3.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
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)


Shire
CONFIDENTIAL
Page 5
SHP615-301 Protocol Amendment 3
Midazolam
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.......................................................................................18
1.1
Status Epilepticus .....................................................................................................18
1.2
Current Treatment Options.......................................................................................19
1.3
Unmet Medical Need for Buccal Midazolam...........................................................20
1.4
Product Background and Clinical Information ........................................................20
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Open-Label Study (SHP615-301) ................................................23
2.2
Study Objectives ......................................................................................................23
2.2.1
Primary Objectives.................................................................................................23
2.2.2
Secondary Objectives.............................................................................................23
3
STUDY DESIGN ...................................................................................................................24
3.1
Study Design ............................................................................................................24
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................25
4
STUDY POPULATION.........................................................................................................26
4.1
Inclusion Criteria......................................................................................................26
4.2
Exclusion Criteria.....................................................................................................26
4.3
Restrictions...............................................................................................................27
4.3.1
Medical Intervention..............................................................................................27
4.4
Reproductive Potential .............................................................................................28
4.4.1
Female Contraception............................................................................................28
4.4.2
Male Contraception................................................................................................28
4.5
Discontinuation of Subjects .....................................................................................28
4.5.1
Reasons for Discontinuation..................................................................................28
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
4.5.3
Stopping Rules.......................................................................................................29
4.5.3.1
Study Level Stopping Rules...................................................................30
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria................................30


Shire
CONFIDENTIAL
Page 6
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.1
Prior Treatment ........................................................................................................31
5.2
Concomitant Treatment............................................................................................31
6
INVESTIGATIONAL PRODUCT ........................................................................................32
6.1
Identity of Investigational Product...........................................................................32
6.1.1
Blinding the Treatment Assignment......................................................................32
6.2
Administration of Investigational Product(s)...........................................................32
6.2.1
Allocation of Subjects to Treatment ......................................................................32
6.2.2
Dose Regimen and Dose Administration...............................................................33
6.2.2.1
Dosing Regimen.....................................................................................33
6.2.2.2
Dose Administration ..............................................................................33
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Labeling .................................................................................................................33
6.3.2
Packaging...............................................................................................................34
6.3.3
Storage ...................................................................................................................34
6.3.4
Special Handling....................................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................36
6.6
Destruction of Investigational Product.....................................................................36
7
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Screening/Baseline Assessments ...........................................................................37
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)........38
7.1.3
Treatment Period (0 minutes to 6 hours postdose) ................................................38
7.1.4
Treatment Period (10 minutes to 24 hours postdose) ............................................39
7.1.5
Follow-up Visit......................................................................................................39
7.1.6
Additional Care of Subjects after the Study ..........................................................40
7.2
Study Evaluations and Procedures ...........................................................................40
7.2.1
Informed Consent...................................................................................................40
7.2.2
Demographic and Other Baseline Characteristics .................................................40
7.2.3
Efficacy..................................................................................................................40
7.2.4
Safety .....................................................................................................................41
7.2.4.1
Medical and Medication History............................................................41
7.2.4.2
Physical Examination.............................................................................41
7.2.4.3
Adverse Event Collection.......................................................................42
7.2.4.4
Vital Signs..............................................................................................42
7.2.4.5
Clinical Laboratory Evaluations.............................................................42
7.2.4.6
Pregnancy Test .......................................................................................43


Shire
CONFIDENTIAL
Page 7
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
7.2.4.7
Electrocardiogram ..................................................................................44
7.2.4.8
Oxygen saturation ..................................................................................44
7.2.5
Others.....................................................................................................................44
7.2.5.1
Pharmacokinetic Assessments................................................................44
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................45
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..........................................................................................46
8.1.2
Relationship Categorization...................................................................................47
8.1.3
Outcome Categorization ........................................................................................47
8.1.4
Symptoms of the Disease Under Study .................................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................48
8.1.6
Pregnancy...............................................................................................................48
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................49
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information................................................................................49
8.2.2
Reporting Procedures.............................................................................................49
8.2.3
Serious Adverse Event Definition .........................................................................50
8.2.4
Serious Adverse Event Collection Time Frame.....................................................51
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................52
8.2.6
Fatal Outcome........................................................................................................52
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting...................52
8.3
Product Quality Complaints.....................................................................................52
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................54
9.1
Data Collection.........................................................................................................54
9.2
Clinical Data Management.......................................................................................54
9.3
Data Handling Considerations..................................................................................54
9.4
Statistical Analysis Process......................................................................................54
9.4.1
Appropriateness of Measurements.........................................................................55
9.4.2
General Considerations..........................................................................................55
9.5
Planned Interim Analysis .........................................................................................55
9.6
Sample Size Calculation and Power Considerations................................................55
9.7
Study Population ......................................................................................................55
9.8
Efficacy Analyses.....................................................................................................56
9.8.1
Primary Efficacy Endpoint ....................................................................................56
9.8.2
Secondary Efficacy Endpoints...............................................................................56
9.8.3
Subgroup Analyses of Efficacy Endpoints ............................................................57


Shire
CONFIDENTIAL
Page 8
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
9.8.4
Exploratory Efficacy Endpoints.............................................................................57
9.9
Safety Analyses........................................................................................................57
9.9.1
Primary Safety Endpoints ......................................................................................57
9.9.2
Secondary Safety Endpoints ..................................................................................57
9.9.3
Clinical Laboratory Tests.......................................................................................58
9.9.4
Vital Signs..............................................................................................................58
9.9.5
Electrocardiography...............................................................................................59
9.10
Pharmacokinetic Analyses .......................................................................................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..................................................61
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
Appendix 3
Bioanalysis: Sample Handling ...............................................................73


Shire
CONFIDENTIAL
Page 9
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................16
Table 2
Recommended Prescreening Procedures and Assessments ..........................38
Table 3
Volume of Blood to Be Drawn from Each Subject.......................................45


Shire
CONFIDENTIAL
Page 10
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
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
Paediatric Investigation Plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PUMA
Paediatric-use marketing authorisation
ROW
rest of world


Shire
CONFIDENTIAL
Page 11
SHP615-301 Protocol Amendment 3
Midazolam
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
VT
ventricular tachycardia


Shire
CONFIDENTIAL
Page 12
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
STUDY SYNOPSIS
Protocol number: SHP615-301
Drug: Midazolam hydrochloride oromucosal solution (MHOS/SHP615) 
Title of the study: A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, Safety, and 
Pharmacokinetics of Buccally Administered MHOS/SHP615 in Pediatric Patients with Status Epilepticus 
(Convulsive) in the Hospital or Emergency Room
Number of subjects (total and for each treatment arm): Approximately 25 subjects (minimum 3 subjects per age 
group)
Investigator(s): Multicenter study (in hospital or healthcare settings)
Site(s) and Region(s): Approximately 25 hospitals in Japan
Study period (planned):
September 2017 to August 2019
Clinical phase:
3
Objectives:
Primary: To assess the efficacy of MHOS/SHP615 administered buccally in pediatric patients with status 
epilepticus (convulsive) in a healthcare setting.
Secondary: To assess the safety and pharmacokinetics of MHOS/SHP615 administered buccally to pediatric 
patients with status epilepticus (convulsive) in a healthcare setting.
Rationale: Under the proprietary name BUCCOLAM® MHOS/SHP615 is currently approved for treatment of 
pediatric patients presenting with status epilepticus (SE) in a hospital or emergency room in several European Union 
(EU) countries. The intravenous (IV) formulation of midazolam is currently administered buccally off label for the 
treatment of SE in a healthcare setting in Japan. This study will provide data to support approval and labeling of 
age-based dosing of MHOS/SHP615 for the treatment of SE in Japanese pediatric patients.
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.
Each pre-filled dosing syringe is individually packed in a protective plastic tube. 
The four available unit dose packs are:

2.5 mg (yellow label) for children aged 3 months (52 weeks corrected gestational age) to <1 year (and 
weight >5 kg)

5 mg (blue label) for children aged 1 year to <5 years

7.5 mg (purple label) for children aged 5 years to <10 years

10 mg (orange label) for children aged 10 years to <18 years
Methodology: SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
MHOS/SHP615 administered buccally to subjects <18 years who present with SE in the healthcare setting. Children 
whose corrected gestational age is 52 weeks (gestational weeks plus the number of weeks after birth) and <18
years, weight >5 kg ,who arrive at the healthcare setting in full seizure, and have not received immediate treatment, 
are eligible to participate in this study providing all inclusion/exclusion 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. Upon 
entry in the SHP615-301 study, subjects will receive a single open-label MHOS/SHP615 treatment, dosing stratified 
by age (2.5, 5, 7.5, 10 mg buccally).


Shire
CONFIDENTIAL
Page 13
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
The efficacy of MHOS/SHP615 in stopping prolonged convulsive seizures will be assessed by measuring the 
percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615 the subject will be treated according to participating 
healthcare setting protocol or guideline. The safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by vital signs, laboratory tests, and ECGs for safety evaluations. All subjects who 
withdraw early or who complete treatment in this study will be followed for 1 week after the dose of SHP615 for 
safety evaluations. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks plus the number 
of weeks after birth) and <18 years, and weight >5 kg, at the time of investigational product administration. 
If the subject’s exact age is not known, the subject should be excluded.
2.
Parent, guardian, or legally authorized representative of the child provides informed consent (and assent,
when applicable per Shire policy and country regulations) to participate in the study prior to participation 
in any protocol specific procedures. The subject may be prescreened by the investigator in their clinical 
practice and parent, guardian, or legally authorized representative may sign informed consent before the 
subject presents to the healthcare setting for treatment of the seizure.
3.
Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the 
preceding hour
b.
Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without 
recovery of consciousness
c.
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 seizures due to illegal drug or acute alcoholic intoxication.
4.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
5.
Subjects with history of 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, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia 
gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] block of second 
or third degree, VT [ventricular tachycardia]).
12. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse 


Shire
CONFIDENTIAL
Page 14
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
transcriptase inhibitors.
13. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or healthcare 
setting.
14. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
15. Subjects 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.
16. Subject has received antiseizure medication prior to arrival in the healthcare setting
17. 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: 1 week
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is the 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 of a single dose of 
MHOS/SHP615 and who have sustained absence of seizure activity for the following time periods after the 
single dose of MHOS/SHP615:
o
1 h
o
4 h
o
6 h

Time to resolution of seizures (convulsions) 

Time to recovery of consciousness

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 according to the participating healthcare setting protocol or 
guideline, 10 minutes after a single dose of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures within the 
4 hours after MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 6, and 
24 hours postdose (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


Shire
CONFIDENTIAL
Page 15
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017

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 ECG

Occurrence of buccal irritation
Pharmacokinetics (population PK)

Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolite(s) will be evaluated. Exploratory evaluation of potential additional metabolite(s) may also be 
performed. PK samples will be collected at 1, 3, and 6 hours (or time of discharge, if earlier than 6 hours) after 
administration of MHOS/SHP615.
Statistical methods
Sample size:  The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is estimated 
based on the expected response rate which is assumed to be 58.5% compared with the threshold of 30% with at least 
80% of statistical power at the 2-sided 5% level.
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.
The primary efficacy analysis will be conducted on the FAS, by constructing the 2-sided, 95% confidence interval 
(CI) for the percentage of subjects reaching therapeutic success 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 lower limit of the 95% CI will be compared with the threshold of 30%, which is equivalent to comparing the 
percentage of success to the threshold at the 2-sided 5% level of significance.
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. TEAEs 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.
Population PK analysis
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolites will be evaluated using the Pharmacokinetic Set. The Pharmacokinetic Set will include subjects who 
receive a single dose of MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 
Pharmacokinetic parameters will be calculated using population PK modeling.


Shire
CONFIDENTIAL
Page 16
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-up
Screening/Baseline
0 min
10 min
30 
(± 5min)
1 h
(± 10min)
3h
(± 30min)
4 h
(± 30min)
6 ha
(± 30min)
24hb
(± 30min)
1 week
(± 1 day)
Informed consent/assent 
Xc
Inclusion/exclusion 
criteria
X
Demographics
X
Medical/procedural 
history
X
Confirmation of status 
epilepticus
X
Evaluation of seizure 
symptomsd
X
X
X
X
X
X
X
X
X
Riker Sedation-Agitation 
Scale
X
X
X
X
X
X
X
Laboratory evaluationse
Xf
X
X
SHP615 administration
X
PK collectiong
X
X
X
Buccal cavity assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Oxygen saturationj
X
X
X
X
X
X
12-Lead ECG
Xk
X
X
X
X
X
Supportive care
X
X
Physical examinationl
X
X
Concomitant medications
X
X
Xa
X
X
Adverse event monitoring
X
Xa
X
X
ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute; PK=pharmacokinetic.


Shire
CONFIDENTIAL
Page 17
SHP615-301 Protocol Amendment 3
Midazolam
18 Dec 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-up
Screening/Baseline
0 min
10 min
30 
(± 5min)
1 h
(± 10min)
3h
(± 30min)
4 h
(± 30min)
6 ha
(± 30min)
24hb
(± 30min)
1 week
(± 1 day)
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 postdose time point will be made if the subject has not been discharged from the healthcare setting; 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 If more than 3 months have elapsed between initial informed consent and seizure, parent, guardian, or legally authorized representative should re-sign the latest at the time of 
admission prior to treatment.
d Seizure symptoms will be assessed based on physician’s clinical judgment and healthcare setting protocol.
e Laboratory evaluations include serum biochemistry and urinalysis (including a urine pregnancy test in women of childbearing potential at screening/baseline).
f
Blood glucose can be measured by local lab or testing kit.
g The PK samples will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
h 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. 
i
Vital signs will include single supine blood pressure, pulse rate, respiratory rate, and body temperature.
j
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. The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of 
oxygen administered.
k If subject is stable enough for ECG.
l
Physical examination will be performed at some point between 0 min (dosing) and 6 hours postdose, when possible.


Shire
CONFIDENTIAL
Page 18
SHP615-301 Protocol Amendment 3 
Midazolam
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).
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 (ILAE) 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 either 10 minutes (Treiman et al., 1998) or 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; Brophy et al., 2012; Lowenstein et al., 1999; 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.


Shire
CONFIDENTIAL
Page 19
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
In Japan, annual incidence of SE in children younger than 17 years is 42 cases per 
100,000 persons. In addition to young age, other risk factors include genetic predisposition and 
acquired brain insults (Fountain, 2000; Working Group on Status Epilepticus, 1993; Shinnar et 
al., 1996; Berg et al., 1999).
Left untreated (or undertreated) SE, depending on the type and duration of seizures, 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 not 
authorized for SE in the United States [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 healthcare setting. 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 to diazepam treatment. 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).


Shire
CONFIDENTIAL
Page 20
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs as 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 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 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 non-IV 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 treatment of 


Shire
CONFIDENTIAL
Page 21
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 healthcare 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) and <18 years. The efficacy and safety 
of buccal midazolam 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; 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% 
confidence interval {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) from the authorized uses is 
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 (AEs) (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 
<6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Pharmacokinetics
Published PK studies in healthy adult volunteers have shown that buccal midazolam is quickly 
absorbed (producing peak concentrations at 30 minutes with a mean buccal midazolam 
bioavailability of 74.5% [Schwagmeier et al., 1998]) and has a rapid effect (≤5-10 minutes) on 
the central nervous system (CNS), shown on electroencephalography (Scott et al., 1998). The 
rapid absorption of midazolam by the buccal route has also been demonstrated in a published 


Shire
CONFIDENTIAL
Page 22
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
study in children with severe malaria and convulsions (peak concentration at 10 [5–40] minutes 
with bioavailability estimated at 87%) (Muchohi et al., 2008).
For this open label SHP615-301 study, the MHOS/SHP615 formulation (the same as the 
HYPNOVEL 10 mg/2 mL formulation) and the proposed fixed doses will be the same as the 
4 pivotal, rectal-diazepam-controlled clinical studies. Thus, the PK/pharmacokinetics should not 
be different for MHOS compared to that in the pivotal efficacy/safety studies.
Always refer to the latest version of the SHP615 Midazolam HCl 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. 


Shire
CONFIDENTIAL
Page 23
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Open-Label Study (SHP615-301)
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the medical 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 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg as 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) Paediatric
Committee as part of the PIP application and by the EMA Committee for Medicinal Products for 
Human Use (CHMP) as part of the review and approval of the Paediatric-use marketing
authorisation (PUMA).
The rationale for this interventional open-label study is to determine the efficacy, safety, and 
pharmacokinetics of MHOS/SHP615 in pediatric patients with CSE.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of MHOS/SHP615 administered 
buccally in pediatric patients with status epilepticus (convulsive) in a healthcare setting.
2.2.2
Secondary Objectives
The secondary objectives of this study are to assess the safety and pharmacokinetics of 
MHOS/SHP615 administered buccally to pediatric patients with status epilepticus (convulsive) 
in a healthcare setting.


Shire
CONFIDENTIAL
Page 24
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
3
STUDY DESIGN
3.1
Study Design 
SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
buccally administered MHOS/SHP615 to pediatric subjects who present with SE in the 
healthcare setting. 
Approximately 25 subjects will be enrolled in this study. Children whose corrected gestational 
age is ≥52 weeks (gestational weeks plus the number of weeks after birth) and <18 years (and 
weight >5 kg) who arrive at the healthcare setting in full seizure, have not received immediate 
treatment, and have parent, guardian, or legally authorized representative informed 
consent/assent (when applicable, per Shire policy and country regulations), are eligible to 
participate 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. Upon entry in the SHP615-301 study, subjects will receive a single open-label 
MHOS/SHP615 treatment, dosing stratified by age (2.5, 5, 7.5, or 10 mg buccally).
The efficacy of MHOS/SHP615 in stopping convulsive seizures will be assessed by measuring 
the percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615, the 
subject will be treated according to the participating healthcare setting protocol or guideline. The 
safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by assessment of TEAEs, vital signs, laboratory tests, oxygen 
saturation, physical examination, and ECGs for safety evaluations. All subjects treated in this 
study will be followed for 1 week after dosing for safety evaluations.
3.2
Duration and Study Completion Definition
The duration of the treatment visit will be at least 6 hours and up to 24 hours, with a follow-up 
visit 1 week after the administration of MHOS/SHP615. It is anticipated that subjects will arrive 
at the healthcare setting while experiencing a seizure. Subjects will be screened and assessed at 
baseline immediately before administration of investigational product even if the informed 
consent and some prescreening assessments were completed at a previous clinical visit. 
Evaluation of seizure symptoms will be conducted up through 6 hours after the administration of 
the investigational product. After 6 hours, the subject may be discharged from the healthcare 
setting study site. 
The subject’s maximum duration of participation is expected to be approximately 1 week. The 
study will be completed in approximately 2 years. 


Shire
CONFIDENTIAL
Page 25
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
The Study Completion Date is defined as the date the final subject, across all sites, completes the 
protocol-defined assessments, or discontinues the study. 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 healthcare setting study sites in Japan. 


Shire
CONFIDENTIAL
Page 26
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
4
STUDY POPULATION
Each subject (parent, guardian, or legally authorized representative) must participate in the 
informed consent process and provide written informed consent/assent (when applicable, per 
Shire policy and country regulations) before any procedures specified in the protocol are 
performed. The subject may be prescreened by the investigator in their clinical practice and the 
parent, guardian, or legally authorized representative may sign informed consent before the 
subject presents to the healthcare setting for treatment of the seizure.
The total enrollment for the SHP615-301 study is expected to be approximately 25 subjects
(minimum 3 subjects per age group) with active generalized tonic-clonic SE with seizures.
Diagnosis of SE will be confirmed through documented medical history and evaluation of 
seizure symptoms conducted either during the screening/baseline assessment period or during
treatment.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator 
before subjects are included in the study.
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks 
plus the number of weeks after birth) and <18 years (and weight >5 kg), at the time of 
investigational product administration. If the subject’s exact age is not known, the subject 
should be excluded.
2. Parent, guardian, or legally authorized representative of the child provides informed consent 
(and assent, when applicable per Shire policy and country regulations) to participate in the 
study prior to participation in any protocol specific procedures. The subject may be 
prescreened by the investigator in their clinical practice and the parent, guardian, or legally 
authorized representative may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure.
3. Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions 
within the preceding hour
b. Currently presenting with seizure (convulsive) and 2 or more convulsions in 
succession without recovery of consciousness
c.
Currently presenting with a single seizure (convulsive) lasting ≥5 minutes
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 


Shire
CONFIDENTIAL
Page 27
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 seizures due to illegal drug or acute alcoholic intoxication.
4. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
5. Subjects with history of 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, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] 
block of second or third degree, VT [ventricular tachycardia]).
12. Subjects who have been receiving HIV protease inhibitors or HIV reverse transcriptase 
inhibitors.
13. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or 
healthcare setting.
14. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
15. Subjects 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.
16. Subject has received antiseizure medication prior to arrival in the healthcare setting.
17. 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 during the study.


Shire
CONFIDENTIAL
Page 28
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Pre-menarchal 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 treatment visit, 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 with the medical monitor prior to withdrawal of a subject from the study, 
if possible.
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 CRF 
and source documents. 
Subjects who discontinue will not be replaced. 
4.5.1
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:


Shire
CONFIDENTIAL
Page 29
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017

AE

Protocol deviation

Withdrawal by subject, parent, guardian, or legally authorized representative

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 CRF 
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 reviewing institutional review board (IRB), or investigational product safety 
problems, or at the discretion of the sponsor. In addition, the sponsor retains the right to 
discontinue development of 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 subjects and subject’s parents, 
guardians, or legally authorized representatives and the healthcare setting pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
4.5.2
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.
4.5.3
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.

2 SAEs of similar type (defined as the 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:


Shire
CONFIDENTIAL
Page 30
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017

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 time point/assessment.
4.5.3.1
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).
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other 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.


Shire
CONFIDENTIAL
Page 31
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the treatment visit 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, non-pharmacological 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 before investigational product administration 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 parent, 
guardian, or legally authorized representative) 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.


Shire
CONFIDENTIAL
Page 32
SHP615-301 Protocol Amendment 3 
Midazolam
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 3 months (52 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 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. 
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 healthcare setting. Additional information is provided in the current version of 
the SHP615 Midazolam HCl 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, and the sponsor study team. Study treatment will only be 
administered by the healthcare setting study investigator or subinvestigator to subjects who have 
a signed and dated IRB-approved 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 present for enrollment. 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.


Shire
CONFIDENTIAL
Page 33
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 the investigator or subinvestigator as a single, 
fixed dose product, banded by age to subjects with CSE in the healthcare setting. For buccal 
administration, MHOS/SHP615 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
3 months (52 weeks corrected gestational age) 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
6.2.2.2
Dose Administration
Only 1 syringe with the specified dose must be given. The full amount of the MHOS pre-filled 
dosing syringe is injected slowly into the buccal mucosa. In some cases, it might be necessary to 
divide the dose so that half of the solution is injected into each side of mouth.
All investigational product is dispensed by the investigator or subinvestigator.
Prior to administration of drug therapy, the airway should be secured and respiratory and cardiac 
function assessed (NICE Guidance National Institute for Health and Care Excellence, 2011). 
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 Quintiles name and address. 


Shire
CONFIDENTIAL
Page 34
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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
The investigational product MHOS/SHP615 will be provided in individual, labeled, single-dose, 
prefilled plastic, oral dosing syringes 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 are 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. 


Shire
CONFIDENTIAL
Page 35
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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. 
Where permissible, tasks may be delegated to a subinvestigator 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 investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying 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 product 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. 


Shire
CONFIDENTIAL
Page 36
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
Returned investigational product 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
All doses of open-label MHOS/SHP615 administered at the investigational site will be by the 
investigator or subinvestigator.
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, trays, 
vials) or at the individual count level for opened containers/packaging. The pharmacist or 
investigator-identified designee 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.


Shire
CONFIDENTIAL
Page 37
SHP615-301 Protocol Amendment 3 
Midazolam
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/Baseline Assessments
Screening/Baseline assessments for subject eligibility into this study occur on the same day as 
the Treatment Period when subjects <18 years present with SE in the healthcare setting after 
informed consent has been obtained. Alternatively, the subject may be prescreened by the 
investigator for subjects at risk of SE in their clinical practice and parent, guardian, or legally 
authorized representative may sign informed consent before the subject presents to the healthcare 
setting for treatment of the seizure. However, confirmation of SE, evaluation of seizure 
symptoms, and collection of blood and urine samples, must be completed in the healthcare 
setting.
Written informed consent must be obtained prior to performing any protocol-specific procedures. 
The complete list of assessments that will be performed in the study is listed below:

Informed consent/assent (when applicable, per Shire policy and country regulations)

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Confirmation of SE 

Evaluation of seizure symptoms (based on clinical judgment and healthcare setting 
procedures)

Riker Sedation Agitation Scale

Obtain blood and urine samples for the following laboratory tests:

Safety laboratory tests for serum biochemistry and urinalysis

Blood glucose can be measured by local lab or testing kit

Urine pregnancy test (females of childbearing potential only)

Vital signs

Review concomitant medications/treatments

Measure oxygen saturation (on room air, if feasible)
Table 2 lists recommend prescreening procedures and assessments that can be performed for 
subjects at risk of SE prior to presenting for treatment.


Shire
CONFIDENTIAL
Page 38
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
Table 2
Recommended Prescreening Procedures and Assessments
Obtain informed consenta
Collect demographic information
Review medical history 
Take blood and urine sample for laboratory analysisb
Review inclusion/exclusion criteria:
Inclusion Criteria
Exclusion Criteria
1. Age
1. Pregnancy
2. Informed consent
4. Known seizures due to drugs/alcohol
7. Contraindications to benzodiazepines
8. History of benzodiazepine abuse
9. Prior non-response to midazolam
12.Prior treatment for HIV
14.Severe cerebral anoxia (except cerebral palsy)
15.Prior study involvement impacting this study
17. Prior placement of a vagus nerve stimulator
Note: Procedures and assessments should be reviewed and reconfirmed when the subject arrives at the hospital or healthcare 
center for SE treatment.
a Verbal consent to be repeated every 3 months if no seizure resulting in study drug administration. Then, re-signing the 
latest ICF required at the time of admission.
b  To be repeated every 6 months if no seizure resulting in study drug administration, if needed.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered investigational 
product(s). Subjects cannot be rescreened once they have been designated as a screen failure. 
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)
Healthcare setting study investigator or subinvestigator will administer investigational product 
MHOS/SHP615 (age-based dose of 2.5, 5, 7.5, or 10 mg) buccally.
The following procedures will be performed:

Evaluate seizure symptoms

Riker Sedation Agitation Scale

Provide supportive care per healthcare setting guidelines

Review concomitant medications/treatments

Monitor AEs
7.1.3
Treatment Period (0 minutes to 6 hours postdose) 

Perform physical examination when possible during the 6 hour time period.


Shire
CONFIDENTIAL
Page 39
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
7.1.4
Treatment Period (10 minutes to 24 hours postdose) 
The following procedures will be performed throughout the Treatment Period at time points 
specified in the Schedule of Assessments (Table 1):

Evaluate seizure symptoms at 10 and 30 (±5) minutes, and 1 (±10 min), 4 (±30 min), 6 (±30 
min), and 24 (±30 min) hours postdose

Evaluate Riker Sedation Agitation Scale and perform standard 12-lead ECG at 30 (±5)
minutes, and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours postdose (if 
subject has not been discharged from the healthcare setting)

4 hours and 24 hours (±30 min) postdose (if subject has not been discharged from the 
healthcare setting): Obtain blood and urine samples for safety laboratory tests for serum 
biochemistry and urinalysis

1 (±10 min), 3 (±30 min), and 6 hours (±30 min) postdose:

Collect blood samples for PK analysis.

10 and 30 (±5) minutes, and 4, 6, and 24 hours (±30 min) postdose (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). 

Measure oxygen saturation (on room air, if feasible).

Administer supportive care throughout this time period.

Review concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
blood sampling).

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.
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 Visit
The follow-up period for this protocol is 1 week after the Treatment Period.


Shire
CONFIDENTIAL
Page 40
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
At the end of this period there will be a follow up visit to evaluate seizure symptoms, review 
concomitant medications, conduct a physical examination, and query for serious adverse events 
(SAEs), AEs. All AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure (see Section 8).
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study. It is the responsibility of the investigator to counsel 
subjects on their treatment alternatives when they exit the 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 informed consent form (ICF) must be executed prior to performing any study-related 
activities and the ICF must be approved by the reviewing IRB. The subject or the subject’s 
parents, guardians, or legally authorized representatives may withdraw consent at any time. The 
subject may be prescreened by the investigator in their clinical practice and the parent, guardian, 
or legally authorized representative may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure. If more than 3 months have elapsed between 
initial informed consent and seizure, the parent, guardian, or legally authorized representative 
should re-sign the latest consent at the time of admission prior to treatment. Participation in the 
study may be terminated at any time without the consent of subjects or subject’s parents, 
guardians, or legally authorized representatives as determined by the investigator.
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 parents or caregivers and will be recorded on the 
source document and CRF.
Medical history (including SE) will capture the subject’s current medical status (current SE or 
CSE disease process), past medical status (past disease processes), history of surgery, allergies, 
and concomitant medications/treatments.
7.2.3
Efficacy
Evaluation of seizure activity will be conducted throughout the study to assess the therapeutic 
success.


Shire
CONFIDENTIAL
Page 41
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017

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.
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.
7.2.4.1
Medical and Medication History
The investigator will perform a complete medical history at Screening, including a medication 
history, and record all information gathered. The investigator must record all clinically or 
medically relevant information regardless of how much time has elapsed since the date of 
diagnosis.
With the consent of parents, guardians, or legally authorized representatives of participating 
subjects, medical records from other treatment providers should be requested. 
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE (eg, dietary, medication, or other), must be recorded on the 
appropriate CRF page.
7.2.4.2
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)

Musculoskeletal


Shire
CONFIDENTIAL
Page 42
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017

Neurological
Abnormalities identified at Screening will be documented in the subject’s source documents and 
on the medical history CRF. Changes after the Screening visit will be captured as AEs on the AE 
CRF page, as deemed by the investigator.
7.2.4.3
Adverse Event Collection
At each study time point, subjects (or parent, guardian, or legally authorized representative) will 
be questioned 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 when the subject with SE
arrives at the hospital or healthcare setting, or if the informed consent has been previously 
signed, from the time the subject begins evaluation and treatment in the hospital or healthcare 
setting for SE, to completion of the follow-up visit. (Please refer to Section 8, Adverse and 
Serious Adverse Events Assessment.)
7.2.4.4
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 the initial vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Clinical Laboratory Evaluations
Clinical laboratory assessments will be performed at Screening, at 4 hours postdose, and at 
24 hours postdose if the subject is still at the healthcare setting. The following clinical laboratory 
assessments will be performed:


Shire
CONFIDENTIAL
Page 43
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 pregnancy testd
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 at screening for women of childbearing potential; may be repeated at the follow-up visit or withdrawal from study if 
pregnancy is suspected.
Aliquots from the PK samples may be retained as back-up for additional parameter testing if 
necessary. Subjects will be in a seated or supine position during blood collection. The total blood 
draw for each subject will be approximately 14.25 mL.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by Quintile’s central 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. 
Blood, serum, and urine samples 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.
7.2.4.6
Pregnancy Test
A urine pregnancy test is performed on all females of childbearing potential at Screening and at 
the follow up visit, if pregnancy is suspected, or upon withdrawal of the subject from the study.


Shire
CONFIDENTIAL
Page 44
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
7.2.4.7
Electrocardiogram 
A standard twelve (12)-lead electrocardiogram (ECG, single recording) will be performed at 
time points specified in the Schedule of Assessments (Table 1).
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.
The investigator or subinvestigator at the investigator site will make comparisons to baseline 
measurements taken at screening, if available. A copy of the ECG should be available as source 
documents for review.  
7.2.4.8
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).
7.2.5
Others 
7.2.5.1
Pharmacokinetic Assessments
Blood samples (~1.25 mL) to provide a minimum of 0.5 mL plasma for the assessment of plasma 
midazolam and 1-hydroxymidazolam concentrations will be collected (from all subjects who 
received investigational product) and analyzed at the specified time points for the duration of the 
study at the time points specified in the Schedule of Assessments (Table 1). The exact time of the 
sample collection should be noted on the source document and data collection tool (eg, CRF).
Samples will be analyzed for midazolam and 1-hydroxymidazolam using a validated assay. The 
methodologies will be appropriately validated in compliance with the CRO’s standard operating 
procedures. 
The address for shipment of serum samples and contact information for the laboratory analysis of 
midazolam and 1-hydroxymidazolam will be provided to the investigator site prior to initiation 
of the trial.


Shire
CONFIDENTIAL
Page 45
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
7.2.6
Volume of Blood to Be Drawn from Each Subject
Table 3
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
1.25
3
3.75
Safety
Biochemistry 
3.5
3
10.5
Total mL
14.25
a If a catheter is used, the first mL is to be discarded; then take 1.25 mL into appropriate tube for PK sample. A total of 
1.25 mL of blood drawn has been used in determination of sample volume.
During this study, it is expected that up to approximately 14.25 mL of blood will be drawn from 
each subject.
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 14.25 mL. Additional considerations may be made for small children 
and infants with sponsor review. 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.


Shire
CONFIDENTIAL
Page 46
SHP615-301 Protocol Amendment 3 
Midazolam
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 the informed consent is signed when the subject with SE
arrives at the hospital or healthcare setting or if the informed consent has been previously signed, 
from the time the subject begins evaluation and treatment in the hospital or healthcare setting for 
SE, until the defined follow-up period stated in Section 7.1.5. 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 change in severity. An event that changes in severity should be captured as a new event. 
Worsening of pre-treatment 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 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.


Shire
CONFIDENTIAL
Page 47
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 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/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


Shire
CONFIDENTIAL
Page 48
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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.
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.


Shire
CONFIDENTIAL
Page 49
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 -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 
non-medical 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 pre-specified total daily dose of the product. 

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.
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 the Quintiles 
Transnational Japan K.K., the 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. 


Shire
CONFIDENTIAL
Page 50
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 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
An 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 a hospital 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.


Shire
CONFIDENTIAL
Page 51
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 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 informed consent is 
signed when the subject with SE arrives at the hospital or healthcare setting, or if the informed 
consent has been previously signed, from the time the subject begins evaluation and treatment in 
the hospital or healthcare setting for SE, until the defined follow-up period stated in Section 7.1.5
and must be reported to Quintiles Transnational Japan K.K., 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.


Shire
CONFIDENTIAL
Page 52
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 ICF, 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, and Site Reporting
The sponsor and Quintiles Transnational Japan K.K. are responsible for notifying the relevant 
regulatory authorities/and institutional IRBs 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 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 PMDA as a 
device malfunction report, regardless of whether or not the event relates to an AE.


Shire
CONFIDENTIAL
Page 53
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
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)


Shire
CONFIDENTIAL
Page 54
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate case report form (CRF).
The 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 the investigator or 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 healthcare setting 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 agent. 
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.


Shire
CONFIDENTIAL
Page 55
SHP615-301 Protocol Amendment 3 
Midazolam
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 study that is designed to evaluate the efficacy and safety of 
MHOS/SHP615 in 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. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% CIs for least squares means will be provided. 
Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th (median), 
and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored 
observations. Plots of the Kaplan-Meier curves and supporting data listings detailing each 
subject’s contribution to the analysis will be provided. 
9.5
Planned Interim Analysis
There is no planned interim analysis for this study.
9.6
Sample Size Calculation and Power Considerations
The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is 
estimated based on the expected response rate which is assumed to be 58.5% compared with the 
threshold of 30% with at least 80% of statistical power at the 2-sided 5% level.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Set will consist of all subjects who have received a single dose of MHOS/SHP615.
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. 
The Pharmacokinetic Set will consist of all subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 


Shire
CONFIDENTIAL
Page 56
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
9.8
Efficacy Analyses
The primary efficacy analysis will be conducted on the FAS.
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 primary efficacy analysis will be conducted on FAS by constructing the 2-sided, 95% CI for 
the percentage of subjects reaching therapeutic success. The lower limit of the 95% CI will be 
compared with the threshold of 30%, which is equivalent to comparing the percentage of success 
to the threshold at the 2-sided 5% level of significance.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes of single 
dose 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 of single 
dose 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 of single 
dose 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

Percentage of subjects who require additional anticonvulsant medication for ongoing 
SE according to the participating healthcare setting protocol or guideline, 10 minutes after a 
single dose 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 according to the participating healthcare setting
protocol or guideline, 10 minutes after a single dose of MHOS/SHP615.


Shire
CONFIDENTIAL
Page 57
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
9.8.3
Subgroup Analyses of Efficacy Endpoints
Selected efficacy endpoints will be evaluated using descriptive statistics by the following 
subgroups, to the extent the data allow:

Age group: 

3 months (52 weeks corrected gestational age) to <1year (and weight >5 kg)

1 to <5 years

5 to <10 years

10 to <18 years

Gender: male and female

Epilepsy etiology (based on the underlying etiology of their epilepsy):

Genetic

Idiopathic

Metabolic 

Symptomatic (Structural)
9.8.4
Exploratory Efficacy Endpoints
A description of the analyses will be included in the SAP.
9.9
Safety Analyses
Safety data will be summarized using descriptive statistics for the Safety Set.
9.9.1
Primary Safety Endpoints
The primary safety endpoints will be respiratory depression, which will include the following 
measures within the 4 hours after MHOS/SHP615 administration:

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 
6, and 24 hours postdose (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)
9.9.2
Secondary Safety Endpoints
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 ECG

Occurrence of buccal irritation


Shire
CONFIDENTIAL
Page 58
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
Adverse events and medical history will be coded using MedDRA. The number of events, 
incidence, and percentage of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by age. 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.
Vital signs (systolic and diastolic blood pressure, pulse, and weight) including potentially 
clinically important vital signs will be summarized using the appropriate descriptive statistics.
The ECG results, including potentially clinically important results, will be summarized.   
9.9.3
Clinical Laboratory Tests 
Clinical laboratory tests will be summarized using the Safety Set. 
Actual values and change from baseline clinical laboratory tests will be summarized. If more 
than 1 laboratory result is reported per study time point per parameter, the last non-missing 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 non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, non-clinically significant result less than the lower limit of normal, within the 
normal range, non-clinically 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 for a subject across study time point to identify any trends.
9.9.4
Vital Signs
Vital signs will be summarized using the Safety Set.
Actual values and changes from baseline in vital signs will be summarized. 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 non-missing result, and the number and percentage 
of subjects with a non-clinically 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. 


Shire
CONFIDENTIAL
Page 59
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 not performed, will be summarized. 
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.
9.10
Pharmacokinetic Analyses
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any 
potential additional metabolite(s) will be evaluated using the Pharmacokinetic population.  
The Pharmacokinetic population will include subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. PK samples 
will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
PK parameters (eg, Cmax, Tmax, AUC and t1/2) will be calculated using population PK modeling.


Shire
CONFIDENTIAL
Page 60
SHP615-301 Protocol Amendment 3 
Midazolam
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 non-pediatric studies as per 
guidance. 


Shire
CONFIDENTIAL
Page 61
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 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 (July 1996). 
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.


Shire
CONFIDENTIAL
Page 62
SHP615-301 Protocol Amendment 3 
Midazolam
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.
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.
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 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.


Shire
CONFIDENTIAL
Page 63
SHP615-301 Protocol Amendment 3 
Midazolam
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 (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 (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,


Shire
CONFIDENTIAL
Page 64
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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 (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.


Shire
CONFIDENTIAL
Page 65
SHP615-301 Protocol Amendment 3 
Midazolam
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 non-commercial 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.


Shire
CONFIDENTIAL
Page 66
SHP615-301 Protocol Amendment 3 
Midazolam
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.


Shire
CONFIDENTIAL
Page 67
SHP615-301 Protocol Amendment 3 
Midazolam
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. & 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.
Baysun, S., Aydin, O. F., Atmaca, E. & Gurer, Y. K. 2005. A comparison of buccal midazolam 
and rectal diazepam for the acute treatment of seizures. Clin Pediatr (Phila), 44, 771-6.
Berg, A. T., Shinnar, S., Levy, S. R. & Testa, F. M. 1999. Status epilepticus in children with 
newly diagnosed epilepsy. Ann Neurol, 45, 618-23.
Brophy, G. M., Bell, R., Claassen, J., Alldredge, B., Bleck, T. P., Glauser, T., Laroche, S. M., 
Riviello, J. J. J., Shutter, L., Sperling, M. R., Treiman, D. M., Vespa, P. M. & Committee, 
N. C. S. S. E. G. W. 2012. Guidelines for the evaluation and management of status 
epilepticus. Neurocrit Care, 17, 3-23.
Dham, B. S., 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, 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/.
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.
Lowenstein, D. H., Bleck, T. & MacDonald, R. L. 1999. It's time to revise the definition of status 
epilepticus. Epilepsia, 40, 120-2.
McIntyre, J., Robertson, S., Norris, E., Appleton, R., Whitehouse, W. P., 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, P. J. & 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.
Muchohi, S. N., Kokwaro, G. O., Ogutu, B. R., Edwards, G., Ward, S. A. & Newton, C. R. 2008. 
Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and 
convulsions. Br J Clin Pharmacol, 66, 529-38.
NICE Guidance National Institute for Health and Care Excellence. 2011. Available: 
https://www.nice.org.uk/guidance/cg137/chapter/Appendix-F [Accessed 24 Jan 2017.


Shire
CONFIDENTIAL
Page 68
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
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. & 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.
Schwagmeier, R., Alincic, S. & Striebel, H. W. 1998. Midazolam pharmacokinetics following 
intravenous and buccal administration. Br J Clin Pharmacol, 46, 203-6.
Scott, R. C., Besag, F. M., Boyd, S. G., Berry, D. & Neville, B. G. 1998. Buccal absorption of 
midazolam: pharmacokinetics and EEG pharmacodynamics. Epilpesia, 39, 290-4.
Scott, R. C., Besag, F. M. & Neville, B. G. 1999. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Shinnar, S., Berg, A. T., Moshe, S. L., O'Dell, C., Alemany, M., Newstein, D., Kang, H., 
Goldensohn, E. S. & 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.
Sirven, J. I. & 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, W. H., Porter, R. J. & 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. & 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. & Brigo, F. 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, M. T., Macleod, S. & O'Regan, M. E. 2004. Nasal/buccal midazolam use in the 
community. Arch Dis Child, 89, 50-1.
Working Group on Status Epilepticus 1993. Treatment of convulsive status epilepticus. 
Recommendations of the Epilepsy Foundation of America's Working Group on Status 
Epilepticus. Jama, 270, 854-9.


Shire
CONFIDENTIAL
Page 69
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
12
APPENDICES




Shire
CONFIDENTIAL
Page 71
SHP615-301 Protocol Amendment 3 
Midazolam
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
2016
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. 


Shire
CONFIDENTIAL
Page 72
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).


Shire
CONFIDENTIAL
Page 73
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
APPENDIX 3
BIOANALYSIS: SAMPLE HANDLING
1.1
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1 to measure plasma 
concentrations of midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s). 
Blood samples (~1.25 mL) for pharmacokinetic analysis will be drawn by in-dwelling catheters 
or direct venipuncture into K2EDTA tubes, capped, and chilled immediately on crushed ice. The 
actual time that the sample was obtained will be recorded in the subject’s source document and 
on the appropriate CRF page. After applying a tourniquet, venous blood will be drawn with a 
disposable needle. If a catheter is used, the first milliliter of blood on each sampling occasion 
will be discarded. Saline can be used to keep catheters patent.
1.2
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after
collection (within <15 minutes) by refrigerated centrifugation (4C, 1500 g, 15 minutes). The 
separated plasma will be transferred into appropriately labeled polypropylene tubes via a plastic 
pipette. Plasma to be split in two aliquots: first tube minimum 0.25 mL (primary sample), second 
tube remaining plasma volume (back-up sample).  Aliquots should be shipped separately to the 
bioanalytical laboratory. All samples will be stored at approximately -80C or colder and the 
freezer temperature will be controlled, monitored, and recorded during the storage period until 
they are transferred in the frozen state to a designated bioanalytical contract laboratory. Samples 
will remain frozen at -80C or colder until analysis. Note: For sites that do not have access 
to -80C storage, samples may be stored at -20C for a limited time (maximum 90 days) before 
shipping to the bioanalytical CRO.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the clinical pharmacology unit. The labels will contain the following information:

Study number

Treatment 

Subject identifier 

Matrix identifier (plasma)

Nominal time
1.3
Shipment of Plasma Samples
Plasma samples should be double bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday to Wednesday only. 
Samples should be transported to ensure that they arrive at the bioanalytical laboratory between 
the hours of 0900 and 1600. The recipient and primary Shire contact must be notified by phone, 


Shire
CONFIDENTIAL
Page 74
SHP615-301 Protocol Amendment 3 
Midazolam
18 Dec 2017
fax, and e-mail when the samples are shipped and must be provided with the shipment tracking 
number. 
Plasma samples, along with the corresponding documentation, will be shipped to:
Name of bioanalytical laboratory: York Bioanalytical Solutions (YBS)
Primary contact: 
Telephone DDI: 
E-mail:
Plasma samples will be stored nominally at -80C prior to and after analysis at York 
Bioanalytical Solutions Limited until their disposal is authorized by Shire.
1.4
Assay Methodology
Drug analysis will be performed at YBS under the guidance of the Department of Nonclinical 
Development, Shire Pharmaceuticals. Plasma sample analysis will be performed according to the 
bioanalytical study plans prepared for the study. 
Plasma samples (K2EDTA) will be analyzed at York Bioanalytical Solutions Limited for 
midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s) using the most 
current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at York Bioanalytical Solutions Limited.

Prot_001.pdf: 
PROTOCOL: SHP615-301
TITLE:
A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, 
Safety, and Pharmacokinetics of Buccally Administered MHOS/SHP615 
in Pediatric Patients with Status Epilepticus (Convulsive) in the Hospital 
or Emergency Room
DRUG:
Midazolam hydrochloride oromucosal solution MHOS/SHP615
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
MEDICAL 
MONITOR:
PROTOCOL 
HISTORY:
Original Protocol: 20 Mar 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure 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.




Shire
CONFIDENTIAL
Page 3
SHP615-301 Protocol 
Midazolam
20 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: 


Shire
CONFIDENTIAL
Page 4
SHP615-301 Protocol 
Midazolam
20 Mar 2017
PRODUCT QUALITY COMPLAINTS
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). 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. For instructions on reporting AEs related to product complaints, 
see Section 8.3.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World (ROW)
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)


Shire
CONFIDENTIAL
Page 5
SHP615-301 Protocol 
Midazolam
20 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
1.
BACKGROUND INFORMATION.......................................................................................18
1.1
Status Epilepticus .....................................................................................................18
1.2
Current Treatment Options.......................................................................................19
1.3
Unmet Medical Need for Buccal Midazolam...........................................................20
1.4
Product Background and Clinical Information ........................................................20
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Open-Label Study (SHP615-301) ................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objectives.................................................................................................22
2.2.2
Secondary Objectives.............................................................................................23
3.
STUDY DESIGN ...................................................................................................................23
3.1
Study Design ............................................................................................................23
3.2
Duration and Study Completion Definition .............................................................23
3.3
Sites and Regions .....................................................................................................24
4.
STUDY POPULATION.........................................................................................................24
4.1
Inclusion Criteria......................................................................................................24
4.2
Exclusion Criteria.....................................................................................................25
4.3
Restrictions...............................................................................................................26
4.3.1
Medical Intervention..............................................................................................26
4.4
Reproductive Potential .............................................................................................26
4.4.1
Female Contraception............................................................................................26
4.4.2
Male Contraception................................................................................................26
4.5
Discontinuation of Subjects .....................................................................................26
4.5.1
Reasons for Discontinuation..................................................................................27
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................27
4.5.3
Stopping Rules.......................................................................................................28
4.5.3.1
Study Level Stopping Rules...................................................................28
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria................................28
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................28


Shire
CONFIDENTIAL
Page 6
SHP615-301 Protocol 
Midazolam
20 Mar 2017
5.1
Prior Treatment ........................................................................................................29
5.2
Concomitant Treatment............................................................................................29
6.
INVESTIGATIONAL PRODUCT ........................................................................................29
6.1
Identity of Investigational Product...........................................................................29
6.1.1
Blinding the Treatment Assignment......................................................................30
6.2
Administration of Investigational Product(s)...........................................................30
6.2.1
Allocation of Subjects to Treatment ......................................................................30
6.2.2
Dose Regimen and Dose Administration...............................................................30
6.2.2.1
Dosing Regimen.....................................................................................30
6.2.2.2
Dose Administration ..............................................................................31
6.3
Labeling, Packaging, Storage, and Handling ...........................................................31
6.3.1
Labeling .................................................................................................................31
6.3.2
Packaging...............................................................................................................31
6.3.3
Storage ...................................................................................................................32
6.3.4
Special Handling....................................................................................................32
6.4
Drug Accountability.................................................................................................32
6.5
Subject Compliance..................................................................................................33
6.6
Destruction of Investigational Product.....................................................................34
7.
STUDY PROCEDURES........................................................................................................34
7.1
Study Schedule.........................................................................................................34
7.1.1
Screening/Baseline Assessments ...........................................................................34
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)........35
7.1.3
Treatment Period (0 minutes to 6 hours postdose) ................................................36
7.1.4
Treatment Period (10 minutes to 24 hours postdose) ............................................36
7.1.5
Follow-up Visit......................................................................................................36
7.1.6
Additional Care of Subjects after the Study ..........................................................37
7.2
Study Evaluations and Procedures ...........................................................................37
7.2.1
Informed Consent...................................................................................................37
7.2.2
Demographic and Other Baseline Characteristics .................................................37
7.2.3
Efficacy..................................................................................................................37
7.2.4
Safety .....................................................................................................................38
7.2.4.1
Medical and Medication History............................................................38
7.2.4.2
Physical Examination.............................................................................38
7.2.4.3
Adverse Event Collection.......................................................................39
7.2.4.4
Vital Signs..............................................................................................39
7.2.4.5
Clinical Laboratory Evaluations.............................................................39
7.2.4.6
Pregnancy Test .......................................................................................41
7.2.4.7
Electrocardiogram ..................................................................................41


Shire
CONFIDENTIAL
Page 7
SHP615-301 Protocol 
Midazolam
20 Mar 2017
7.2.5
Others.....................................................................................................................41
7.2.5.1
Pharmacokinetic Assessments................................................................41
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................42
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................42
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................42
8.1.1
Severity Categorization..........................................................................................43
8.1.2
Relationship Categorization...................................................................................43
8.1.3
Outcome Categorization ........................................................................................44
8.1.4
Symptoms of the Disease Under Study .................................................................44
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................44
8.1.6
Pregnancy...............................................................................................................45
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................45
8.2
Serious Adverse Event Procedures ..........................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................46
8.2.3
Serious Adverse Event Definition .........................................................................46
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
8.2.6
Fatal Outcome........................................................................................................48
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting...................49
8.3
Product Quality Complaints.....................................................................................49
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................50
9.1
Data Collection.........................................................................................................50
9.2
Clinical Data Management.......................................................................................50
9.3
Data Handling Considerations..................................................................................50
9.4
Statistical Analysis Process......................................................................................50
9.4.1
Appropriateness of Measurements.........................................................................51
9.4.2
General Considerations..........................................................................................51
9.5
Planned Interim Analysis .........................................................................................51
9.6
Sample Size Calculation and Power Considerations................................................51
9.7
Study Population ......................................................................................................51
9.8
Efficacy Analyses.....................................................................................................52
9.8.1
Primary Efficacy Endpoint ....................................................................................52
9.8.2
Secondary Efficacy Endpoints...............................................................................52
9.8.3
Subgroup Analyses of Efficacy Endpoints ............................................................52
9.8.4
Exploratory Efficacy Endpoints.............................................................................53
9.9
Safety Analyses........................................................................................................53


Shire
CONFIDENTIAL
Page 8
SHP615-301 Protocol 
Midazolam
20 Mar 2017
9.9.1
Primary Safety Endpoints ......................................................................................53
9.9.2
Secondary Safety Endpoints ..................................................................................53
9.9.3
Clinical Laboratory Tests.......................................................................................54
9.9.4
Vital Signs..............................................................................................................54
9.9.5
Electrocardiography...............................................................................................55
9.10
Pharmacokinetic Analyses .......................................................................................55
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................55
10.1
Sponsor’s Responsibilities .......................................................................................55
10.1.1 Good Clinical Practice Compliance.......................................................................55
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..................................................56
10.2
Investigator’s Responsibilities .................................................................................56
10.2.1 Good Clinical Practice Compliance.......................................................................56
10.2.2 Protocol Adherence and Investigator Agreement..................................................57
10.2.3 Documentation and Retention of Records.............................................................57
10.2.3.1
Case Report Forms.................................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection.....................................................................................58
10.2.3.4
Financial Disclosure...............................................................................58
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 ....................................................................................59
10.4
Privacy and Confidentiality......................................................................................60
10.5
Study Results/Publication Policy .............................................................................60
11. REFERENCES .......................................................................................................................62
12. APPENDICES ........................................................................................................................64


Shire
CONFIDENTIAL
Page 9
SHP615-301 Protocol 
Midazolam
20 Mar 2017
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................16
Table 2
Recommended Prescreening Procedures and Assessments ..........................35
Table 3
Volume of Blood to Be Drawn from Each Subject.......................................42
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................64
Appendix 2
Scales and Assessments .........................................................................65
Appendix 3
Bioanalysis: Sample Handling ...............................................................67


Shire
CONFIDENTIAL
Page 10
SHP615-301 Protocol 
Midazolam
20 Mar 2017
ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CHMP
Committee for Medicinal Products for Human Use
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSE
convulsive status epilepticus
ECG
electrocardiogram
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
Paediatric Investigation Plan
PK
pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PQC
Product Quality Complaint
PQCROW
Product Quality Complaint Rest of World
PUMA
Paediatric-use marketing authorisation


Shire
CONFIDENTIAL
Page 11
SHP615-301 Protocol 
Midazolam
20 Mar 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
VT
ventricular tachycardia


Shire
CONFIDENTIAL
Page 12
SHP615-301 Protocol 
Midazolam
20 Mar 2017
STUDY SYNOPSIS
Protocol number: SHP615-301
Drug: Midazolam hydrochloride oromucosal solution 
(MHOS/SHP615) 
Title of the study: A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, Safety, and 
Pharmacokinetics of Buccally Administered MHOS/SHP615 in Pediatric Patients with Status Epilepticus 
(Convulsive) in the Hospital or Emergency Room
Number of subjects (total and for each treatment arm): Approximately 25 subjects (minimum 3 subjects per 
age group)
Investigator(s): Multicenter study (in hospital or healthcare settings)
Site(s) and Region(s): Approximately 25 hospitals in Japan
Study period (planned):
July 2017 to June 2019
Clinical phase:
3
Objectives:
Primary: To assess the efficacy of MHOS/SHP615 administered buccally in pediatric patients with status 
epilepticus (convulsive) in a healthcare setting.
Secondary: To assess the safety and pharmacokinetics of MHOS/SHP615 administered buccally to pediatric 
patients with status epilepticus (convulsive) in a healthcare setting.
Rationale: Under the proprietary name BUCCOLAM® MHOS/SHP615 is currently approved for treatment of 
pediatric patients presenting with status epilepticus (SE) in a hospital or emergency room in several European 
Union (EU) countries. The intravenous (IV) formulation of midazolam is currently administered buccally off 
label for the treatment of SE in a healthcare setting in Japan. This study will provide data to support approval 
and labeling of age-based dosing of MHOS/SHP615 for the treatment of SE in Japanese pediatric patients.
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.
Each pre-filled dosing syringe is individually packed in a protective plastic tube. 
The four available unit dose packs are:

2.5 mg (yellow label) for children aged 3 months (52 weeks corrected gestational age) to <1 year (and 
weight >5 kg)

5 mg (blue label) for children aged 1 year to <5 years

7.5 mg (purple label) for children aged 5 years to <10 years

10 mg (orange label) for children aged 10 years to <18 years
Methodology: SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
MHOS/SHP615 administered buccally to subjects <18 years who present with SE in the healthcare setting. 
Children whose corrected gestational age is 52 weeks (gestational weeks plus the number of weeks after birth) 
and <18 years, weight >5 kg ,who arrive at the healthcare setting in full seizure, and have not received 
immediate treatment, are eligible to participate in this study providing all inclusion/exclusion 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.


Shire
CONFIDENTIAL
Page 13
SHP615-301 Protocol 
Midazolam
20 Mar 2017
This study consists of a 24-hour, open-label treatment period followed by a 1-week safety follow-up period.
Upon entry in the SHP615-301 study, subjects will receive a single open-label MHOS/SHP615 treatment,
dosing stratified by age (2.5, 5, 7.5, 10 mg buccally).
The efficacy of MHOS/SHP615 in stopping prolonged convulsive seizures will be assessed by measuring the 
percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615 the subject will be treated according to participating 
healthcare setting protocol or guideline. The safety and pharmacokinetics of MHOS/SHP615 will also be 
assessed.
Subjects will be monitored by vital signs, laboratory tests, and ECGs for safety evaluations. All subjects who 
withdraw early or who complete treatment in this study will be followed for 1 week after the dose of SHP615 
for safety evaluations. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks plus the 
number of weeks after birth) and <18 years, and weight >5 kg, at the time of informed consent.
2.
Parent, guardian, or legally authorized representative of the child provides informed consent (and
assent, when applicable per Shire policy) to participate in the study prior to participation in any 
protocol specific procedures. The subject may be prescreened by the investigator in their clinical 
practice and parents or legal guardians may sign informed consent before the subject presents to the 
healthcare setting for treatment of the seizure.
3.
Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the 
preceding hour
b.
Currently presenting with seizure (convulsive) and 2 or more convulsions in succession 
without recovery of consciousness
c.
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 seizures due to illegal drug or acute alcoholic intoxication.
4.
Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
5.
Subjects with history of seizures of psychogenic origin.
6.
Subjects with known history of hypersensitivities, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, use of drugs that inhibit or 
induce CYP3A).
7.
Subjects with a known history of benzodiazepine abuse.
8.
Subjects who, in the judgment of the healthcare provider, 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.


Shire
CONFIDENTIAL
Page 14
SHP615-301 Protocol 
Midazolam
20 Mar 2017
10. Subjects with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] block of 
second or third degree, VT [ventricular tachycardia]).
11. Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV 
reverse transcriptase inhibitors.
12. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or 
healthcare setting.
13. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare 
provider.
14. Subjects 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.
15. Subject has received antiseizure medication prior to arrival in the healthcare setting
16. 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: 1 week
Endpoints and statistical analysis:
Efficacy
The primary efficacy endpoint is the 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 of a single dose of 
MHOS/SHP615 and who have sustained absence of seizure activity for the following time periods after 
the single dose of MHOS/SHP615:
o
1 h
o
4 h
o
6 h

Time to resolution of seizures (convulsions) 

Time to recovery of consciousness

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 according to the participating healthcare setting protocol or 
guideline, 10 minutes after a single dose of MHOS/SHP615.
Safety
The primary safety endpoints will be respiratory depression, which will include the following measures within 
the 4 hours after MHOS/SHP615 administration

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 6, and 24 
hours postdose (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]).


Shire
CONFIDENTIAL
Page 15
SHP615-301 Protocol 
Midazolam
20 Mar 2017

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 ECG

Occurrence of buccal irritation
Pharmacokinetics (population PK)

Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential 
additional metabolite(s) will be evaluated. Exploratory evaluation of potential additional metabolite(s) may
also be performed. PK samples will be collected at 1, 3, and 6 hours (or time of discharge, if earlier than 6 
hours) after administration of MHOS/SHP615.
Statistical methods
Sample size:  The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is 
estimated based on the expected response rate which is assumed to be 58.5% compared with the threshold of 
30% with at least 80% of statistical power at the 2-sided 5% level.
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.
The primary efficacy analysis will be conducted on the FAS, by constructing the 2-sided, 95% confidence 
interval (CI) for the percentage of subjects reaching therapeutic success 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 lower limit of the 95% CI will be compared with the threshold of 30%, which is equivalent to comparing 
the percentage of success to the threshold at the 2-sided 5% level of significance.
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. TEAEs 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.
Population PK analysis
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any potential additional 
metabolites will be evaluated using the Pharmacokinetic Set. The Pharmacokinetic Set will include subjects who 
receive a single dose of MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 
Pharmacokinetic parameters will be calculated using population PK modeling.


Shire
CONFIDENTIAL
Page 16
SHP615-301 Protocol 
Midazolam
20 Mar 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-up
Screening/Baseline
0 min
10 
min
30 
(± 5min)
1 h
(± 10min)
3h
(± 30min)
4 h
(± 30min)
6 ha
(± 30min)
24hb
(± 30min)
1 week
(± 1 day)
Informed consent/assent 
X
Inclusion/exclusion criteria
Xc
Demographics
X
Medical/procedural history
X
Confirmation of status 
epilepticus
X
Evaluation of seizure 
symptomsd
X
X
X
X
X
X
X
X
X
Riker Sedation-Agitation Scale
X
X
X
X
X
X
X
X
Laboratory evaluationse
Xf
X
X
SHP615 administration
X
PK collectiong
X
X
X
Buccal cavity assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Oxygen saturation
X
X
X
X
X
12-Lead ECG
Xj
Xj
X
X
X
X
Supportive care
X
X
Physical examinationk
X
X
Concomitant medications
X
X
Xa
X
X
Adverse event monitoring
X
X
Xa
X
X
ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute; PK=pharmacokinetic.
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 postdose time point will be made if the subject has not been discharged from the healthcare setting; 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 If more than 3 months have elapsed between initial informed consent and seizure, parent or legal guardian should re-sign at the time of admission prior to treatment.
d Seizure symptoms will be assessed based on physician’s clinical judgment and healthcare setting protocol.


Shire
CONFIDENTIAL
Page 17
SHP615-301 Protocol 
Midazolam
20 Mar 2017
Table 1
Schedule of Assessments
Assessment
Treatment Period - Time from SHP615 Administration
Follow-up
Screening/Baseline
0 min
10 
min
30 
(± 5min)
1 h
(± 10min)
3h
(± 30min)
4 h
(± 30min)
6 ha
(± 30min)
24hb
(± 30min)
1 week
(± 1 day)
e Laboratory evaluations include hematology, serum biochemistry, and urinalysis (including a urine pregnancy test in women of childbearing potential at screening/baseline).
f
Blood glucose can be measured by local lab or testing kit
g The PK samples will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
h 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. 
i
Vital signs will include single supine blood pressure, pulse rate, respiratory rate, and body temperature.
j
If subject is stable enough for ECG
k Physical examination will be performed at some point between 0 min (dosing) and 6 hours postdose, when possible.


Shire
CONFIDENTIAL
Page 18
SHP615-301 Protocol 
Midazolam
20 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).
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 (ILAE) 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 either 10 minutes (Treiman et al., 1998) or 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; Brophy et al., 2012; Lowenstein et al., 1999; 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 of SE in children younger than 17 years 
is 42 cases per 100,000 persons. In addition to young age, other risk factors include genetic 


Shire
CONFIDENTIAL
Page 19
SHP615-301 Protocol 
Midazolam
20 Mar 2017
predisposition and acquired brain insults (Fountain, 2000; Working Group on Status Epilepticus, 
1993; Shinnar et al., 1996; Berg et al., 1999).
Left untreated (or undertreated) SE, depending on the type and duration of seizures, 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 not 
authorized for SE in the United States {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 healthcare setting. 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 to diazepam treatment. 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).


Shire
CONFIDENTIAL
Page 20
SHP615-301 Protocol 
Midazolam
20 Mar 2017
1.3
Unmet Medical Need for Buccal Midazolam
To fulfill such unmet needs as 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 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 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 non-IV 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 treatment of 
prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents (from 


Shire
CONFIDENTIAL
Page 21
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 healthcare 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) and <18 years. The efficacy and safety 
of buccal midazolam 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; 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% confidence 
interval {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) from the authorized uses is 
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 (AEs) (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 
<6 months of age are particularly vulnerable to airway obstruction and hypoventilation.
Pharmacokinetics
Published PK studies in healthy adult volunteers have shown that buccal midazolam is quickly 
absorbed (producing peak concentrations at 30 minutes with a mean buccal midazolam 
bioavailability of 74.5% [Schwagmeier et al., 1998]) and has a rapid effect (≤5-10 minutes) on 
the central nervous system (CNS), shown on electroencephalography (Scott et al., 1998). The 


Shire
CONFIDENTIAL
Page 22
SHP615-301 Protocol 
Midazolam
20 Mar 2017
rapid absorption of midazolam by the buccal route has also been demonstrated in a published 
study in children with severe malaria and convulsions (peak concentration at 10 [5–40] minutes 
with bioavailability estimated at 87%) (Muchohi et al., 2008).
For this open label SHP615-301 study, the MHOS/SHP615 formulation (the same as the 
HYPNOVEL 10 mg/2 mL formulation) and the proposed fixed doses will be the same as the 4 
pivotal, rectal-diazepam-controlled clinical studies. Thus, the PK/pharmacokinetics should not be 
different for MHOS compared to that in the pivotal efficacy/safety studies.
Always refer to the latest version of the SHP615 Midazolam HCl 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. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Open-Label Study (SHP615-301)
For treatment of acute seizures in children, rectal diazepam is the medication most commonly 
used when IV access is not possible either in the medical 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 has been specifically developed as a single, age-specific, fixed dose 
(approximately 0.25 to 0.5 mg/kg as 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) Paediatric
Committee as part of the PIP application and by the EMA Committee for Medicinal Products for 
Human Use (CHMP) as part of the review and approval of the Paediatric-use marketing
authorisation (PUMA).
The rationale for this interventional open-label study is to determine the efficacy, safety, and 
pharmacokinetics of MHOS/SHP615 in pediatric patients with CSE.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to assess the efficacy of MHOS/SHP615 administered 
buccally in pediatric patients with status epilepticus (convulsive) in a healthcare setting.


Shire
CONFIDENTIAL
Page 23
SHP615-301 Protocol 
Midazolam
20 Mar 2017
2.2.2
Secondary Objectives
The secondary objectives of this study are to assess the safety and pharmacokinetics of 
MHOS/SHP615 administered buccally to pediatric patients with status epilepticus (convulsive) 
in a healthcare setting.
3.
STUDY DESIGN
3.1
Study Design 
SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
buccally administered MHOS/SHP615 to pediatric subjects who present with SE in the 
healthcare setting. 
Approximately 25 subjects will be enrolled in this study. Children whose corrected gestational 
age is ≥52 weeks (gestational weeks plus the number of weeks after birth) and <18 years (and 
weight >5 kg) who arrive at the healthcare setting in full seizure, have not received immediate 
treatment, and have parental/caregiver informed consent/assent (when applicable, per Shire 
policy), are eligible to participate 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. Upon entry in the SHP615-301 study, subjects will receive a single open-label 
MHOS/SHP615 treatment, dosing stratified by age (2.5, 5, 7.5, or 10 mg buccally).
The efficacy of MHOS/SHP615 in stopping convulsive seizures will be assessed by measuring 
the percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615, the 
subject will be treated according to the participating healthcare setting protocol or guideline. The 
safety and pharmacokinetics of MHOS/SHP615 will also be assessed.
Subjects will be monitored by assessment of TEAEs, vital signs, laboratory tests, oxygen 
saturation, physical examination, and ECGs for safety evaluations. All subjects treated in this 
study will be followed for 1 week after dosing for safety evaluations.
3.2
Duration and Study Completion Definition
The duration of the treatment visit will be at least 6 hours and up to 24 hours, with a follow-up 
visit 1 week after the administration of MHOS/SHP615. It is anticipated that subjects will arrive 
at the healthcare setting while experiencing a seizure. Subjects will be screened and assessed at 
baseline immediately before administration of investigational product even if the informed 
consent and some prescreening assessments were completed at a previous clinical visit. 


Shire
CONFIDENTIAL
Page 24
SHP615-301 Protocol 
Midazolam
20 Mar 2017
Evaluation of seizure symptoms will be conducted up through 6 hours after the administration of 
the investigational product. After 6 hours, the subject may be discharged from the healthcare 
setting study site. 
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 the 
protocol-defined assessments, or discontinues the study. 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 healthcare setting study sites in Japan. 
4.
STUDY POPULATION
Each subject (parent or legal guardian) must participate in the informed consent process and 
provide written informed consent/assent (when applicable, per Shire policy) before any 
procedures specified in the protocol are performed. The subject may be prescreened by the 
investigator in their clinical practice and parents or legal guardians may sign informed consent 
before the subject presents to the healthcare setting for treatment of the seizure.
The total enrollment for the SHP615-301 study is expected to be approximately 25 subjects
(minimum 3 subjects per age group) with active generalized tonic-clonic SE with seizures.
Diagnosis of SE will be confirmed through documented medical history and evaluation of 
seizure symptoms conducted either during the screening/baseline assessment period or during
treatment.
4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by the investigator or subinvestigator 
before subjects are included in the study.
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Male and female subjects whose corrected gestational age is ≥52 weeks (gestational weeks 
plus the number of weeks after birth) and <18 years (and weight >5 kg), when obtaining 
informed consent.
2. Parent, guardian, or legally authorized representative of the child provides informed consent 
(and assent, when applicable per Shire policy) to participate in the study prior to participation 
in any protocol specific procedures. The subject may be prescreened by the investigator in 
their clinical practice and parents or legal guardians may sign informed consent before the 
subject presents to the healthcare setting for treatment of the seizure.


Shire
CONFIDENTIAL
Page 25
SHP615-301 Protocol 
Midazolam
20 Mar 2017
3. Subjects with 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:
a.
Currently presenting with seizure (convulsive) activity and 3 or more convulsions 
within the preceding hour
b. Currently presenting with seizure (convulsive) and 2 or more convulsions in 
succession without recovery of consciousness
c.
Currently presenting with a single seizure (convulsive) lasting ≥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 seizures due to illegal drug or acute alcoholic intoxication.
4. Subjects with known or suspected recurrent seizures due to illegal drug or alcohol 
withdrawal.
5. Subjects with history of seizures of psychogenic origin.
6. Subjects with known history of hypersensitivities, non-responsiveness or contraindications to 
benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, 
myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, use of drugs that 
inhibit or induce CYP3A).
7. Subjects with a known history of benzodiazepine abuse.
8. Subjects who, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (eg, atrioventricular [AV] 
block of second or third degree, VT [ventricular tachycardia]).
11. Subjects who have been receiving HIV protease inhibitors or HIV reverse transcriptase 
inhibitors.
12. Subjects with current hypoglycemia (glucose <60 mg/dL) upon presentation at the hospital or 
healthcare setting.
13. Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the 
healthcare provider.
14. Subjects 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.
15. Subject has received antiseizure medication prior to arrival in the healthcare setting.


Shire
CONFIDENTIAL
Page 26
SHP615-301 Protocol 
Midazolam
20 Mar 2017
16. 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 during the study.
4.4
Reproductive Potential
4.4.1
Female Contraception
Female children and adolescent subjects should be either:

Pre-menarchal 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 treatment visit, 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 with the medical monitor prior to withdrawal of a subject from the study, 
if possible.
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 CRF and source documents. 


Shire
CONFIDENTIAL
Page 27
SHP615-301 Protocol 
Midazolam
20 Mar 2017
Subjects who discontinue will not be replaced. 
4.5.1
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:

AE

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 CRF 
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 reviewing institutional review board (IRB), or investigational product safety 
problems, or at the discretion of the sponsor. In addition, the sponsor retains the right to 
discontinue development of 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 subjects and subject’s parents, 
guardians, or legally authorized representatives and the healthcare setting pharmacy (if 
applicable) within 28 days. As directed by the sponsor, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
4.5.2
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.


Shire
CONFIDENTIAL
Page 28
SHP615-301 Protocol 
Midazolam
20 Mar 2017
4.5.3
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.

2 SAEs of similar type (defined as the 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 time point/assessment.
4.5.3.1
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).
4.5.3.2
Follow-up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other 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.
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the treatment visit and through the final study contact (including 
protocol-defined follow-up period) must be recorded on the appropriate CRF page.


Shire
CONFIDENTIAL
Page 29
SHP615-301 Protocol 
Midazolam
20 Mar 2017
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, non-pharmacological 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 before investigational product administration 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-
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 3 months (52 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 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. 
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 


Shire
CONFIDENTIAL
Page 30
SHP615-301 Protocol 
Midazolam
20 Mar 2017
community and healthcare setting. Additional information is provided in the current version of 
the SHP615 Midazolam HCl 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, and the sponsor study team. Study treatment will only be 
administered by the healthcare setting study site staff to subjects who have a signed and dated 
IRB-approved 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 present for enrollment. 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 study site staff as a single, fixed dose product, 
banded by age to subjects with CSE in the healthcare setting. For buccal administration, 
MHOS/SHP615 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
3 months (52 weeks corrected gestational age) to <1 year (and weight 
>5 kg)
5 mg
1 to <5 years
7.5 mg
5 to <10 years


Shire
CONFIDENTIAL
Page 31
SHP615-301 Protocol 
Midazolam
20 Mar 2017
10 mg
10 to <18 years
6.2.2.2
Dose Administration
Only 1 syringe with the specified dose must be given. The full amount of the MHOS pre-filled 
dosing syringe is injected slowly into the buccal mucosa. In some cases, it might be necessary to 
divide the dose so that half of the solution is injected into each side of mouth.  
The investigator, or an approved representative (eg, subinvestigator), will ensure that all 
investigational product is dispensed by qualified staff members. 
Prior to administration of drug therapy, the airway should be secured and respiratory and cardiac 
function assessed (NICE Guidance National Institute for Health and Care Excellence, 2011). 
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 Quintiles 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
The investigational product MHOS/SHP615 will be provided in individual, labeled, single-dose, 
prefilled plastic, oral dosing syringes 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 are packaged and dispensed 


Shire
CONFIDENTIAL
Page 32
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 
receipt of the investigational product, documenting shipment content and condition. Accurate 


Shire
CONFIDENTIAL
Page 33
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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. 
Where permissible, tasks may be delegated to a qualified designee (eg, a subinvestigator) 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 investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying 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 product 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 product 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
All doses of open-label MHOS/SHP615 administered at the investigational site will be under the 
direct supervision of the investigator or qualified healthcare setting study site personnel 
designated by the investigator.
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, trays, 
vials) or at the individual count level for opened containers/packaging. The pharmacist or 
investigator-identified designee will record details on the drug accountability form.


Shire
CONFIDENTIAL
Page 34
SHP615-301 Protocol 
Midazolam
20 Mar 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/Baseline Assessments
Screening/Baseline assessments for subject eligibility into this study occur on the same day as 
the Treatment Period when subjects <18 years present with SE in the healthcare setting after 
informed consent has been obtained. Alternatively, the subject may be prescreened by the 
investigator for subjects at risk of SE in their clinical practice and parents or legal guardians may 
sign informed consent before the subject presents to the healthcare setting for treatment of the 
seizure. However, confirmation of SE, evaluation of seizure symptoms, blood and urine samples, 
and AE monitoring must be completed in the healthcare setting.
Written informed consent must be obtained prior to performing any protocol-specific procedures. 
The complete list of assessments that will be performed in the study is listed below:

Informed consent/assent (when applicable, per Shire policy)

Inclusion/exclusion criteria (Sections 4.1 and 4.2)

Demographics

Medical/procedural history

Confirmation of SE 

Evaluation of seizure symptoms (based on clinical judgment and healthcare setting 
procedures)

Riker Sedation Agitation Scale

Obtain blood and urine samples for the following laboratory tests:

Safety laboratory tests for hematology, serum biochemistry, and urinalysis

Blood glucose can be measured by local lab or testing kit

Urine pregnancy test (females of childbearing potential only)

Vital signs


Shire
CONFIDENTIAL
Page 35
SHP615-301 Protocol 
Midazolam
20 Mar 2017

Review concomitant medications/treatments

Monitor AEs
Table 2 lists recommend prescreening procedures and assessments that can be performed for 
subjects at risk of SE prior to presenting for treatment.
Table 2
Recommended Prescreening Procedures and Assessments
Obtain informed consent
Collect demographic information
Review medical history 
Review inclusion/exclusion criteria:
Inclusion Criteria
Exclusion Criteria
1. Age
1. Pregnancy
2. Informed consent
4. Known seizures due to drugs/alcohol
6. Contraindications to benzodiazepines
7. History of benzodiazepine abuse
8. Prior non-response to midazolam
11.Prior treatment for HIV
13.Severe cerebral anoxia (except cerebral palsy)
14.Prior study involvement impacting this study
Note: Procedures and assessments should be reviewed and reconfirmed when the subject arrives at the hospital or healthcare 
center for SE treatment.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered investigational 
product(s). Subjects cannot be rescreened once they have been designated as a screen failure. 
7.1.2
Treatment Period Procedures (0 min from MHOS/SHP615 administration)
Healthcare setting study staff will administer investigational product MHOS/SHP615 (age-based 
dose of 2.5, 5, 7.5, or 10 mg) buccally.
The following procedures will be performed:

Evaluate seizure symptoms

Riker Sedation Agitation Scale

Provide supportive care per healthcare setting guidelines

Review concomitant medications/treatments

Monitor AEs


Shire
CONFIDENTIAL
Page 36
SHP615-301 Protocol 
Midazolam
20 Mar 2017
7.1.3
Treatment Period (0 minutes to 6 hours postdose) 

Perform physical examination when possible during the 6 hour time period
7.1.4
Treatment Period (10 minutes to 24 hours postdose) 
The following procedures will be performed throughout the Treatment Period at time points 
specified in the Schedule of Assessments (Table 1):

Evaluate seizure symptoms and Riker Sedation Agitation Scale at 10 and 30 (±5) minutes, 
and 1 (±10 min), 4 (±30 min), 6 (±30 min), and 24 (±30 min) hours postdose

4 hours and 24 hours (±30 min) postdose (if subject has not been discharged from the 
healthcare setting): Obtain blood and urine samples for safety laboratory tests for 
hematology, serum biochemistry, and urinalysis

1 (±10 min), 3 (±30 min), and 6 hours (±30 min) postdose:

Collect blood samples for PK analysis.

10 and 30 (±5) minutes, and 4, 6, and 24 hours (±30 min) postdose (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). 

Measure oxygen saturation.

Perform standard 12-lead ECG.

Administer supportive care throughout this time period.

Review concomitant medications/treatments.

Monitor AEs (minimum 6-hour observation period after dosage for safety monitoring and 
blood sampling).

Assess buccal cavity where MHOS/SHP615 was administered between cheek and gum line 
for redness, inflammation, and ulceration (at 1, 4, and 6 hours postdose)
Note:  Evaluate by telephone if subject is discharged between 6 hours (±30 min) and 24 hours 
(±1 hour) after SHP615 administration.

Telephone contact: The subject’s parent or caregiver should be contacted by telephone by 
qualified medical personnel 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 Visit
The follow-up period for this protocol is 1 week after the Treatment Period.


Shire
CONFIDENTIAL
Page 37
SHP615-301 Protocol 
Midazolam
20 Mar 2017
At the end of this period there will be a follow up visit to evaluate seizure symptoms, review 
concomitant medications, conduct a physical examination, and query for serious adverse events 
(SAEs), AEs. All AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure (see Section 8).
7.1.6
Additional Care of Subjects after the Study
No aftercare is planned for this study. It is the responsibility of the investigator to counsel 
subjects on their treatment alternatives when they exit the 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 informed consent form (ICF) must be executed prior to performing any study-related 
activities and the ICF must be approved by the reviewing IRB. The subject or the subject’s 
parents, guardians, or legally authorized representatives may withdraw consent at any time. The 
subject may be prescreened by the investigator in their clinical practice and parents or legal 
guardians may sign informed consent before the subject presents to the healthcare setting for 
treatment of the seizure. Participation in the study may be terminated at any time without the 
consent of subjects or subject’s parents, guardians, or legally authorized representatives as 
determined by the investigator.
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 parents or caregivers and will be recorded on the source 
document and CRF.
Medical history (including SE) will capture the subject’s current medical status (current SE or 
CSE disease process), past medical status (past disease processes), history of surgery, allergies, 
and concomitant medications/treatments.
7.2.3
Efficacy
Evaluation of seizure activity will be conducted throughout the study to assess the therapeutic 
success.


Shire
CONFIDENTIAL
Page 38
SHP615-301 Protocol 
Midazolam
20 Mar 2017

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.
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.
7.2.4.1
Medical and Medication History
The investigator will perform a complete medical history at Screening, including a medication 
history, and record all information gathered. The investigator must record all clinically or 
medically relevant information regardless of how much time has elapsed since the date of 
diagnosis.
With the consent of parents, guardians, or legally authorized representatives of participating 
subjects, medical records from other treatment providers should be requested. 
Refer to Section 5.1 for full details on collection of prior treatment. Prior treatment information, 
including any prior treatments for SE (eg, dietary, medication, or other), must be recorded on the 
appropriate CRF page.
7.2.4.2
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, sub investigator, or a 
qualified health professional 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)

Musculoskeletal


Shire
CONFIDENTIAL
Page 39
SHP615-301 Protocol 
Midazolam
20 Mar 2017

Neurological
Abnormalities identified at Screening will be documented in the subject’s source documents and 
on the medical history CRF. Changes after the Screening visit will be captured as AEs on the AE 
CRF page, as deemed by the investigator.
7.2.4.3
Adverse Event Collection
At each study time point, subjects (or their parents or caregivers) will be questioned 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 when the subject with SE arrives at the hospital or 
healthcare setting, or if the informed consent has been previously signed, from the time the 
subject begins evaluation and treatment in the hospital or healthcare setting for SE, to completion 
of the follow-up visit. (Please refer to Section 8, Adverse and Serious Adverse Events 
Assessment.)
7.2.4.4
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.
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 the initial vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Clinical Laboratory Evaluations
Clinical laboratory assessments will be performed at Screening, at 4 hours postdose, and at 24 
hours postdose if the subject is still at the healthcare setting. The following clinical laboratory 
assessments will be performed:


Shire
CONFIDENTIAL
Page 40
SHP615-301 Protocol 
Midazolam
20 Mar 2017
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
RBC morphology (if 
needed)
INR
BUN and Creatininea
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 pregnancy testd
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 at screening for women of childbearing potential; may be repeated at the follow-up visit or withdrawal from study 
if pregnancy is suspected.
Aliquots from the PK samples may be retained as back-up for additional parameter testing if 
necessary. Subjects will be in a seated or supine position during blood collection. The total blood 
draw for each subject will be approximately 30.75 mL.
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by Quintile’s central 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. 


Shire
CONFIDENTIAL
Page 41
SHP615-301 Protocol 
Midazolam
20 Mar 2017
Blood, serum, and urine samples 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.
7.2.4.6
Pregnancy Test
A urine pregnancy test is performed on all females of childbearing potential at Screening and at 
the follow up visit, if pregnancy is suspected, or upon withdrawal of the subject from the study.
7.2.4.7
Electrocardiogram 
A standard twelve (12)-lead electrocardiogram (ECG, single recording) will be performed at 
time points specified in the Schedule of Assessments (Table 1).
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.
The investigator or a qualified individual (eg, subinvestigator) at the investigator site will make 
comparisons to baseline measurements taken at screening, if available. A copy of the ECG 
should be available as source documents for review.  
7.2.5
Others 
7.2.5.1
Pharmacokinetic Assessments
Blood samples (~1.25 mL) to provide a minimum of 0.5 mL plasma for the assessment of plasma 
midazolam and 1-hydroxymidazolam concentrations will be collected (from all subjects who 
received investigational product) and analyzed at the specified time points for the duration of the 
study at the time points specified in the Schedule of Assessments (Table 1). The exact time of the 
sample collection should be noted on the source document and data collection tool (eg, CRF).
Samples will be analyzed for midazolam and 1-hydroxymidazolam using a validated assay. The 
methodologies will be appropriately validated in compliance with the CRO’s standard operating 
procedures. 
The address for shipment of serum samples and contact information for the laboratory analysis of 
midazolam and 1-hydroxymidazolam will be provided to the investigator site prior to initiation 
of the trial.


Shire
CONFIDENTIAL
Page 42
SHP615-301 Protocol 
Midazolam
20 Mar 2017
7.2.6
Volume of Blood to Be Drawn from Each Subject
Table 3
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
1.25
3
3.75
Safety
Biochemistry 
5
3
15
Hematology
4
3
12
Total mL
30.75
a
If a catheter is used, the first mL is to be discarded; then take 1.25 mL into appropriate tube for PK sample. A total 
of 1.25 mL of blood drawn has been used in determination of sample volume.
During this study, it is expected that up to approximately 30.75 mL of blood will be drawn from 
each subject.
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 30.75 mL. Additional considerations may be made for small children 
and infants with sponsor review. 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.
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 when the subject with SE
arrives at the hospital or healthcare setting or if the informed consent has been previously signed, 
from the time the subject begins evaluation and treatment in the hospital or healthcare setting for 
SE, until the defined follow-up period stated in Section 7.1.5. 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.


Shire
CONFIDENTIAL
Page 43
SHP615-301 Protocol 
Midazolam
20 Mar 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 change in severity. An event that changes in severity should be captured as a new event. 
Worsening of pre-treatment 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 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/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:


Shire
CONFIDENTIAL
Page 44
SHP615-301 Protocol 
Midazolam
20 Mar 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.


Shire
CONFIDENTIAL
Page 45
SHP615-301 Protocol 
Midazolam
20 Mar 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 -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 
non-medical 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)


Shire
CONFIDENTIAL
Page 46
SHP615-301 Protocol 
Midazolam
20 Mar 2017

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of the product. 

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.
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 the Quintiles 
Transnational Japan K.K., the 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
An 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 


Shire
CONFIDENTIAL
Page 47
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 hospital 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: 

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;


Shire
CONFIDENTIAL
Page 48
SHP615-301 Protocol 
Midazolam
20 Mar 2017

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 informed consent is 
signed when the subject with SE arrives at the hospital or healthcare setting, or if the informed 
consent has been previously signed, from the time the subject begins evaluation and treatment in 
the hospital or healthcare setting for SE, until the defined follow-up period stated in Section 7.1.5
and must be reported to Quintiles Transnational Japan K.K., 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 ICF, 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. 


Shire
CONFIDENTIAL
Page 49
SHP615-301 Protocol 
Midazolam
20 Mar 2017
8.2.7
Regulatory Agency, Institutional Review Board, and Site Reporting
The sponsor and Quintiles Transnational Japan K.K. are responsible for notifying the relevant 
regulatory authorities/and institutional IRBs 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 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 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.
Please use the information below as applicable to report the Product Quality Complaint (PQC):
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World (ROW)
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)


Shire
CONFIDENTIAL
Page 50
SHP615-301 Protocol 
Midazolam
20 Mar 2017
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
All data collected are to be recorded on the appropriate case report form (CRF).
The 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 the investigator or 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 healthcare setting 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 agent. 
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.


Shire
CONFIDENTIAL
Page 51
SHP615-301 Protocol 
Midazolam
20 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 study that is designed to evaluate the efficacy and safety of 
MHOS/SHP615 in 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. Where applicable, estimates from statistical model of least 
squares means, standard errors, and 95% CIs for least squares means will be provided. 
Time-to-event data will be summarized using Kaplan-Meier estimates of the 25th, 50th (median), 
and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored 
observations. Plots of the Kaplan-Meier curves and supporting data listings detailing each 
subject’s contribution to the analysis will be provided. 
9.5
Planned Interim Analysis
There is no planned interim analysis for this study.
9.6
Sample Size Calculation and Power Considerations
The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is 
estimated based on the expected response rate which is assumed to be 58.5% compared with the 
threshold of 30% with at least 80% of statistical power at the 2-sided 5% level.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Set will consist of all subjects who have received a single dose of MHOS/SHP615.
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. 
The Pharmacokinetic Set will consist of all subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 


Shire
CONFIDENTIAL
Page 52
SHP615-301 Protocol 
Midazolam
20 Mar 2017
9.8
Efficacy Analyses
The primary efficacy analysis will be conducted on the FAS.
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 primary efficacy analysis will be conducted on FAS by constructing the 2-sided, 95% CI for 
the percentage of subjects reaching therapeutic success. The lower limit of the 95% CI will be 
compared with the threshold of 30%, which is equivalent to comparing the percentage of success 
to the threshold at the 2-sided 5% level of significance.
9.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints will include:

Percentage of subjects whose seizure event(s) stopped within 10 minutes of single dose 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 of single dose 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 of single dose 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

Percentage of subjects who require additional anticonvulsant medication for ongoing SE 
according to the participating healthcare setting protocol or guideline, 10 minutes after a 
single dose 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 according to the participating healthcare setting
protocol or guideline, 10 minutes after a single dose of MHOS/SHP615.
9.8.3
Subgroup Analyses of Efficacy Endpoints
Selected efficacy endpoints will be evaluated using descriptive statistics by the following 
subgroups, to the extent the data allow:


Shire
CONFIDENTIAL
Page 53
SHP615-301 Protocol 
Midazolam
20 Mar 2017

Age group: 

3 months (52 weeks corrected gestational age) to <1year (and weight >5 kg)

1 to <5 years

5 to <10 years

10 to <18 years

Gender: male and female

Epilepsy etiology (based on the underlying etiology of their epilepsy):

Genetic

Idiopathic

Metabolic 

Symptomatic (Structural)
9.8.4
Exploratory Efficacy Endpoints
A description of the analyses will be included in the SAP.
9.9
Safety Analyses
Safety data will be summarized using descriptive statistics for the Safety Set.
9.9.1
Primary Safety Endpoints
The primary safety endpoints will be respiratory depression, which will include the following 
measures within the 4 hours after MHOS/SHP615 administration:

Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 4, 
6, and 24 hours postdose (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)
9.9.2
Secondary Safety Endpoints
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 ECG

Occurrence of buccal irritation
Adverse events and medical history will be coded using MedDRA. The number of events, 
incidence, and percentage of TEAEs will be calculated overall, by system organ class, by 
preferred term, and by age. Treatment-emergent adverse events will be further summarized by 


Shire
CONFIDENTIAL
Page 54
SHP615-301 Protocol 
Midazolam
20 Mar 2017
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Vital signs (systolic and diastolic blood pressure, pulse, and weight) including potentially 
clinically important vital signs will be summarized using the appropriate descriptive statistics.
The ECG results, including potentially clinically important results, will be summarized.   
9.9.3
Clinical Laboratory Tests 
Clinical laboratory tests will be summarized using the Safety Set. 
Actual values and change from baseline clinical laboratory tests will be summarized. If more 
than 1 laboratory result is reported per study time point per parameter, the last non-missing 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 non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, non-clinically significant result less than the lower limit of normal, within the 
normal range, non-clinically 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 for a subject across study time point to identify any trends.
9.9.4
Vital Signs
Vital signs will be summarized using the Safety Set.
Actual values and changes from baseline in vital signs will be summarized. 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 non-missing result, and the number and percentage 
of subjects with a non-clinically 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. 


Shire
CONFIDENTIAL
Page 55
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 not performed, will be summarized. 
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.
9.10
Pharmacokinetic Analyses
Plasma concentrations of midazolam, its active metabolite (1-hydroxymidazolam), and any 
potential additional metabolite(s) will be evaluated using the Pharmacokinetic population.  
The Pharmacokinetic population will include subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. PK samples 
will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615.
PK parameters (eg, Cmax, Tmax, AUC and t1/2) will be calculated using population PK modeling.
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.


Shire
CONFIDENTIAL
Page 56
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 non-pediatric 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), 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.


Shire
CONFIDENTIAL
Page 57
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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.
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) 


Shire
CONFIDENTIAL
Page 58
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 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).


Shire
CONFIDENTIAL
Page 59
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 (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 (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.


Shire
CONFIDENTIAL
Page 60
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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 (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 


Shire
CONFIDENTIAL
Page 61
SHP615-301 Protocol 
Midazolam
20 Mar 2017
publication steering committee is to act as a non-commercial 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.
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.


Shire
CONFIDENTIAL
Page 62
SHP615-301 Protocol 
Midazolam
20 Mar 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. & 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.
Baysun, S., Aydin, O. F., Atmaca, E. & Gurer, Y. K. 2005. A comparison of buccal midazolam 
and rectal diazepam for the acute treatment of seizures. Clin Pediatr (Phila), 44, 771-6.
Berg, A. T., Shinnar, S., Levy, S. R. & Testa, F. M. 1999. Status epilepticus in children with 
newly diagnosed epilepsy. Ann Neurol, 45, 618-23.
Brophy, G. M., Bell, R., Claassen, J., Alldredge, B., Bleck, T. P., Glauser, T., Laroche, S. M., 
Riviello, J. J. J., Shutter, L., Sperling, M. R., Treiman, D. M., Vespa, P. M. & Committee, 
N. C. S. S. E. G. W. 2012. Guidelines for the evaluation and management of status 
epilepticus. Neurocrit Care, 17, 3-23.
Dham, B. S., 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, 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/.
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.
Lowenstein, D. H., Bleck, T. & MacDonald, R. L. 1999. It's time to revise the definition of status 
epilepticus. Epilepsia, 40, 120-2.
McIntyre, J., Robertson, S., Norris, E., Appleton, R., Whitehouse, W. P., 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, P. J. & 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.
Muchohi, S. N., Kokwaro, G. O., Ogutu, B. R., Edwards, G., Ward, S. A. & Newton, C. R. 2008. 
Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and 
convulsions. Br J Clin Pharmacol, 66, 529-38.
NICE Guidance National Institute for Health and Care Excellence. 2011. Available: 
https://www.nice.org.uk/guidance/cg137/chapter/Appendix-F [Accessed 24 Jan 2017.


Shire
CONFIDENTIAL
Page 63
SHP615-301 Protocol 
Midazolam
20 Mar 2017
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. & 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.
Schwagmeier, R., Alincic, S. & Striebel, H. W. 1998. Midazolam pharmacokinetics following 
intravenous and buccal administration. Br J Clin Pharmacol, 46, 203-6.
Scott, R. C., Besag, F. M., Boyd, S. G., Berry, D. & Neville, B. G. 1998. Buccal absorption of 
midazolam: pharmacokinetics and EEG pharmacodynamics. Epilpesia, 39, 290-4.
Scott, R. C., Besag, F. M. & Neville, B. G. 1999. Buccal midazolam and rectal diazepam for 
treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet,
20, 623-6.
Shinnar, S., Berg, A. T., Moshe, S. L., O'Dell, C., Alemany, M., Newstein, D., Kang, H., 
Goldensohn, E. S. & 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.
Sirven, J. I. & 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, W. H., Porter, R. J. & 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. & 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. & Brigo, F. 2015. Pharmacotherapy for status epilepticus. 
Drugs, 75, 1499-521.
Wilson, M. T., Macleod, S. & O'Regan, M. E. 2004. Nasal/buccal midazolam use in the 
community. Arch Dis Child, 89, 50-1.
Working Group on Status Epilepticus 1993. Treatment of convulsive status epilepticus. 
Recommendations of the Epilepsy Foundation of America's Working Group on Status 
Epilepticus. Jama, 270, 854-9.




Shire
CONFIDENTIAL
Page 65
SHP615-301 Protocol 
Midazolam
20 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
2016
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. 


Shire
CONFIDENTIAL
Page 66
SHP615-301 Protocol 
Midazolam
20 Mar 2017
http://www.icudelirium.org/sedation.html (Accessed 21 July 2016).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Shire
CONFIDENTIAL
Page 67
SHP615-301 Protocol 
Midazolam
20 Mar 2017
APPENDIX 3 BIOANALYSIS: SAMPLE HANDLING
1.1
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1 to measure plasma 
concentrations of midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s). 
Blood samples (~1.25 mL) for pharmacokinetic analysis will be drawn by in-dwelling catheters 
or direct venipuncture into K2EDTA tubes, capped, and chilled immediately on crushed ice. The 
actual time that the sample was obtained will be recorded in the subject’s source document and 
on the appropriate CRF page. After applying a tourniquet, venous blood will be drawn with a 
disposable needle. If a catheter is used, the first milliliter of blood on each sampling occasion 
will be discarded. Saline can be used to keep catheters patent.
1.2
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after
collection (within <15 minutes) by refrigerated centrifugation (4C, 1500 g, 15 minutes). The 
separated plasma will be transferred into appropriately labeled polypropylene tubes via a plastic 
pipette. Plasma to be split in two aliquots: first tube minimum 0.25 mL (primary sample), second 
tube remaining plasma volume (back-up sample).  Aliquots should be shipped separately to the 
bioanalytical laboratory. All samples will be stored at approximately -70C or colder and the 
freezer temperature will be controlled, monitored, and recorded during the storage period until 
they are transferred in the frozen state to a designated bioanalytical contract laboratory. Samples 
will remain frozen at -70C or colder until analysis.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the clinical pharmacology unit. The labels will contain the following information:

Study number

Treatment 

Subject identifier 

Matrix identifier (plasma)

Nominal time
1.3
Shipment of Plasma Samples
Plasma samples should be double bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday to Wednesday only. Samples 
should be transported to ensure that they arrive at the bioanalytical laboratory between the hours 


Shire
CONFIDENTIAL
Page 68
SHP615-301 Protocol 
Midazolam
20 Mar 2017
of 0900 and 1600. The recipient and primary Shire contact must be notified by phone, fax, and e-
mail when the samples are shipped and must be provided with the shipment tracking number. 
Plasma samples, along with the corresponding documentation, will be shipped to:
Name of bioanalytical laboratory: York Bioanalytical Solutions (YBS)
Primary contact: 
Telephone DDI: 
E-mail:
Plasma samples will be stored nominally at -70C prior to and after analysis at York 
Bioanalytical Solutions Limited until their disposal is authorized by Shire.
1.4
Assay Methodology
Drug analysis will be performed at YBS under the guidance of the Department of Nonclinical 
Development, Shire Pharmaceuticals. Plasma sample analysis will be performed according to the 
bioanalytical study plans prepared for the study. 
Plasma samples (K2EDTA) will be analyzed at York Bioanalytical Solutions Limited for 
midazolam, 1-hydroxymidazolam, and any potential additional metabolite(s) using the most 
current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at York Bioanalytical Solutions Limited.

SAP_000.pdf: 


Shire 
CONFIDENTIAL 
Page 2 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................5 
ABBREVIATIONS .........................................................................................................................6 
1. 
INTRODUCTION ....................................................................................................................8 
2. 
STUDY DESIGN .....................................................................................................................9 
2.1 
General Study Design .................................................................................................9 
2.2 
Randomization ...........................................................................................................9 
2.3 
Blinding ......................................................................................................................9 
2.4 
Schedule of Assessments ...........................................................................................9 
2.5 
Determination of Sample Size ..................................................................................12 
2.6 
Multiplicity Adjustments for Type I Error Control ..................................................12 
3. 
OBJECTIVES .........................................................................................................................13 
3.1 
Primary Objective ....................................................................................................13 
3.2 
Secondary Objectives ...............................................................................................13 
4. 
SUBJECT POPULATION SETS ...........................................................................................14 
4.1 
Screened Set .............................................................................................................14 
4.2 
Safety Set ..................................................................................................................14 
4.3 
Full Analysis Set ......................................................................................................14 
4.4 
Per Protocol Set ........................................................................................................14 
4.5 
Pharmacokinetic Set .................................................................................................14 
5. 
SUBJECT DISPOSITION ......................................................................................................15 
6. 
PROTOCOL DEVIATIONS ..................................................................................................16 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................17 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .......................................19 
9. 
PRIOR AND CONCOMITANT MEDICATION ..................................................................20 
10. EFFICACY ANALYSES .......................................................................................................21 
10.1 
Primary Efficacy Endpoint and Analysis .................................................................21 
10.2 
Secondary Efficacy Endpoints and Analysis ...........................................................22 
10.2.1 
Percentage of Subjects Whose Seizure Event(s) Stopped Within 10 
Minutes of Single Dose of MHOS/SHP615 and who Have Sustained 
Absence of Seizure Activity for At Least 1 Hour/4 Hours/6 Hours .................22 
10.2.2 
Time to Resolution of Seizures (Convulsions) .................................................23 
10.2.3 
Time to Recovery of Consciousness .................................................................23 


Shire 
CONFIDENTIAL 
Page 3 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.4 
Percentage of Subjects Who Require Additional Anticonvulsant 
Medication for Ongoing SE 10 Minutes After a Single Dose of 
MHOS/SHP615 .................................................................................................24 
10.2.5 
Percentage of Subjects Who Fail to Respond to Treatment ..............................24 
10.3 
Exploratory Efficacy Endpoint(s) and Analyses ......................................................24 
10.4 
Sensitivity Analyses .................................................................................................24 
11. SAFETY ANALYSES ...........................................................................................................25 
11.1 
Primary Safety Endpoint and Analysis ....................................................................25 
11.2 
Secondary Safety Endpoint and Analysis ................................................................25 
11.2.1 
Adverse Events..................................................................................................26 
11.2.2 
Clinical Laboratory Variables ...........................................................................27 
11.2.3 
Vital Signs .........................................................................................................28 
11.2.4 
Electrocardiogram (ECG) .................................................................................29 
11.2.5 
Riker Sedation-Agitation Scale (SAS) ..............................................................29 
11.2.6 
Oxygen Saturation .............................................................................................29 
11.2.7 
Buccal Irritation ................................................................................................30 
11.3 
Other Safety Variables .............................................................................................30 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ............31 
13. OTHER ANALYSES .............................................................................................................32 
14. INTERIM ANALYSIS ...........................................................................................................33 
15. DATA MONITORING/REVIEW COMMITTEE .................................................................34 
16. COMPUTER METHODS ......................................................................................................35 
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .................................................36 
18. DATA HANDLING CONVENTIONS ..................................................................................37 
18.1 
General Data Reporting Conventions ......................................................................37 
18.1.1 
Descriptive Statistics Presentation ....................................................................37 
18.1.2 
Decimal Places and Rounding Rules ................................................................37 
18.1.3 
Format of Tables/Listings .................................................................................38 
18.2 
Derived Efficacy Endpoints .....................................................................................38 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters .................................38 
18.4 
Missing Date of Investigational Product ..................................................................38 
18.5 
Missing Date Information for Prior or Concomitant Medications ...........................39 
18.5.1 
Incomplete Start Date/Time ..............................................................................39 
18.5.2 
Incomplete Stop Date ........................................................................................40 
18.6 
Missing Date Information for Adverse Events ........................................................40 
18.6.1 
Incomplete Start Date ........................................................................................40 


Shire 
CONFIDENTIAL 
Page 4 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18.6.2 
Incomplete Stop Date ........................................................................................40 
18.7 
Missing Severity Assessment for Adverse Events ...................................................40 
18.8 
Missing Relationship to Investigation Product for Adverse Events ........................40 
18.9 
Character Values of Clinical Laboratory Variables .................................................41 
19. REFERENCES .......................................................................................................................42 
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS ..............................43 
21. APPENDIX: SAMPLE SAS CODES ....................................................................................44 
21.1 
Sample SAS Code for the Primary Endpoint Analysis ............................................44 
21.2 
Sample SAS Code for Time to Event Analysis with Competing Events .................44 


Shire 
CONFIDENTIAL 
Page 5 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments .....................................................................................10 
Table 2 
Coding of Special Character Values for Clinical Laboratory Variables .............41 


Shire 
CONFIDENTIAL 
Page 6 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CIF 
cumulative incidence function 
CTMS 
clinical trial management system 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
KM 
Kaplan-Meier 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHOS/SHP615 midazolam hydrochloride oromucosal solution 
PD 
pharmacodynamic 
pH 
potential of hydrogen 
PK 
pharmacokinetic 
PopPK 
population pharmacokinetic 
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 
SD 
standard deviation 
SE 
status epilepticus 
SEM 
standard error of the mean 


Shire 
CONFIDENTIAL 
Page 7 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SI 
international system of units 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 


Shire 
CONFIDENTIAL 
Page 8 
Statistical Analysis Plan 
SHP615-301 
 
11 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. Specifications for tables, figures, and listings are included in a separate 
document. 
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. 


Shire 
CONFIDENTIAL 
Page 9 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
SHP615-301 is a Phase 3, multicenter, interventional, nonrandomized, open-label study of 
buccally administered MHOS/SHP615 to pediatric subjects who present with status epilepticus 
(SE) in the healthcare setting. 
Approximately 25 subjects will be enrolled in this study. Children whose corrected gestational 
age is ≥52 weeks (gestational weeks plus the number of weeks after birth) and <18 years (and 
weight >5 kg) who arrive at the healthcare setting in full seizure, have not received immediate 
treatment, and have parent, guardian, or legally authorized representative informed 
consent/assent (when applicable, per Shire policy and country regulations), are eligible to 
participate 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. Upon entry in the SHP615-301 study, subjects will receive a single open-label 
MHOS/SHP615 treatment, dosing stratified by age (2.5, 5, 7.5, or 10 mg buccally). 
The efficacy of MHOS/SHP615 in stopping convulsive seizures will be assessed by measuring 
the percentage of subjects whose initial seizure stops 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 a single dose of MHOS/SHP615, the 
subject will be treated according to the participating healthcare setting protocol or guideline. The 
safety and pharmacokinetics of MHOS/SHP615 will also be assessed. 
Subjects will be monitored by assessment of treatment-emergent adverse events (TEAEs), vital 
signs, laboratory tests, oxygen saturation, physical examination, and electrocardiogram (ECGs) 
for safety evaluations. All subjects treated in this study will be followed for 1 week after dosing 
for safety evaluations. 
2.2 
Randomization 
Not applicable. 
2.3 
Blinding 
Not applicable. 
2.4 
Schedule of Assessments  
Table 1 below presents the schedule of activities in the study. 


Shire 
CONFIDENTIAL 
Page 10 
Statistical Analysis Plan 
SHP615-301 
 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 
Schedule of Assessments 
Assessment 
Treatment Period - Time from SHP615 Administration 
Follow-up 
Screening/Baseline 
0 min 
10 min 
30  
(± 5min) 
1 h 
(± 10min) 
3h 
(± 30min) 
4 h 
(± 30min) 
6 ha 
(± 30min) 
24hb 
(± 30min) 
1 week  
(± 1 day) 
Informed consent/assent  
Xc 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/procedural 
history 
X 
 
 
 
 
 
 
 
 
 
Confirmation of status 
epilepticus 
X 
 
 
 
 
 
 
 
 
 
Evaluation of seizure 
symptomsd 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Riker Sedation-Agitation 
Scale 
X 
X 
 
X 
X 
 
X 
X 
X 
 
Laboratory evaluationse 
Xf 
 
 
 
 
 
X 
 
X 
 
SHP615 administration 
 
X 
 
 
 
 
 
 
 
 
PK collectiong 
 
 
 
 
X 
X 
 
X 
 
 
Buccal cavity assessmenth 
 
 
 
 
X 
 
X 
X 
 
 
Vital signsi 
X 
 
X 
X 
 
 
X 
X 
X 
 
Oxygen saturationj 
X 
 
X 
X 
 
 
X 
X 
X 
 
12-Lead ECG 
Xk 
 
 
X 
X 
 
X 
X 
X 
 
Supportive care 
 
X 
X 
 
Physical examinationl 
 
X 
 
X 
Concomitant medications 
X 
X 
Xa 
X 
X 


Shire 
CONFIDENTIAL 
Page 11 
Statistical Analysis Plan 
SHP615-301 
 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 
Schedule of Assessments 
Assessment 
Treatment Period - Time from SHP615 Administration 
Follow-up 
Screening/Baseline 
0 min 
10 min 
30  
(± 5min) 
1 h 
(± 10min) 
3h 
(± 30min) 
4 h 
(± 30min) 
6 ha 
(± 30min) 
24hb 
(± 30min) 
1 week  
(± 1 day) 
Adverse event monitoring 
 
X 
Xa 
X 
X 
ECG=electrocardiogram; h=hour; MHOS=midazolam hydrochloride oromucosal solution; min=minute; PK=pharmacokinetic. 
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 postdose time point will be made if the subject has not been discharged from the healthcare setting; 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 If more than 3 months have elapsed between initial informed consent and seizure, parent, guardian, or legally authorized representative should re-sign the latest at the time of 
admission prior to treatment. 
d Seizure symptoms will be assessed based on physician’s clinical judgment and healthcare setting protocol. 
e Laboratory evaluations include serum biochemistry and urinalysis (including a urine pregnancy test in women of childbearing potential at screening/baseline). 
f Blood glucose can be measured by local lab or testing kit. 
g The PK samples will be collected at 1, 3, and 6 hours after administration of MHOS/SHP615. 
h 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.  
i Vital signs will include single supine blood pressure, pulse rate, respiratory rate, and body temperature. 
j 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. The investigator will record the oxygen saturation as well as the oxygen delivery system and amount of 
oxygen administered. 
k If subject is stable enough for ECG. 
l Physical examination will be performed at some point between 0 min (dosing) and 6 hours postdose, when possible. 


Shire 
CONFIDENTIAL 
Page 12 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.5 
Determination of Sample Size 
The target sample size (approximately 25 subjects; minimum 3 subjects per age group) is 
estimated based on the expected response rate which is assumed to be 58.5% compared with the 
threshold of 30% with at least 80% of statistical power at the 2-sided 5% level. 
2.6 
Multiplicity Adjustments for Type I Error Control 
Not applicable. 


Shire 
CONFIDENTIAL 
Page 13 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to assess the efficacy of MHOS/SHP615 administered 
buccally in pediatric patients with SE (convulsive) in a healthcare setting. 
3.2 
Secondary Objectives 
The secondary objectives of this study are to assess the safety and pharmacokinetics of 
MHOS/SHP615 administered buccally to pediatric patients with SE (convulsive) in a healthcare 
setting. 


Shire 
CONFIDENTIAL 
Page 14 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
SUBJECT POPULATION SETS 
4.1 
Screened Set  
The Screened Set will consist of all subjects who have signed an informed consent/assent. 
4.2 
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. 
4.3 
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. 
4.4 
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  
4.5 
Pharmacokinetic Set  
The Pharmacokinetic Set (PK Set) will consist of all subjects who receive a single dose of 
MHOS/SHP615 and for whom at least 1 post-dose PK blood sample was collected. 


Shire 
CONFIDENTIAL 
Page 15 
Statistical Analysis Plan 
SHP615-301 
 
11 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 number of subjects included in each subject population set (i.e., Screened, Safety, FAS, PPS 
and PK Set) will be summarized. In addition, the reason for exclusion from the PPS will be 
summarized. 
The number and percentage of subjects who completed or prematurely discontinued the study 
will be presented for the Safety Set. Reasons for premature discontinuation from the study as 
recorded on the disposition page of the eCRF will be summarized (number and percentage) for 
the Safety Set. All subjects who prematurely discontinued the study will be listed by 
discontinuation reason for the Safety Set. 


Shire 
CONFIDENTIAL 
Page 16 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 table of major protocol deviations and a listing of 
all protocol deviations by subject will be presented for the Safety Set. 


Shire 
CONFIDENTIAL 
Page 17 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive summaries of demographic and baseline characteristics will be presented for the 
Safety Set and FAS overall and by 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 summarized in the following order in the 
tables:  
• 
Age (years) – calculated as [(number of months between date of birth and investigational 
product administration)/12] 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) – calculated as 10000*weight (kg)/ height (cm)2 
History of epilepsy and confirmation of SE pre-dose will also be summarized 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. 


Shire 
CONFIDENTIAL 
Page 18 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In addition, the epilepsy diagnosis name will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 20.0 or higher. Epilepsy history will be presented by 
System Organ Class (SOC) and Preferred Term (PT). SOC will be sorted alphabetically and PT 
within SOC will be sorted by descending incidence. 
Similar summaries by SOC and PT will be presented for medical history other than epilepsy. 
All medical history will be listed for the Safety Set. 


Shire 
CONFIDENTIAL 
Page 19 
Statistical Analysis Plan 
SHP615-301 
 
11 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: 3 months (52 weeks corrected gestational age) 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 
Exposure to investigational product for the Safety Set will be summarized in terms of actual dose 
received. Actual dose is the planned dose when the drug administration was documented to be 
complete on the study drug administration eCRF form. Descriptive statistics (n, mean, standard 
deviation (SD), minimum, median, and maximum) for the actual dose received will be presented 
overall and by age group (age at the time of investigational product administration). The number 
and percentage of subjects who had a complete or incomplete study drug administration will also 
be presented. 
A listing will be created by subject number giving the date and time of study drug 
administration. 


Shire 
CONFIDENTIAL 
Page 20 
Statistical Analysis Plan 
SHP615-301 
 
11 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. 
Prior and concomitant medication usage will be summarized by the number and proportion of 
subjects receiving medication within each therapeutic class (level 3) and preferred name for the 
Safety Set. Multiple medication usage by a subject in the same category (i.e., therapeutic class or 
preferred name) will be counted only once. These summaries of prior and concomitant 
medication usage will be presented separately by indication as follows: 
• 
Anticonvulsant medication for ongoing SE (rescue treatment) 
• 
Anticonvulsant medication (prophylaxis treatment) 
• 
Any other indication 
Prior and concomitant therapies will be summarized similarly except that MedDRA SOC and PT 
will be used instead of therapeutic class and preferred name and there will be no summary by 
indication. 
All prior and concomitant medications (therapies) will be listed. 


Shire 
CONFIDENTIAL 
Page 21 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. EFFICACY ANALYSES 
All efficacy analyses will be based on the FAS. All confidence intervals will be 2-sided 95% 
confidence intervals (CI), unless stated otherwise. 
10.1 
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. 
The primary efficacy analysis will be conducted on the FAS by constructing the 2-sided, 95% 
Wald CI for the percentage of subjects reaching therapeutic success. The lower limit of the 95% 
CI will be compared with the threshold of 30%, which is equivalent to comparing the percentage 
of success to the threshold at the 2-sided 5% level of significance. The 2-sided p-value of the 
Wald test will also be provided. A sample SAS code for the primary efficacy analysis is provided 
in the Appendix. 
In addition, the primary efficacy endpoint, response rate, will be evaluated using descriptive 
statistics for the following subgroups: 
• 
Age group (age at the time of investigational product administration):  
• 
<1 year 
• 
1 to <5 years 
• 
5 to <10 years 
• 
10 to <18 years 
• 
Gender: male and female 
• 
Epilepsy etiology (based on the underlying etiology of their epilepsy): 
- 
Genetic 
- 
Idiopathic 


Shire 
CONFIDENTIAL 
Page 22 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
Metabolic  
- 
Symptomatic (Structural) 
The number and percentage of subjects achieving therapeutic success will be presented along 
with the corresponding exact 95% Clopper-Pearson CI for each subgroup category. The exact 
Clopper-Pearson CI will be used because the sample size could be small in some subgroups.  
10.2 
Secondary Efficacy Endpoints and Analysis  
The secondary efficacy endpoints will include: 
• 
Percentage of subjects whose seizure event(s) stopped within 10 minutes of single dose 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 of single dose 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 of single dose 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 a 
single dose 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 according to the participating healthcare 
setting protocol or guideline, 10 minutes after a single dose of MHOS/SHP615. 
Details of the statistical analyses used for the secondary efficacy endpoints are provided in the 
subsections below. 
In addition, the secondary efficacy endpoints will be evaluated for the following subgroups 
defined in Section 10.1: Age group, gender, epilepsy etiology. 
10.2.1 
Percentage of Subjects Whose Seizure Event(s) Stopped Within 10 Minutes of 
Single Dose 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 a 
single dose of MHOS/SHP615. 


Shire 
CONFIDENTIAL 
Page 23 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Two-sided, 95% Wald CI for the percentage of subjects reaching therapeutic success will be 
constructed on 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. Administration of rescue anticonvulsant medication for ongoing initial 
seizure will be treated as a competing event. 
Cumulative incidence function (CIF) of resolution of seizures will be estimated and a plot will be 
provided. In addition, CIF estimates and 95% CI will be provided at several time points post 
dose. 
 A supporting data listing detailing each subject’s contribution to the analysis will also be 
provided. 
A sample SAS code for this analysis is provided in the Appendix. 
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. Administration of rescue anticonvulsant medication prior to recovery of 
consciousness will be treated as a competing event. 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 or PK 
sample collection, ECG or time the subject was discharged from the hospital.  
CIF of recovery of consciousness will be estimated and a plot will be provided. In addition, CIF 
estimates and 95% CI will be provided at several time points post dose. 
A supporting data listing detailing each subject’s contribution to the analysis will also be 
provided. 
The sample SAS code provided in the Appendix for time to resolution of seizures (see Section 
10.2.2) can be used as reference for this analysis. 


Shire 
CONFIDENTIAL 
Page 24 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.4 
Percentage of Subjects Who Require Additional Anticonvulsant Medication for 
Ongoing SE 10 Minutes After a Single Dose of MHOS/SHP615 
Anticonvulsant medication for ongoing SE (rescue treatment) are captured on the “prior and 
concomitant medications” eCRF form. The percentage of 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 presented along with the 
corresponding 95% Wald CI. 
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 
a single dose of MHOS/SHP615. A Treatment failure/Non-responder is defined as a subject with 
continuing seizure activity 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. 
The percentage of subjects who fail to respond to treatment will be presented along with the 
corresponding 95% Wald CI. 
10.3 
Exploratory Efficacy Endpoint(s) and Analyses  
No exploratory efficacy endpoints are defined.  
10.4 
Sensitivity Analyses 
Analyses of the primary efficacy endpoint and secondary efficacy endpoints will be repeated for 
subjects in the Per Protocol Set. 
The analyses will be the same as specified in Sections 10.1 and 10.2 for the primary and 
secondary efficacy endpoints, respectively. The 2-sided nominal p-value of the Wald test will be 
presented for the analysis of therapeutic success based on the PPS and no multiplicity adjustment 
will be performed for this sensitivity analysis. If the PPS and the FAS are identical, these 
sensitivity analyses will not be performed. 


Shire 
CONFIDENTIAL 
Page 25 
Statistical Analysis Plan 
SHP615-301 
 
11 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 definition of baseline and the way unscheduled assessments will be 
handled in safety analyses. 
11.1 
Primary Safety Endpoint and Analysis 
The primary safety endpoint will be respiratory depression, which will include the following 
measures within the 4-24 hours after MHOS/SHP615 administration: 
• 
Persistent decrease in oxygen saturation to <92% measured at 10 minutes, 30 minutes, and 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. 
The number and percentage of subjects with respiratory depression will be presented along with 
the corresponding 95% Wald CI. 
11.2 
Secondary Safety Endpoint and Analysis 
The secondary safety endpoints include the following: 
• 
Aspiration pneumonia 
• 
Sedation or agitation as measured by the Riker SAS 


Shire 
CONFIDENTIAL 
Page 26 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Incidences/monitoring of TEAEs, vital sign measurements, laboratory tests, oxygen 
saturation, and ECG 
• 
Occurrence of buccal irritation 
Details of the statistical analyses of secondary safety endpoints are provided in the subsections 
below. 
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. 
An overall summary of TEAEs will be presented, including the number and percentage of 
subjects with any TEAEs, serious TEAEs (and serious categories), TEAEs related to 
investigational product, severe TEAEs and TEAEs leading to discontinuation from the study. 
The overall summary of TEAEs will be repeated for the following age groups (age at the time of 
investigational product administration): 
• 
<1 year 
• 
1 to <5 years 
• 
5 to <10 years 
• 
10 to <18 years 
The number/percentage of subjects reporting TEAEs and number of events will be tabulated by 
SOC and PT overall and by age group. A similar summary will be presented by PT only (sorted 
by descending frequency of PT). Serious TEAEs, TEAEs considered related to investigational 
product, TEAEs leading to discontinuation from the study and TEAEs leading to death will also 
be summarized by SOC and PT.  
A summary of the number and percentage of subjects with TEAEs by SOC, PT and highest 
severity will also be provided. If more than one TEAE occurs with the same SOC/PT for the 
same subject, then the subject will be counted only once for that SOC/PT using the highest 
severity category. 
A summary of the number and percentage of subjects with the following TEAEs of special 
interest will be provided by SOC and PT overall, by age group and by highest severity: 


Shire 
CONFIDENTIAL 
Page 27 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
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. 
The summaries of TEAEs described above (overall summary and TEAEs by SOC and PT) will 
be repeated by study period as follows: 
• 
TEAEs which started before hospital discharge 
• 
TEAEs which started after hospital discharge 
Listings will include both TEAEs and Non-TEAEs (unless specified otherwise) and will be 
provided for any AEs, serious AEs, AEs of special interest (aspiration pneumonia, respiratory 
depression, buccal irritation), AEs leading to death, and AEs leading to discontinuation from the 
study. Listings will indicate whether an AE is treatment emergent or not and whether it started 
before or after hospital discharge. 
11.2.2 
Clinical Laboratory Variables 
The following clinical laboratory variables are assessed in this study and will be presented in the 
tables and 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, amylase 
total 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 only except for 
blood glucose at baseline. For blood glucose, if central laboratory result is not available at 
baseline, the local laboratory value will be used instead. 
Descriptive statistics of clinical laboratory actual values (in SI units) and changes from baseline 
will be presented at each scheduled time point for quantitative variables overall and by age 
group. If more than one laboratory result is reported per study time point per parameter, the last 
non-missing 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 non-missing result, 


Shire 
CONFIDENTIAL 
Page 28 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal (LLN), non-clinically significant result less than the LLN, within the normal 
range, non-clinically 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 one 
laboratory result is reported per study time point per parameter, the result yielding the most 
severe classification will be selected for analysis. 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable (e.g., “<X”), a coded 
value will be used in the analysis instead as specified in Section 18.9. However, the actual values 
as reported in the database will be presented in data listings. 
For quantitative urinalysis results, the number and percentage of subjects in each category will 
be presented by scheduled time point overall and by age group. If more than one 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 for a subject across study time points to identify any trends. 
11.2.3 
Vital Signs 
Descriptive statistics for vital signs actual values and their changes from baseline will be 
presented at each scheduled time point overall and by age group for the following parameters: 
Systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), respiratory rate 
(breaths/min) and body temperature (C). 
If more than one vital sign result is reported per study time point per parameter, the last non-
missing result will be selected for analysis. 
In addition, spaghetti plots of individual subject’s actual values will be presented by scheduled 
time point for each vital sign parameter. 
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage 
of subjects with a non-clinically 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. 
All vital sign data will be presented in subject listings. 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.  


Shire 
CONFIDENTIAL 
Page 29 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.4 
Electrocardiogram (ECG) 
Descriptive statistics for ECG variables and their changes from baseline will be presented at each 
scheduled assessment time point overall and by age group 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. 
For the analysis of quantitative ECG parameters, if more than one ECG result is reported per 
study time point per parameter, the last non-missing result will be selected for analysis. 
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, as assessed by the investigator, or ECG not 
performed, will be summarized at each scheduled assessment time point. For the analysis of 
qualitative ECG parameters, if more than one ECG 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 ECG results will be listed. 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) 
Descriptive statistics for Riker SAS score actual value and change from baseline will be 
presented at each scheduled time point.  
The Riker SAS score actual value will also be treated as a qualitative variable and the number 
and percentage of subjects in each score category will be summarized by scheduled time point. 
If more than one Riker SAS score is reported per study time point per parameter, the last non-
missing result will be selected for analysis. 
11.2.6 
Oxygen Saturation 
Descriptive statistics for oxygen saturation (%) actual value and change from baseline will be 
presented at each scheduled time point for measurements performed on room air. 
In addition, the number and percentage of subjects with oxygen saturation <92% on room air for 
2 minutes or more will be presented by scheduled time point. 
If more than one oxygen saturation result is reported per study time point per parameter, the last 
non-missing result will be selected for analysis. 
A spaghetti plot of individual subject’s oxygen saturation actual values will be presented by 
scheduled time point for measurements performed on room air. 


Shire 
CONFIDENTIAL 
Page 30 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2.7 
Buccal Irritation 
The number and percentage of subjects with normal and abnormal buccal cavity assessment 
result or assessment not performed will be summarized at each scheduled assessment time point. 
In addition, the number and percentage of subjects with redness/inflammation, ulceration or 
other abnormality will be presented at each scheduled time point. 
If more than one buccal cavity assessment is reported per study time point per parameter, the last 
non-missing result will be selected for analysis. 
Details of the buccal cavity assessments for each subject, including the specification of other 
abnormality will be presented in the listings. 
11.3 
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. 


Shire 
CONFIDENTIAL 
Page 31 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
All PK analyses will be performed by Certara (the PK vendor). 
Plasma midazolam, its active metabolite (1-hydroxymidazolam), and potential additional 
metabolite(s) concentrations will be evaluated using the PK set defined in Section 4.5 from blood 
samples collected at 1, 3, and 6 hours (or time of discharge, if earlier than 6 hours) after 
administration of MHOS/SHP615. 
Concentration data will be summarized by dose (2.5, 5, 7.5, and 10 mg) and nominal sample 
time (1, 3, and 6 hours). Descriptive summary statistics including n, minimum, maximum, mean, 
median, SD, % coefficient of variation (CV), and standard error of the mean (SEM) will be 
presented. A listing for PK concentration data will be provided. Plots of the concentration-time 
data by dose will be provided. 
No noncompartmental or compartmental analyses are planned. 
Population pharmacokinetic (PopPK) analysis may also be considered and consideration will 
depend on assessment of data collected and likely incremental informative value to the program. 
Should additional PopPK analyses be considered further, a PopPK-specific analysis plan will be 
written then. 
No pharmacokinetic/pharmacodynamic (PK/PD) analyses are planned. 


Shire 
CONFIDENTIAL 
Page 32 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. OTHER ANALYSES 
No other analyses are planned for this study. 


Shire 
CONFIDENTIAL 
Page 33 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14. INTERIM ANALYSIS 
There is no formal interim analysis planned for this study. 


Shire 
CONFIDENTIAL 
Page 34 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring committee for this study. 


Shire 
CONFIDENTIAL 
Page 35 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. COMPUTER METHODS  
All statistical analyses will be performed using SAS Version 9.4 or higher (SAS Institute, 
Cary, NC, USA 27513). 


Shire 
CONFIDENTIAL 
Page 36 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
There is no major change compared to analyses specified in the protocol. 


Shire 
CONFIDENTIAL 
Page 37 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18. DATA HANDLING CONVENTIONS 
18.1 
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 
For continuous variables, the number of subjects (n), mean, median, SD, minimum, and 
maximum values will be presented. For the by-time-point summaries, the number of subjects at 
each timepoint (n) represents the number of subjects who had a non-missing result for a given 
parameter at that timepoint. 
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. Unless otherwise stated, 
the denominator for percentages is N (the number of subjects in the analysis set). Note that for 
any summary by subgroup (e.g. by age group), the denominator is the number of subjects in that 
subgroup within that analysis set. 
18.1.2 
Decimal Places and Rounding Rules 
• 
For measures of median and mean, use 1 decimal place beyond those used for the 
measurement. 
• 
For measures of SD and SEM, use 2 decimal places beyond those used for the measurement. 
• 
For measures of minimum and maximum values, use the same number of decimal places as 
those used for the measurement. 
• 
Percentages shall be reported to 1 decimal place, except when the percentage equals exactly 
100 where it shall be displayed as an integer (100). For zero, only count and no percentage 
will be displayed. This rule also applies to %CV. 
• 
BMI, age, duration of SE history and years since epilepsy diagnosis should be rounded to 1 
decimal place for reporting. 
• 
For p-values use 3 decimal places. Display p-values that would round to 0.000 as <0.001. 


Shire 
CONFIDENTIAL 
Page 38 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18.1.3 
Format of Tables/Listings 
The compound name and study number shall appear in the top left corner of the page in the 
format of SHP615-301. 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; frequency counts are aligned centrally 
within a cell and lined up by decimal point; statistical summaries for continuous variables are 
centrally aligned. Column headers shall follow the alignment of their data. 
For cases in which there are no observations contributing to a table, the table 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. For each cross reference, the listing 
number shall be preceded by the word “Listing”. 
Final tables shall be combined into one bookmarked PDF file. 
18.2 
Derived Efficacy Endpoints  
Derivations for efficacy endpoints are described in Section 10. 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters  
For each safety variable, the last value collected before the date/time of the investigational 
product administration (including unscheduled assessments if any) will be used as baseline for 
all analyses of that safety variable. 
In general, for by-time point summaries, data recorded at the nominal time point will be 
presented. Unscheduled measurements will not be included in by-time point summaries. Listings 
will include all scheduled and unscheduled assessments. 
Rules for handling safety parameters with more than one assessment reported per study time 
point are given in the corresponding safety parameter subsections of Section 11. 
18.4 
Missing Date of Investigational Product  
Not applicable in this single dose study. 


Shire 
CONFIDENTIAL 
Page 39 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18.5 
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 
• 
If either the year is after the year of the date of investigational product administration or if 


Shire 
CONFIDENTIAL 
Page 40 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
18.6 
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.  
18.7 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of investigational product 
administration, then a severity of “Severe” will be assigned. The imputed values for severity 
assessment will be used for incidence summaries, while the actual values will be used in data 
listings. 
18.8 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date of 
investigational product administration, a causality of “Related” will be assigned. The imputed 


Shire 
CONFIDENTIAL 
Page 41 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
values for relationship to investigational product will be used for incidence summaries, while the 
actual values will be presented in data listings. 
18.9 
Character Values of Clinical Laboratory Variables  
In general, 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 converted to X for 
quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
Exceptions to this rule are provided in Table 2. 
Table 2 
Coding of Special Character Values for Clinical Laboratory Variables 
 
Clinical Laboratory Test 
Possible Results (in SI units) 
Coded Value for Analysis 
Chemistry:  Total Bilirubin 
<2 
1 


Shire 
CONFIDENTIAL 
Page 42 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19. REFERENCES 
Not applicable. 


Shire 
CONFIDENTIAL 
Page 43 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS 
See separate file with Tables, figures and listings specifications. 


Shire 
CONFIDENTIAL 
Page 44 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21. APPENDIX: SAMPLE SAS CODES 
21.1 
Sample SAS Code for the Primary Endpoint Analysis  
The analysis of the primary endpoint, response rate, is described in Section 10.1. The following 
sample SAS code can be used to perform this analysis. 
Consider the subject level dataset SUCCESS which contains the variable RESP indicating 
response status for each patient. RESP=1 if response is achieved and RESP=2 if response is not 
achieved. PROC FREQ can be used as follows to obtain the response rate, Wald 95% CI and 2-
sided p-value needed for the primary endpoint analysis. 
ods output BinomialCLs=PropCI BinomialTest=Pval (where=(Name1="P2_BIN")); 
proc freq data=SUCCESS; 
   table RESP / binomial (CL=wald p=0.3 VAR=SAMPLE) alpha=.05; 
run; 
The response rate is contained in variable PROPORTION of dataset PROPCI. The associated 
lower limit and upper limit of the 95% CI are contained in variables LOWERCL and UPPERCL, 
respectively, of dataset PROPCI. Note that the response rate, lower limit and upper limit are 
given as rates and need to be converted to percentages in the analysis (if R is the rate, the 
associated percentage P is given as P=R*100). 
The 2-sided p-value is contained in variable NVALUE1 of dataset PVAL. 
Note that a similar SAS code can be used for secondary endpoint analyses described in Sections 
10.2.1, 10.2.4 and 10.2.5 except that the p-value will not be presented:  
ods output BinomialCLs=PropCI; 
proc freq data=SUCCESS; 
   table RESP / binomial (CL=wald) alpha=.05; 
run; 
For subgroup analyses of the primary/secondary endpoints, the exact Clopper-Pearson 
confidence interval will be used and the p-value will not be presented: 
ods output BinomialCLs=PropCI; 
proc freq data=SUCCESS; 
   by SUBGROUP; 
   table RESP / binomial (CL=exact) alpha=.05; 
run; 
The BY statement of PROC FREQ is used to obtain the results for each category of one 
subgroup. 
21.2 
Sample SAS Code for Time to Event Analysis with Competing Events 
The analysis of time to resolution of seizures (see Section 10.2.2) is based on time to event 
analysis with competing events. Resolution of seizures (convulsions) is the event of primary 
interest. Administration of rescue anticonvulsant medication for ongoing initial seizure is the 
competing event in these analyses. The following SAS code is proposed for analyses of time to 
resolution of seizures. 


Shire 
CONFIDENTIAL 
Page 45 
Statistical Analysis Plan 
SHP615-301 
 
11 Sep 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider the subject level dataset SEIZEND which contains the variables RESTIME and 
STATUS.  RESTIME is the time in minutes from investigational product administration to the 
end of the initial seizure or administration of rescue anticonvulsant medication, whichever occurs 
first. STATUS=1 if the initial seizure resolves without administration of rescue anticonvulsant 
medication beforehand and STATUS=2 if rescue anticonvulsant medication is administered prior 
to resolution of the initial seizure. PROC LIFETEST can be used as follows to obtain the CIF 
plot and CIF estimates at 2, 3, 5, 7, 10, 15, 20 and 30 minutes. 
ods graphics on; 
ods output FailureSummary=Summary CIF=CIFTIME; 
proc lifetest data=SEIZEND plots=CIF timelist=2 3 5 7 10 15 20 30; 
   time RESTIME*STATUS(0)/eventcode=1; 
run; 
Note that the SAS code above specifies that STATUS=0 is associated with censoring. However, 
as specified in Section 10.2.2, no subject will be censored in the analysis and this has no impact 
to the outcome of PROC LIFETEST (but is needed for the SAS code to run properly). 
Note also that the timelist=2 3 5 7 10 15 20 30 is given as an example only and the time points 
will be refined based on the actual data. 
Dataset SUMMARY contains the number of events of primary interest and number of competing 
events in variables EVENT and COMPETE, respectively. 
The CIF estimates at the prespecified time points are contained in variable CIF of dataset 
CIFTIME. The associated lower limit and upper limit of the 95% CIs are contained in variables 
CIF_LCL and CIF_UCL, respectively, of dataset CIFTIME. Note that CIF estimates, lower and 
upper limit of the 95% CIs are given as rates and need to be converted to percentages in the 
analysis (if R is the rate, the associated percentage P is given as P=R*100). 
The analyses of time to recovery of consciousness (see Section 10.2.3) will be conducted 
similarly. Note that in this analysis, censoring can occur and the variable STATUS=0 is used to 
indicate censored observations. The number of censored observations is given in variable 
CENSORED of dataset SUMMARY.