An Open-Label Safety Study of USL261 in the Outpatient Treatment of Subjects With Seizure Clusters
Phase: PHASE3
Conditions: Epilepsy
Sponsor: UCB Biopharma S.P.R.L.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
2 of 124
Upsher-Smith Laboratories, Inc.
SYNOPSIS
Sponsor: Upsher-Smith Laboratories, Inc. (USL)
Name of Development Product: USL261 (intranasal midazolam)
Study Title: An Open-Label Safety Study of USL261 in the Outpatient Treatment of Subjects with 
Seizure Clusters
Study Number: P261-402
Study Phase: III
Study Objective(s):  
To evaluate the long-term safety and tolerability of USL261 in the treatment of seizure clusters using the 
following assessments:
1.
Caregiver-recorded respiration rate at 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours and 
4 hours after study drug administration.
2.
Adverse events (AEs).
3.
Clinical laboratory tests.
4.
Physical, nasal and neurological examinations.
5.
Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiration rate, and 
temperature) as recorded by the study center personnel.
6.
Brief Smell Identification Test (B-SIT)
7.
Columbia-Suicide Severity Rating Scale (C-SSRS).
8.
Requirement for unscheduled emergency room (ER) or emergency medical service (EMS) 
visits within 24 hours after study drug administration.
Study Design: 
This is an open-label, multicenter, safety extension study of USL261 in subjects with seizure clusters 
who have completed study P261-401 (ARTEMIS-1). However, if study P261-401 is terminated, subjects 
who have completed the Test Dose Visit (Visit 2) of study P261-401 will also be eligible to enter this 
study (P261-402). Each seizure cluster episode will be treated with a single dose of 5.0 mg USL261. A 
second dose of 5.0 mg USL261 may be given if the seizure cluster has not terminated within 10 minutes 
after initial study drug administration or if another seizure occurs between 10 minutes and 6 hours after 
administration of the study drug. However, the second dose will not be administered if the subject has a 
respiratory rate < 8 breaths per minute, requires emergency rescue treatment with assisted breathing or 
intubation, or has excessive, uncharacteristic sedation (as defined by the investigator in the Patient 
Management Plan). After each USL261-treated seizure cluster episode, the caregiver will call the study 
center as soon as possible, but no later than 24 hours after USL261administration.  
After obtaining informed consent and determining that the subject meets the eligibility requirements for 
this study, the subject/caregiver will be provided with enough study drug to treat one seizure cluster 
episode (1 treatment kit containing two 5.0 mg doses of USL261) at Visit 1.  After one USL261-treated 
seizure cluster, the subject and caregiver will return to the study center for Visit 2 within 120 hours 
(5 days) of USL261 administration. At Visit 2, the subject/caregiver will again be provided with enough 
study drug to treat 1 seizure cluster episode (1 treatment kit containing two 5.0 mg doses of USL261). 
After one USL261-treated seizure cluster, the subject and caregiver will return to the study center for 
Visit 3 within 120 hours (5 days) of USL261 administration. At Visit 3 and all subsequent visits (except 
for the Final Visit or Early Termination Visit) the subject/caregiver will be provided with enough study 
drug to treat 2 seizure cluster episodes (2 treatment kits, each containing two 5.0 mg doses of USL261). 
After Visit 3, subjects and caregivers will return to the study center after every second USL261-treated 
seizure cluster episode. Each of these visits will occur within 120 hours (5 days) after the last USL261
administration. 
The duration of each subject’s participation will be up to approximately 4 years from the date of 
enrollment (Visit 1). After this period, the study duration may be extended until marketing approval or a 
time period as approved by the Heath Authority where the study is being conducted. A minimum of 
3 days (72 hours) is required between treatments (1 treatment is defined as the use of one or two 5.0 mg 
doses of USL261 from one study drug treatment kit to treat a single seizure cluster episode). There is no 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
3 of 124
Upsher-Smith Laboratories, Inc.
limitation on the total number of seizure cluster episodes treated during the subject’s participation in the 
study.  
Before any subject is enrolled in this open-label extension study, he/she must have completed study 
P261-401, or, if Study P261-401 has been terminated, subjects must have completed the Test Dose Visit 
(Visit 2) of study P261-401. Subjects must meet all other eligibility criteria for this study.  Since 
enrollment is limited to subjects who have participated in study P261-401, a maximum of 240 subjects 
(the planned number of subjects completing the Comparative Phase in P261-401) are expected to enroll.  
Inclusion/Exclusion Criteria:
Inclusion
1.
Subject or subject’s legally acceptable representative (LAR) has provided written informed 
consent, and subject has provided written assent where required by local law or Institutional 
Review Board (IRB) / Independent Ethics Committee (IEC) policy.
2.
Subject has a competent, adult (age ≥ 18 years) caregiver(s) who is able to recognize and 
observe the subject’s seizure cluster episodes, who is willing to be trained in the study 
procedures, and has provided written informed consent; the caregiver(s) must be a relative, 
partner, friend, or LAR of the subject, or a person who provides daily care to the subject who 
has a significant personal relationship with the subject.
3.
Subject is 12 years of age or older at Visit 1.
4.
Subject has an established diagnosis of partial or generalized epilepsy.
5.
Subject has a documented history of seizure clusters that includes all the following:
a.
The subject’s seizure cluster pattern is observable, stereotyped, and recognizably 
different from the subject’s other non-cluster seizure activity (if any) in seizure type, 
duration, severity, or frequency, and of the same type that was approved by the central 
reviewer in study P261-401.
b.
A documented history of seizure clusters lasting a minimum of 10 minutes from the 
time the seizure cluster is recognized.
c.
As part of the subject’s stereotyped seizure cluster pattern, a second seizure typically 
occurs within 6 hours from the time of recognition of the seizure cluster.
d.
The subject’s stereotyped seizure cluster pattern is composed of multiple (≥ 2) partial 
or generalized seizures.
e.
The subject’s stereotyped seizure cluster pattern was established > 3 months before 
Visit 1 of study P261-401.
f.
A frequency of ≥ 3 stereotyped seizure clusters during the year before Visit 1 of study 
P261-401.
g.
At least 1 stereotyped seizure cluster occurring at least once in the 4 months before 
Visit 1 of study P261-401.
6.
Subject has successfully completed study P261-401 and the subject and caregiver have
demonstrated adequate compliance with P261-401 study procedures as determined by the 
investigator, OR, if Study P261-401 has been terminated, the subject completed the Test Dose 
Visit (Visit 2) of study P261-401 and the subject did not meet any Visit 2 exclusion criteria in 
study P261-401.
7.
Subject is not likely to conceive, as indicated by a “yes” answer to at least 1 of the following 
questions:
a.
Is the subject a male?
b.
Is the subject a postmenopausal female as determined in study P261-401?
c.
Is the subject a female who has written medical documentation of being permanently 
sterilized (e.g. hysterectomy, double oophorectomy, bilateral salpingectomy)?
d.
Has the subject agreed to use two effective methods of contraception during the entire 
study if she is sexually active or will become sexually active during the study (except 
where local law or regulation differs; approval by USL or designee is required in such 
cases)?
Examples of two effective methods of contraception include the following:

A diaphragm and a condom with spermicide.

An intrauterine device (IUD) used in combination with a barrier method (e.g. 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
4 of 124
Upsher-Smith Laboratories, Inc.
condom, diaphragm, or cervical cap with spermicide).

Hormonal methods (e.g., high-dose birth control pills, Depo-Provera) or tubal 
ligation used in combination with a barrier method (e.g., condom, diaphragm, or 
cervical cap with spermicide).
Note that hormonal contraception alone is not considered adequate for this study and must 
be used in combination with another method. The type of birth control used must be 
approved by the investigator or designee.
Exclusion
1.
Subject experienced a seizure cluster progressing to status epilepticus during or since his/her 
participation in Study P261-401.
2.
Subject has a positive pregnancy test at any visit or is pregnant, considering becoming 
pregnant, or is breastfeeding (female subjects only).
3.
Subject who, in the opinion of the investigator, is experiencing an ongoing, uncontrolled, 
clinically significant adverse event(s) from P261-401 at Visit 1 or did experience a clinically 
significant adverse event in study P261-401 that might prevent the subject from safely 
participating in the study.
4.
Subject has consumed any clinically significant CYP450 3A inhibitor/inducer, opioid, or other 
respiratory depressant, not including antiepileptic drugs (AEDs), within the required washout 
period before Visit 1 (see Appendix 1, Prohibited Concomitant Substances).
5.
Subjects using chronic benzodiazepine(s); chronic use is defined as use for 4 or more days in a 
7-day period on average.
6.
Subject has a neurological disorder that is likely to progress in the next year.
7.
Subject has a history of acute narrow-angle glaucoma.
8.
Subject has a medical condition including uncontrolled cardiac, pulmonary, renal, hepatic, or 
gastrointestinal disease that could interfere with the study, subject safety/safety monitoring, or 
is not stable despite current therapy.
9.
Subject has severe chronic cardio-respiratory disease with baseline room air oxygen saturations 
< 90%, New York Heart Association class III or IV functional status, or the need for 
ambulatory oxygen.
10. Subject has had psychogenic, non-epileptic seizure(s) during or since the P261-401 study.
11. Subject has suicidality, defined as any of the following: a) active suicidal plan/intent or active 
suicidal thoughts during or since the P261-401 study as defined by a Columbia-Suicide Severity 
Rating Scale (C-SSRS) suicidal ideation score ≥ 3, b) any suicide attempt during or since the 
P261-401 study as determined by the C-SSRS or medical history, or c) other clinically 
significant suicidality as determined by the investigator.
12. Subject, in the investigator’s opinion, has met the criteria for a major depressive episode during 
or since the P261-401 study (criteria defined by the current edition of the Diagnostic and 
Statistical Manual of Mental Disorders).
13. Subject has or has had psychosis during or since the P261-401 study, excluding postictal 
psychosis
14. Subject has a history of drug or alcohol abuse during or since study P261-401.
15. Subject has a history of allergy or any significant adverse reaction (including rash) to 
midazolam
16. Subject is currently using an investigational drug or device or has used such (other than the 
study drug during P261-401) within 30 days prior to Visit 1.
17. Subject has plasma phenobarbital concentrations > 35 μg/mL at Visit 1 (phenobarbital 
concentration will be measured in subjects taking phenobarbital and in subjects for which the 
investigator deems it necessary).
18. Subject is not appropriate for the study for any other reason as determined by the investigator.
Study Population: Since enrollment is limited to subjects who have participated in study P261-401, a 
maximum of 240 subjects (the planned number of subjects completing the Comparative Phase in P261-
401) is expected to enroll.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
5 of 124
Upsher-Smith Laboratories, Inc.
Test/Reference Product, Dose, and Mode of Administration:
Test Product: USL261 (intranasal midazolam); 5.0 mg per actuation for intranasal administration.
Reference Product: None
Duration of Treatment: Each seizure cluster episode will be treated with one 5.0-mg dose of USL261 
followed by a second 5.0-mg dose of USL261 if the seizure(s) has not terminated within 10 minutes 
after study drug administration or if another seizure occurs between 10 minutes and 6 hours after 
administration of the drug and the subject does not have excessive, uncharacteristic sedation (as defined 
by the investigator in the Patient Management Plan), does not have a respiratory rate < 8 breaths per 
minute, and does not require emergency rescue treatment with assisted breathing or intubation. There 
must be at least 3 days (72 hours) between treatments. There will be no limitation on the total number of 
seizure cluster episodes treated.  
Duration of Subject Participation:
Screening: Up to 28 days for transition from P261-401 protocol.
Treatment Phase: The duration of each subject’s participation will be variable. If the subject continues 
to be eligible, s/he can continue in the study for up to approximately 4 years from the date of enrollment 
(Visit 1). After this period, the study duration may be extended until marketing approval or a time period 
as approved by the Heath Authority where the study is being conducted or until a time determined by the 
Sponsor (Upsher-Smith Laboratories, Inc.)
Safety Assessments: 
Collection of AEs, physical, nasal and neurological examinations, clinical laboratory evaluations, vital 
sign measurements, caregiver-recorded respiration rate, C-SSRS, ER or EMS visits, and B-SIT.
Efficacy Assessments:
!
Date and time of study drug administration.
!
Seizure activity:
!
For the first 2 years of participation in the study the date, start, and stop time of each 
seizure within 24 hours after any study drug administration. 
!
After the first 2 years participation in the study the date and start time of next seizure 
within 10 minutes to 24 hours after administration of the first and second dose of study 
drug.
Statistical Methods:
All analyses will be descriptive and no hypothesis tests will be conducted. Data will be listed and 
tabulated overall.  Continuous variables will be summarized using descriptive statistics (n, mean, 
standard deviation [SD], median, minimum, and maximum).  Categorical data will be presented using 
counts and percentages.
The Safety Population includes all subjects who are enrolled in the open-label study and received at least 
one dose of open-label study drug.  The Efficacy Evaluable Population includes all subjects in the Safety 
Population who received at least 1 dose of study drug during the open-label study and who have any 
post-treatment efficacy assessment.
The following safety endpoints will be summarized using the Safety Population:
!
Treatment Emergent Adverse Events (TEAEs) will be presented by treatment received, 
severity, relationship to study drug and age group (< 18, ≥ 18 - <65 years, ≥65 years). 
!
Clinical laboratory results will be presented by visit.
!
Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiration rate, and 
temperature) performed by study center staff will be summarized at each visit.
!
Caregiver-recorded respiration rate will be presented using descriptive statistics at each time 
point and for each treatment. The number of subjects who have < 8 breaths per minute and > 24 
breaths per minute after study drug administration will be presented by time point and for each 
treatment.
!
Number of subjects requiring an unscheduled ER or EMS visit within 24 hours after study drug 
administration will be presented for each treatment.
!
Suicidal behavior and ideation using the C-SSRS will be summarized at each visit.
!
Physical, nasal and neurological examination results will be presented by visit.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
6 of 124
Upsher-Smith Laboratories, Inc.
!
Olfactory assessment results will be presented by treatment group and visit
The following efficacy endpoints will be summarized using the Efficacy Evaluable Population:
!
Short and long term efficacy of USL261 as the outpatient treatment of seizure clusters based on 
Treatment Success based on appropriate longitudinal model
!
Kaplan-Meier analysis of time to return to baseline functionality
The following questionnaires will be summarized using the Safety Population:
!
SF-12v2 Health Survey (SF-12v2).
!
Treatment Satisfaction Questionnaire for Medication (TSQM).
!
Intranasal Therapy Impact Questionnaire (ITIQ).
!
Caregiver Questionnaire.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
7 of 124
Upsher-Smith Laboratories, Inc.
Table 1.
Procedure Schedule
Phase
Screening
Treatment Phase
Study 
Termination
Visit Number
Visit 1[a]
Visits 2 and 
3 [b]
Visit X [c]
Treatment 
[d]
Final Visit or 
Early 
Termination
Study Assessment
Obtain Informed Consent[e]
X
Contact IRT System
X
X
X
X
Confirm Inclusion/Exclusion 
Criteria
X
Caregiver training[f]
X
X
X
Medical / Surgical / 
Medication History[g]
X
Concomitant therapy review[g]
X
X
X
X
ER and EMS Visit Review [h]
X
X
X
Update PMP[i]
X
Physical Examination
X[j]
X
X
X
Neurological Examination
X[j,k]
X[l]
X[l]
X[k]
Nasal Examination
X[j]
X
X
X
B-SIT
X
X
X
Pregnancy Test – Urine[m]
X
X
X
X
Clinical Laboratory Testing[n]
X
X
X
X
Height
X
X
Body weight
X
X
X
X
Vital Sign measurements[o]
X
X
X
X
Study drug administration
X
Caregiver call to study center
X
Record seizure activity for 24 
hours after study drug 
administration in the subject 
workbook
X[p]
Evaluate subject’s return to 
baseline functionality[q]
X
Caregiver-recorded respiration 
rate[r]
X
C-SSRS[s]
X
X
X
X
Outcome questionnaires[t]
X
X
X
X
Dispense Study Materials 
Kit[u]
X[v]
Study Drug Kit [v]
X
X
Drug Accountability
X
X
X
Collect and review Subject 
Workbook 
X
X
X
AE Assessment
X
X
X
X
X
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
8 of 124
Upsher-Smith Laboratories, Inc.
Telephone Follow-Up [w]
Approximately every 30 days (between visits that are at least 
30 days apart)
[a] Procedures at Visit 1 may occur at the same time as Visit 4 of the preceding double-blind study (P261-401) or up to 28 
days after Visit 4 of study P261-401. If Visit 1 of this study (P261-402) is on the same day as Visit 4 of study P261-401, 
the procedures performed at Visit 4 of study P261-401 that are common to Visit 1 will be used for both studies. If Visit 
1 for this study (P261-402) is not on the same day as Visit 4 of P261-401, all necessary procedures will be repeated, 
except for physical exam, neurological exam, nasal exam, and clinical laboratory testing (hematology, serum chemistry 
and urinalysis).
[b] Visits 2 and 3 will take place within 120 hours (5 days) following each of the first 2 USL261-treated seizure cluster 
episodes.
[c] After Visit 3, each subject will return to the study center for a visit after every second USL261-treated episode. There is 
no limit on the number of seizure cluster episodes treated.
[d] These assessments are to be completed by the caregiver(s) outside of the study center.
[e] Informed consent provided by the subject (or subject’s LAR) and caregiver before any other study-specific procedures; 
assent may also be required for some subjects and subjects with LARs (see Section 5.4, Informed Consent).
[f] Caregiver training for P261-402 is required before study drug is dispensed at Visit 1. Review and re-instruct subjects and 
caregivers on the information provided in the training at all subsequent visits, except Final Visit or Early Termination 
Visit. Caregivers are also required to have a current CPR training certificate throughout the entire study.
[g] Update from Study P261-401.
[h] Collect number of calls to EMS and ER visits for a seizure cluster or other seizure emergency since last visit or follow-
up phone call
[i] PMP from P261-401 will be updated for this study (see Section 9.3.1). PMP updates should be completed before a subject 
receives the study materials kit at Visit 1.
[j] The physical, nasal, and neurological examinations performed at Visit 4 of Study P261-401 will be used for Visit 1 of this 
study.
[k] Complete neurological examination.
[l] Brief neurological examination.
[m] Pregnancy tests required only for females of childbearing potential as described in Section 6.2.2.4.
[n]Hematology, serum chemistry, and urinalysis for all subjects; phenobarbital screen/levels for subjects taking phenobarbital
and in subjects for which the investigator deems it necessary. 
[o] Blood pressure (BP), heart rate (HR), respiration rate, and body temperature.
[p] For the first 2 years of participation in the study the date, start, and stop time of each seizure within 24 hours after any 
study drug administration will be recorded. After the first 2 years participation in the study, the date and start time of next 
seizure within 10 minutes to 24 hours after administration of the first and second dose of study drug will be recorded.
[q] Caregiver will evaluate the subject’s return to baseline functionality after each treated seizure cluster episode and record 
the time when the subject was able to return to what he/she was doing.
[r]Caregiver counts the number of breaths taken by the subject during a 30-second interval.  Caregivers will measure 
respiration rate at approximately 10, 15 and 30 minutes and 1, 2, and 4 hours after USL261 administration (see Section 
6.1.3).
[s] The Since Last Visit version is administered at all visits.
[t] The outcome questionnaires SF-12v2, TSQM, ITIQ and Caregiver Questionnaire are optional (see Section 6.2.3)
[u] The study materials kit will include at a minimum: Individualized PMP, summary of the PMP, Subject Workbook (used 
for collecting and recording seizure activity information, study drug administration, respiration rate, and other 
observations made by the caregiver), study drug kit, and dosing instructions.
[v] One study drug kit will be dispensed at Visit 1 and Visit 2.  Two study drug kits will be dispensed at Visit 3 and each 
Visit X.
[w] After Visit 1, telephone follow-up calls with the caregiver(s) and subject (if subject is able to communicate adequately 
as determined by the investigator) are to occur at least once each month (every 30 days) between visits that are at least 1 
month apart until the subject has completed or prematurely discontinued from the study.
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale; IRT = Interactive Response Technology system; PMP = 
Patient Management Plan
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
9 of 124
Upsher-Smith Laboratories, Inc.
CONTACT INFORMATION
Sponsor of Clinical Trial:
Name:
Upsher-Smith Laboratories, Inc.
Address:
Contact:
6701 Evenstad Drive
Maple Grove, MN 55369
 Pharm.D.
Sr. Clinical Research Scientist
Upsher-Smith Laboratories, Inc.
6701 Evenstad Drive
Maple Grove, MN 55369-6026
Phone number: 
Monitor of Clinical Trial:
Name:
inVentiv Health Clinical, LLC
Medical Monitor:
Name:
, MD
Senior Medical Director, Medical and Scientific Affairs                          
inVentiv Health Clinical, LLC
Address:
504 Carnegie Center
Princeton, NJ 08543
Mobile Phone:
E-mail:
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
10 of 124
Upsher-Smith Laboratories, Inc.
Table of Contents
SYNOPSIS......................................................................................................................... 2
TABLE OF CONTENTS ................................................................................................ 10
LIST OF TABLES .......................................................................................................... 14
LIST OF FIGURES......................................................................................................... 15
LIST OF ABBREVIATIONS ......................................................................................... 16
1
INTRODUCTION ............................................................................................ 18
1.1
Background Information ......................................................................... 18
1.2
Nonclinical Information........................................................................... 20
1.3
Clinical Studies......................................................................................... 23
1.3.1
Results of Completed Studies.................................................................. 27
2
STUDY OBJECTIVES..................................................................................... 30
3
DESCRIPTION OF STUDY ............................................................................ 31
3.1
Overview................................................................................................... 31
3.2
Screening .................................................................................................. 34
3.3
Treatment Phase....................................................................................... 35
4
RATIONALE.................................................................................................... 36
4.1
Rationale for the Study ............................................................................ 36
4.2
Rationale for the Study Design ................................................................ 37
4.3
Rationale for the Dosage .......................................................................... 37
5
SUBJECT SELECTION................................................................................... 38
5.1
Number of Subjects.................................................................................. 38
5.2
Inclusion Criteria ..................................................................................... 39
5.3
Exclusion Criteria .................................................................................... 40
5.4
Informed Consent..................................................................................... 42
5.5
Authorization to Use and Disclose Medical Information........................ 44
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
11 of 124
Upsher-Smith Laboratories, Inc.
6
STUDY METHODOLOGY ............................................................................. 45
6.1
Study Procedures ..................................................................................... 45
6.1.1
Visit 1 (Screening Visit).......................................................................... 46
6.1.2
Visit 2 through Visit X ............................................................................ 47
6.1.3
Treatment – First 2 Years in the Study..................................................... 48
6.1.4
Treatment – After 2 Years in the Study.................................................... 50
6.1.5
Final Visit or Early Termination Visit ..................................................... 51
6.1.6
Telephone Follow-Up and Support.......................................................... 52
6.1.7
Dosage Instructions................................................................................. 53
6.2
Methods of Assessment ............................................................................ 54
6.2.1
Efficacy Assessments.............................................................................. 54
6.2.2
Safety Assessments ................................................................................. 54
6.2.3
Outcomes Questionnaires ........................................................................ 59
6.2.4
Treatment Compliance ............................................................................ 60
6.3
Prior and Concomitant Therapy ............................................................. 60
6.3.1
Permitted Medications and Devices......................................................... 60
6.3.2
Prohibited Substances.............................................................................. 61
6.3.3
Use of Benzodiazepines........................................................................... 61
6.4
Restrictions during the Study .................................................................. 62
6.4.1
Activity Restrictions................................................................................ 62
6.4.2
Food and Fluid Intake.............................................................................. 62
6.5
Subject Withdrawal or Discontinuation.................................................. 62
6.5.1
Withdrawal or Discontinuation Procedures.............................................. 63
6.6
Treating Overdose.................................................................................... 64
6.7
Pregnancy ................................................................................................. 65
7
ADVERSE EVENT MANAGEMENT............................................................. 65
7.1
Definitions:  Adverse Events and Serious Adverse Events ..................... 65
7.2
Reporting of Adverse Events and Serious Adverse Events .................... 69
7.3
Clinical Laboratory Abnormalities and Other Abnormal Assessments 71
8
RANDOMIZATION AND BLINDING METHODS ...................................... 71
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
12 of 124
Upsher-Smith Laboratories, Inc.
8.1
Randomization ......................................................................................... 71
8.2
Blinding..................................................................................................... 71
9
MATERIALS AND SUPPLIES ....................................................................... 72
9.1
Study Drug ............................................................................................... 72
9.1.1
Controlled Substance Documentation...................................................... 72
9.2
Study Drug Labeling................................................................................ 72
9.3
Additional Study Supplies........................................................................ 73
9.3.1
Patient Management Plan ........................................................................ 73
9.3.2
Subject Workbook................................................................................... 74
9.3.3
Caregiver Training .................................................................................. 75
9.4
Study Drug Inventory and Storage.......................................................... 76
9.4.1
Drug Storage at Research Centers............................................................ 76
9.4.2
Dispensing of Study Drug ....................................................................... 77
9.4.3
Return or Destruction of Study Drug ....................................................... 77
10
DATA ANALYSIS AND STATISTICAL PROCEDURES ............................ 78
10.1
Populations for Analysis .......................................................................... 78
10.2
Subject Disposition................................................................................... 79
10.3
Medical and Surgical History .................................................................. 79
10.4
Prior and Concomitant Therapy ............................................................. 79
10.5
Safety and Efficacy Endpoints................................................................. 79
10.5.1 Safety Analyses....................................................................................... 80
10.5.2 Efficacy Analyses.................................................................................... 81
10.5.3 Exploratory Analyses .............................................................................. 82
10.5.4 Outcomes Analyses ................................................................................. 83
10.5.5 Data and Safety Monitoring Board .......................................................... 83
10.6
Sample Size Justification.......................................................................... 83
11
ADMINISTRATIVE PROCEDURES ............................................................. 84
11.1
Regulatory Approval................................................................................ 84
11.2
Institutional Review Board or Independent Ethics Committee 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
13 of 124
Upsher-Smith Laboratories, Inc.
Approval
................................................................................................................... 84
11.3
Study Personnel........................................................................................ 85
11.4
Ongoing Information for Independent Ethics Committee...................... 85
11.5
Completion of Electronic Case Report Forms ........................................ 85
11.6
Study Monitoring ..................................................................................... 86
11.7
Quality Assurance Procedures................................................................. 87
11.7.1 Access to Source Documentation............................................................. 87
11.7.2 Auditing Procedures................................................................................ 88
11.8
USL Policy on Fraud in Clinical Studies................................................. 89
11.9
Use of Information and Publication......................................................... 89
11.10
Amendment to Protocol ........................................................................... 90
11.11
Deviations from Protocol ......................................................................... 90
11.12
Records of Study ...................................................................................... 91
11.13
Completion of Study................................................................................. 91
11.14
Study Funding.......................................................................................... 91
11.15
Financial Disclosure ................................................................................. 92
12
REFERENCE LIST.......................................................................................... 92
APPENDIX 1.   PROHIBITED CONCOMITANT SUBSTANCES ............................. 96
APPENDIX 2.   MIDAZOLAM INJECTION, USP, PACKAGE INSERT 
(HOSPIRA).................................................................................................................... 100
APPENDIX 3.   AMENDMENT 4................................................................................ 120
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
14 of 124
Upsher-Smith Laboratories, Inc.
LIST OF TABLES
Table 1. Procedure Schedule........................................................................................... 7
Table 2. USL261 Animal Toxicity Studies.................................................................... 21
Table 3.  Summary of Completed and Ongoing Clinical Studies with USL261............ 24
Table 4. Clinical Laboratory Tests ............................................................................... 57
Table 5. Serious Adverse Event Reporting Requirements........................................... 70
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
15 of 124
Upsher-Smith Laboratories, Inc.
LIST OF FIGURES
Figure 1. Study Flow Chart............................................................................................ 34
Figure 2. Flow of Informed Consent .............................................................................. 44
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
16 of 124
Upsher-Smith Laboratories, Inc.
LIST OF ABBREVIATIONS
Abbreviation
Definition or Term
AE
Adverse Event
AED
Antiepileptic drug
ALT
Alanine aminotransferase (same as SGPT)
AP
Alkaline phosphatase
ARS
Acute repetitive seizures
ARTEMIS-1
Acute Rescue Therapy in Epilepsy with Midazolam Intranasal Spray-1
AST
Aspartate aminotransferase (same as SGOT)
AUC0-t
Area under the plasma concentration time curve from time 0 to time of last 
measurable concentration
AUC0-∞
Area under the plasma concentration time curve from time 0 extrapolated to 
infinity
β-HCG
Beta-human chorionic gonadotropin
BP
Blood pressure
BUN
Blood urea nitrogen
B-SIT
Brief Smell Identification Test
CBC
Complete blood count
CFR
Code of Federal Regulations
Cmax
Maximum plasma concentration
CPR
Cardiopulmonary resuscitation
CRO
Clinical research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
DSMB
Data Safety Monitoring Board
eCRF
Electronic case report form
EDC
Electronic data capture
EMS
Emergency medical services
ER
Emergency room
ET
Early termination
FDA
Food and Drug Administration
GCP
Guideline for Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GLP
Good Laboratory Practice
Hct
Hematocrit
Hgb
Hemoglobin
HIPAA
Health and Insurance Portability and Accountability Act (of 1996)
HR
Heart rate
ICF
Informed consent form
ICH
International Conference on Harmonization
IDs
Identifications 
IEC
Independent ethics committee
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
17 of 124
Upsher-Smith Laboratories, Inc.
Abbreviation
Definition or Term
IM
Intramuscular 
IN
Intranasal 
IND
Investigational new drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITI
Ikano Therapeutics, Inc.
ITIQ
Intranasal Therapy Impact Questionnaire
IUD
Intrauterine device
IV 
Intravenous 
LAR
Legally acceptable representative
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPEG
Methoxy polyethyleneglycol
NF
The National Formulary
NOAEL
No observable adverse effect level
OAA/S
Observer’s Assessment of Alertness/Sedation
PD
Pharmacodynamic
PEG
Polyethylene glycol
PMP
Patient management plan
PK
Pharmacokinetic
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
TSQM
Treatment Satisfaction Questionnaire for Medication
US
United States
USL
Upsher-Smith Laboratories, Inc., (study sponsor)
USL261
Intranasal midazolam, study drug (formerly ITI-111)
USP
United States Pharmacopeia
VNS
Vagus nerve stimulator
WBC
White blood cell 
WHO
World Health Organization
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
18 of 124
Upsher-Smith Laboratories, Inc.
1
INTRODUCTION
1.1
Background Information
Seizure clusters, also known as acute repetitive seizures (ARS), occur in a subset of epilepsy
patients.  Seizure clusters often have distinguishable characteristics that can be recognized 
by the patients, caregivers, and physician. These characteristics may include a predictable
onset, stereotyped auras or other prodrome, or a particular seizure manifestation that is 
temporally associated with subsequent seizures.  Although a patient will usually recover 
between individual seizures within the cluster, seizure clusters range in duration from 
several minutes to hours.[1] When a cluster of seizures occurs outside the hospital, patients 
must often be transported to an acute care facility so that trained medical personnel can 
administer intravenous (IV) therapy to stop the seizure activity.[2]  
Seizure clusters can evolve into prolonged seizures with worsening epileptogenesis if 
treatment is not prompt and effective.[3, 4] Furthermore, if left untreated, seizure clusters
may progress to status epilepticus, a life-threatening, prolonged epileptic crisis.[5] The 
primary goals of seizure cluster treatment are cessation of the seizure(s) and prevention of 
seizure recurrence.[1] Acute benzodiazepine treatment is effective for seizure control and 
often results in rapid termination of the seizure cluster; however, most treatment options rely 
on intervention by emergency medical personnel and therefore delay treatment while the 
patient is transported to a medical facility.[6] The development of an easily administered 
outpatient treatment of seizure clusters may reduce emergency medical intervention and 
decrease seizure cluster duration. Rectal diazepam gel (Diastat®, Valeant Pharmaceuticals 
International) is currently available in the United States (US), but has limitations in that a 
portion of the population does not respond adequately to this treatment.[7] Additionally, the 
rectal route of administration is more burdensome and may be unacceptable to some patients 
and caregivers.[7] As such, an approved treatment is needed that effectively terminates 
seizure cluster activity, has a rapid onset of action, and is easily administered in an 
outpatient setting.
Midazolam is a benzodiazepine that has inhibitory activity at the GABA-A receptor 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
19 of 124
Upsher-Smith Laboratories, Inc.
resulting in anticonvulsant properties.[8]  In adults, midazolam is usually administered IV or 
intramuscularly (IM) at doses of 1 to 10 mg.[9] In pediatric patients, the dose of midazolam 
is usually on a mg/kg basis. Like other benzodiazepines, midazolam administration may 
cause sedation, anxiolysis, and amnesia.[10, 11] Sedative effects usually occur within 
5 minutes after IV administration and within 15 minutes after IM administration. Depending 
on the dose, route of administration, concurrent medications, and patient’s age, peak 
sedation occurs within 30 to 60 minutes after dosing.[12]
Intranasal (IN) midazolam may be safe and effective for the rapid cessation of seizure 
activity in outpatient settings. Use of intranasal midazolam was originally described in the 
late 1980s.[10] Over 20 studies in the last 15 years have found midazolam to be a safe and 
efficacious treatment for seizure control in both adult and pediatric patient populations.[7,
10, 13-31] Furthermore, use of IN midazolam for treatment of seizures has also been 
advocated by several review articles and editorials.[32-35]
Much of the published work investigating the effects of IN midazolam on seizure control
has used midazolam sterile injection solution (5.0 mg/mL) approved for IV delivery 
administered IN with a needless syringe at doses ≤ 0.6 mg/kg. The delivery of IV-approved 
midazolam sterile injection solution intranasally has not been optimized, nor is it approved 
by the US Food and Drug Administration (FDA). In fact, the volume of midazolam sterile 
injection solution usually ranges from 1 to 2 mL,[11] which exceeds the recommended 
volume for optimal nasal delivery (≤200 μL).[34] Despite the sub-optimal formulation and 
delivery system, IN delivery of midazolam has been very effective in many settings without 
major safety concerns. The most common adverse effects have been described as local 
nasal irritation and discomfort. Unpleasant taste was also commonly reported, suggesting 
possible oral ingestion of midazolam IV solution, perhaps caused by the suboptimal delivery 
volumes.[11]  
Ikano Therapeutics Inc. (ITI, [previously Intranasal Therapeutics, Inc.]) initiated 
development of a midazolam rescue treatment designed specifically for IN delivery (ITI-
111) for patients who require control of intermittent bouts of seizure activity, including 
seizure clusters. In June 2010, Upsher-Smith Laboratories, Inc. (USL), obtained exclusive 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
20 of 124
Upsher-Smith Laboratories, Inc.
global rights to ITI-111 (renamed as USL261) assuming all continued development, testing, 
and clinical trials for the treatment of seizure clusters. The proprietary formulation delivers 
adequate drug concentrations in a small volume (100 μL). Preliminary human studies show 
positive pharmacokinetic (PK) and bioavailability properties with good safety and 
tolerability. The present study was designed to provide extended subject access to USL261 
as a treatment option for subjects completing study P261-401 and to establish the long-term 
safety and tolerability of USL261 (see Section 3, Description of Study).  
1.2
Nonclinical Information
To establish the safety, and to supplement the existing body of toxicology data for USL261, 
four nonclinical studies have been performed using USL261 administered IN (Table 2).
These studies included a 14-day IN toxicology study in beagle dogs using the 
container/closure system (a unit dose spray pump) intended for clinical trials, a 14-day study 
in rats, a 90-day study in beagle dogs, and a 6-month study in rats.  All four studies were 
conducted in accordance with Good Laboratory Practice (GLP).
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
22 of 124
Upsher-Smith Laboratories, Inc.
approval in 1985.  A complete overview of the preclinical development and pharmacology 
of midazolam has previously been published.[36]
A 6-month IN study (including a 3-month interim sacrifice group) was conducted in rats 
(Experimur 10-610). The dose levels and the experimental design were the same as in the 
14-day rat study (0, 1, 3, and 6 mg/day).  All effects noted were consistent with the 14-day 
rat study, WIL-637002.  Gross necropsy revealed dose-related increases in liver weights 
consistent with the known effects of chronic midazolam administration.  No other gross 
lesions or significant findings were noted.  Histopathologic examination of the tissues 
showed no remarkable changes in the nasal tissues or other tissues associated with twice 
daily nasal administration.   Intranasal instillation of Midazolam to Sprague-Dawley rats at 
dose levels up to 6 mg/day for 6 months was considered well-tolerated.  Based on the lack 
of histological changes observed in this study, the NOAEL (no-observed-adverse-effect 
level) was considered to be 6 mg/day after 6 months of treatment.  
USL261 contains midazolam, EP/ USP in formulation with excipients 
 
 
. The effects of the 
excipient, 
, were studied in the 4 completed USL261 nonclinical studies 
mentioned above. Additionally, a genotoxicology program and a nasal-disposition program 
in rats and dogs to ascertain the nasal absorption potential of 
0 were completed. 
Although absorption of the excipient 
 via IN administration was detected, all 
studies completed to date suggest no significant genotoxicity or development/reproductive 
effects.
In summary, intranasal dosing of high levels of midazolam at high multiples of the clinical 
doses resulted in no significant changes in any endpoints. Minor clinical signs observed 
were consistent with the known effects of midazolam by other approved routes of 
administration.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
23 of 124
Upsher-Smith Laboratories, Inc.
1.3
Clinical Studies
Table 3 presents a summary of the completed and ongoing studies with USL261. Section 
1.3.1  provides additional details on the results of the completed studies.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
27 of 124
Upsher-Smith Laboratories, Inc.
1.3.1
Results of Completed Studies
1.3.1.1
Study MZ0714
ITI conducted an initial phase I clinical trial (MZ0714) investigating the safety, bioavailability, 
PK, and pharmacodynamic (PD) properties of USL261 entitled “A single-dose, open-label, 
five-way crossover, randomized, bioavailability and pharmacodynamic study comparing 
intranasal midazolam administration to intravenous midazolam administration in healthy human 
volunteers.” Safety, bioavailability, PK, and PD parameters for 3 doses of USL261 (2.5 mg, 
5.0 mg, and 7.5 mg in 0.1 mL) were compared with administration of IV-approved midazolam
sterile injection solution administered IV (2.5 mg in 5 mL) and IN (5.0 mg in 1 mL) via a 
needleless syringe.
Results suggested that maximum plasma concentration (Cmax) of midazolam was achieved in all 
dose groups within 10 minutes to 15 minutes post-administration.  The Cmax for all doses of 
USL261 were within the range of those achieved following IV and IN administration of 
midazolam sterile injection solution.  USL261 demonstrated linear PK parameters.  The absolute 
bioavailability of all USL261 doses was higher (range: 62% – 73%) than 5.0 mg midazolam
sterile injection solution administered intranasally (50%). 
Changes in PD measures were dependent on midazolam dose; subjects receiving the highest dose 
of USL261 (7.5 mg) reported the largest changes from baseline for all PD measures (Stanford 
Sleepiness Scale, Digit-Symbol Substitution Task, Observers Assessment of Alertness/Sedation 
[OAA/S]).  Route of administration (IV compared with IN) had a significant effect on the PD of 
midazolam.  For example, the maximal sedation effects for all IN midazolam formulations were 
observed between 45 minutes – 1 hour post-dose; however, maximal sedation occurred within 
15 minutes in subjects administered IV midazolam.  It is important to note that no significant 
differences in PD parameters were reported between IN treatments.
Overall, the proportion of subjects who experienced treatment-emergent adverse events (TEAEs) 
did not increase with ascending doses of IN midazolam. No TEAEs were reported after 
administration of 2.5 mg IV midazolam. All TEAEs were mild in intensity and the majority of 
TEAEs (95.7%) were considered related to study drug. No serious adverse events (SAEs) or 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
28 of 124
Upsher-Smith Laboratories, Inc.
deaths were reported, and no subject discontinued due to a TEAE. Overall, the most common 
drug-related TEAEs (reported by ≥10% of subjects) were increased nasal discomfort (84%), 
throat irritation (84%), increased lacrimation (76%), dysgeusia (72%), headache (20%), cough 
(12%), and rhinorrhea (12%). These TEAEs were only observed when midazolam was 
administered intranasally (IV or IN formulations), which suggested that they were related to 
route of administration. 
1.3.1.2
Study MZ0815
A second phase I clinical trial (MZ0815) also investigated the safety, tolerability, PK, and PD 
characteristics of USL261 but in adult and adolescent epilepsy patients rather than healthy 
volunteers. MZ0815 is a multicenter, in-patient study that evaluated an ascending single-dose 
and 2-dose administration of USL261 (2.5 mg, 5.0 mg, and 7.5 mg) given at 2 study visits 
separated by ≥3 days. USL261 was absorbed rapidly (approximately 13 minutes to 20 minutes
after a single dose; approximately 20 to 30 minutes after the 2-dose regimen) and the midazolam
Cmax, area under the plasma concentration time curve from time 0 to time of last measurable 
concentration (AUC0-t), and area under the plasma concentration time curve from time 0 
extrapolated to infinity (AUC0-∞) generally increased with total dose. Midazolam Cmax was 
lower in adolescents as compared to adults. The mean t1/2 ranged from 2.75 to 4.39 hours.
USL261 was deemed safe when administered at doses of 2.5 mg to 15.0 mg (total dose) to 
adolescent and adult epilepsy patients who were taking concomitant AEDs. Of the 90 enrolled 
subjects, 88 (98%) experienced at least 1 TEAE. No deaths or SAEs were reported, and no study 
subject prematurely discontinued due to intolerable AEs. Most TEAEs were mild to moderate in 
intensity and deemed to be probably related to study drug. The most frequently-reported TEAEs 
(reported by ≥10% of subjects) associated with study drug were dysgeusia (86%), oropharyngeal 
pain (57%), rhinalgia (31%), and burning sensation (11%). One subject, who was administered 
USL261 at a total dose of 12.5 mg, experienced moderate hypoxia approximately 90 minutes 
after administration of the second dose; however, the event was transient and not associated with 
sedation, hypoventilation, or changes in vital signs.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
29 of 124
Upsher-Smith Laboratories, Inc.
1.3.1.3
Study P261-201
Study P261-201 was a single-center, in-patient trial investigating the safety, tolerability, PK, and 
PD of escalating single- and two-dose regimens of USL261 compared to placebo in adult 
subjects with epilepsy.  Subjects were assigned sequentially to 1 of 4 cohorts to receive either 
USL261 (10.0 mg, 15.0 mg, 17.5 mg, or 20.0 mg) or placebo at two dosing visits separated by ≥ 
3 days.  Each subject received USL261 or placebo at Visit 2.  At Visit 3, each subject received 
the same total dose as he/she received at Visit 2 administered as a divided dose.  
USL261 was absorbed rapidly (approximately 9 minutes to 19 minutes after a single dose; 
approximately 19 to 22 minutes after the two-dose regimen). Following either single dose or 
repeat dose administration, PK parameters for both MZ and 1-OH MZ were similar across 
cohorts and did not exhibit dose dependent changes. Exposure to MZ and 1-OH MZ (as indicated 
by Cmax and AUC parameters) was not dose proportional following single dose or repeat dose 
administration of 10.0 mg to 20.0 mg. Effects of USL261 on sedation and psychomotor 
performance were transient following single and repeat dose administration and were consistent 
across USL261 doses. Consistent with PK results, no dose response was observed in SSS or 
OAA/S Sum and Composite scores or their corresponding PD parameters from 10.0 to 20.0 mg 
USL261 following either single or repeat dose administration.
USL261 was generally safe and well-tolerated following single- or repeat-dose administration up 
to the maximum evaluated total dose level of 20 mg in adult subjects with epilepsy taking 
concomitant AEDs. In total, 58 subjects (96.7%) reported 179 TEAEs. All of the reported 
TEAEs were considered mild in severity with the majority (96.0%) were considered “probably 
related” to study drug. Treatment-emergent AEs reported in ≥20% of subjects in any group were 
nasal discomfort and throat irritation, which occurred in 96% of subjects administered MDZ NS. 
However, there was no clear dose relationship and these events also occurred frequently in 
placebo subjects. Nasal mucosal disorder, headache, dysgeusia, and hiccups were also common 
TEAEs, occurring in ≥10% MDZ NS subjects.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
30 of 124
Upsher-Smith Laboratories, Inc.
1.3.1.4
Study P261-102
Study P261-102 was a single-center trial investigating the safety, tolerability, PK, and PD of 
single 2.5 mg and 5.0 mg doses of USL261 in generally healthy geriatric and non-geriatric 
subjects.  Enrollment was stratified into non-geriatric (18 – 40 years old, inclusive) and geriatric 
(≥ 65 years old) groups such that there were 12 subjects in the non-geriatric range and 18 
subjects in the geriatric range.  Subjects were randomly assigned to receive single doses of both 
2.5 mg and 5.0 mg USL261 in a 2x2 crossover fashion with a washout period of 4 – 10 days 
between dosing.  Mean systemic exposure (AUC) and peak plasma concentrations (Cmax) of 
MDZ were 20–45% higher in the geriatric subjects compared with nongeriatric subjects. 
Geriatric subjects exhibited greater cognitive effects than nongeriatric subjects, whereas 
maximum and overall sedation effects were comparable between the two groups.
Of the 30 enrolled subjects, 26 subjects (87%) reported at least one TEAE during the study with 
more geriatric subjects reporting a TEAE than younger subjects. All reported TEAEs (n=115) 
were considered mild in severity; most (91.3%) were considered “probably related” to the study 
drug. No SAEs or deaths were reported, and no subject discontinued study participation due to a 
TEAE. Although there were some differences between the 2.5 mg and 5.0 mg doses with regard 
to the incidence of the more frequently reported AEs, there did not appear to be a consistent 
association with dose. 
1.3.1.5
Study P261-401
Study P261-401 is an ongoing, phase III, randomized, double-blind, placebo-controlled,
multicenter study of the safety and efficacy of intranasal midazolam in the outpatient treatment 
of subjects with seizure clusters; the study consists of 2 distinct phases (Test-dose phase and 
Comparative phase) and 4 study center visits. Subjects need to complete study P261-401 in 
order to enroll in this study (P261-402).
2
STUDY OBJECTIVES
To evaluate the long-term safety and tolerability of USL-261 in the treatment of seizure clusters 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
31 of 124
Upsher-Smith Laboratories, Inc.
using the following:
!
Caregiver-recorded respiration rate at 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 
hours and 4 hours after study drug administration.
!
AEs
!
Clinical laboratory tests.
!
Physical, nasal, and neurological examinations.
!
Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiration 
rate, and temperature) as recorded by the study center personnel.
!
B-SIT
!
C-SSRS
!
Requirement for unscheduled emergency room (ER) or emergency medical service 
(EMS) visits within 24 hours after study drug administration.
3
DESCRIPTION OF STUDY
3.1
Overview
This is an open-label, multicenter, safety extension study of USL261 in subjects with seizure 
clusters who have completed study P261-401 (ARTEMIS-1). However if study P261-401 is 
terminated, subjects who have completed the Test Dose Visit (Visit 2) of study P261-401 will 
also be eligible to enter this study (P261-402).  Each seizure cluster episode will be treated with a 
single dose of 5.0 mg USL261. A second dose of 5.0 mg USL261 may be given if the seizure 
cluster has not terminated within 10 minutes after initial study drug administration or if another 
seizure occurs between 10 minutes and 6 hours after administration of study drug. However, the 
second dose will not be administered if the subject has a respiratory rate < 8 breaths per minute,
requires emergency rescue treatment with assisted breathing or intubation, or has excessive, 
uncharacteristic sedation (as defined by the investigator in the Patient Management Plan [PMP]).
After each USL261-treated seizure cluster episode, the caregiver will call the study center as 
soon as possible, but no later than 24 hours after USL261administration.  
After obtaining informed consent and determining that the subject meets the eligibility 
requirements for this study, the subject/caregiver will be provided with enough study drug to 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
32 of 124
Upsher-Smith Laboratories, Inc.
treat one seizure cluster episode (1 treatment kit containing two 5.0 mg doses of USL261) at 
Visit 1.  After one USL261-treated seizure cluster, the subject and caregiver will return to the 
study center for Visit 2 within 120 hours (5 days) of USL261 administration. At Visit 2, the 
subject/caregiver will again be provided with enough study drug to treat 1 seizure cluster episode 
(1 treatment kit containing two 5.0 mg doses of USL261). After one USL261-treated seizure 
cluster, the subject and caregiver will return to the study center for Visit 3 within 120 hours 
(5 days) of USL261 administration. At Visit 3 and all subsequent visits (except for the Final 
Visit or Early Termination Visit) the subject/caregiver will be provided with enough study drug 
to treat 2 seizure cluster episodes (2 treatment kits, each containing two 5.0 mg doses of 
USL261). 
After Visit 3, subjects and caregivers will return to the study center after every second 
USL261-treated seizure cluster episode.  Each of these visits will occur within 120 hours 
(5 days) after the last USL261 administration.  
The duration of each subject’s participation will vary and will be up to approximately 4 years 
from the date of enrollment (Visit 1). After this period, the study duration may be extended until 
marketing approval or a time period as approved by the Heath Authority where the study is being 
conducted or sooner, as deemed appropriate by the sponsor, Upsher-Smith Laboratories, Inc. 
The study will be reviewed on an ongoing basis and immediate discontinuation of the study may 
occur if:  a) safety concerns/issues are noted or have arisen during the conduct of the P261-402 
study or other USL261 studies, b) USL261 does not demonstrate efficacy in controlled clinical 
studies, c) a regulatory authority (regardless of country) requests that clinical studies be 
interrupted or discontinued, or d) USL discontinues or will discontinue development of USL261.
A minimum of 3 days (72 hours) is required between treatments (1 treatment is defined as the 
use of one or two 5.0 mg doses of USL261 from one study drug treatment kit to treat a single 
seizure cluster episode).  There is no limitation on the total number of seizure cluster episodes 
treated during the subject’s participation in the study.  
Before any subject is enrolled in this open-label extension study, he/she must have completed 
study P261-401 or, if Study P261-401 has been terminated, subjects must have completed the 
Test Dose Visit (Visit 2) of study P261-401. Subjects must meet all other eligibility criteria for 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
33 of 124
Upsher-Smith Laboratories, Inc.
this study.  Since enrollment is limited to subjects who have participated in study P261-401, a 
maximum of 240 subjects (the planned number of subjects completing the Comparative Phase in 
P261-401) are expected to enroll.  
This study will be conducted in accordance with the study protocol, International Conference on 
Harmonization (ICH) E6, Guideline for Good Clinical Practice (GCP), and applicable regulatory 
requirements including the US Code of Federal Regulations dealing with clinical studies 
(21 Code of Federal Regulations [CFR] including § 50, 54, 56 and 312 concerning protection of 
human subjects, financial disclosure by clinical investigators, Institutional Review Board [IRB] 
regulations and investigational new drug application, respectively).
A study flow chart is shown in Figure 1, and the Schedule of Procedures is presented in Table 1.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
34 of 124
Upsher-Smith Laboratories, Inc.
Figure 1. Study Flow Chart
P261-402 
VISIT 1 (Screening)
same as 
P261-401 Visit 4
P261-402 
VISIT 1 (Screening) 
within 28 days of 
P261-401 Visit 4
Are all eligibility 
criteria for this study
(P261-402) met?
Enroll at Visit 1
VISIT 3
VISIT Xb
Yes
VISIT 2
No
No further 
study participation
Dispense 1 study drug 
treatment kita
Dispense 1 study drug 
treatment kita
Dispense 2 study drug 
treatment kitsa
Dispense 2 study drug 
treatment kitsa
Final Visit or Early Termination
1 USL261-treated seizure 
cluster episode
1 USL261-treated seizure 
cluster episode
2 USL261-treated seizure 
cluster episodes
2 USL261-treated seizure 
cluster episodes
a Each study drug treatment kit contains two 5.0 mg doses of USL261
b Visits will continue until the Final Visit or Early Termination
3.2
Screening
After subjects and their caregivers have provided informed consent (and, when appropriate, 
assent), subjects will undergo screening procedures at Visit 1 (which may occur at the same time 
as or up to 28 days after Visit 4 of the preceding double-blind study P261-401). If Visit 1 of this 
study (P261-402) is on the same day as Visit 4 of study P261-401, the procedures performed at 
Visit 4 of study P261-401 that are common to Visit 1 will be used for both studies. If Visit 1 for 
this study (P261-402) is not on the same day as Visit 4 of P261-401, all necessary procedures 
will be repeated, except for physical exam, neurological exam, nasal exam, and clinical 
laboratory testing (hematology, serum chemistry and urinalysis).  The time between Visit 4 of 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
35 of 124
Upsher-Smith Laboratories, Inc.
study P261-401 and Visit 1 of study P261-402 will be a maximum of 28 days. The time between 
Visit 4 of study P261-401 and Visit 1 of study P261-402 may be extended in certain cases; 
however, the extension must be approved by the Sponsor or CRO designee. If an extension is 
granted for a given subject, that subject may have to undergo repeat screening laboratory 
assessments within 28 days prior to dispensing study drug.
If the subject meets the eligibility requirements for this study, the subject/caregiver will be 
provided with a study materials kit at Visit 1. The study materials kit will contain at a minimum
the Subject Workbook, the subject’s individualized Patient Management Plan (PMP), summary 
of PMP, one study drug treatment kit containing two 5.0 mg doses of USL261, and dosing 
instructions.  The PMP will specify at a minimum the criteria for seizure cluster recognition and
a rescue protocol individualized for the subject.  
3.3
Treatment Phase
Caregivers will administer the first 5.0 mg dose of USL261 at the time of recognition of a seizure 
cluster that meets study criteria (according to the subject’s PMP). A second dose of USL261
5.0 mg may be administered if (a) the treated seizure cluster has not terminated within 
10 minutes after the first dose, or (b) another seizure occurs between 10 minutes and 6 hours 
after administration of the study drug, AND (in both a and b) the subject does not have a 
respiratory rate < 8 breaths per minute, does not require emergency rescue treatment with 
assisted breathing or intubation, and does not have excessive, uncharacteristic sedation (as 
defined by the investigator in the PMP).  The caregiver will monitor the subject for 24 hours 
after study drug administration to record safety and efficacy assessments. The caregiver will call 
the study center as soon as possible, but no later than 24 hours, after each USL261-treated 
seizure cluster episode. If seizure cluster activity persists or recurs following the administration 
of the second dose, caregivers will initiate the rescue protocol as outlined in the subject’s PMP.  
For Visits 2 and 3, which occur after each of the first 2 USL261-treated seizure cluster episodes, 
the subject and caregiver will return to the study center within 120 hours (5 days) of study drug 
administration. 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
36 of 124
Upsher-Smith Laboratories, Inc.
After Visit 3, if the study drug has successfully treated the subject’s seizure cluster episodes, the 
subject has tolerated the study drug treatment well in the judgment of the investigator, and the 
subject and caregiver have been compliant with the study procedures including completion of the 
Subject Workbooks and return of the study drug (used and unused), the subject and caregiver 
will be instructed to return to the study center after every second seizure cluster episode treated 
with USL261 until the Final Visit or Early Termination. A minimum of 3 days (72 hours) is 
required between treatments with study drug.
All study drug containers dispensed, whether used or unused, and Subject Workbooks are to be 
returned at the next study visit throughout the study.  The study center will make monthly 
telephone calls between visits to caregiver(s) and subject (if subject is able to communicate 
adequately as determined by the investigator) when visits are more than 1 month apart.  If 
6 months pass without the subject having a seizure cluster episode, the subject and caregiver will 
be asked to come to the study center for re-training on study procedures.
The subject or caregiver will immediately report to the investigator (or his/her designee) as soon 
as possible any significant medical event (including events that are life-threatening or that result 
in death, hospitalization or prolonged hospitalization, persistent or significant disability, or 
incapacity of the subject) that occurs to the subject from the time written informed consent is 
obtained until completion of the final study visit or 7 days after last administration of study drug 
, whichever is later. The subject or caregiver may also call the study center at any time during 
the study for help or advice regarding study procedures.  
4
RATIONALE
4.1
Rationale for the Study
This study was designed to provide extended subject access to USL261 as an outpatient
treatment option for seizure clusters in subjects with partial or generalized epilepsy with a 
documented history of seizure clusters who participated in study P261-401 and to establish the 
long-term safety and tolerability of USL261.  
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
37 of 124
Upsher-Smith Laboratories, Inc.
4.2
Rationale for the Study Design
The open-label study design allows subjects who participated in study P261-401 to continue 
receiving long-term treatment with USL261 at the same investigational dose and to provide 
long-term safety data of USL261.
4.3
Rationale for the Dosage
The proposed dosage in this study (P261-402) is from the double-blind study (P261-401); 
therefore, it will be continued in this open-label extension study.  The 5.0 mg midazolam 
USL261 dose is expected to be safe and efficacious, and the 10 mg total dose of USL261 is well 
within the range of doses correlated with efficacy and has been found to be safe.[18, 31]
The 5.0 mg dose of USL261 used for this phase III trial is based on safety data reported in 2 
ITI-sponsored phase I clinical trials as well as the published literature.  The ITI-sponsored 
clinical trials are described briefly below.
!
MZ0714: an open-label, 5-way crossover PK/PD safety trial in which 25 healthy adult 
volunteers were randomly assigned to 1 of 5 treatment sequences.  Subjects received 
single treatments of USL261 at doses of 2.5 mg, 5.0 mg, and 7.5 mg; 2.5 mg midazolam 
IV infusion over 15-minutes as sterile injection solution; and 5.0 mg midazolam sterile 
injection solution administered intranasally.
!
MZ0815: an open-label, in-patient, PK/PD/safety study of ascending single dose and 
2 doses of USL261 (2.5 mg, 5.0 mg, and 7.5 mg) given to 90 adult and adolescent 
epilepsy patients on separate study visits separated by 3 or more days.  At Visit 1,
subjects received a single dose of USL261 (2.5 mg, 5.0 mg, or 7.5 mg). At Visit 2, 
subjects were provided a 2-dose regimen of USL261 with the total dosage ranging from 
5.0 mg to 15.0 mg over a 15-minute period.  The first dose of USL261 at Visit 2 was 
identical to the dose strength of USL261 they received at Visit 1.  The second dose, 
administered 15 minutes later, was either identical in strength to previous doses or lower 
than the previously administered doses.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
38 of 124
Upsher-Smith Laboratories, Inc.
The PK parameters from the adult subjects in these 2 studies were generally similar, with the
exception of AUC values, which were approximately 25% −39% lower in MZ0815 compared 
with those in MZ0714.  This difference may be due to the different populations studied;  healthy 
adults (MZ0714) versus subjects diagnosed with epilepsy (MZ0815) who were taking 
concomitant medications, including AEDs known to induce CYP450 3A.  Data from MZ0815 
showed increasing midazolam plasma concentrations with increasing doses. Midazolam Cmax
was lower in adolescents as compared to adults.
The results from MZ0815 are similar to published PK data for midazolam in adults with 
epilepsy.  In a study of 12 subjects with epilepsy, midazolam was administered IM in doses of 
5.0 mg, 7.0 mg, and 10 mg. IM-administered midazolam resulted in a range of mean 
AUC values from 138 to 167 mg*hr/L and mean Cmax values from 22 to 78 ng/mL with no report 
of SAEs, such as respiratory depression.[12]  Furthermore, data from the published literature 
demonstrated that 0.1 to 0.3 mg/kg of the IV formulation of midazolam administered intranasally 
(5 mg to > 20 mg fixed-dose per subject) effectively terminated seizure activity in most 
subjects.[21, 25, 39]  These doses have seldom caused excessive sedation or respiratory 
depression.[40] 
Based on the current literature, a single 5.0 mg dose of USL261 should provide the majority of 
subjects the appropriate balance of safety and efficacy.  High inter-subject PK variability has 
been attributed to the cerebral GABAA receptor binding characteristics of midazolam as well as 
the drug’s complex distribution and metabolism. Therefore, for subjects who do not respond 
within 10 minutes after administration of 5.0 mg USL261, a second 5.0 mg dose may be 
administered.  
5
SUBJECT SELECTION
5.1
Number of Subjects
Since enrollment is limited to subjects who have participated in Study P261-401, a maximum of 
240 subjects (the planned number of subjects completing the Comparative Phase in P261-401) 
are expected to enroll in the study.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
39 of 124
Upsher-Smith Laboratories, Inc.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subject or subject’s legally acceptable representative (LAR) has provided written 
informed consent, and subject has provided written assent where required by local law or 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) policy.
2. Subject has a competent, adult (age ≥ 18 years) caregiver(s) who is able to recognize and 
observe the subject’s seizure cluster episodes, who is willing to be trained in the study 
procedures, and has provided written informed consent; the caregiver(s) must be a 
relative, partner, friend, or LAR of the subject, or a person who provides daily care to the 
subject who has a significant personal relationship with the subject.
3. Subject is 12 years of age or older at Visit 1.
4. Subject has an established diagnosis of partial or generalized epilepsy.
5. Subject has a documented history of seizure clusters that includes all of the following:
a.
The subject’s seizure cluster pattern is observable, stereotyped, and recognizably 
different from the subject’s other non-cluster seizure activity (if any) in seizure 
type, duration, severity, or frequency, and of the same type as that approved by 
the central reviewer in study P261-401.
b. A documented history of seizure clusters lasting a minimum of 10 minutes from 
the time the seizure cluster is recognized.
c.
As part of the subject’s stereotyped seizure cluster pattern, a second seizure 
typically occurs within 6 hours from the time of recognition of the seizure cluster.
d. The subject’s stereotyped seizure cluster pattern is composed of multiple (≥ 2) 
partial or generalized seizures.
e.
The subject’s stereotyped seizure cluster pattern was established > 3 months 
before Visit 1 of study P261-401.
f.
A frequency of ≥ 3 stereotyped seizure clusters during the year before Visit 1 of 
study P261-401.
g. At least 1 stereotyped seizure cluster occurring at least once in the 4 months 
before Visit 1 of study P261-401.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
40 of 124
Upsher-Smith Laboratories, Inc.
6. Subject has successfully completed study P261-401, and the subject and caregiver have
demonstrated adequate compliance with P261-401 study procedures as determined by the 
investigator OR, if Study P261-401 has been terminated, the subject completed the Test 
Dose Visit (Visit 2) of Study P261-401 and the subject did not meet any Visit 2 exclusion 
criteria in Study P261-401.
7. Subject is not likely to conceive, as indicated by a “yes” answer to at least 1 of the 
following questions:
a.
Is the subject a male?
b. Is the subject a postmenopausal female as determined in study P261-401?
c.
Is the subject a female who has written medical documentation of being 
permanently sterilized (e.g. hysterectomy, double oophorectomy, bilateral 
salpingectomy)?
d. Has the subject agreed to use two effective methods of contraception during the 
entire study if she is sexually active or will become sexually active during the 
study (except where local law or regulation differs; approval by USL or designee 
is required in such cases)?
Examples of two effective methods of contraception include the following: 
 A diaphragm and a condom with spermicide
 An intrauterine device (IUD) used in combination with a barrier method (e.g., 
condom, diaphragm, or cervical cap with spermicide)
 Hormonal methods (e.g., high-dose birth control pills, Depo-Provera) or tubal 
ligation used in combination with a barrier method (e.g., condom, diaphragm, 
or cervical cap with spermicide)
Note that hormonal contraception alone is not considered adequate for this study and 
must be used in combination with another method.  The type of birth control used 
must be approved by the investigator or designee.
5.3
Exclusion Criteria
Any subject who meets 1 or more of the following criteria will be excluded from the study:
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
41 of 124
Upsher-Smith Laboratories, Inc.
1. Subject experienced a seizure cluster progressing to status epilepticus during or since 
his/her participation in Study P261-401.
2. Subject has a positive pregnancy test at any visit or is pregnant, considering becoming 
pregnant, or is breastfeeding (female subjects only).
3. Subject who, in the opinion of the investigator, is experiencing an ongoing, uncontrolled, 
clinically significant adverse event(s) from P261-401 at Visit 1 or did experience a 
clinically significant adverse event in study P261-401 that might prevent the subject from 
safely participating in the study.
4. Subject has consumed any clinically significant CYP450 3A inhibitor/inducer, opioid, or 
other respiratory depressant, not including antiepileptic drugs (AEDs), within the 
required washout period before Visit 1 (see Appendix 1, Prohibited Concomitant 
Substances).
5. Subjects using chronic benzodiazepine(s); chronic use is defined as use for 4 or more 
days in a 7-day period on average.
6. Subject has a neurological disorder that is likely to progress in the next year.
7. Subject has a history of acute narrow-angle glaucoma.
8. Subject has a medical condition including uncontrolled cardiac, pulmonary, renal, 
hepatic, or gastrointestinal disease that could interfere with the study, subject 
safety/safety monitoring, or is not stable despite current therapy.
9. Subject has severe chronic cardio-respiratory disease with baseline room air oxygen 
saturations < 90%, New York Heart Association class III or IV functional status, or the 
need for ambulatory oxygen.
10. Subject has had psychogenic, non-epileptic seizure(s) during or since the P261-401 study.
11. Subject has suicidality, defined as any of the following: a) active suicidal plan/intent or 
active suicidal thoughts during or since the P261-401 study as defined by a C-SSRS 
suicidal ideation score ≥ 3, b) any suicide attempt during or since the P261-401 study as 
determined by the C-SSRS or medical history, or c) other clinically significant suicidality
as determined by the investigator.
12. Subject, in the investigator’s opinion, has met the criteria for a major depressive episode 
during or since the P261-401 study (criteria defined by the current edition of the 
Diagnostic and Statistical Manual of Mental Disorders).
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
42 of 124
Upsher-Smith Laboratories, Inc.
13. Subject has or has had psychosis during or since the P261-401 study, excluding postictal 
psychosis.
14. Subject has a history of drug or alcohol abuse during or since study P261-401.
15. Subject has a history of allergy or any significant adverse reaction (including rash) to 
midazolam.
16. Subject is currently using an investigational drug or device or has used such (other than 
the study drug during P261-401) within 30 days prior to Visit 1.
17. Subject has plasma phenobarbital concentrations > 35 μg/mL at Visit 1 (phenobarbital 
concentration will be measured in subjects taking phenobarbital and in subjects for which 
the investigator deems it necessary).
18. Subject is not appropriate for the study for any other reason as determined by the 
investigator.
5.4
Informed Consent
Each prospective subject or the subject’s LAR will provide written informed consent before any 
P261-402-specific screening evaluations or other study procedures are performed at Visit 1.  
Legally acceptable representative is defined as an individual, judicial, or other body authorized 
under applicable law to consent on behalf of a prospective subject to the subject’s participation 
in the procedure(s) involved in the research.  In addition, each subject’s competent caregiver(s)
will sign a separate caregiver consent form before any study procedures are performed on the 
subject.
Informed consent will be given by means of a standard statement, written in non-technical 
language, which explains the nature of the study, its purpose, procedures, expected duration, 
alternative therapy available, the benefits and risks involved in study participation, and any 
discomfort study participation may entail. The investigator or his/her designee must emphasize 
to the subject, the subject’s LAR (if applicable), and the caregiver that study participation is 
entirely voluntary and that consent regarding study participation may be withdrawn at any time 
without penalty or loss of benefits to which the subject is otherwise entitled or affecting
subsequent medical treatment or relationship with the treating physician.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
43 of 124
Upsher-Smith Laboratories, Inc.
The subject, or subject’s LAR, will read and consider the statement and be allowed to ask any 
questions before signing and dating it, and he/she should be given a copy of the signed 
document. The person conducting the informed consent discussions must personally date and 
sign the informed consent form (ICF).  The investigator will retain the original signed ICF.
Some subjects will provide written consent in the form of an assent form before any screening 
evaluation or other study procedure is performed, if required by local law or IRB/IEC policy.  In 
these cases, the ICF will be signed by the subject’s LAR.  The assent form will provide similar 
information as the ICF, and the same procedures will be followed as described above for the ICF.  
The assent form must be signed and dated by the subject and the qualified research professional 
obtaining the consent. 
No subject can enter the study and no study-related procedures can be performed before 
informed consent has been obtained.  The time at which consent was provided will also be 
recorded on the consent form.
Prior to consenting subjects, the investigator or designee must submit the ICF with the study 
protocol for IRB/IEC approval. All proposed ICFs must be reviewed and approved by the 
sponsor or its designee before submission to the IRB/IEC. All informed consent and assent 
forms will be reviewed by the IRB/IEC and approved (IRB) or a favorable opinion received 
(IEC) before use in this study. Informed consent will be obtained in a manner consistent with 
GCP. A copy of the approved version must be provided to the sponsor or the study monitor after 
IRB approval/IEC favorable opinion.
The flow of informed consent is detailed in Figure 2.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
44 of 124
Upsher-Smith Laboratories, Inc.
Figure 2. Flow of Informed Consent
5.5
Authorization to Use and Disclose Medical Information
Each subject will be identified by initials (3 letters), date of birth, and a unique study number.  In 
countries where the subjects’ initials and/or date of birth cannot be used by local regulations, 
study centers will use dummy initials and/or year of birth only.
All countries must follow local law(s) for authorization to use and disclose medical information.  
The remainder of this section (Section 5.5) only applies to study centers in the US.
Under US federal law, subject study records cannot be used or disclosed for research purposes 
unless an authorization to use and disclose medical information is signed by each subject prior to 
participation in the study. The investigator or designated assistant will explain to each subject or 
subject’s LAR the purpose of the subject authorization and the disclosures agreed to by signing 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
45 of 124
Upsher-Smith Laboratories, Inc.
the authorization document. Subjects will be given an authorization document and will have the 
opportunity to ask questions.  Subjects must also be informed of the following:
!
They may not participate in the study unless the authorization is signed; however, they 
have the right to revoke this authorization (in writing) at any time.
!
If they discontinue from the study, they are not required to revoke the authorization to use 
and disclose their medical information.
!
If they discontinue from the study and do decide to revoke their authorization to use and 
disclose their medical information, the information that has already been collected in 
their study records may be used and disclosed as necessary to protect the integrity of the 
research project.
After this explanation and before any study-specific procedures have been performed, the subject 
or subject’s LAR will voluntarily sign and date an authorization document.  Prior to participation 
in the study, the subject or subject’s LAR will receive a copy of the signed and dated written 
authorization. Authorization to disclose Protected Health Information for research will be 
obtained in accordance with Health Insurance Portability and Accountability Act (HIPAA) 
regulations 45 CFR Parts 160 and 164.  
6
STUDY METHODOLOGY
6.1
Study Procedures
The following section describes in detail all study procedures. A summary table of all required 
study procedures is presented in Table 1, and the timing for each procedure is described in the 
appropriate subsection. An electronic case report form (eCRF) is provided for data collection for 
all subjects.
The duration of each subject’s participation will be up to approximately 4 years from the date of 
enrollment (Visit 1). After this period, the study duration may be extended until marketing 
approval or a time period as approved by the Heath Authority where the study is being 
conducted. There is no limitation on the total number of seizure cluster episodes treated during 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
46 of 124
Upsher-Smith Laboratories, Inc.
the subject’s participation in the study.  Therefore, the number of visits in the study will vary for 
each subject.
6.1.1
Visit 1 (Screening Visit)
Before any study procedure unique to this study (P261-402) is performed, the subject (or 
subject’s LAR) will provide written informed consent (see Section 5.4, Informed Consent).  
Procedures at Visit 1 may occur at the same time as Visit 4 of the preceding double-blind study 
(P261-401) or up to 28 days after Visit 4 of study P261-401.  If Visit 1 of this study (P261-402) 
is on the same day as Visit 4 of study P261-401, the procedures performed at Visit 4 of Study 
P261-401 that are common to Visit 1 will be used for both studies. If Visit 1 for this study 
(P261-402) is not on the same day as Visit 4 of P261-401, all necessary procedures will be 
repeated, except for physical examination, neurological examination, nasal examination, and 
clinical laboratory testing (hematology, serum chemistry, and urinalysis).
At Visit 1 (Screening)
!
Obtain informed consent of subject (or subject’s LAR).
!
Obtain assent of subject, if applicable.
!
Obtain informed consent of caregiver(s).
!
Contact Interactive Response Technology (IRT) system to register subject and obtain the 
study drug kit number.
!
Assessment of inclusion/exclusion criteria.
!
Caregiver training on study procedures.
!
Verify that caregiver has a valid CPR training certificate. If the caregiver does not have 
one, he/she needs to complete CPR training before the subject/caregiver takes home the 
study drug.
!
Update medical and surgical history from Study P261-401, including seizure history.
!
Collect concomitant medications.
!
Update PMP, if necessary; PMP must be final before subject receives study materials kit.
!
Complete physical, nasal, and neurological examinations.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
47 of 124
Upsher-Smith Laboratories, Inc.
!
Collect blood and urine samples for clinical laboratory testing (serum chemistry, 
hematology, urinalysis, and phenobarbital levels for subjects taking phenobarbital and 
subjects for which the investigator deems it necessary).
!
Perform urine pregnancy test (all females of childbearing potential; see Section 6.2.2.4).
!
Measure height.
!
Measure body weight.
!
Measure vital signs (BP, HR, respiration rate, temperature).
!
Perform C-SSRS, Since Last Visit version.
!
Subject and caregiver to complete the outcomes questionnaires (see Section 6.2.3).
!
Collect and record AEs.
Eligible subjects/caregivers will receive a study materials kit at Visit 1, which includes the 
following at minimum:
!
Individualized PMP.
!
Summary of the PMP.
!
Subject Workbook.
!
Study drug (1 study drug kit containing two 5.0-mg doses of USL261).
!
Dosing instructions.
6.1.2
Visit 2 through Visit X
Visits 2 and 3 will take place within 120 hours (5 days) following each of the first 2 
USL261-treated seizure cluster episodes. All subsequent visits will take place within 120 hours 
(5 days) after every second seizure cluster episode treated with USL261. 
At Visits 2, 3, and all subsequent visits (except for the Final Visit or Early Termination Visit),
the investigator or other qualified study personnel will perform the following procedures:
!
Contact Interactive Response Technology (IRT) system to obtain study drug kit number
!
Review, assess, and re-instruct subjects and caregivers on study procedures.
!
Verify that caregiver has a valid CPR training certificate. If the caregiver does not have 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
48 of 124
Upsher-Smith Laboratories, Inc.
one, he/she needs to complete CPR training before the subject/caregiver takes home the 
study drug.
!
Collect concomitant therapy.
!
Collect number of calls to EMS and ER visits for a seizure cluster or other seizure 
emergency since last visit or follow-up phone call.
!
Perform physical, nasal, and brief neurological examinations.
!
Administer B-SIT (see Section 6.2.2.6)
!
Perform clinical laboratory assessments (hematology, serum chemistry, and urinalysis).
!
Perform urine pregnancy test (all females of childbearing potential; see Section 6.2.2.4).
!
Measure body weight.
!
Measure vital signs (BP, HR, respiration rate, temperature).
!
Perform C-SSRS, Since Last Visit version.
!
Subject and caregiver to complete outcomes questionnaires (see Section 6.2.3).
!
Dispense study drug: One study drug kit will be dispensed at Visit 2. Two study drug 
kits will be dispensed at Visit 3 and all subsequent visits (except for the Final Visit or ET
Visit).
!
Collect used and unused study drug containers and perform drug accountability.
!
Collect and review Subject Workbook and re-dispense new Subject Workbook to 
caregiver/subject.
!
Collect and record AEs.
6.1.3
Treatment – First 2 Years in the Study
During the first 2 years of participation in the study, the caregiver will document in the Subject 
Workbook all seizure activity that occurs on the day of the seizure cluster (beginning when the 
seizure cluster is recognized and for 24 hours after the subject receives USL261). Seizure
activity will be documented by writing the date and time of onset of each seizure, the date and 
time of seizure termination, the type of seizure experienced, and any additional treatment 
intervention (e.g., medication, call for EMS) for each seizure or seizure cluster. Unwitnessed 
seizures should also be recorded, with the information estimated to the best of the subject’s or 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
49 of 124
Upsher-Smith Laboratories, Inc.
caregiver’s ability.
When a seizure cluster episode is identified that meets the study criteria as outlined in the 
subject’s individualized PMP, the caregiver will do the following:
!
Note the time of recognition of seizure cluster onset (clock time).
!
Administer a 5.0 mg dose of USL261 to the subject.
!
Note the time that USL261 was administered and the nostril into which it was
administered.
!
Call the study center as soon as possible, but no later than 24 hours, after study drug 
administration.
!
Measure and record the subject’s respiration rate by counting the breaths taken in a 
30-second interval at approximately the following times after study drug administration: 
10, 15 and 30 minutes, then 1, 2, and 4 hours. Respiration rate will be measured at these 
times whether or not the seizure cluster has ended, unless, for reasons of subject safety, 
this assessment cannot be performed.
!
Administer the second dose of USL261 5.0 mg if the initial seizure cluster episode has 
not terminated within 10 minutes after the initial drug administration or another seizure 
occurs between 10 minutes and 6 hours after administration of the study drug AND the 
subject does not have a respiratory rate < 8 breaths per minute, does not require
emergency rescue treatment with assisted breathing or intubation, and does not have 
excessive, uncharacteristic sedation (as defined by the investigator in the PMP). If 
seizure activity persists or recurs following the administration of the second dose, 
caregivers will initiate the rescue protocol as outlined in the subject’s PMP.
When the seizure cluster episode ends, the caregiver will do the following:
!
Note and record the time in the Subject Workbook.
!
Evaluate the subject’s return to baseline functionality by recording the time when the 
subject was able to return to what he/she was doing in the Subject Workbook.
!
Ensure that the Subject Workbook is completed as accurately as possible.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
50 of 124
Upsher-Smith Laboratories, Inc.
The caregiver will continue to record all seizure activity in the Subject Workbook for 24 hours 
after the subject received study drug. Any changes in the subject’s overall health, medications 
that the subject received, and device use by the subject for 24 hours after the subject received 
study drug will also be recorded in the Subject Workbook.
Caregivers must contact the study center after every treated cluster episode as soon as possible, 
but no later than 24 hours after study drug administration.
6.1.4
Treatment – After 2 Years in the Study
After the first 2 years of participation in the study the caregiver will document in the Subject 
Workbook seizure activity that occurs on the day of the seizure cluster treated with USL261.  
Seizure activity will be documented by writing the date and time of recognition of the seizure 
cluster, the date and time of study drug administration (first and second dose, if given), if there is 
an ongoing seizure at 10 minutes after administration of the first dose (yes/no), start date and 
time of the first seizure that occurs between 10 minutes and 24 hours from first and second (if 
given) USL261 dose.
When a seizure cluster episode is identified that meets the study criteria as outlined in the 
subject’s individualized PMP, the caregiver will do the following:
!
Note the time of recognition of seizure cluster onset (clock time).
!
Administer a 5.0 mg dose of USL261 to the subject.
!
Note the time that USL261 was administered and the nostril into which it was 
administered.
!
Call the study site as soon as possible, but no later than 24 hours, after study drug 
administration.
!
Measure and record the subject’s respiration rate by counting the breaths taken in a 
30-second interval at approximately the following times after study drug administration:  
10, 15 and 30 minutes, then 1, 2, and 4 hours. Respiration rate will be measured at these 
times whether or not the seizure cluster has ended, unless, for reasons of subject safety, 
this assessment cannot be performed.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
51 of 124
Upsher-Smith Laboratories, Inc.
!
Record if there is ongoing seizure activity at 10 minutes after the first study drug dose 
(yes/no).
!
Record the start time of the next seizure following first study drug dose, if it occurs 
within 24 hours of the first dose administration.
!
Administer the second dose of USL261 5.0 mg if the initial seizure cluster episode has 
not terminated within 10 minutes after the initial drug administration or another seizure 
occurs between 10 minutes and 6 hours after administration of the study drug AND the 
subject does not have a respiratory rate < 8 breaths per minute, does not require
emergency rescue treatment with assisted breathing or intubation, and does not have 
excessive, uncharacteristic sedation (as defined by the investigator in the PMP). If 
seizure activity persists or recurs following the administration of the second dose, 
caregivers will initiate the rescue protocol as outlined in the subject’s PMP.
!
Record the start time of the next seizure following second dose of study drug, if it occurs 
within 24 hours of the second dose administration.
When the seizure cluster episode ends, the caregiver will do the following:
!
Note and record the time in the Subject Workbook.
!
Evaluate the subject’s return to baseline functionality by recording the time when the 
subject was able to return to what he/she was doing in the Subject Workbook.
!
Ensure that the Subject Workbook is completed as accurately as possible.
The caregiver will record any changes in the subject’s overall health, medications that the subject 
received, and device use by the subject for 24 hours after the subject received study drug in the 
Subject Workbook.
Caregivers must contact the study center after every treated cluster episode as soon as possible, 
but no later than 24 hours after study drug administration.
6.1.5
Final Visit or Early Termination Visit
Subjects and caregivers will return to the study center for the Final Visit. Subjects who are 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
52 of 124
Upsher-Smith Laboratories, Inc.
prematurely discontinued or who terminate their study participation after Visit 1 will also have 
Final Visit / Early Termination (ET) procedures performed as soon as possible, but within 7 days 
after withdrawal or discontinuation.  At the Final Visit or ET Visit, study center staff will collect 
the following items or information:
!
The Subject Workbook (the Subject Workbook will also be reviewed by the study center 
staff with the caregiver).
!
The used and unused study drug container(s) (drug accountability will also be 
performed).
!
Other study materials provided to the subject/caregiver.
Additionally, the following will be measured or performed:
!
Contact Interactive Response Technology (IRT) system.
!
Concomitant medication review.
!
Collect number of calls to EMS and ER visits for a seizure cluster or other seizure 
emergency since last visit or follow-up phone call.
!
Complete physical, nasal and neurological examinations.
!
Administer B-SIT (see Section 6.2.2.6)
!
Perform urine pregnancy test (all females of childbearing potential; see Section 6.2.2.4).
!
Collect blood and urine samples for clinical laboratory testing (serum chemistry, 
hematology, urinalysis, and phenobarbital [if necessary]).
!
Measure height.
!
Measure body weight.
!
Measure vital signs (BP, HR, respiration rate, temperature).
!
Perform C-SSRS, Since Last Visit version.
!
Subject and caregiver to complete outcomes questionnaires (see Section 6.2.3).
!
Collect and record AEs.
6.1.6
Telephone Follow-Up and Support
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
53 of 124
Upsher-Smith Laboratories, Inc.
After Visit 1, the study coordinator or designee will call the caregiver(s) and subject (if subject is 
able to communicate adequately as determined by the investigator) at least once every 30 days
(between visits that are at least 1 month apart) until the subject has completed or prematurely 
discontinued from the study. On these telephone calls, a member of the study center personnel 
will perform the following at a minimum:
!
Verify that at least 1 caregiver is still available.
!
Verify that caregiver has a valid CPR training certificate.  If the caregiver does not have 
one, he/she needs to complete CPR training before administering study drug.
!
Ask about any seizure clusters that occurred.
!
Ask about whether the study drug kit is still accessible and available.
!
Review study procedures and retrain, if necessary.
!
Answer any questions the caregiver or subject may have about the study or study 
procedures.
!
Collect AEs.
!
Collect changes in concomitant medications.
!
Collect number of calls to EMS and ER visits for a seizure cluster or other seizure 
emergency since last visit or follow-up phone call.
6.1.7
Dosage Instructions
For each seizure cluster episode treated with study drug, subjects will receive USL261 5.0 mg,
administered as a single actuation into either nostril.  In addition, each subject may receive a 
second dose of USL261 5.0 mg administered into the opposite nostril if either of the following 
occurs:
!
The seizure cluster has not terminated within 10 minutes after the first 5.0-mg dose of 
USL261 was administered provided that the subject does not have a respiratory rate
< 8 breaths per minute, does not require emergency rescue treatment with assisted 
breathing or intubation, and does not have excessive, uncharacteristic sedation (as 
defined by the investigator in the PMP).
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
54 of 124
Upsher-Smith Laboratories, Inc.
OR
!
Another seizure occurs between 10 minutes and 6 hours after study drug administration 
provided that the subject does not have a respiratory rate < 8 breaths per minute, does not 
require emergency rescue treatment with assisted breathing or intubation, and does not 
have excessive, uncharacteristic sedation (as defined by the investigator in the PMP).
6.2
Methods of Assessment
6.2.1
Efficacy Assessments
Information recorded in the Subject Workbook (see Section 9.3.2) will be used for analysis of 
the efficacy endpoints (see Section 10.5.1). 
Efficacy will be determined using the following information at a minimum, which will be 
recorded by the caregiver in the Subject Workbook:
!
Date and time of study drug administration.
!
Seizure activity:
o
For the first 2 years of participation in the study the date, start, and stop time of 
each seizure within 24 hours after any study drug administration.
o
After the first 2 years participation in the study the date and start time of next 
seizure within 10 minutes to 24 hours after administration of the first and second 
dose of study drug.
!
Date and time when subject has returned to full baseline functionality after the treated 
seizure cluster, as determined by the caregiver. The caregiver will evaluate subject’s 
return to baseline functionality by recording the time when the subject was able to return 
to what he/she was doing.
6.2.2
Safety Assessments
6.2.2.1
Medical History
Any changes in medical history since the last visit of Study P261-401 will be recorded for each 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
55 of 124
Upsher-Smith Laboratories, Inc.
subject by qualified medical personnel at Visit 1. Changes to medical history during the study 
will be reviewed by the investigator and noted as an AE, if appropriate.
6.2.2.2
Physical, Nasal, and Neurological Examinations
Physical, nasal, and neurological examinations will be conducted by a qualified investigator or 
sub-investigator. The complete physical examination will include height and weight 
measurements, assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, 
abdomen, lymph nodes, and extremities. The nasal cavity examination will be performed using a 
nasal speculum.
At Visit 1 (which may occur at the same time as or up to 28 days after Visit 4 of the preceding 
double-blind Study P261-401), subjects will undergo complete physical, nasal, and neurological 
examinations. The physical, nasal, and neurological examinations performed at Visit 4 of
Study P261-401 will be used for Visit 1 of this study.
At Visits 2, 3, and all subsequent visits (except for the Final Visit or ET Visit), subjects will 
undergo a complete physical examination, nasal examination, and a brief neurological 
examination. At the Final Visit or ET Visit, subjects will undergo complete physical, nasal and 
neurological examinations.
Height will be measured at Visit 1 and the Final Visit or ET Visit only.
Any new clinically significant findings/abnormalities or worsening of Visit 1 findings that meet 
the definition of an AE must be recorded as both an examination finding and as an AE.
6.2.2.3
Vital Signs
Vital signs will be measured by qualified study personnel at least once during each study visit. 
At each visit, the following vital signs will be measured while the subject is seated and has been 
seated for at least 5 minutes:
!
Systolic and diastolic BP
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
56 of 124
Upsher-Smith Laboratories, Inc.
!
HR
!
Respiration rate
!
Body temperature
During the study, caregivers will measure respiration rate at approximately 10, 15 and 30 
minutes and 1, 2 and 4 hours after study drug administration, and record the findings in the 
Subject Workbook. To determine respiration rate, the caregiver will count the number of breaths 
taken by the subject during a 30-second interval and will record the number of breaths in the 
Subject Workbook. These timed respiration rate measurements will start over if the second dose 
is given.
6.2.2.4
Clinical Laboratory Assessments
All subjects will have the clinical laboratory tests performed as listed in Table 4.  The total 
volume of blood collected will be approximately 30 mL (2 tablespoons) per subject. Subject 
fasting is not required before collection of clinical laboratory blood or urine samples.
Female subjects of childbearing potential will undergo urine pregnancy tests for beta-human 
chorionic gonadotropin (β-hCG) at all visits. Test results must be negative at these visits for a 
subject to be enrolled or continue in the study. Females of childbearing potential will be those 
who are not one of the following:
!
A postmenopausal female with greater than 1 year since last menses and a FSH value 
greater than 40 mIU/mL at Visit 1 of study P261-401 or during studies P261-401 and 
P261-402
!
A female who has written documentation of being permanently sterilized (e.g. 
hysterectomy, double oophorectomy, bilateral salpingectomy). Note that tubal ligation is 
not considered a permanent form of sterilization for this study.
A report of the laboratory values will be sent to the study center by the central laboratory; the 
investigator will review the laboratory report and indicate the clinical significance of all 
abnormal values, and then sign and file the laboratory report in the subject’s study file.  
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
58 of 124
Upsher-Smith Laboratories, Inc.
Urine pregnancy tests will be performed by qualified research staff at the study center. Blood 
samples will be collected while the subject is in a seated or supine position.
6.2.2.4.2
Abnormal Clinical Laboratory Findings
Laboratory tests must be repeated if the result is abnormal and clinically significant regardless of 
causality. The investigator will exercise medical judgment in deciding whether abnormal 
laboratory values are clinically significant.  In some cases, significant changes within the range 
of normal will require similar judgment by the investigator. If the investigator considers the 
confirmed abnormal laboratory value to be clinically significant, see Section 7.3 to report as an 
AE.
6.2.2.5
Columbia-Suicide Severity Rating Scale
The C-SSRS is a clinician-rated scale that assesses suicidal behavior and ideation.  The Since 
Last Visit version will be administered at all visits. The C-SSRS will be administered by 
qualified, trained raters.  In cases where the subject is cognitively impaired and not able to 
provide responses to the C-SSRS interview, every effort should be made to complete the scale 
using other sources of information from the subject’s medical records, caregiver, LAR, guardian, 
parent(s), teacher(s), and/or relative(s).
6.2.2.6
Brief Smell Identification Test (B-SIT)
The Brief Smell Identification Test (B-SIT) will be conducted to assess olfactory function. The B-
SIT is a brief 12-item, self-administered microencapsulated odorant test for measuring olfactory 
function. 
The B-SIT will be conducted at Visit 2 through X and the Final or ET Visit, except in cases 
where obtaining this information is not feasible or appropriate, as determined by the investigator. 
In addition, the B-SIT will be performed only if a validated version in the appropriate language 
is available.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
59 of 124
Upsher-Smith Laboratories, Inc.
6.2.3
Outcomes Questionnaires
The outcomes questionnaires should be completed at each visit described below except in cases 
where the subject or caregiver refuses or obtaining this information is not feasible; in these 
situations the questionnaires listed below are optional.
6.2.3.1
SF-12v2 Health Survey (SF-12v2)
The SF-12v2 is a 7-question, short-form health survey that is designed to collect data on patient 
and caregiver health-related quality of life.  The SF-12v2 will be self-administered by both the 
subject and by the caregiver individually at Visit 1 and the Final Visit or ET Visit.
6.2.3.2
Treatment Satisfaction Questionnaire for Medication (TSQM)
The TSQM is a general measure of a patient’s overall satisfaction with his/her medication. The 
TSQM will be self-administered by the subject at all visits.  
6.2.3.3
Intranasal Therapy Impact Questionnaire (ITIQ)
The ITIQ is a questionnaire that collects data regarding a patient’s or a caregiver’s perception of 
how having access to an intranasal seizure therapy might impact their lives.  It contains 2 
questions. The ITIQ will be self-administered by both the subject and the caregiver individually
at all visits.  
6.2.3.4
Caregiver Questionnaire
The Caregiver Questionnaire is self-administered by the primary caregiver and consists of 
Caregiver demographics (completed at Visit 1 or if there is a change in primary caregiver during 
the study).  
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
60 of 124
Upsher-Smith Laboratories, Inc.
6.2.4
Treatment Compliance
Outpatient treatment compliance will be determined by the return of used and unused study 
medication, as well as the dosing information recorded in the Subject Workbook.
6.3
Prior and Concomitant Therapy
Any changes in medication / device use since the last visit of Study P261-401 will be recorded 
for each subject by qualified medical personnel at Visit 1.
If the subject is using or has used any of the food, beverage, or medicinal products listed in
Appendix 1, Prohibited Concomitant Substances since completion of study P261-401, the 
investigator or designee will inform the subject of the required washout period.
Concomitant therapy is defined as any medication (prescription or non-prescription), nutritional 
supplement, herbal preparation or device use (e.g., VNS magnet) taken or used from Visit 1 
through the Final Visit or ET Visit. Concomitant therapy will be updated with any changes at 
each study visit.
6.3.1
Permitted Medications and Devices
A subject’s AED regimen (with or without intermittent use of benzodiazepines) may be adjusted 
during this open-label study, but changes must be recorded in the Subject Workbook. Similarly,
vagus nerve stimulator (VNS) settings may be adjusted, but changes must be recorded in the 
Subject Workbook. The use of a magnet with the VNS must also be documented in the Subject 
Workbook.
Use of sedating antihistamines and alcohol is allowed during the study. However, the subject
and caregiver should be instructed that sedating antihistamines and alcohol are not to be used for 
at least 24 hours after study drug administration. In addition, caregivers should be instructed to 
forego administration of the study drug within the 24 hours after a subject takes a sedating 
antihistamine or uses alcohol.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
61 of 124
Upsher-Smith Laboratories, Inc.
6.3.2
Prohibited Substances
None of the medications listed in Appendix 1, Prohibited Concomitant Substances, are permitted 
during the study period. This includes CYP450 3A inhibitors /inducers, opioids, other 
respiratory depressants and other sedating medications.  If a subject is or was taking any of these 
medications at or before the Screening Visit, the subject must discontinue the prohibited 
substance and return for Visit 1 after at least the minimum washout time shown in Appendix 1.
However, Visit 1 may not occur more 28 days after Visit 4 of Study P261-401.  The time 
between Visit 4 of study P261-401 and Visit 1 of study P261-402 may be extended in certain 
cases; however, the extension must be approved by the Sponsor or CRO designee. If an
extension is granted for a given subject, that subject may have to undergo repeat screening 
laboratory assessments within 28 days before Visit 2.
If a subject takes any of these medications after Visit 1 and the usage is chronic or to be taken on 
recurring basis, the subject should be discontinued from study. If the usage of that medication 
is/was temporary and not expected to be recurrent, the subject should not take the study 
medication until the time between the last dose of that substance and the date allowable to 
resume study medication for a qualifying seizure cluster is equal to or greater than the minimum 
washout shown in Appendix 1, Prohibited Concomitant Substances. The subject and/or caregiver 
should be reinstructed on prohibited medications.
6.3.3
Use of Benzodiazepines
Benzodiazepines that are used for rescue therapy of seizures or for non-epilepsy indications are 
allowed provided they are typically used ≤ 3 days in a 7-day period on average. Benzodiazepines 
for rescue therapy of seizures or for non-epilepsy indications are not to be used within 24 hours 
prior to study drug administration and not for at least 6 hours after study drug administration.  
Use of a benzodiazepine as a chronic AED (more than 3 days per week on average) is not 
permitted.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
62 of 124
Upsher-Smith Laboratories, Inc.
6.4
Restrictions during the Study
6.4.1
Activity Restrictions
There are no restrictions on subject activity required by this study.  
6.4.2
Food and Fluid Intake
Foods and beverages that are not permitted during the study (from Visits 1 through the Final 
Visit or ET Visit) include star fruit (see Appendix 1, Prohibited Concomitant Substances, for a 
complete list). Consuming these substances during the study may alter the subjects’ response to 
treatment with midazolam. For this reason subjects consuming these substances during the study 
may be withdrawn (terminated) from the study.
If a subject consumes any of these substances, the subject should not take the study medication 
until the time between the last dose of that substance and the date allowable to resume study 
medication for a qualifying seizure cluster is equal to or greater than the minimum washout 
shown in Appendix 1, Prohibited Concomitant Substances. The subject and/or caregiver should 
be reinstructed on prohibited food and beverage substances.
6.5
Subject Withdrawal or Discontinuation
A subject may voluntarily withdraw from participation in the study at any time for any reason.  
Similarly, a subject’s caregiver may withdraw from study participation at any time.  If the 
caregiver withdraws from the study without a suitable, trained replacement, the subject will be 
discontinued from the study. The investigator or sponsor may also withdraw the subject from 
further participation in the study at any time, if it is considered in the best interest of the subject 
or the study, without prejudice to the subject’s future medical care. The investigator may also 
discontinue a subject’s study participation if the subject has not experienced a seizure cluster 
meeting the study criteria within 6 months after enrollment in the open-label study. A subject 
who prematurely discontinues from the study should return to the study center within 7 days to 
undergo the ET visit evaluations.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
63 of 124
Upsher-Smith Laboratories, Inc.
The primary reason for a subject’s premature discontinuation from the study should be selected 
from the following standard categories and documented in the source documents:
!
Adverse event:  One or more clinical or laboratory events which, in the medical 
judgment of the investigator, are grounds for discontinuation even if the event does not 
appear to be related to study medication.  The subject may withdraw because of an AE 
even if the investigator does not feel that it is grounds for discontinuation.  This category 
includes subject death.
!
Withdrawal of consent:  Subject or Caregiver desires to withdraw from further 
participation in the study.
!
Lost to follow-up:  In the case of subjects who do not return for study visits and cannot 
be contacted, vigorous and repeated attempts (minimum of 3) by study center personnel 
to contact the subject should be made and recorded in the source data, e.g., telephone 
reports, letters, progress notes.  Attempts to contact the subject must include at least 
1 certified mail receipt.  If all attempts to contact the subject have failed that subject is 
considered to be lost to follow-up and discontinued from the study.
!
Protocol violation: Failure to adhere to the protocol requirements (e.g., subject’s 
caregiver withdraws from the study without a suitable replacement).
!
Subject has not experienced a seizure cluster meeting the study criteria within 
6 months after enrollment.
!
Pregnancy: Subject pregnancy.
!
Administrative/Other:  Premature termination for reason other than the above, such as 
illness of investigator, theft or loss of study drug, or termination of study by study 
sponsor.
6.5.1
Withdrawal or Discontinuation Procedures 
If a subject withdraws or is discontinued prematurely from the study, the investigator must 
document the primary reason for discontinuation in the source documents and appropriate eCRF, 
and the investigator should make every effort to perform all ET Visit evaluations. In the event 
that a subject elects not to return to the study center for the ET Visit, the investigator must make 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
64 of 124
Upsher-Smith Laboratories, Inc.
every effort to contact the subject to review all AEs. If a subject discontinues prematurely due to 
an AE or SAE, the event will be followed until it resolves (returns to normal or baseline values) 
or stabilizes, or until it is judged by the investigator to be no longer clinically significant. In the 
case of subjects who do not return for study visits and cannot be contacted, vigorous and 
repeated attempts (minimum of 3) by the study center personnel to contact the subject should be 
made and recorded in the source data, e.g., telephone reports, letters, progress notes.  Attempts to 
contact the subject must include at least 1 certified mail receipt.
Subjects who prematurely discontinue from the study will not be replaced.
6.6
Treating Overdose
Refer to the Midazolam Injection, USP, Package Insert (Hospira) for full details on midazolam 
overdose (see Appendix 2).  In the case of suspected overdose, respiration, HR, and BP should 
be monitored and general supportive measures should be employed. Attention should be given 
to the maintenance of a patent airway and support of ventilation, including administration of 
oxygen. An IV infusion should be started. Should hypotension develop, treatment may include 
IV fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, 
if indicated, and other appropriate countermeasures. There is no information as to whether 
peritoneal dialysis, forced diuresis, or hemodialysis is of any value in the treatment of midazolam 
overdose. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the
complete or partial reversal of the sedative effects of benzodiazepines and may be used in 
situations when an overdose with a benzodiazepine is known or suspected. However, the 
reversal of benzodiazepine effects may be associated with the onset of seizures in certain 
high-risk patients. The prescriber should be aware of a risk of seizure in association with 
flumazenil treatment.
An overdose is not recorded as an AE unless signs or symptoms of the overdose occur, in which 
case the signs or symptoms are recorded as AEs and attributed to the overdose of study drug.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
65 of 124
Upsher-Smith Laboratories, Inc.
6.7
Pregnancy
If any female subject becomes pregnant while enrolled in the study, she must be discontinued 
from the study and undergo the ET Visit evaluations.  The investigator or designee must notify 
USL or its designee within 24 hours of learning about the pregnancy.  The investigator or 
designee must complete the Pregnancy Notification Form provided by USL or its designee. The 
investigator or designee must diligently follow the subject until delivery or termination of the 
pregnancy, providing necessary updated information to USL or its designee. Information on the 
status of the mother and the child will also be forwarded to USL or its designee. Generally, 
follow-up will occur within 6 to 8 weeks following the estimated delivery date.  Any premature 
termination of the pregnancy will also be reported.
Although pregnancy occurring in a clinical study is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or SAE and will be followed as such. A spontaneous abortion is always 
considered to be a SAE.
7
ADVERSE EVENT MANAGEMENT
7.1
Definitions:  Adverse Events and Serious Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product whether or not a causal relationship with this treatment exists.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Examples of AEs include, but are not limited to, the following:
!
Exacerbation of a pre-existing illness following the start of the study.
!
Increase in frequency or intensity of a pre-existing episodic event or condition.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
66 of 124
Upsher-Smith Laboratories, Inc.
!
Condition detected or diagnosed after the start of the study even though it may have been 
present prior to the start of the study.
!
Condition that leads to a medical or surgical procedure (e.g., surgery, endoscopy, tooth 
extraction, transfusion) may be an AE, but the procedure itself is not an AE.
An AE does not include the following:
!
Day to day fluctuations of pre-existing disease or conditions present or detected at the 
start of the study that do not represent a worsening of the disease or condition.
!
Situations where an untoward medical occurrence has not occurred (e.g., hospitalizations 
for cosmetic elective surgery; medical or surgical procedures such as endoscopy, tooth 
extraction, or transfusion; social and/or convenience admissions).
!
The disease or disorder being studied or sign or symptom associated with the disease or 
disorder unless more severe or at an increased frequency than that expected for the 
subject’s condition.  Accordingly, seizures in this subject population are anticipated, and 
therefore will not be considered AEs unless the investigator deems a particular seizure(s) 
to represent a worsening of the patient’s seizure disorder.  Seizures that result in 
hospitalization or are considered to be medically significant will be considered to be 
SAEs and will be reported as stated in Section 7.2. 
!
Overdose of either study drug or concurrent medication without any signs or symptoms.
The investigator will evaluate AEs using the following guidelines:
!
Description of Event (if the event consists of a cluster of signs and symptoms, a 
diagnosis should be recorded [e.g., flu syndrome] rather than each sign and symptom).
!
Onset Date
!
Stop Date 
!
Intensity should be recorded as mild, moderate, or severe.  Intensity is defined as one of 
the following:
o
Mild:  awareness of sign or symptom, but easily tolerated
o
Moderate:  discomfort sufficient to cause interference with normal activities
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
67 of 124
Upsher-Smith Laboratories, Inc.
o
Severe:  incapacitating, with inability to perform normal activities
It is important to distinguish between SAEs and severe AEs.  Severity is a measure of intensity;
whereas seriousness is defined by the criteria provided below.  An AE of severe intensity need 
not necessarily be considered serious.  For example, a migraine headache that incapacitates a 
subject for many hours may be considered a severe AE but not a SAE.
!
Seriousness: As provided in FDA Title 21 CFR Part 312.32 (a) and the guidelines of 
ICH GCP (CPMP/ICH/135/95), an SAE is any untoward medical occurrence that at any 
dose:
o
Results in death
o
Is life-threatening:  The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at immediate risk of death at the time 
of the event; it does not refer to an event which hypothetically might have become 
life-threatening or caused death if it were more severe.
o
Requires inpatient hospitalization or prolongation of existing hospitalization:  
Complications that occur during hospitalization are AEs.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered to be an AE.  Hospitalization requires an 
admission to the hospital.
o
A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions.
o
Is a congenital anomaly/birth defect:  See Pregnancy Information (Section 6.7
Pregnancy).
o
Important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed 
in the definition above should also be considered serious.  Examples of such 
events are intensive treatment in an ER or at home for allergic bronchospasm, or 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
68 of 124
Upsher-Smith Laboratories, Inc.
blood dyscrasias that do not result in hospitalization; or development of drug 
dependency or drug abuse.  
For this study, the diagnosis of status epilepticus (as determined by the investigator) will 
ALWAYS be considered serious and follow the procedure for reporting SAEs. 
The investigator must record whether or not the AE meets the definition of serious.  If the event 
is serious, the investigator must complete an SAE Report Form.
!
Relationship to Study Drug
The investigator must make a causality assessment (relationship to study drug) based on the 
following four causality terms:
o
Related: Study drug and AE occurrence definitely related in time and AE more 
clearly or more likely explained by study drug exposure than by other mechanism.
o
Possibly Related: Study drug administration and AE occurrence reasonably 
related in time and the AE explained equally well by causes other than study drug.
o
Unlikely Related: Study drug administration and AE occurrence is not 
reasonably correlated with study drug administration or the AE is possibly 
explained by another cause.
o
Not Related: The time or occurrence of the AE is not correlated with study drug 
administration or the AE is clearly explained by another cause.
!
Frequency: The investigator must record whether the AE is a single event or an 
intermittent event (an AE that occurs more than once and each event is considered to be 
of the same intensity/not worsening).
!
Outcome: Outcome of AEs should be recorded as resolved, resolved with sequelae, not 
resolved, improved, or fatal.  If an AE is not resolved at the time of discontinuation, the 
AE should be followed until it is resolved (returns to normal or baseline) or the subject’s 
condition has stabilized, or until it is judged by the investigator to be no longer clinically 
significant or, when applicable, the subject is receiving appropriate medical care.
!
Action Taken: All applicable action(s) taken with regard to study drug should be 
recorded as either no change, permanent discontinuation or temporarily stopped
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
69 of 124
Upsher-Smith Laboratories, Inc.
7.2
Reporting of Adverse Events and Serious Adverse Events
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE, as provided in Section 7.1.  All AEs and SAEs that are 
observed, queried, or spontaneously volunteered by the subjects occurring from the time written 
informed consent is obtained until completion of the final study visit (Final Visit or ET visit) or 7 
days after last administration of study drug, whichever is later, will be recorded in the source 
documents and will be entered on the appropriate eCRF even if the AE is assessed by the 
investigator as not related to study drug.  Information to be collected includes the nature, date of 
onset, stop date, intensity, duration, treatment, causality, and outcome of the event. SAEs that 
occur after completion of the final study visit (Final Visit or ET visit) or 7 days following the last 
administration of study drug, whichever is later, will be collected only if they are considered by 
the investigator to be related to study drug.
All SAEs, regardless of expectedness or causality, must be reported on the SAE Report Form by 
email or fax to designated Clinical Research Organization (CRO) [inVentiv Health Clinical]
immediately, but no later than 1 business day of the Investigator’s or any other study center 
personnel’s knowledge of the event.  In the event of any fatal or life-threatening SAE, the 
investigator must also inform a Medical Monitor at inVentiv Health Clinical by telephone or 
email immediately.  In addition, any AE resulting in permanent study discontinuation for a 
subject must be reported within 2 business days to inVentiv Health Clinical.
A completed SAE Report Form and pertinent source documents (e.g., relevant medical records 
or pages from Subject Workbook) should be emailed or faxed to inVentiv Health Clinical within 
1 business day of the investigator’s or any study center personnel’s knowledge of a SAE.  An 
updated SAE Report Form should be emailed or faxed to inVentiv Health Clinical within 1 
business day of receipt of new / updated information.  The SAE Reporting Requirements are 
outlined in Table 5.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
70 of 124
Upsher-Smith Laboratories, Inc.
Table 5.
Serious Adverse Event Reporting Requirements
Type of AE
Reporting
Time Frame
Reporting
Method
Telephone Number,
Fax Number, or e-mail address
All SAEs, including 
fatal or life-threatening 
SAEs
Immediate but 
no later than 
1 business day
E-mail or 
Fax the SAE 
report 
form[a]
United States and Canada:
E-mail: SAEReportingUS@pharmanet-i3.com
Fax #: +1-609-951-6670
Rest of World:
E-mail: SAEReportingUS@pharmanet-i3.com
Fax #: +44-1628-461141
Fatal or 
Life-Threatening SAEs 
Immediate
Telephone 
or E-mail
Medical 
Monitor[b]
North and South America: 
 (mobile)
 (e-mail)
Rest of World: 
(office)
(mobile)
(e-mail)
Immediate but 
no later than 1 
business day
E-mail or 
Fax the SAE 
report 
form[a]
United States and Canada:
Email: 
SAEReportingUS@pharmanet-i3.com
Fax #: 1-609-951-6670
Rest of World: 
Email: 
SAEReportingUS@pharmanet-i3.com
Fax #: +44-1628-461141
[a] E-mail is the preferred method for SAE report forms
[b] Telephone is the preferred method for immediate contact after a fatal or life-threatening SAE
The investigator will comply with the applicable local regulatory requirements related to 
reporting of SAEs to their IRB / IEC. 
All AEs and SAEs must be followed until they are resolved (return to normal or baseline) or the 
subject’s condition has stabilized, or until they are judged by the investigator to be no longer 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
71 of 124
Upsher-Smith Laboratories, Inc.
clinically significant.  Supplemental measurements and/or evaluations may be necessary to 
investigate fully the nature and/or causality of an AE or SAE.  This may include additional 
laboratory tests, diagnostic procedures, or consultation with other healthcare professionals.  If the 
subject dies, a death certificate and any available postmortem findings (including histopathology) 
must be provided to USL (or its designee).
7.3
Clinical Laboratory Abnormalities and Other Abnormal Assessments
Abnormal laboratory findings should not be listed on the AE eCRF page unless signs or 
symptoms are present or the laboratory finding is deemed clinically significant by the 
investigator (confirmed by repeat laboratory testing).  If a laboratory value or assessment is 
related to a medically defined new or worsening of a pre-existing diagnosis or syndrome, the 
diagnosis or syndrome will be recorded on the AE eCRF page, not the individual laboratory 
values.  If a medically defined diagnosis or syndrome cannot be made and the subject is 
asymptomatic, a clinically significant laboratory value will be recorded as an AE.
All clinically significant abnormal laboratory results or assessments will be followed until they 
resolve (return to normal or baseline values) or stabilize, or until they are judged by the 
Investigator to be no longer clinically significant.
8
RANDOMIZATION AND BLINDING METHODS
8.1
Randomization
Randomization is not needed for this study as all subjects will receive open-label USL261.  Each
subject will retain the study identification number from the P261-401 study for use in this study.
8.2
Blinding
Study drug will not be blinded as this is an open-label study.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
72 of 124
Upsher-Smith Laboratories, Inc.
9
MATERIALS AND SUPPLIES
9.1
Study Drug
USL261 contains midazolam, EP/USP as the active ingredient, and the inactive ingredients 
 
 
 A 5.0 mg dose of USL261 (0.1 mL dose of a filtered midazolam 50 mg/mL solution) is 
delivered with a single actuation of the unit dose pump.  The dosage unit contains sufficient 
solution to provide a single 5.0 mg dose of USL261 and overfill for the pump to work correctly.
USL261 is designated as a Schedule IV controlled substance with abuse potential by the 
US Controlled Substances Act (21 Code of Federal Regulations [CFR] §1308).
9.1.1
Controlled Substance Documentation
Midazolam is a controlled substance (Schedule IV) under the US Controlled Substances Act 
(21 CFR §1308). Prior to shipment of study drug, the investigator must provide USL or designee 
with a copy of a controlled substance license (or local country equivalent) that clearly identifies 
the registrant and address of the registrant.  Study drug supplies will be shipped to the registrant 
and address noted on the certificate.
9.2
Study Drug Labeling
USL261 nasal spray containers will be provided as ready-to-use assemblies packaged to prevent 
accidental actuation. The drug product utilizes a Unit Dose Nasal Spray System consisting of a 
stoppered glass vial containing study drug which is inserted into a vial holder, which is in turn 
held in a white plastic nasal spray actuator. The vial holder is pushed into the nasal actuator, 
which sprays the dose out of the nasal spray actuator tip.
Study drug will be shipped to an authorized and licensed drug distribution company or 
companies for labeling and packaging. Since the active drug product is classified as a 
Schedule IV Controlled Substance (21 CFR §1308), all clinical supplies will be stored, 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
73 of 124
Upsher-Smith Laboratories, Inc.
distributed, and destroyed in compliance with US Drug Enforcement Administration (DEA) 
regulations (or local country equivalent).
The study drug supplies will be labeled appropriate to their use. USL261 5.0 mg containers will 
be identified as open-label treatments. The label will contain at a minimum the following 
information for the US (additional items will be added as required for other study countries):
!
Protocol number
!
Name of drug
!
Kit identification number 
!
Instructions for use
“Caution: New Drug – Limited by Federal law to investigational use” will also appear on the 
immediate package of each nasal spray product used during the study as required by 
21 CFR §312.6.
9.3
Additional Study Supplies
9.3.1
Patient Management Plan
The individualized PMP prepared for each subject during the double-blind study P261-401 will 
be used for this study (P261-402). The PMP contains the following information at a minimum:
!
A description of the seizure cluster eligible for treatment with study drug.
!
A definition of what is to be considered excessive, uncharacteristic sedation for the 
patient.
!
Instructions for the caregiver on when to administer study drug.
!
A Rescue Protocol for persistent or recurrent seizure activity or other safety concern.
The PMP will be updated with any necessary changes during Visit 1. Any changes to the PMP 
must be finalized before the subject / caregiver receives the study materials kit to take home.
The description of the subject’s seizure cluster pattern must be the same as that approved by the 
central reviewer in study P261-401. Only editorial updates are allowed to the seizure cluster 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
74 of 124
Upsher-Smith Laboratories, Inc.
description in the PMP. Updates to the Rescue Protocol and other sections of the PMP are 
allowed. 
Subjects and caregivers will receive a copy of the PMP at Visit 1.  A summary of the PMP
(i.e., laminated card for convenient reference) will also be provided.
9.3.2
Subject Workbook
Subjects and caregivers will receive a Subject Workbook at each visit except the Final or ET 
Visit. In this study, the Subject Workbook is a critical source document for collecting and 
recording outpatient information during the Treatment phase of this study.  The Subject 
Workbook will be used to record the following:
!
Seizure activity:
o For the first 2 years of participation in the study seizure activity that occurs in the 
24 hours after study drug is administered will be documented by legibly recording 
the date and time of onset of each seizure, the date and time of seizure 
termination, the type of seizure experienced, and any treatment intervention (e.g., 
medication, call for EMS), for each seizure or seizure cluster. Unwitnessed 
seizures should also be recorded, with the information (e.g., date, seizure start,
and stop time) estimated to the best of the caregiver’s ability.
o After the first 2 years participation in the study seizure activity will be 
documented by legibly recording the date and time of recognition of the seizure 
cluster, if there is ongoing seizure activity at 10 minutes after administration of 
the first dose (yes/no), start date and time of the first seizure that occurs between 
10 minutes and 24 hours from first and second (if given) USL261 dose.
!
The date and time of study drug administration.
!
The subject’s respiration rate at specified time points after study drug administration.
!
The date and time of return to baseline function after the treated seizure cluster (as
assessed by the caregiver).
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
75 of 124
Upsher-Smith Laboratories, Inc.
!
Medications that the subject received and device use by the subject within 24 hours after 
study drug administration
!
Changes in the subject’s overall health in the 24 hours after study drug administration.
!
Changes in medication type and/or dosing.
!
All other safety observations.
The Subject Workbook will also contain information and instructions for administering study 
drug, assessing respiration rate, and completing the Subject Workbook. The caregiver will be 
instructed by the study center personnel as to how to complete the Subject Workbook.  The 
subject or caregiver is required to return the completed Subject Workbook to qualified research 
staff at each follow-up visit (Visits 2 through the Final Visit or ET Visit). A new Subject 
Workbook will be dispensed at each subsequent visit (except the Final or ET Visit).
9.3.3
Caregiver Training
Caregivers will be trained in study procedures by qualified study personnel at Visit 1 and 
retrained as needed at each follow-up visit and/or telephone follow-up call. If 6 months pass 
without the subject having a seizure cluster episode, the subject and caregiver will be asked to 
come to the study center for re-training on study procedures. Topics of the caregiver training 
will include, but are not limited to the following:
!
Overview of the study.
!
Training on the subject’s individualized PMP, including how to recognize the subject’s 
seizure cluster episode and when contact EMS or go to the ER.
!
How and when to give the study drug.
!
Performing study assessments (e.g., measuring respiration rate, seizure diary, etc.)
!
Completing the Subject Workbook.
Caregivers are also required to have a current CPR training certificate throughout the entire 
study.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
76 of 124
Upsher-Smith Laboratories, Inc.
9.4
Study Drug Inventory and Storage
USL requires sponsored investigators to maintain adequate drug inventory and security at all 
times.  Upon receipt of the study drug, the investigator or designee will perform an inventory of 
the shipment, comparing the shipment inventory to actual study drug received, and complete and 
sign an inventory log. The investigator or designee must count and verify that the shipment 
contains all the items appearing on the shipment inventory. The investigator must immediately 
notify USL (or designee) or the drug distribution contractor of any damaged or unusable study 
drug that the study center receives, and document any damaged or unusable study drug in the 
inventory log.
Only after receipt of all required documentation from a clinical study center will USL or its 
designee notify the drug distribution contractor to distribute the initial study drug to that center. 
Additional study drug will be shipped as needed.  The investigator or designee will retain a copy 
of the shipment inventory received with the drug supply in the study file.  Each time study drug 
is dispensed to a subject / caregiver, the investigator or designee will record the quantity and a 
description (e.g., kit identification code, subject identification number) on the drug 
accountability log. The investigator / designee will also document any subsequent returns or 
losses of study drug on the drug accountability log.
Drug accountability records will be available to the study monitor for review at each site visit.  
The study monitor will inspect drug supplies and accountability records throughout the study 
conduct at the study center to confirm inventory control and proper study drug storage.  The 
study monitor will record any discrepancies and/or deficiencies and report them to the 
investigator and to USL or designee and will document the investigator’s plan for resolution of 
any drug inventory or storage issues.
9.4.1
Drug Storage at Research Centers
Since midazolam is a controlled substance (Schedule IV), drug supplies must be kept in a secure, 
double-locked, substantially constructed enclosure to which access is limited (e.g., locked 
cabinet inside a locked room). The investigator will take adequate precautions, including locked 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
77 of 124
Upsher-Smith Laboratories, Inc.
storage, to prevent theft or diversion of the study drug, consistent with 21 CFR § 312.69. Within 
the locked storage area, study drug will be stored in accordance with the conditions specified on 
the drug labels until dispensed (i.e., controlled room temperature, with excursions between 15° 
and 30°C [59∀and 86°F]).
Before an investigator is allowed to participate in this study, the drug storage area at his/her 
study center must be inspected by USL or designee. The study monitor (or designee) will also 
discuss drug storage responsibilities with the investigator.
9.4.2
Dispensing of Study Drug
All study drug will be dispensed by the study center pharmacist or other qualified individual, and 
each study drug kit dispensed will be documented in the drug accountability log.  Study drug will 
be dispensed as follows:
!
Visits 1 and 2: dispense 1 study drug kit at each visit.
!
Visits 3 and each subsequent visit (except for the Final Visit or ET Visit):  dispense 
2 study drug kits at each visit.
Each study drug kit will consist of two 5.0 mg doses of USL261. When dispensing the study 
drug, qualified study center personnel will also tell or remind subjects/caregivers:  (1) to store 
study drug at room temperature (see Section 9.4.1, Drug Storage at Research Centers); and (2) to 
return study drug containers (used or unused) to study center staff at the next visit.
9.4.3
Return or Destruction of Study Drug
At Visits 2, 3 and every visit thereafter, the subject / caregiver must return all used and unused 
study drug containers to the study center, which the staff will collect for reconciliation.
At the conclusion of the study, the Study Monitor (or designee) and investigator (or designee) 
will perform a final inventory of study drug shipped to, dispensed by, and remaining at the site.  
This reconciliation will be logged on the drug accountability form, which will then be signed and 
dated.  If any supplies are missing, this discrepancy must be indicated on the drug 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
78 of 124
Upsher-Smith Laboratories, Inc.
accountability / return forms together with an explanation of the discrepancy.  Any discrepancies 
noted will be investigated, resolved, and documented prior to return or destruction of unused 
study drug.  The investigator or designee must return all used and unused medication to USL or 
designee unless alternative arrangements for drug disposal are authorized by USL.  Drug 
accountability records should be returned to USL, and the investigator or designee must retain 
copies of these drug accountability records for his/her files in accordance with 21 CFR § 312.59.
No study drug will be retained at any clinical site when the study is completed; all study drug 
will be returned to USL or its designee.
10 DATA ANALYSIS AND STATISTICAL PROCEDURES
All statistical analyses will be performed using appropriate procedures in SAS version 9.2 or 
higher. No hypothesis tests will be conducted.  
Data will be listed and tabulated overall. Continuous variables will be summarized using 
descriptive statistics (n, mean, standard deviation [SD], median, minimum, and maximum).
Categorical data will be presented using counts and percentages.  
Detailed descriptions of all definitions and analyses will be available in the Statistical Analysis 
Plan (SAP). The SAP will be finalized prior to database lock.  
10.1
Populations for Analysis
Safety Population:  The Safety Population includes all subjects who are enrolled in the 
open-label study and received at least one dose of open-label study drug.  
Efficacy Evaluable Population:  The Efficacy Evaluable Population includes all subjects in the 
Safety Population who received at least 1 dose of study drug during the open-label study and 
who have any post-treatment efficacy assessment.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
79 of 124
Upsher-Smith Laboratories, Inc.
10.2
Subject Disposition
A summary of subject disposition will display the number of subjects who completed study 
P261 401, were screened for the open-label study P261-402, enrolled in the open-label study 
P261-402, and received open-label study drug.  The number of subjects who discontinued will be 
summarized according to the primary reason for withdrawal.
The number of seizure cluster episodes treated with USL261 will also be summarized.
Descriptive statistics of the demographic profile and baseline characteristics will be summarized 
for the Safety Population.  No formal statistical analyses of these data are planned.
10.3
Medical and Surgical History
Updates to medical and surgical history from the end of study P261-401 and during this study 
will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA®) and 
will be listed.
10.4
Prior and Concomitant Therapy
All medications will be classified according to the World Health Organization (WHO) Drug 
Dictionary and the incidences will be tabulated by drug class and/or generic name for the Safety 
Population. Concomitant drug therapy will include all medications (prescription or 
non-prescription), nutritional supplement, herbal preparation or devices (e.g., VNS) taken/used
from the date of enrollment in the open-label study through the Final Visit or ET Visit.  
Concomitant AEDs will be summarized separately.
10.5
Safety and Efficacy Endpoints
The data to assess the safety and efficacy endpoints will be obtained from the Subject 
Workbooks, which include a seizure diary, and safety data collected at each visit as entered into 
the Electronic Data Capture (EDC) system.  
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
80 of 124
Upsher-Smith Laboratories, Inc.
10.5.1
Safety Analyses
Evaluation of safety will be performed for all subjects in the safety population. Besides regular 
summary tabulations, additional safety analyses may be conducted to account for the potential 
difference in drug exposure or follow-up time among patients. Further details on the analysis will 
be provided in the SAP prior to the database lock. The following endpoints will be summarized 
using the Safety Population:
!
Caregiver-recorded respiration rate: Caregiver-recorded respiration rates will be 
presented using descriptive statistics at each time point for each USL261-treated seizure 
cluster episode.  The number of subjects who have < 8 breaths per minute and > 24 
breaths per minute after study drug administration will be presented by time point.
!
Requirement for unscheduled ER or EMS visit: The proportion of subjects requiring 
an unscheduled ER or EMS visit within 24 hours after study drug administration will be 
summarized for each successive seizure cluster episode.
!
Adverse Events:  AE verbatim text will be coded using MedDRA and summarized by 
System Organ Class (SOC) and Preferred Term.  Treatment-emergent AEs will be 
defined as those AEs that begin on or after study drug administration and up to 30 days 
after the last dose of study drug in the open-label study, or increase in severity on or after 
study drug administration.  
Subjects who experience at least one TEAE or SAE will be presented for each SOC and 
Preferred Term.  Summaries of TEAEs will also be provided by severity and relationship 
to study drug.  Treatment emergent adverse events will also be tabulated by age group 
(<18, ≥ 18 - <65 years, ≥65 years).  Serious AEs and AEs leading to discontinuation will 
be summarized.  
Adverse events that occur within 30 days prior to the first study drug administration in 
the open-label study will be identified in the listings but will not be summarized.  
!
Clinical Laboratory Data: Clinical laboratory results for serum chemistry, hematology, 
and urinalysis will be presented by visit using summary statistics.  Changes from baseline 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
81 of 124
Upsher-Smith Laboratories, Inc.
will also be displayed.  Normal range shift tables will be generated for selected
parameters.  In addition, clinically significant abnormalities, as predefined in the SAP, 
will be tabulated.
!
Vital Signs Measurements: Vital sign measurements performed by study site staff will 
be presented using descriptive statistics.  Systolic and diastolic BP (millimeters of
mercury [mm Hg]), HR (beats per minute), respiration rate (breaths per minute), and 
temperature (degrees Celsius [°C]) will be summarized at each visit.  Changes from 
baseline will also be displayed.
!
Physical, Nasal, and Neurological Examinations: For physical, neurological, and nasal 
examinations the number and percent of subjects with normal and abnormal results 
(clinically significant vs. not clinically significant) for each body system or assessment 
will be presented for each visit.
!
C-SSRS: C-SSRS results will be summarized at each visit.  The number and percentage 
of subjects with each suicidal behavior and ideation will be displayed.  The number and 
percentage of subjects with any suicidal behavior and any suicidal ideation, along with 
the number and percentage of subjects with at least 1 occurrence of suicidal behavior or 
ideation, will be calculated.  In addition, the number of suicidal behaviors of each type 
(attempts, aborted attempts, and interrupted attempts) will be presented.  Scores for 
suicidal ideation severity will be calculated for each type of ideation, and the total score 
will be summarized.
!
B-SIT: For olfactory examination, the B-SIT scores and changes from baseline will be 
presented and plotted by visits. Further analysis adjusted by exposure and time may be 
conducted. Details will be included in the SAP.
10.5.2
Efficacy Analyses
The following endpoints will be analyzed using the Efficacy Evaluable Population:  
Treatment Success: Treatment Success is a composite measure of efficacy that is defined as 
achieving both of the following criteria:
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
82 of 124
Upsher-Smith Laboratories, Inc.
!
Termination of seizure(s) within 10 minutes after study drug administration, and
!
No recurrence of seizure beginning 10 minutes after study drug administration to 6 hours 
after study drug administration.
Subjects who receive the second open-label dose of USL261 within 6 hours of the first dose will 
not meet the definition of treatment success. 
Treatment Success is a repeated efficacy measurement at every seizure cluster episode. All 
subjects included in the Efficacy Evaluable Population will be fitted into a generalized linear 
mixed model with appropriate link function and time-trend coefficients to study the short and 
long-term efficacy effect of USL261.  This model will be able to address the data dependency 
within-subject and at the same time estimate subject-specific differences in the propensity to 
respond over time.  Descriptive statistics will also be presented.  
Time to return to baseline functionality (as determined by the caregiver):  Time to return to 
baseline functionality after study drug administration will be summarized using Kaplan-Meier 
analysis for each successive seizure episode. Censoring rules will be described in detail in the 
SAP.
10.5.3
Exploratory Analyses
The following exploratory endpoints will be analyzed using the Efficacy Evaluable Population if 
there is sufficient evaluable data. The methods of analysis will be described in detail in the SAP.
!
Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study drug
administration to 4 hours after study drug administration.
!
Time to next seizure with a start time >10 minutes after study drug administration.
!
Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study drug
administration to 24 hours after study drug administration.
!
Time from administration of the first open-label dose of study drug to the second 
open-label dose of study.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
83 of 124
Upsher-Smith Laboratories, Inc.
10.5.4
Outcomes Analyses
The following questionnaires will be summarized using the Safety Population:
SF-12v2 Health Survey (SF-12v2): The eight domains of the SF-12 will be summarized at 
Visit 1 and the Final Visit or ET using descriptive statistics.  The change from Visit 1 to the 
Final/ET Visit will also be presented.  
Treatment Satisfaction Questionnaire for Medication (TSQM): The TSQM responses will 
be summarized by visit.  
Intranasal Therapy Impact Questionnaire (ITIQ): Responses to the 2 questions of the ITIQ 
will be summarized for both patients and caregivers by visit.  
Caregiver Questionnaire: Caregiver demographics will be summarized using descriptive 
statistics, counts, and percentages as appropriate.  
10.5.5
Data and Safety Monitoring Board
The Data and Safety Monitoring Board (DSMB) constituted for the P261-401 study will have 
access to the data from this study for informational purposes and as supportive data during their 
review of the P261-401 study.  
Details of the DSMB membership, meeting schedule, and data review and analysis will be 
documented in the DSMB Charter for the P261-401 study.
10.6
Sample Size Justification
Since enrollment is limited to subjects who have participated in Study P261-401, a maximum of 
240 subjects (the planned number of subjects completing the Comparative Phase in P261-401) 
are expected to enroll in the study.  
The subjects enrolled in this study will be a subset of the subjects participating in the P261-401 
study. Thus, the sample size will depend on the number of subjects who participate from 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
84 of 124
Upsher-Smith Laboratories, Inc.
P261-401 and is not based on any statistical calculation.
11 ADMINISTRATIVE PROCEDURES
11.1
Regulatory Approval
This study requires application to the appropriate regulatory authorities in the countries 
concerned.  The study will only be undertaken following receipt of written approval or 
acknowledgement of receipt (depending on local regulation) from the regulatory authorities by 
USL, or following submission to appropriate authorities, whichever is required by the respective 
countries.  
This study requires authorization by any member state Regulatory Authority where the clinical 
study will be conducted in accordance with National law requirements.  The study will only be 
undertaken by USL following receipt of written approval from the Regulatory Authority.
This protocol will be submitted to the US FDA under Investigational New Drug (IND) 
Application No. 77,421 prior to study initiation.  
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before implementing this study, the study protocol, the proposed informed consent and assent 
forms, and other study materials will be approved or favorably reviewed by a properly 
constituted IRB / IEC.  
USL or its designee must receive signed and dated written confirmation that the study protocol 
and ICF have been approved or favorably reviewed by the IRB/IEC before the study site will be 
initiated. The IRB / IEC Membership Roster (or assurance number, if applicable) must also be 
supplied to USL or its designee prior to site initiation.  
Any amendment(s) to the study protocol that affect the study design, study procedures, or risk to 
study subjects, and any corresponding change to the informed consent or assent forms, must be 
approved by the IRB / IEC before the change is implemented, in conformance with GCP.  If any 
such changes are made to the informed consent or assent forms, subjects and/or caregivers that 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
85 of 124
Upsher-Smith Laboratories, Inc.
are still active in the study will be re-consented using the new form(s).
11.3
Study Personnel
The investigator should maintain a list of appropriately qualified persons who are delegated to 
perform significant study-related duties.  In addition, the investigator should maintain a signature 
sheet to document signatures, initials, and study responsibilities of all persons authorized to 
make entries and/or corrections to the eCRF.
11.4
Ongoing Information for Independent Ethics Committee
Unless otherwise instructed by the IRB / IEC, the investigator or designee must submit to the 
IRB / IEC at a minimum:
!
Information on SAEs from the investigator’s site, as soon as possible.
!
Expedited safety reports from the sponsor or its representatives, as soon as possible.
!
Periodic or annual reports on the progress of the study.
11.5
Completion of Electronic Case Report Forms
The investigator is responsible for the accuracy and quality of the data recorded for this study.  
These recorded data should be a complete and accurate account of each subject’s record 
collected during the study.  Subject data that are collected may be substantiated by 2 types of 
source documents at the study center, paper and electronic (electronic source data is defined as 
electronic information not directly entered into the EDC system). Source data collected 
electronically or via paper will be entered onto the eCRFs in the EDC system. The Subject 
Workbook completed by the caregiver is considered a source document. The eCRFs will be 
completed according to guidelines provided by USL or its designee.
Access to the EDC system will be granted to trained and authorized study personnel only, and 
user identifications (IDs) and passwords must not be shared with other individuals.  Only staff 
designated by the principal investigator on the Delegation of Authority form in the study file 
notebook will be eligible to enter or make edits to the data. Qualified research personnel will 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
86 of 124
Upsher-Smith Laboratories, Inc.
accurately enter data from both study center- and subject / caregiver-generated source documents 
into the eCRFs provided for this study. Data will be entered into the eCRF shortly after each 
subject’s visit. Study center personnel will exercise due diligence to ensure that study data are 
entered accurately and in their entirety from the study center’s source documents into the 
appropriate data fields.
The investigator must review all data entries on a regular basis for completeness and accuracy.  
When changes or corrections are made to existing entries in the EDC system, the reason for the 
change must be clearly delineated.  The investigator agrees to transfer study data into the EDC 
system in a timely fashion and to make the records available to the study monitor for full 
inspection.  In addition, data queries should be answered promptly.
Although the study eCRF is the primary database for the study, all data entered into the eCRF
must be recorded in the source documents, and any missing data must be explained. Source data 
will be retained by the study center as described in Section 11.12, Records of Study.
At the end of the study, by electronically signing the eCRFs, the investigator is attesting to 
his/her responsibility for the quality of all data recorded, as well as attesting that the data 
represent a complete and accurate record of each subject’s participation in the study.
11.6
Study Monitoring
USL, as sponsor of this study, is responsible to regulatory authorities for ensuring the proper 
conduct of the study as regards to protocol adherence and validity of the data recorded on the 
eCRFs presented to the regulatory authorities.  USL (or designated CRO [inVentiv Health 
Clinical]) has assigned study monitors and medical monitors to this study.  Their duties are to aid 
the investigator and at the same time, USL, in the maintenance of complete, legible, 
well-organized, and easily retrievable data.  In addition, a monitor will explain and ensure the 
investigator’s understanding of all applicable regulations concerning the clinical evaluation of a 
pharmaceutical product (whether licensed or unlicensed), and ensure an understanding of the 
protocol, reporting responsibilities, and the validity of the data.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
87 of 124
Upsher-Smith Laboratories, Inc.
In order to perform their role well, the monitors must be given direct access to primary subject 
data that support data on the eCRFs for the study (e.g., Subject Workbooks, hospital and general 
practice charts, appointment books, original laboratory records).  The investigator must make 
available such records to USL, designated CRO, quality assurance, IRB, and regulatory 
personnel for inspection and copying.  Because this enters into the realm of subject 
confidentiality, this fact must be included in the information signed by the subject.
The investigator should agree, as a minimum requirement, to record the following information in 
the subject notes:
!
Protocol identification number
!
Date that the subject gave written informed consent
!
All visit dates
!
All AEs
!
All concomitant medications
Entries in the subject notes must contain the signature or initials of the person making the entries.
The study monitor will perform source data verification at each monitoring visit.
11.7
Quality Assurance Procedures
Quality assurance activities include monitoring and source data verification by the study 
monitor.  It is possible that USL Compliance Audit Unit personnel or their agents may audit the 
study center(s).
11.7.1
Access to Source Documentation
Source data are all original records of clinical findings, observations, or other activities in a 
clinical study, which are necessary to achieve study objectives and protect subject safety.
Source data are contained in source documents. Examples of these original documents and data 
records include the following: 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
88 of 124
Upsher-Smith Laboratories, Inc.
!
Hospital records.
!
Clinical and office charts.
!
Laboratory notes.
!
Memoranda.
!
Subjects’ workbooks, diaries, or evaluation checklists.
!
Pharmacy dispensing records.
!
Recorded data from automated instruments.
!
Copies or transcriptions certified after verification as being accurate and complete.
!
X-rays, microfiches, photographic negatives, microfilm, or magnetic media.
!
Subject files, including records kept at the pharmacy, laboratories, and at 
medico-technical departments involved in the clinical study.
Source documents are the originals of any document used by the investigator or
hospital / institution that allows verification of the existence of the subject and substantiates the 
integrity of data collected during the trial.  Source documents will be available to support all data 
recorded in the eCRF, unless this is otherwise specified in the eCRF. The investigator must 
allow designated representatives of the sponsor and regulatory inspectors to have direct access to 
the source documents to verify the data reported in the eCRFs.  
The investigator must maintain source documents for each subject in the study, including source 
documents that are generated by the subject. All information in the eCRFs must be traceable to 
these source documents, which are generally maintained in the subject’s file. The source 
documents should contain all demographic and medical information as well as a copy of the 
ICFs provided by subject and caregiver.  
11.7.2
Auditing Procedures
The investigator will permit USL, USL representatives (designated CRO [inVentiv Health 
Clinical] and/or other designee), and regulatory authorities to conduct inspections during the 
study or after study completion. If a regulatory authority requests an inspection, the investigator 
must immediately inform USL (or CRO) of the request.  
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
89 of 124
Upsher-Smith Laboratories, Inc.
11.8
USL Policy on Fraud in Clinical Studies
In accordance with GCP, it is USL’s policy always to investigate suspected cases of fraud.  
11.9
Use of Information and Publication
It is intended that the results of the study may be published in the scientific literature.  Results 
may also be used in submissions to regulatory authorities.  The following conditions are to 
protect commercial confidential materials (e.g., patents), not to restrict publication.  
All information concerning the drug currently under study, USL operations (such as patent 
applications, formula, manufacturing processes, basic scientific data, or formulation information 
supplied to the investigator by USL and not previously published) is considered confidential by 
USL and shall remain the sole property of USL.  The investigator agrees not to use it for other 
purposes without USL written consent.  
It is understood by the investigator that USL will use the information developed in this clinical 
study in connection with the development of the drug currently under study and, therefore, this 
information may be disclosed as required to other USL investigators or any appropriate 
regulatory authorities.  To allow for the use of information derived from this clinical study, the 
investigators understand that they have an obligation to obtain all necessary authorizations from 
study subjects in order to provide USL with complete test results and all data developed during 
this study.  
A manuscript or abstract should not be submitted for publication or presentation until a New 
Drug Application is approved by the US FDA or permission is granted in writing by USL. In 
accordance with generally recognized principles of scientific collaboration, co-authorship with 
USL personnel will be discussed and mutually agreed upon before submission of a manuscript to 
a publisher.  
Following completion of the study, the data may be considered for reporting at a scientific 
meeting(s) or for publication in a scientific journal. For specific information regarding 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
90 of 124
Upsher-Smith Laboratories, Inc.
publications of this study, refer to the signed agreement between USL and the investigator.  
Results of this study may also be used in submissions to regulatory authorities.
11.10 Amendment to Protocol
Approval of a protocol amendment by the investigator’s IRB must be obtained before 
implementation, with the following exceptions:
!
When necessary to eliminate apparent immediate hazard to the subject.
!
When the change involves logistical or administrative aspects of the study.
The protocol amendment must be signed and dated by both USL and the investigator.  USL will 
submit protocol amendments to the appropriate regulatory authorities (if required)/ Ethics 
Committee (if required) and notify other investigators using this protocol.  
11.11 Deviations from Protocol
Deviations from a written protocol for individual subjects are inherent to clinical research and 
are categorized by USL as departures from protocol.  A departure from protocol is a deviation of 
such magnitude as to affect whether the data can be evaluated for the subject or to potentially 
compromise the statistical analysis.  Examples of deviations include the following:
!
Violation of inclusion/exclusion criteria.
!
Error in study drug randomization.
!
Administration of an excluded concomitant medication during the course of the study.
The IRB / IEC will be informed of protocol deviations in a timely manner that is consistent with 
their requirements.
If the same protocol deviation occurs for multiple subjects, it must be recorded separately for 
each subject.  
The investigator should contact USL or designee if continuing the subjects in the study is in 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
91 of 124
Upsher-Smith Laboratories, Inc.
question as a result of the protocol deviation.  
11.12 Records of Study
The investigator will retain essential study documents for at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product, USL261.  Examples of 
essential documents include the following:
!
IRB / IEC correspondence indicating approval / favorable opinion for the study protocol, 
ICFs, and all amendments to either of these documents.
!
All source documents and laboratory records
!
Informed consent forms signed by the subject or his/her LAR, and by the subject’s 
caregiver.
!
When applicable, subject assent forms.
!
Completed Form FDA 1572.
!
Statement of investigator.
If required by the applicable regulatory requirements or by an agreement with USL, these 
documents should be retained for a longer period (approximately 15 years).  In the event that the 
investigator has a change of address or is planning to transfer these documents to another 
investigator’s possession, the investigator must notify USL of such change.  
11.13 Completion of Study
It is agreed that USL may terminate this study before the expiration of the agreed time period, 
provided a written notice is submitted a reasonable time in advance of intended termination.  
11.14 Study Funding
The costs necessary to perform the study will be agreed with the investigator and/or the 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
92 of 124
Upsher-Smith Laboratories, Inc.
management of the study facility and will be documented in a separate financial agreement that 
will be signed by the investigator and USL.  
11.15 Financial Disclosure
Clinical investigators are required to provide financial disclosure information to allow the 
sponsor (USL) to submit the complete and accurate certification or financial disclosure 
statements to FDA as required under 21 CFR § 54. As defined in 21 CFR § 54.2, a clinical 
investigator is a listed or identified investigator or sub-investigator who is directly involved in 
the treatment or evaluation of research subjects. The term “clinical investigator” also includes 
the spouse and each dependent child of the investigator. In addition, investigators must promptly 
update financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study.  
12 REFERENCE LIST
1.
Cereghino JJ. Identification and treatment of acute repetitive seizures in children and 
adults. Curr Treat Options Neurol. 2007;9:249-255.
2.
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338:970-976.
3.
Sankar R, Rho JM. Do seizures affect the developing brain? Lessons from the laboratory. 
J Child Neurol. 2007;22:21S-9S.
4.
Bergen DC. Do seizures harm the brain? Epilepsy Curr. 2006;6:117-118.
5.
Lowe MN, Palmer KJ, Wilde MI. Management of acute repetitive seizures: defining the 
role of rectal diazepam gel. Dis Manage Health Outcomes. 2000;8:355-368.
6.
Glauser TA. Designing practical evidence-based treatment plans for children with 
prolonged seizures and status epilepticus. J Child Neurol. 2007;22:38S-46S.
7.
Fisgin T, Gurer Y, Tezic T, et al. Effects of intranasal midazolam and rectal diazepam on 
acute convulsions in children: prospective randomized study. J Child Neurol. 2002;17:123-
126.
8.
Charney DS, Mihic SJ, Harris RA. Goodman & Gilman's The Pharmacological Basis of 
Therapeutics. 11th ed. New York: McGraw-Hill; 2006.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
93 of 124
Upsher-Smith Laboratories, Inc.
9.
Versed [Prescribing Information]. Bedford, OH: Ben Venue Laboratories, Inc.; 2001.
10.
Wilton NC, Leigh J, Rosen DR, Pandit UA. Preanesthetic sedation of preschool children 
using intranasal midazolam. Anesthesiology. 1988;69:972-975.
11.
Griffith N, Howell S, Mason DG. Intranasal midazolam for premedication of children 
undergoing day-case anaesthesia: comparison of two delivery systems with assessment of 
intra-observer variability. Br J Anaesth. 1998;81:865-869.
12.
Bell DM, Richards G, Dhillon S, et al. A comparative pharmacokinetic study of 
intravenous and intramuscular midazolam in patients with epilepsy. Epilepsy Res. 
1991;10:183-1890.
13.
Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectal diazepam for the home 
treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med. 
2010;164:747-753.
14.
Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute 
childhood seizures. Pediatr Neurol. 2006;34:355-359.
15.
Fisgin T, Gurer Y, Senbil N, et al. Nasal midazolam effects on childhood acute seizures. J 
Child Neurol. 2000;15:833-835.
16.
Holsti M, Sill BL, Firth SD, Filloux FM, Joyce SM, Furnival RA. Prehospital intranasal 
midazolam for the treatment of pediatric seizures. Pediatr Emerg Care. 2007;23:148-153.
17.
Jeannet PY, Roulet E, Maeder-Ingvar M, Gehri M, Jutzi A, Deonna T. Home and hospital 
treatment of acute seizures in children with nasal midazolam. Eur J Paediatr Neurol. 
1999;3:73-77.
18.
Kendall JL, Reynolds M, Goldberg R. Intranasal midazolam in patients with status 
epilepticus. Ann Emerg Med. 1997;29:415-417.
19.
Kutlu NO, Yakinci C, Dogrul M, Durmaz Y. Intranasal midazolam for prolonged 
convulsive seizures. Brain Dev. 2000;22:359-361.
20.
Mittal P, Manohar R, Rawat AK. Comparative study of intranasal midazolam and 
intravenous diazepam sedation for procedures and seizures. Indian J Pediatr. 2006;73:975-
978.
21.
Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal 
midazolam with intravenous diazepam for treating febrile seizures in children: prospective 
randomised study. BMJ. 2000;321:83-86.
22.
Lahat E, Goldman M, Barr J, Eshel G, Berkovitch M. Intranasal midazolam for childhood 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
94 of 124
Upsher-Smith Laboratories, Inc.
seizures. Lancet. 1998;352:620.
23.
O'Regan ME, Brown JK, Clarke M. Nasal rather than rectal benzodiazepines in the 
management of acute childhood seizures? Dev Med Child Neurol. 1996;38:1037-1045.
24.
Kyrkou M, Harbord M, Kyrkou N, Kay D, Coulthard K. Community use of intranasal 
midazolam for managing prolonged seizures. J Intellect Dev Disabil. 2006;31:131-138.
25.
Mahmoudian T, Zadeh MM. Comparison of intranasal midazolam with intravenous 
diazepam for treating acute seizures in children. Epilepsy Behav. 2004;5:253-255.
26.
McGlone R, Smith M. Intranasal midazolam. An alternative in childhood seizures. Emerg 
Med J. 2001;18:234.
27.
Scheepers M, Comish S, Cordes L, Clough P, Scheepers B. Buccal midazolam and rectal 
diazepam for epilepsy. Lancet. 1999;353:1797-1798.
28.
Scheepers M, Scheepers B, Clarke M, Comish S, Ibitoye M. Is intranasal midazolam an 
effective rescue medication in adolescents and adults with severe epilepsy? Seizure. 
2000;9:417-422.
29.
Scheepers M, Scheepers B, Clough P. Midazolam via the intranasal route: an effective 
rescue medication for severe epilepsy in adults with learning disability. Seizure. 
1998;7:509-512.
30.
Segal DC, Vofsi O, Katz Y. An alternative route of drug administration in acute 
convulsions. Isr Med Assoc J. 2000;2:629.
31.
Wilson MT, Macleod S, O'Regan ME. Nasal/buccal midazolam use in the community. 
Arch Dis Child. 2004;89:50-51.
32.
Koren G. Intranasal midazolam for febrile seizures. A step forward in treating a common 
and distressing condition. BMJ. 2000;321:64-65.
33.
Smith M, Carley S. Best evidence topic report. Intranasal midazolam in patients with fits. 
Emerg Med J. 2005;22:436-437.
34.
Rey E, Treluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy for 
acute seizures. Focus on delivery routes. Clin Pharmacokinet. 1999;36:409-424.
35.
Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. 
Am J Emerg Med. 2006;24:343-346.
36.
Pieri L, Schaffner R, Scherschlicht R, et al. Pharmacology of midazolam. 
Arzneimittelforschung. 1981;31:2180-2201.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
95 of 124
Upsher-Smith Laboratories, Inc.
37.
Lyseng-Williamson KA, Yang LP. Topiramate: a review of its use in the treatment of 
epilepsy. Drugs. 2007;67:2231-2256.
38.
French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic 
drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of 
the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 
2004;45:410-423.
39.
Wermeling DP. Intranasal delivery of antiepileptic medications for treatment of seizures. 
Neurotherapeutics. 2009;6:352-358.
40.
End-of-Phase-2 Briefing Document for FDA, Appendix 3a. Intranasal Therapeutics, Inc.;
2008 Oct 21. Report No.: SN 0016.
41.
Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer's 
Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin 
Psychopharmacol. 1990;10:244-251.
42.
ICH Topic M 3 [R2]: Non-Clinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals.
43.
Pellock JM, Faught E, Leppik IE et al. Felbamate: consensus of current clinical 
experience. Epilepsy Res. 2006;71:89-101.
44.
O'Regan ME, Brown JK, Clarke M. Nasal rather than rectal benzodiazepines in the 
management of acute childhood seizures? Dev Med Child Neurol 1996;38(11):1037-45.
45.
Kyrkou M, Harbord M, Kyrkou N et al. Community use of intranasal midazolam for 
managing prolonged seizures. J Intellect Dev Disabil 2006;31(3):131-8.
46.
Holsti M, Dudley N, Schunk J et al. Intranasal midazolam vs rectal diazepam for the home 
treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med
2010;164(8):747-53.
47.
Thakker A, Shanbag P. A randomized controlled trial of intranasal-midazolam versus 
intravenous-diazepam for acute childhood seizures. J Neurol 2012.
48.
Rey E, Delaunay L, Pons G, Murat I, Richard MO, Saint-Maurice C, et al. 
Pharmacokinetics of midazolam in children: comparative study of intranasal and 
intravenous administration. Eur J Clin Pharmacol 1991;41(4):355-7.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
96 of 124
Upsher-Smith Laboratories, Inc.
Appendix 1.  Prohibited Concomitant Substances
The medications listed below are prohibited from Visit 1 through the Final Visit or ET Visit.  If 
the subject was taking any of these medications at or before Visit 1, the time between the last 
dose of that substance and when the subject receives the study materials kit must be equal to or 
greater than the minimum washout time shown below. 
The first listing (Listing 1) of substances represents inhibitors or inducers of the cytochrome 
P450 3A family of enzymes, and may alter the PK of midazolam. Food or beverage substances 
are shown in italic font; drugs, herbals, or nutritional supplements are shown in regular font.
The second listing (Listing 2) of substances represents opioids, other respiratory depressants
or other sedating medications.
The following substances are prohibited when administered orally, by injection, or any other 
method intended for systemic delivery. Usage of topical, intravaginal, or ophthalmic 
formulations containing prohibited substances is allowable provided that such the usage is 
unlikely to achieve meaningful systemic levels. Listing 1 and Listing 2 may not be all-
inclusive; any questions should be directed to the Medical Monitor.
Listing 1.
Inhibitors or Inducers of Cytochrome P450 3A Family of Enzymes
Generic or Substance 
Name
Other Name
(US Brand Name or Research Designation
Minimum Washout
Period (days)
A
Amiodarone 
Cordarone, Nexterone
710 (24 months)
Aprepitant
Emend
7
B
Boceprevir
Victrelis
7
C
Chloramphenicol
Alficetyn, Amphicol, Biomicin, Chlornitromycin, 
Chloromycetin Brochlor, Golden Eye, Optrex, Oftan 
Chlora, Phenicol, Medicom, Nevimycin Vernacetin, 
Veticol
7
Cisapride
Propulsid
7
Clarithromycin
Biaxin, Biaxin XL
7
D
Danazol
Danocrine
7
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
97 of 124
Upsher-Smith Laboratories, Inc.
Generic or Substance 
Name
Other Name
(US Brand Name or Research Designation
Minimum Washout
Period (days)
Delavirdine 
Rescriptor
7
Diethyldithio-
carbamate
(diethyldione,
Diethyldithio-carbamic 
acid)
—
7
E
Efavirenz 
Efavirenz
11
G
Gestodene
Minesse 
7
I 
Imatinib
Gleevec 
7
Indinavir
Crixiban
7
Itraconazole
Sporanox 
7
K 
Ketoconazole
Nizoral 
7
L
Lopinavir
Kaletra, Aluvia
7
M
Mibefradil 
Posicor (withdrawn from US market) 
7
Oral Miconazole[a]
Oravig
7
Mifepristone 
Mifeprex 
7
N
Nefazodone 
Serzone
7
Nelfinavir 
Viracept 
7
Nevirapine 
Viramune
9
P
Posaconazole
Noxafil, Posanol
10
Q
Quinidine
Quin-Release, Quinaglute Dura-Tabs, Quinidex 
Extentabs
7
R
Rifabutin 
Mycobutin 
13
Rifampin 
Rifadin 
7
Ritonavir
Kaletra, Norvir
7
S
Saquinavir
Fortovase, Invirase
7
Star fruit
—
7
St. John’s Wort
—
7
T
Tacrolimus
FK506, Prograf
8
Telithromycin
Ketek
7
Thalidomide
Thalomid
7
Troleandomycin
Tao
7
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
98 of 124
Upsher-Smith Laboratories, Inc.
Generic or Substance 
Name
Other Name
(US Brand Name or Research Designation
Minimum Washout
Period (days)
V
Voriconazole
VFEND
7
Z
Zafirlukast
Accolate
7
[a] Topical and vaginal miconazole are allowed.
Listing 2.
Opioids or other Respiratory Depressants
Generic or 
Substance Name
Other Name
(US Brand Name or Research Designation)
Minimum Washout
Period (days)
Opiate Agonist
A
Alfentanil  
Alfenta
1
C
Codeine 
1
F
Fentanyl
Fentora, Duragesic
1 (for acute 
intravenous) 
7 (any other route)
H
Hydrocodone  
Lorcet
1
Hydromorphone  
Dilaudid
1
L
Levorphanol 
Levo-Dromoran
2
M
Methadone   
Dolophine
2
Meperidine  
Demerol
1
Morphine
Duramorph 
1 (for acute 
intravenous) 
7 (any other route)
O
Oxycodone  
Oxycontin
1
Oxymorphone  
Numorphan 
1
P
Propoxyphene
Darvon
7
S
Sufentanil  
Sufenta
1
T
Tramodol  
Ultram
1
Opiate Agonist-antagonist or Partial Agonists
B
Buprenorphine 
Buprenex
1
Butorphanol
Stadol
7
N
Nalbuphine 
Nubain
1
P
Pentazocine 
Talwin NX
1
Other Sedating Medications
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
99 of 124
Upsher-Smith Laboratories, Inc.
Generic or 
Substance Name
Other Name
(US Brand Name or Research Designation)
Minimum Washout
Period (days)
B
Buspirone
Ansial, Ansiced, Anxiron, Axoren, Bespar, BuSpar, 
Buspimen, Buspinol, Buspisal, Narol, Spitomin, Sorbon
7
P
Pimozide
Orap 15
15
Propofol
Diprivan
1 (infusions ≤ 10 hours) 
7 (infusions >10 hours)
T
Tetrahydrocanna-
binol
Marinol, Dronabinol, marijuana
7
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
100 of 124
Upsher-Smith Laboratories, Inc.
Appendix 2.  Midazolam Injection, USP, Package Insert (Hospira)
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
102 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
103 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
104 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
105 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
106 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
107 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
108 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
109 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
110 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
111 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
112 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
113 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
114 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
115 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
116 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
117 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
118 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
119 of 124
Upsher-Smith Laboratories, Inc.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
120 of 124
Upsher-Smith Laboratories, Inc.
Appendix 3.   Amendment 4
Protocol Number: P261-402
Protocol Title: 
An Open-Label Safety Study of USL261 in the Outpatient Treatment of Subjects with Seizure 
Clusters
REASON FOR CHANGE TO PROTOCOL
Change 1
While the most common peripheral cause of dysosmia is olfactory neuron loss due to upper 
respiratory tract infection (URTI), nasal products have also been associated with smell 
disturbances. For example, Zicam Cold Remedy Nasal Gel and Swabs, was withdrawn from the 
U.S. market in 2009 due to long lasting or permanent loss of smell. The Brief Smell 
Identification Test (B-SIT) was added to assess the long-term effects of USL261 on olfaction. 
Change 2
The introduction section was updated to reflect current study status.
SECTIONS OF PROTOCOL AFFECTED BY CHANGE
Change 1
Synopsis – Study Objective(s):
!
Brief Smell Identification Test (B-SIT)
Synopsis – Safety Assessments:
Collection of AEs, physical, nasal and neurological examinations, clinical laboratory evaluations, 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
122 of 124
Upsher-Smith Laboratories, Inc.
10.5.1 Safety Analyses
!
B-SIT: For olfactory examination, the B-SIT scores and changes from baseline will 
be presented and plotted by visits. Further analysis adjusted by exposure and time 
may be conducted. Details will be included in the SAP.
Change 2
1.3.1.3 Study P261-201
Study P261-201 was a single-center, in-patient trial investigating the safety, tolerability, PK, and 
PD of escalating single- and two-dose regimens of USL261 compared to placebo in adult subjects 
with epilepsy.  Subjects were assigned sequentially to 1 of 4 cohorts to receive either USL261 
(10.0 mg, 15.0 mg, 17.5 mg, or 20.0 mg) or placebo at two dosing visits separated by ≥ 3 days.  
Each subject received USL261 or placebo at Visit 2.  At Visit 3, each subject received the same 
total dose as he/she received at Visit 2 administered as a divided dose.  The results of this study 
are pending.
USL261 was absorbed rapidly (approximately 9 minutes to 19 minutes after a single dose; 
approximately 19 to 22 minutes after the two-dose regimen). Following either single dose or 
repeat dose administration, PK parameters for both MZ and 1-OH MZ were similar across 
cohorts and did not exhibit dose dependent changes. Exposure to MZ and 1-OH MZ (as 
indicated by Cmax and AUC parameters) was not dose proportional following single dose or 
repeat dose administration of 10.0 mg to 20.0 mg. Effects of USL261 on sedation and 
psychomotor performance were transient following single and repeat dose administration 
and were consistent across USL261 doses. Consistent with PK results, no dose response was 
observed in SSS or OAA/S Sum and Composite scores or their corresponding PD parameters 
from 10.0 to 20.0 mg USL261 following either single or repeat dose administration.
USL261 was generally safe and well-tolerated following single- or repeat-dose administration 
up to the maximum evaluated total dose level of 20 mg in adult subjects with epilepsy taking 
concomitant AEDs. In total, 58 subjects (96.7%) reported 179 TEAEs. All of the reported 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

Confidential 
Protocol P261-402
Approved Protocol Version: 
Amendment 4, 20 May 2015
123 of 124
Upsher-Smith Laboratories, Inc.
TEAEs were considered mild in severity with the majority (96.0%) were considered 
“probably related” to study drug. Treatment-emergent AEs reported in ≥20% of subjects in 
any group were nasal discomfort and throat irritation, which occurred in 96% of subjects 
administered MDZ NS. However, there was no clear dose relationship and these events also 
occurred frequently in placebo subjects. Nasal mucosal disorder, headache, dysgeusia, and 
hiccups were also common TEAEs, occurring in ≥10% MDZ NS subjects.
1.3.1.4 Study P261-102
Study P261-102 was a single-center trial investigating the safety, tolerability, PK, and PD of single 
2.5 mg and 5.0 mg doses of USL261 in generally healthy geriatric and non-geriatric subjects.  
Enrollment was stratified into non-geriatric (18 – 40 years old, inclusive) and geriatric (≥ 65 years 
old) groups such that there were 12 subjects in the non-geriatric range and 18 subjects in the 
geriatric range.  Subjects were randomly assigned to receive single doses of both 2.5 mg and 5.0 
mg USL261 in a 2x2 crossover fashion with a washout period of 4 – 10 days between dosing.  
Preliminary results indicate that although systemic exposures after administration of IN USL261 
were approximately 20 45% higher in the geriatric group compared to non geriatric volunteers, 
maximum and overall sedation effect was comparable, and no increase in moderate or severe AEs 
was observed for the geriatric group. Mean systemic exposure (AUC) and peak plasma 
concentrations (Cmax) of MDZ were 20–45% higher in the geriatric subjects compared with 
nongeriatric subjects. Geriatric subjects exhibited greater cognitive effects than nongeriatric 
subjects, whereas maximum and overall sedation effects were comparable between the two 
groups.
Of the 30 enrolled subjects, 26 subjects (87%) reported at least one TEAE during the study
with more geriatric subjects reporting a TEAE than younger subjects. All reported TEAEs 
(n=115) were considered mild in severity; most (91.3%) were considered “probably related” 
to the study drug. No SAEs or deaths were reported, and no subject discontinued study 
participation due to a TEAE. Although there were some differences between the 2.5 mg and 
5.0 mg doses with regard to the incidence of the more frequently reported AEs, there did not 
appear to be a consistent association with dose.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.