Clinical trial NCT01529034
Conditions: Epilepsy
Keywords: Epilepsy seizure clusters acute repetitive seizures rescue treatment
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2012-07-01; Completion date: 2017-04-01
Enrollment: 175 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to examine the long-term safety and tolerability of USL261 in the treatment of seizure clusters.

Detailed description:
Participants who completed study P261-401 (NCT01390220), a randomized double-blind study of USL261 (intranasal midazolam) versus placebo to acutely treat a seizure cluster episode, were eligible to to enroll in this open-label extension study (P261-402). The participant's caregiver administered a USL261 5 milligram (mg) dose for a seizure episode meeting study criteria. A second USL261 5 mg dose could be administered after 10 minutes and up to 6 hours after the first dose for persistent or recurrent seizures, unless the participant met exclusions to administration of the second dose. A participant could have more than 1 seizure cluster episode treated during his/her study participation.

Arms: arm 1: Intranasal midazolam 5 mg
Interventions: intervention 1: USL261
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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Protocol P261-402
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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 
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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. 
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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.
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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.
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!
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.
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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
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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
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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:
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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
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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
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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 
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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
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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
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LIST OF FIGURES
Figure 1. Study Flow Chart............................................................................................ 34
Figure 2. Flow of Informed Consent .............................................................................. 44
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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
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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
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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 
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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 
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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).
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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.
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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.
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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 
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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.
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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.
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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 
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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 
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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 
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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.
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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 
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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. 
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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.  
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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.
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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.
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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.
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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:
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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).
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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.
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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.
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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 
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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 
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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.
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!
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 
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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 
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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.
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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.
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!
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 
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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
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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).
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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 
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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
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!
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.  
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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.
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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).  
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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.
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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.
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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.
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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 
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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.
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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.
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!
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
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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 
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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
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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.
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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 
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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.
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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, 
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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 
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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).
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!
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.
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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 
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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 
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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.
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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.  
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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 
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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:
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!
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.
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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 
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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 
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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 
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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.
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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: 
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!
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.  
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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 
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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 
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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 
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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.  
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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.
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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
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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
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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
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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
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Appendix 2.  Midazolam Injection, USP, Package Insert (Hospira)
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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, 
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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 
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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.
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Statistical Analysis Plan for Protocol No.: P261-402 
 
15May2017
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LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
2. 
STUDY DESIGN .........................................................................................................6 
2.1. 
General Study Design and Plan ....................................................................................6 
2.2. 
Randomization and Method of Treatment Assignment ..............................................10 
2.3. 
Study Procedures ........................................................................................................10 
3. 
STUDY OBJECTIVES AND CLINICAL ENDPOINTS ..........................................13 
3.1. 
Study Objectives .........................................................................................................13 
3.2. 
Clinical Endpoints ......................................................................................................13 
3.2.1. 
Safety Endpoints .........................................................................................................13 
3.2.2. 
Efficacy Endpoints ......................................................................................................13 
3.2.3. 
Exploratory Efficacy Endpoints .................................................................................13 
3.2.4. 
Outcome Endpoints ....................................................................................................14 
4. 
ANALYSIS POPULATIONS ....................................................................................14 
4.1. 
Enrolled Population ....................................................................................................14 
4.2. 
Safety Population ........................................................................................................14 
4.3. 
Efficacy Evaluable Population ...................................................................................14 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................14 
5.1. 
General Consideration ................................................................................................14 
5.2. 
Baseline .......................................................................................................................14 
5.3. 
Handling of Missing Data ...........................................................................................15 
5.4. 
Interim Analysis ..........................................................................................................15 
5.5. 
Data and Safety Monitoring Board (DSMB) ..............................................................16 
5.6. 
Multiple Comparisons and Multiplicity......................................................................16 
6. 
STATISTICAL ANALYSIS ......................................................................................16 
6.1. 
Subject Disposition .....................................................................................................16 
6.2. 
Treatment Exposure and Treated Seizure Clusters .....................................................16 
6.3. 
Protocol Deviations ....................................................................................................17 
6.4. 
Demographics and Baseline Characteristics ...............................................................17 
6.5. 
Medical and Surgical History .....................................................................................18 
6.6. 
Prior and Concomitant Medications ...........................................................................18 
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Statistical Analysis Plan for Protocol No.: P261-402
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6.7. 
Analyses of Efficacy and Outcome Endpoints ...........................................................19 
6.7.1. 
Efficacy Endpoint .......................................................................................................19 
6.7.2. 
Exploratory Efficacy Endpoints .................................................................................21 
6.7.3. 
Subject and Caregiver Outcome Assessments ............................................................23 
6.8. 
Safety Analyses ..........................................................................................................24 
6.8.1. 
Adverse Events (AEs) .................................................................................................25 
6.8.2. 
Requirement for Unscheduled ER or EMS Visit ........................................................27 
6.8.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................27 
6.8.4. 
Physical, Nasal, and Neurological Examinations .......................................................28 
6.8.5. 
Olfactory testing with Brief Smell Identification Test (B-SIT)..................................28 
6.8.6. 
Laboratory Parameters ................................................................................................28 
6.8.7. 
Vital Signs / Weight ....................................................................................................29 
6.8.8. 
Caregiver-Recorded Respiration Rate ........................................................................29 
7. 
DEVIATIONS FROM THE PROTOCOL SPECIFIED ANALYSIS .......................29 
8. 
MOCK TABLES, FIGURES, AND DATA LISTINGS ............................................29 
9. 
REFERENCES ...........................................................................................................30 
Appendix 1 Potentially Clinically Significant Laboratory Values .................................................31 
Appendix 2 List of AEs of special interest .....................................................................................32 
 
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Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         5 
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AE
Adverse event
AED
Antiepileptic Drugs
ATC
Anatomic Therapeutic Chemical
B-SIT
Brief Smell Identification Test
C-SSRS
Columbia-Suicide Severity Rating Scale
CI
Confidence interval
CRO
Contract Research Organization
DSMB
Data and Safety Monitoring Board
EMS
Emergency Medical Services
ER
Emergency Room
ET
Early Termination
IN
Intranasal
IRT
Interactive Response Technology
ITI
Intranasal Therapeutics, Inc.
ITIQ
Intranasal Therapy Impact Questionnaire
IV
Intravenous
LAR
Legally acceptable representative
MCS
Mental Health Component Score (SF-12v2)
Mg
Milligram
MedDRA
Medical Dictionary for Regulatory Activities
PCI
Potentially clinically important
PCS
Potentially clinically significant
PHCS
Physical Health Component Score (SF-12v2)
PK
Pharmacokinetic
PMP
Patient Management Plan
PT
Preferred Term in MedDRA
SF-12v2
SF-12v2 Health Survey
SAS
Statistical Analysis Software
SD
Standard deviation
USL
Upsher-Smith Laboratories, Inc.
USL261
Intranasal midazolam, study drug (formerly ITI-111)
SOC
System Organ Class in MedDRA
TEAE
Treatment-emergent adverse event
TSQM
Treatment Satisfaction Questionnaire for Medication
VNS
Vagus Nerve Stimulator
WHO
World Health Organization
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Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         6 

,1752'8&7,21
Acute repetitive seizures and seizure clusters occur in a subset of epilepsy patients. Seizure 
clusters have distinguishable characteristics that are easily recognized by patients, caregivers, 
and physicians and include a consistent onset (auras, prodrome) that may be indicative of 
convulsive or non-convulsive symptoms. Although patients typically recover between 
seizures, these seizure can last anywhere from minutes to hours.1 When a cluster of seizures 
occurs outside a hospital, the patient must often be transported to an acute care facility so 
medical personnel can administer intravenous (IV) therapy to stop the seizure(s).2
The primary goals of seizure cluster treatment are seizure cessation and prevention of seizure 
recurrence.1 Acute benzodiazepine treatment is effective for seizure control and often results 
in rapid seizure cluster termination; however, most treatment options rely on intervention by 
emergency medical personnel and therefore delay treatment while the patient is transported
to a medical facility.3 The development of an easily administered outpatient treatment of 
seizure clusters may reduce the need for emergency medical intervention and decrease 
seizure cluster duration. 
This statistical analysis plan covers the detailed procedures for performing statistical analyses 
and producing tables, listings, and figures in the Phase III study described in Upsher-Smith 
Laboratories, Inc. Protocol P261-402 (Fifth Issue, Amendment 4, 20 May 2015).
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This is an open-label, multicenter, safety extension study of USL261 in subjects with seizure 
clusters who have completed study P261-401.  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 
USL261 administration.
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 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         7 
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. 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. 
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.  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.  
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 into this extension study.
Figure 1 of study flow chart on next page shows the overall study scheme. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         8 
)LJXUH
6WXG\)ORZ&KDUW
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
6FUHHQLQJ
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 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 
Contract Research Organization (CRO) designee. If an extension is granted for a given 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         9 
subject, that subject may have to undergo repeat screening laboratory assessments within 28 
days prior to dispensing study drug. 
7UHDWPHQW3KDVH
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.
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. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         10

5DQGRPL]DWLRQDQG0HWKRGRI7UHDWPHQW$VVLJQPHQW
Randomization and treatment assignment are 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. 

6WXG\3URFHGXUHV
The schedule of study procedures and evaluations is summarized in Table 1.
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         11
7DEOH
6FKHGXOHRIWKH6WXG\3URFHGXUHV
3KDVH
6FUHHQLQJ
7UHDWPHQW3KDVH
6WXG\
7HUPLQDWLRQ
9LVLW1XPEHU
9LVLW>D@
9LVLWVDQG
>E@
9LVLW;>F@
7UHDWPHQW
>G@
)LQDO9LVLWRU
(DUO\
7HUPLQDWLRQ
6WXG\$VVHVVPHQW
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
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         12
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 protocol 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 protocol 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 protocol 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 protocol 
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 protocol 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: B-SIT = Brief Smell Identification Test; BP = blood pressure; C-SSRS = Columbia-Suicide Severity Rating 
Scale; HR = heart rate; IRT = Interactive Response Technology system; LAR = legally acceptable representative; PMP = 
Patient Management Plan; TSQM = Treatment Satisfaction Questionnaire for Medication  ; ITIQ = Intranasal Therapy Impact 
Questionnaire
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         13

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
6WXG\2EMHFWLYHV
The study objectives are to evaluate the long-term safety and tolerability of USL-261 in the treatment
of seizure clusters using the following safety endpoints: 
x
Caregiver-recorded respiration rate at approximately 10 minutes, 15 minutes, 30 minutes, 1 
hour, 2 hours and 4 hours after study drug administration
x
Adverse events (AEs) 
x
Clinical laboratory tests
x
Physical, nasal, and neurological examinations 
x
Vital sign measurements (systolic and diastolic blood pressure, pulse rate, respiration rate, 
and temperature) as recorded by the study center personnel 
x
Brief Smell Identification Test (B-SIT)
x
Columbia-Suicide Severity Rating Scale (C-SSRS) 
x
Requirement for unscheduled emergency room (ER) or emergency medical service (EMS) 
visits within 24 hours after study drug administration 

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
6DIHW\(QGSRLQWV
The safety endpoints are listed above under Section 3.1, study objectives. 

(IILFDF\(QGSRLQWV
x
Treatment Success (defined in Section 6.7.1) 
x
Time to return to full baseline functionality (as determined by the caregiver)  

([SORUDWRU\(IILFDF\(QGSRLQWV
x
Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study drug 
administration to 4 hours after study drug administration
x
Time to next seizure with a start time >10 minutes after study drug administration
x
Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study drug 
administration to 24 hours after study drug administration 
x
Time from administration of the first open-label dose of study drug to the second open-label 
dose of study drug (for subjects receiving the second dose)
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         14

2XWFRPH(QGSRLQWV
x
SF-12v2 Health Survey (SF-12v2) 
x
Treatment Satisfaction Questionnaire for Medication (TSQM) 
x
Intranasal Therapy Impact Questionnaire (ITIQ) 
x
Caregiver Questionnaire

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
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The Enrolled Population includes subjects who completed study P261-401, or if Study P261-401 had 
been terminated, also subjects who completed the Test Dose Visit (Visit 2) of Study P261-401 will 
also be eligible to enter this study (P261-402).  All subjects must meet all the eligibility criteria in 
P261-402. 

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The Safety Population includes all subjects who are enrolled in this open-label study (P261-402) and 
received at least one dose of open-label study drug during this open-label study (P261-402). 

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The Efficacy Evaluable Population includes all subjects in the Safety Population who have any post-
treatment efficacy assessment in Study P261-402. 

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
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All datasets and output will be produced using SAS® Version 9.2 or higher (SAS Institute, Inc., Cary, 
North Carolina, USA). 

%DVHOLQH
This study (P261-402) serves as an open-label extension for subjects who have completed study P261-
401, or at least completed the test dose, if study P261-401 is terminated.  The data presentations for 
study P261-402 will include, but are not limited to, summary of the change from baseline for the 
continuous safety endpoints and the outcome questionnaires (when applicable).  In order to facilitate 
data summarization relative to exposure to active study medication, baseline endpoints will be defined 
as the latest non-missing value prior to Test Dose administration of USL261 from Study P261-401. 
Detailed baseline definitions of each endpoint of interest are presented in Table 2. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         15
7DEOH
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Efficacy
Data displays not dependent on defining baseline 
Vital Signs
The last non-missing value prior to the first dose of 
study drug administration at Visit 2 in study 
P261-401 (note the data displays for ITIQ and 
Caregiver Questionnaire are not dependent on 
defining baseline)
Weight
Laboratory Parameters
B-SIT
Outcome Questionnaires (SF12-V2, TSQM) 
Physical Exam
Data displays not dependent on defining baseline 
Neurological Exam 
Nasal Exam
AEs/SAEs
C-SSRS

+DQGOLQJRI0LVVLQJ'DWD
Any specific imputation procedures for missing or incomplete data will be discussed in the section 
describing analytic or summary methods for the corresponding variable in question.  Unless otherwise 
stated, observed data will be presented in tables and listings without imputation of missing values.
AEs with missing start dates will be considered treatment-emergent if the stop date has been recorded 
and is after the first dose date (first dose date refers to the first treatment with active study drug during 
study P261-402). 
Missing AE relationship will be presented as ‘related’ in tables and as missing in listings.  Missing AE 
intensity will be considered as ‘severe’ in tables but will be reported as missing in listings.

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Although no interim analysis is planned for decision making regarding this study, a snapshot of the 
data contained in the clinical database will be taken at the appropriate times in order for the safety data 
accrued in this study to be included in any regulatory submissions for this compound. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         16

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The DSMB constituted for the P261-401 study will have access to the data from this study, if requested 
by the DSMB, 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. 

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Since this is an open-label extension study, there is no formal hypothesis testing. Where 95% 
confidence intervals are presented, there is no adjustment for multiple times of testing. 
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All analyses will be descriptive with p-values presented for the change from baseline for selected 
outcome assessments. 
Data will be listed and tabulated overall.  Continuous variables, including the change from baseline 
(when appropriate), will be summarized using descriptive statistics [n, mean, standard deviation (SD), 
minimum, median, maximum].  Categorical variables will be summarized using counts and 
percentages.  Time to event variables will be summarized using Kaplan-Meier estimates.
Baseline is defined in Section 5.2 above, or if not included in 5.2, as the last data point prior to the first 
dose of study P261-402 open-label study drug administration, unless otherwise stated. 
Data listings will include all subjects with at least one applicable value.  Listings will be sorted by site, 
subject number, and date/time (if applicable).

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Individual subject disposition data will be listed by investigator site for the enrolled population. 
A summary of subject disposition will display the number of subjects who completed study P261-401 
and 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 study participation will be 
summarized according to the primary reason for early withdrawal.

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Treatment exposure will include exposure to USL261 in study P261-402.  Exposure to active study 
treatment will be summarized descriptively by the total number of milligrams of USL261 received per 
subject. Exposure data (comparative dose assignment and open-label dose usage) from study P261-401 
will only be presented in listing.
The total number of seizure cluster episodes treated with USL261 will be summarized descriptively as 
well as categorically (number of single 5.0 mg dose [no second 5.0 mg dose] administrations of 
USL261, number of repeat [5.0 mg + 5.0 mg] administrations of USL261, number of total 5.0 mg 
administrations of USL261). For the total number of seizure cluster episodes less than or equal to 5, 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         17
categorical variables will be summarized as 1, 2 - 3 , 4 - 5. For the total number of seizure cluster 
episodes greater than 5, categorical variables will be summarized in groups of 5, i.e. 6 - 10, 11 - 15, 16 
- 20 and so on, until the maximum number based on the data. 
The time on study (number of days from informed consent to the last completion / early termination 
visit) in study P261-402 will be summarized descriptively as well as categorically (0 – 6 months, 6 – 
12 months, 12 – 24 months, and > 24 months). 
The frequency of treated seizure clusters (average per year)  will be summarized descriptively as well 
as categorically (<2 years, 2 - <4 years, 4 - <12 years, 12 - <26 years, 26 - <52 years, >52 years).
The time between successive treated seizure clusters will be summarized descriptively as well as 
categorically (<=7 days, >7 - <=14 days, >14 - <=30 days, >30 - <=90 days, >90 - <=180 days, >180 
days). 

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All instances of protocol non-compliance in study P261-402 will be tracked during the study and CSR 
reportable protocol deviations will be finalized by a Sponsor review prior to database lock.  Protocol 
deviation categories will be presented in a data listing and summarized using counts and percentages.  
Deviations that may materially affect the evaluation of efficacy or safety will be identified as CSR 
Reportable.  CSR Reportable protocol deviations may include, but are not limited to:
x
Failure to obtain informed consent 
x
Failure to report a Serious Adverse Event (SAE) 
x
Enrolling patients outside of inclusion/exclusion criteria
x
Drug dispensing/dosing errors 

'HPRJUDSKLFVDQG%DVHOLQH&KDUDFWHULVWLFV
Demographics and baseline characteristics for subjects continuing in this P261-402 open-label 
extension study (unless otherwise specified, based on the data as collected in the preceding P261-401 
study) will be presented for the Enrolled, Safety and Efficacy Evaluable Populations. Subject 
demographics include age (calculated as the integer number of years between date of birth and 
informed consent date of P261-402), age group, gender, race, ethnicity, clinical site region, height, 
weight, weight category, BMI, BMI category, and inducer status (based on AED exposure in 
P261-402). Weight recorded in pounds will be converted to kilograms and height recorded in inches 
will be converted to centimeters. BMI will be calculated based on weight and height using below 
formula: 
BMI (kg/cm2) = Weight/Height2
In addition subject age (years) will be categorized as follows:
x
< 18 years
x
- < 65 years
x
\HDUV
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         18
Subject baseline characteristics include: IQ (if available), developmentally delayed status, EEG 
history, CT scan and/or MRI history, previous and current seizure types, seizure etiology including 
primary cause of epilepsy, and seizure cluster episode history. 

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Updates to medical and surgical history after the end of P261-401 study will be collected.  Medical and 
surgical history will be coded using the MedDRA coding dictionary version 16.1.  SOC will be sorted 
alphabetically and then preferred term will be sorted in order of frequency of the total column within 
each SOC.  At each level of summarization, a subject will be counted only once for each medical and 
surgical history he/she has within that level.  Subject listings of coded medical history terms will be 
provided.

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Prior medications are defined as medications in study P261-401 and P261-402 which started prior to 
the inform consent date in study P261-402.  Concomitant drug therapy will include all medications 
(prescription or non-prescription), nutritional supplement, herbal preparation or devices (e.g., VNS) in 
study P261-401 and P261-402 taken/used from the inform consent date in the P261-402 open-label
study through the Final Visit or ET Visit, including any with missing stop dates (or with partial 
missing stop dates that allow for the possibility the medication was taken after the inform consent date 
in study P261-402). 
The World Health Organization Drug Dictionary (WHO Drug) of version December 2011 will be used 
to classify prior and concomitant by therapeutic class and preferred name based on ATC code level 4.
Concomitant medications will be summarized for the Safety population.  Levels of summarization will 
include global, WHO Anatomic Therapeutic Chemical (ATC) Classification System level 3 drug class,
ATC level 4 drug class, and WHO preferred name. 
At each level of summarization, a subject will be counted only once for each concurrent medication 
he/she has within that level.  The percentage of subjects having had at least one medication at each 
level will be calculated.
Concomitant medications excluding AEDs, prior AEDs,  concomitant AEDs, concomitant AEDs used 
for epilepsy, and concomitant AEDs used for indications other than epilepsy will be summarized 
separately and similar to all concomita6nt medications. 
Both Prior and Concomitant AEDs will be further broken down into enzyme-inducing and non-
inducing AEDs. 
Separate listings will be provided for all medications and AEDs for all subjects, with medications 
classified as prior flagged in the listings. AEDs collected from AED page on CRF will be presumed to 
have ‘Epilepsy’ as indication. AEDs collected from concomitant medication page will be listed by 
indication captured on CRF. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         19

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Information recorded by the caregiver in the Subject Workbook will be used for analysis of the 
efficacy endpoints.  Any seizures occurring within 24 hours after administration of study drug will be 
recorded.
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All analyses of the efficacy endpoints will be conducted for the Efficacy Evaluable Population. 

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Treatment Success is a composite measure of efficacy that is defined as achieving both of the 
following criteria:
x
Termination of seizure(s) within 10 minutes after study drug administration, and 
x
No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours 
after study drug administration.
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Treatment Success will be determined based on data reported in the CRFs and derived 
programmatically for each treated seizure cluster.  There are three components to be assessed in the 
programmatic derivation: 
1. 7HUPLQDWLRQRIVHL]XUHVZLWKLQPLQXWHV7KHLQLWLDOVHL]XUHVWRSSHGZLWKLQPLQXWHV
from the time of dosing and any subsequent seizures also stopped within 10 minutes of dosing. 
2. No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours 
after study drug administration. The times of reported seizures will be used to assess if there are 
DQ\VHL]XUHVZLWKVWDUWWLPHIURP!PLQXWHVXSWRKRXUVDIWHr the first dose of study 
drug. 
3. No second dose given within 6 hours of the first dose of study drug administration as receiving 
WKHVHFRQGGRVHZLWKLQKRXUVFRQIRXQGVWKHHIILFDF\HYDOXDWLRQRIWKHILUVWGRVH
For each treated seizure cluster, subjects who meet all three of these components will be defined as a 
“Treatment Success” for that seizure cluster.  If a subject does not meet all three of these components, 
(which may or may not be due to missing data), they will be defined as “Not a Treatment Success” for 
that particular seizure cluster. As subjects may be treated for multiple seizure clusters, it is possible 
they could meet the criteria for “Treatment Success” for some seizure clusters, but not for all. 
Possible scenarios for seizure data start and stop times within the 6 hour period following the first dose 
of study drug are displayed below, along with the treatment success endpoint derivation (assuming no 
second dose was given): 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         20
The percentage of subjects achieving Treatment Success and its components (seizure termination and 
recurrence) will be summarized for each USL261-treated seizure cluster (first, second, etc.).  
Additionally, all treated seizure clusters will be pooled (across all subjects) with the proportion of 
Treatment Successes (this data presentation may be broken down by the number of within-subject 
treated seizure clusters, based on the data observed; for example, presented by subjects treated for 1-2 
seizure clusters, 2-5 clusters, 5-10 clusters, etc.).  Descriptive statistics for the percentage of each 
subject’s USL261-treated seizure clusters that met the criteria for Treatment Success will also be 
presented.

7LPHWR5HWXUQWR)XOO%DVHOLQH)XQFWLRQDOLW\DV'HWHUPLQHGE\WKH&DUHJLYHU
Time to return to full baseline functionality after study P261-402 open-label study drug administration
will be summarized and plotted using Kaplan-Meier estimates for each successive seizure episode
(first, second, etc.) and also pooled across all treated seizure clusters.  Subjects who have no records on 
time of return to baseline functionality within 24 hours of study drug administration and have not been 
administered the 2nd dose of study drug will be censored at the end of the observation period.  For each 
seizure cluster episode, subjects who were administered the 2nd dose of open-label study drug prior to 
returning to baseline functionality will be censored at the time that the 2nd open-label dose was 
administered.
Seizure Scenarios for Deriving Treatment Success Endpoint
First Dose 
Administered
10 min
6 hr
= Seizure Start
Derived 
Endpoint
= Seizure Stop
Treatment 
Success
Treatment 
Success
Not a Treatment 
Success
Not a Treatment 
Success
Not a Treatment 
Success
Each scenario displayed assumes 
a second dose was not given 
within six hours of the first dose.
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         21

([SORUDWRU\(IILFDF\(QGSRLQWV
All exploratory efficacy analyses will be based on the Efficacy Evaluable Population. 

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$GPLQLVWUDWLRQRI2SHQ/DEHO6WXG\'UXJWR+RXUVDIWHU
Subjects who have been administered the second dose of the study drug (ie, 5.0 mg dose of USL261) 
within 4 hours of the first dose for the episode will be assumed to have had a recurrent seizure. The 
proportion of subjects with recurrence of seizure(s) recorded in the diary with start time >10 minutes 
DQG hours after the administration of study P261-402 open-label study drug will be summarized for 
each successive seizure cluster (first, second, etc.) and also pooled across all treated seizure clusters.
Subjects who do not have a seizure recorded, or whose next seizure occurs > 4 hours after study drug 
administration, will be counted as not having a seizure in this particular analysis.

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$GPLQLVWUDWLRQ
Kaplan-Meier estimates and plots will be used to summarize the time-to-next seizure after study 
P261-402 open-label study drug administration for each successive seizure episode (first, second, etc.) 
and also pooled across all treated seizure clusters.  Subjects who do not have another seizure before the 
end of the 24-hour observation period, and have not been administered the second dose of open-label 
study drug will be censored at the end of the observation period.  Subjects who have been administered 
the second dose of open-label study drug and did not have a seizure before the administration of the 
second dose will be censored at the time of the second dose administration.  The time-to-next seizure 
percentiles (defined based on the data) with associated 95% confidence intervals (CIs) will be 
displayed.  The probabilities of experiencing the next seizure after open-label study drug 
administration at each hour up to 24 hours with associated standard error and 95% confidence intervals 
will be presented.

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6WXG\'UXJ$GPLQLVWUDWLRQWR+RXUVDIWHU6WXG\'UXJ$GPLQLVWUDWLRQ
7KHSURSRUWLRQRIVXEMHFWVZLWKUHFXUUHQFHRIVHL]XUHVZLWKDVWDUWWLPH!PLQXWHVDQGKRXUV
after study P261-402 open-label study drug administration will be summarized for each successive 
seizure episode (first, second, etc.) and also pooled across all treated seizure clusters. Subjects who 
have been administered the second dose of open-label study drug within 24 hours will be assumed to 
have had a seizure.  Subjects who do not have a seizure recorded with a VWDUWWLPH!PLQXWHVDQG
hours after the administration of open-label study drug will be counted as not having a seizure in this 
particular analysis.
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Seizure cluster episodes where both the first and second (provided 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) administrations of USL261 are 
given are included in the following data presentations. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         22
 7UHDWPHQW6XFFHVVRIWKH6HFRQG'RVHRI6WXG\'UXJPJRI86/
Treatment Success of the second dose for subjects receiving the second dose of USL261 will be 
presented for each successive seizure episode (first, second, etc.) and also pooled across all treated 
seizure clusters. 
For this analysis, Treatment Success of the second dose is defined as achieving the following: 
x
Termination of seizure(s) within 10 minutes after the second dose of study drug (5.0 mg of 
USL261) 
x
No recurrence of seizure(s) beginning 10 minutes after administration of the second dose of 
study drug (ie, 5.0 mg of USL261) to 6 hours after the second dose of study drug (5.0 mg of 
USL261) 
Subjects whose Subject Workbook indicates seizure termination within 10 minutes of the second dose 
and who have no seizures recorded with start time >10 minutes and <6 hours after the second dose of 
study drug will be considered a Treatment Success of the second dose.  Subjects who do not meet 
either of these criteria will not be considered a Treatment Success of the second dose.  Similar 
derivation rules as used for Section 6.7.1.1 Treatment Success endpoint will be used for defining 
Treatment Success of the second dose, with the exception of not including the rule pertaining to the 
second dose. 
Number and percentage will be presented for Treatment Success of the second dose and each 
component (seizure termination and recurrence) for subjects who received two doses of study drug.  
The 95% CIs for the proportions will also be presented. 
 7LPHIURP$GPLQLVWUDWLRQRIWKH)LUVW'RVHRI2SHQ/DEHO6WXG\'UXJWRWKHQG'RVH
For each successive seizure episode (first, second, etc.) and also pooled across all treated seizure 
clusters, time (in hours) from the administration of the first dose of study P261-402 open-label study 
drug to the 2nd dose (provided 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) will be descriptively summarized. In addition to the total number of 
subjects receiving this second dose, counts of subjects receiving the second dose in specific time 
FDWHJRULHVSRVWILUVWGRVHWRPLQXWHV!PLQXWHVWRKU, > 1 hr) will also be presented.  For 
each seizure cluster episode, only subjects who received both doses of open-label study drug will be 
included in this data presentation.
Kaplan-Meier estimates will be used to summarize the time-to-second dose for each successive seizure 
episode (first, second, etc.) and also pooled across all treated seizure clusters.  Subjects who do not 
receive the second dose of study drug within 6 hours of the initial study drug administration will be 
censored at the end of this 6 hour period.  The time-to-second dose percentiles (defined based on the 
data) with associated 95% CIs will be displayed. Kaplan-Meier curves by treatment group will also be 
presented.
Kaplan-Meier estimates will also be used to summarize the time-to-next seizure following the second 
dose for each successive seizure episode (first, second, etc.) and also pooled across all treated seizure 
clusters.  Subjects who do not have another seizure before the end of the 24-hour observation period 
following the second dose of study drug will be censored at the end of this observation period.  The 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         23
time-to-next seizure following the second dose percentiles (defined based on the data) with associated 
95% CIs will be displayed.  The probabilities of experiencing the next seizure following the second 
dose at each hour with associated standard error and 95% confidence intervals will be presented.  
Kaplan-Meier curves by treatment group will also be presented.
 7UHDWPHQW6XFFHVVIRUDOO'RVHVRI6WXG\'UXJ
An analysis similar to that in Section 6.7.2.4.1 Treatment Success of the Second Dose of Study Drug, 
will be performed including all study drug administrations (regardless of 1st dose or 2nd dose). 

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The subjects and caregiver outcome assessments will be summarized using the efficacy evaluable
population. 

6)Y
The SF-12v2 is a 12-item questionnaire which will be administered to both the subject and caregiver at 
Visit 1 and Final/ET Visit in study P261-402.  All summaries will be presented separately for the 
subject and caregiver.  Eight domains make up the SF-12v2: physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, and mental health.  In addition, the 
Physical Health Component Score (PHCS) and the Mental Health Component Score (MCS) will be 
calculated.  The scores for each domain, the PHCS and the MCS range from 0 to 100, where zero 
indicates the lowest level of health by the scales and 100 indicates the highest level of health.4
Summary scores for PHCS and MCS for each subject will be computed using published 
algorithms.4 Each summary measure is scored and standardized using a t-score transformation, such 
that a higher score represents better health status, with a mean score of 50 and a standard deviation of 
10 in the general population.5  Missing data on the SF-12v2 will be handled as follows: domain scores 
will not be calculated for domains in which data are missing. Subsequently, component scores in 
which domain scores are missing will not be calculated.
The domain and component scores will be summarized descriptively at Baseline (defined as the last 
data point prior to the first dose of study drug administration at Visit 2 in study P261-401) and for Visit 
1 and Final/ET Visit for study P261-402.  Change from baseline will be summarized at Visit 1 and
Final/ET Visit for study P261-402.  For each domain and component score a paired t-test will be used 
to assess the within-group mean change from baseline.
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The TSQM is a 14-item questionnaire that will be administered to the subject.  The four TSQM scale 
scores calculated from the questionnaire are: effectiveness, side-effects, convenience, and global 
satisfaction.  The TSQM scale scores are computed by adding the items loading on each factor.  The 
lowest possible score is subtracted from the composite score and divided by the greatest possible score 
minus the lowest possible score.  This will provide a transformed score between 0 and 1 that is then 
multiplied by 100.  If more than one item is missing from each scale, the scale will not be calculated.  
Calculation of each scale score is provided below.6
(IIHFWLYHQHVV
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         24
([Q1 + Q2 + Q3) – 3]/18) * 100 
If one item is missing then, ([Qx + Qy – 2]/12) * 100 where x and y = 1, 2, oUZLWK[\
6LGH(IIHFWV
If Q4 is ‘No’ then score = 100 
Else, ([Q5 + Q6 + Q7 + Q8 – 4]/16) * 100 
If one item is missing then, ([Qx + Qy + Qz – 3]/12) * 100 where x, y, and z = 5, 6, 7, or 8, 
with [\]
&RQYHQLHQFH
([Q9 + Q10 + Q11) – 3]/18) * 100 
If one item is missing then, ([Qx + Qy – 2]/12) * 100 where x and y = 9, 10, or 11. 
*OREDO6DWLVIDFWLRQ
([Q12 + Q13 + Q14) – 3]/14) * 100 
If one item is missing then, ([Qx + Qy – 2]/8) * 100 where x and y = 12, 13, or 14. 
The 4 scale scores will be summarized descriptively for all visits and change from baseline (baseline is 
defined as the last data point prior to the first dose of study drug administration at Visit 2 in study 
P261-401) will be summarized for all post baseline visits. For each domain and component score a 
paired t-test will be used to assess the within-group mean change from baseline to each post baseline 
visits.

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The ITIQ is a two item questionnaire that is completed by both the subject and caregiver at all Visits.  
The level of anxiety change since subject received intranasal therapy is a scale with a range from -7 to 
7, and confidence about travelling having a spray the subject can take with them is a scale from 1 to 5.  
The change in level of anxiety and change since subject received intranasal therapy will be 
summarized descriptively.  Counts and percentages will be used to summarize the confidence about 
travelling having a spray the subject can take with them at each visit.

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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) and 
resource utilization (completed at all visits).
All caregiver’s questionnaire resource utilization data collected during the study will be presented in 
the listings.  In addition, utilization endpoints will be summarized, including all treated seizure clusters
(that is, pooled), by the categories "treatment success" and "not a treatment success" as derived for 
each treated seizure cluster. 

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All safety analyses will be presented based on the Safety Population unless otherwise specified. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         25

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Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
actual MedDRA version used will be noted in the footnote of each corresponding output.  Coding 
includes system organ class (SOC) and preferred term (PT).  All verbatim descriptions and coded 
terms will be listed for all AEs.
3UHWUHDWPHQW$(V
Pre-treatment AEs will be defined as any AE that was ongoing at the end of study P261-401, or that 
started after the completion of study P261-401, and either ended before or did not increase in severity 
following open label study drug administration in P261-402.  Pre-treatment AEs will be presented in a 
listing separate from treatment-emergent AEs (TEAEs).  All summaries of AEs will be based only on 
TEAEs, excluding pre-treatment AEs.
7UHDWPHQWHPHUJHQW$(V7($(V
The following AEs will be defined as TEAEs: 
x
Any AE that begins after the first study P261-402 open-label study drug  administration;
x
Any AE that begins prior to the first study P261-402 open-label study drug administration 
and worsens in severity following open-label study drug administration;
All AEs will be listed by subject and by MedDRA SOC and PT. 
The number of events and the frequency and percentage of subjects with TEAEs/SAEs will be 
summarized for the Safety Population. Summary tables of TEAEs and SAEs will be presented by SOC 
and PT.  At each summary level, a subject will be counted only once for each AE he/she experienced
within that level, regardless of how many occurrences of that AE that subject experienced.  The 
percentage of subjects having had at least one TEAE/SAE at each level will be calculated.  All the 
TEAE analyses will also be repeated for the subset of all TEAEs that started within two days of study 
drug administration.
Tabular summaries will include all TEAEs, TEAEs by age group \HDUV- \HDUV
years), TEAEs by severity (mild, moderate, severe), TEAEs by relationship to study drug, TEAEs 
related to study drug by severity (mild, moderate, severe), TEAEs of special interest (AESIs), serious 
TEAEs (SAEs) with SAEs leading to permanent discontinuation and death, SAEs by severity, and
SAEs by relationship to study drug.  If there are any deaths while on the study, they will be presented 
in a listing that includes the AE leading to death, demographic data, details of study treatment, and 
relationship of the AE leading to death to the study drug.  In addition, listings of all TEAEs, SAEs, 
TEAEs of special interest (AESIs), and AEs leading to discontinuation will be presented.
The following AEs of special interest (AESIs) are discussed in this section by AESI category. 
x
Taste and smell disorders
x
Acute central respiratory depression
x
Route of administration
x
Depression and suicidality/self-injury 
x
Abuse-related AEs
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         26
Abuse-related TEAEs will be further broken out by the following categories:  
x
Drug Abuse, Dependence, Withdrawal and Substance-Related Disorders, Including 
Diversion 
x
Euphoria-related Term
x
CNS Depressant Effects
x
Stimulation and Anxiety Symptoms
x
Perceptual Disturbances/Psychotomimetic Effects
x
Mood Disorders and Disturbances 
x
Mental and Cognitive Impairment 
SMQs and/or a USL-defined algorithm will be used to search AESIs. Search strategies are described 
in Table 3.
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6HDUFK6WUDWHJ\
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Modified Taste and Smell Disorders SMQ - broad 
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ
Modified Acute Central Respiratory Depression SMQ - broad 
'HSUHVVLRQDQG6XLFLGDOLW\6HOI,QMXU\
Modified Depression and Suicidality/Self-Injury SMQ – broad
5RXWHRIDGPLQLVWUDWLRQ
USL-defined [Oral Soft Tissue Conditions HLT 
(Gastrointestinal Disorders SOC); Respiratory Disorders NEC 
(Respiratory, Thoracic and Mediastinal Disorders SOC); 
Upper Respiratory Tract Disorders (Exclude Infections) 
(Respiratory, Thoracic and Mediastinal Disorders SOC)] – 
excluding overlapping terms with Acute Central Respiratory 
Depression SMQ and terms unrelated to MDZ NS’s nasal 
route of administration, e.g., terms for conditions in the 
respiratory tract below the larynx or terms with defined causes
$EXVHUHODWHG$(V
USL-defined algorithm 
$EEUHYLDWLRQV HLT=High Level Term; SMQ=Standardized MedDRA Queries; NEC=Not Elsewhere Classified.
Standard MedDRA Queries (SMQs) defined by the CIOMS Working Group are groupings of terms 
from one or more MedDRA SOCs that relate to a defined medical condition or area of interest.
Modifications of SMQs will be documented.  For hierarchical SMQs, the portion of the hierarchy to be 
used will be that part or those parts determined to be most relevant.  A list of AEs in each category is 
presented in Appendix 2. Summary tables will be presented by SOC and preferred term.
In addition, "potentially clinically important" AESI will be presented for each category of AESI. AE 
which meets at least one of the following criteria is defined as a potentially clinically important AE: 
x
AE is an SAE
x
AE led to discontinuation 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         27
x
AE is severe in intensity and related to study drug  
x
AE required intervention and is related to study drug 
In instances where a subject may have multiple TEAEs with differing levels of severity or relatedness, 
the most severe or most related event, respectively, will be reported for the severity and relatedness 
tables.  For the purpose of summary, TEAEs with a reported relatedness of  “Related”, ”Possibly 
Related”, “Unlikely Related”, or  missing the relationship will be classified as related to study drug.  
TEAEs assessed as “Not Related” will be classified as not related to study drug.  TEAEs with missing 
severity will be presented as severe in the tables but will be listed as missing.

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The number and percent of subjects requiring an unscheduled ER or EMS visit within 24 hours after 
study drug administration will be presented for each successive treated seizure cluster episode (first, 
second, etc.).  In addition, the number of subjects requiring an unscheduled ER or EMS visit for any 
seizure cluster episode or other seizure emergency (treated or untreated) will be summarized 
(separately, for ER or EMS visit at any time, or visit within 24 hours after study drug administration). 
The total number of unscheduled ER or EMS visits will also be presented in a data listing. 

&ROXPELD6XLFLGH6HYHULW\5DWLQJ6FDOH&6656
The C-SSRS is collected at all visits using the ‘Since Last Visit’ version.
6XLFLGDO,GHDWLRQ
The number and percent of subjects with each of the following suicidal ideation scores will be 
summarized for each visit. The highest score for suicide ideation will be used for each subject by visit. 
Suicidal Ideation Scores 
Suicidal ideation
Score
Wish to be dead
1
Non-specific active suicidal thoughts
2
Active suicidal ideation with any methods (not planned) without intent to act
3
Active suicidal ideation with some intent to act, without specific plan
4
Active suicidal ideation with specific plan and intent
5
Any suicidal ideation regardless of type will also be presented. 
Each suicidal ideation severity rating will range from 0 (no ideation present) to 5 (active ideation with 
plan of intent).  Descriptive statistics will be presented for suicidal ideation severity rating at each visit. 
Descriptive statistics will also be presented for suicidal ideation intensity at each visit.  The five 
intensity items (frequency, duration, controllability, deterrents, and reason for ideation) will be 
combined to create a total, sum score ranging between 0 and 25.  If the subject did not have any 
suicidal ideation, the total score will be 0.  If the subject had suicidal ideation and if one intensity item 
is missing, the total score will not be calculated.
6XLFLGDO%HKDYLRU
The number and percent of the following suicidal behaviors will be summarized for each visit.
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         28
x
Actual attempt
x
Engaged in non-suicidal self-injurious behavior 
x
Aborted attempt 
x
Interrupted attempts
x
Preparatory acts or behavior
x
Suicidal behavior 
x
Any suicidal behavior regardless of type 
x
Completed suicide 
Descriptive statistics will be presented for the following suicidal behaviors for each visit.
x
Number of attempts
x
Aborted attempts
x
Interrupted attempts
The number and percent of subjects with any suicidal ideation or behavior will be presented for each 
visit.

3K\VLFDO1DVDODQG1HXURORJLFDO([DPLQDWLRQV
The number and percent of patients having normal and abnormal findings (clinically significant vs. not 
clinically significant) for each body system or assessment will be presented by visit for each of these 
exams.

2OIDFWRU\WHVWLQJZLWK%ULHI6PHOO,GHQWLILFDWLRQ7HVW%6,7
Descriptive statistics for the summary score and changes from baseline for olfactory testing with B-SIT 
over time will be presented by visit. All B-SIT data will be presented in a listing.

/DERUDWRU\3DUDPHWHUV
Clinical laboratory parameters for serum chemistry, hematology, and urinalysis will be summarized 
descriptively at baseline and each study P261-402 visit. Mean and mean change from baseline values 
will be presented at each study visit. Change from baseline will be calculated at each post baseline 
visit as the value at that visit minus the baseline value.  If either the baseline or post baseline visit value 
is missing, the observation will not be included in the change from baseline summary at that visit.
Baseline is defined as the latest non-missing value prior to Test Dose administration of USL261 from 
Study P261-401. 
Each laboratory result will be classified as low (L), normal (N), and high (H) at each visit according to 
the laboratory-supplied normal range. The shift from baseline (as defined in Section 5.2) will be 
presented. 
Potentially clinically significant (PCS) laboratory abnormalities will be identified using standardized 
criteria in Appendix 1 prior to database lock and will be presented using counts and percentages. 
Additional displays of PCS may be presented. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         29

9LWDO6LJQV:HLJKW
Vital sign measurements, including body weight, performed by study site staff will be presented using 
descriptive statistics. Vital signs, including systolic and diastolic blood pressure (mmHg), pulse 
(beats/min), respiration rate (breaths/min), and temperature (degrees Celsius [° C]), along with body 
weight, will be summarized descriptively at baseline and each study P261-402 visit.  Change from 
baseline will be calculated as post-baseline measurement minus baseline measurement.  If either the 
baseline or post-baseline value is missing, the observation will not be included in the change from 
baseline summary at that visit. Baseline is defined as the latest non-missing value prior to Test Dose 
administration of USL261 from Study P261-401. 
The number of subjects meeting the following criteria will be presented by visit, and by time point:
x
< 8 breaths per minute after study drug administration
x
> 24 breaths per minute after study drug administration
x
systolic blood pressure < 85 mm Hg 
x
DFKDQJHIURPEDVHOLQHLQV\VWROLFSUHVVXUHPP+J
x
diastolic blood pressure < 50 mm Hg 
x
DFKDQJHIURPEDVHOLQHLQGLDVWROLFSUHVVXUH0 mm Hg
x
pulse > 120 beats per minute 
x
pulse < 50 beats per minute 
x
a change from baseline in pulse EHDWVSHUPLQXWH

&DUHJLYHU5HFRUGHG5HVSLUDWLRQ5DWH
The caregiver-recorded respiration rate will be presented using descriptive statistics at the scheduled 
collection times of (approximately) 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours 
after the first dose of study P261-402 open-label study drug for each successive seizure cluster episode
(first, second, etc.).  The number of subjects who have <8 and >24 breaths per minute will be presented 
by time point, across time points for each seize cluster, and across all treated seizure clusters. 

'(9,$7,216)5207+(35272&2/63(&,),('$1$/<6,6
The subjects and caregiver outcome assessments (detailed in Section 6.7.3) will be summarized using
the efficacy evaluable population, instead of the safety population as specified in the protocol. 

02&.7$%/(6),*85(6$1''$7$/,67,1*6
The mock TLGs will be provided in a separate document. 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         30

5()(5(1&(6
1. Cereghino JJ. Identification and treatment of acute repetitive seizures in children and adults.  
&XUU7UHDW2SWLRQV1HXURO.  2007;9:249-255. 
2. Lowenstein DH, Alldredge BK.  Status epilepticus. 1(QJO-0HG  1988;338:970-976. 
3. Glauser TA.  Designing practical evidence-based treatment plans for children with prolonged 
seizures and status epilepticus-&KLOG1HXURO  2007;22:38S-46S. 
4. Utah Department of Health.  Interpreting the SF12.  8WDK+HDOWK6WDWXV6XUYH\.  2001: 1-
17.
5. Web. < http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434659/> 
6. Web. <www.qualitymeasures.ahrq.gov> 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         31
$SSHQGL[
3RWHQWLDOO\&OLQLFDOO\6LJQLILFDQW/DERUDWRU\9DOXHV

9DULDEOH

8QLWV
9DOXHV
/RZ
+LJK
+DHPDWRORJ\
Haemoglobin
g/L
< 10
Not applicable
g/L
> 2 decrease from 
baseline
> 2 increase above ULN*
Lymphocytes (Absolute)
109/L
< 0.8
Not applicable
Neutrophils (Absolute)
109/L
< 1.5
Not applicable
Platelet count
109/L
< 75
Not applicable
White blood cell (WBC) count
109/L
< 3
Not applicable
6HUXP&KHPLVWU\
Albumin 
g/L
< 30
Not applicable
Alkaline phosphotase (AP)
U/L
Not applicable
> 2.5xULN
Alanine aminotransferase (ALT) Grade 1
U/L
Not applicable
!8/1	[8/1
Alanine aminotransferase (ALT) Grade 2
U/L
Not applicable
![8/1	[8/1
Alanine aminotransferase (ALT) Grade 3
U/L
Not applicable
![8/1	[8/1
Alanine aminotransferase (ALT) Grade 4
U/L
Not applicable
> 20xULN
Aspartate aminotransferase (AST) Grade 1
U/L
Not applicable
!8/1	[8/1
Aspartate aminotransferase (AST) Grade 2
U/L
Not applicable
![8/1	[8/1
Aspartate aminotransferase (AST) Grade 3
U/L
Not applicable
> [8/1	[8/1
Aspartate aminotransferase (AST) Grade 4
U/L
Not applicable
> 20xULN
Bicarbonate 
mmol/L
d 15.9 
Not applicable
Calcium 
mmol/L
< 2
> 2.9
Cholesterol (Total) 
mmol/L
Not applicable
> 7.75
Creatinine 
umol/L
Not applicable
> 1.5xULN
umol/L
Not applicable
> 2x baseline
Gamma glutamyl transferase (GGT)
U/L
Not applicable
> 2.5xULN
Glucose 
mmol/L
< 3.0
> 8.9
Phosphorus 
mmol/L
< 0.8
Not applicable
Potassium 
mmol/L
< 3.0
> 5.5
Sodium 
mmol/L
< 130
> 150
Total Bilirubin 
umol/L
Not applicable
> 1.5xULN
Triglycerides 
mmol/L
Not applicable
> 3.42
*ULN=Upper Limit of Normal
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         32
$SSHQGL[
/LVWRI$(VRIVSHFLDOLQWHUHVW
$EXVHUHODWHG$(V0HG'5$3UHIHUUHG7HUP
'UXJ$EXVH'HSHQGHQFH:LWKGUDZDODQG6XEVWDQFH5HODWHG'LVRUGHUV,QFOXGLQJ'LYHUVLRQ
Accidental death
Multiple drug overdose intentional
Accidental overdose
Nasal necrosis
Accidental poisoning 
Nasal septum perforation
Dependence
Nasal septum ulceration
Drug abuser
Needle track marks
Drug administered at inappropriate site  
Neonatal complications of substance abuse
Drug dependence
Overdose
Drug detoxification
Poisoning 
Drug diversion
Polysubstance dependence
Drug tolerance
Prescription form tampering
Drug tolerance increased
Product tampering
Drug toxicity  
Product used for unknown indication
Drug Withdrawal
Rebound effect 
Drug withdrawal convulsions  
Substance abuse
Drug withdrawal headache 
Substance abuser
Drug withdrawal syndrome 
Substance use
Intentional drug misuse
Substance-induced mood disorder
Intentional overdose
Substance-induced psychotic disorder
Multiple drug overdose
Treatment noncompliance
Multiple drug overdose accidental
Withdrawal Syndrome
(XSKRULDUHODWHG7HUPV
Dizziness
Feeling drunk
Elevated mood
Feeling of relaxation
Euphoric mood
Inappropriate affect
Feeling abnormal
&16'HSUHVVDQW(IIHFWV
Fatigue
Sluggishness
Lethargy
Somnolence
Sedation
Stupor
6WLPXODWLRQDQG$Q[LHW\6\PSWRPV
Agitation
Hypervigilance
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         33
Anxiety
Nervousness
Energy increased
Psychomotor hyperactivity
Feeling jittery
Restlessness
3HUFHSWXDO'LVWXUEDQFHV3V\FKRWRPLPHWLF(IIHFWV
Abnormal dreams
Hallucinations, mixed
Acute psychosis
Hostility
Aggression
Hypoaesthesia
Alice in wonderland syndrome
Ideas of reference
Altered state of consciousness
Illogical thinking
Altered visual depth perception
Illusion
Anger
Incoherent
Communication disorder
Indifference 
Confusional state
Jamais vu
Consciousness fluctuating
Loose associations
Déjà vu
Magical thinking
Delirium
Muscle rigidity
Delusion
Nightmare
Depersonalisation
Paraesthesia
Derailment
Paranoia
Derealisation
Paroxysmal perceptual alteration
Disinhibition
Psychotic disorder
Disorientation
Reactive psychosis
Dissociation
Sensory disturbance
Dissociative disorder
Sensory level abnormal
Dissociative identity disorder
Somatic delusion
Dysarthria
Somatic hallucination
Fear
Staring
Flashback
Suspiciousness
Flight of ideas
Tangentiality
Formication
Thinking abnormal
Hallucination
Thought blocking
Hallucination, auditory
Thought broadcasting
Hallucination, olfactory
Thought insertion
Hallucination, synaesthetic
Thought withdrawal
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         34
Hallucination, tactile
Transient psychosis
Hallucination, visual
0RRG'LVRUGHUVDQG'LVWXUEDQFHV
Abnormal behaviour
Asocial behaviour
Affective disorder
Attention-seeking behaviour
Affect lability
Belligerence
Depressed mood
Blunted affect
Depression
Compulsions
Emotional disorder
Confusional arousal
Emotional distress
Disturbance in social behaviour
Impatience
Feeling of despair
Mood altered
Flat effect
Mood swings
Impulsive behaviour
Personality change
Mania
Anhedonia
Panic attack
Antisocial behaviour
Panic reaction
Apathy
Parasomnia
0HQWDODQG&RJQLWLYH,PSDLUPHQW
Amnesia
Mental disorder
Cognitive disorder
Mental status changes
Disturbance in attention
Paramnesia
Memory impairment
Psychomotor retardation
Mental impairment
Retrograde amnesia
Psychomotor skills impaired
Transient global amnesia
Amnestic disorder
Impaired driving ability
Anterograde amnesia
Impaired reasoning
Balance disorder
Dyslogia
Coordination abnormal 
Bradyphrenia
Executive dysfunction
Confabulation
Judgement impaired
 
(2)AEs related to acute central respiratory depression: 
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
Cardiac disorders
Cyanosis
Acrocyanosis
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         35
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
Cardiac disorders
Cardiac arrest
Arrest cardiac
Cardiac disorders
Cardiac arrest
Asystole
Cardiac disorders
Cardiac arrest
Asystolia
Cardiac disorders
Cardiac arrest
Asystolic
Cardiac disorders
Cyanosis
Blue lips
Cardiac disorders
Cardiac arrest
Cardiac arrest
Cardiac disorders
Cardiac arrest
Cardiac arrest transient
Cardiac disorders
Cardio-respiratory arrest
Cardio-respiratory arrest
Cardiac disorders
Cardio-respiratory arrest
Cardiopulmonary arrest
Cardiac disorders
Cardiac arrest
Congestive cardioplegia
Cardiac disorders
Cyanosis
Cyanosed
Cardiac disorders
Cyanosis
Cyanosis
Cardiac disorders
Cyanosis
Cyanosis NOS
Cardiac disorders
Cyanosis
Cyanosis of lip
Cardiac disorders
Cyanosis
Cyanosis peripheral
Cardiac disorders
Cyanosis
Cyanotic
Cardiac disorders
Cardiac arrest
Heart arrest
Cardiac disorders
Cardiac arrest
Hypoxic arrest
Cardiac disorders
Cyanosis
Lips cyanosed
Cardiac disorders
Cyanosis
Nails cyanosed
Cardiac disorders
Cardiac arrest
Standstill cardiac
Cardiac disorders
Cardiopulmonary failure
Cardio-respiratory failure
Cardiac disorders
Cardio-respiratory distress
Cardio-respiratory distress
Cardiac disorders
Cardiopulmonary failure
Cardiopulmonary insufficiency
Cardiac disorders
Cardiopulmonary failure
Cardiopulmonary failure
Cardiac disorders
Cyanosis
Circumoral cyanosis
Cardiac disorders
Cyanosis
Cyanosis aggravated
Infections and infestations
Severe acute respiratory syndrome
Severe acute respiratory syndrome
Infections and infestations
Severe acute respiratory syndrome
SARS
Injury, poisoning and procedural 
complications
Respiratory fume inhalation disorder
Respiratory fume inhalation disorder 
NOS
Injury, poisoning and procedural 
complications
Respiratory fume inhalation disorder
Upper respiratory inflammation due 
to fumes and vapors
Injury, poisoning and procedural 
Respiratory fume inhalation disorder
Upper respiratory inflammation due 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         36
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
complications
to fumes and vapours
Injury, poisoning and procedural 
complications
Respiratory fume inhalation disorder
Smoke inhalation
Injury, poisoning and procedural 
complications
Respiratory fume inhalation disorder
Respiratory fume inhalation disorder
Injury, poisoning and procedural 
complications
Postoperative respiratory failure
Postoperative respiratory failure
Investigations
Blood gases abnormal
ABGs abnormal
Investigations
Blood gases abnormal
Abnormal arterial blood gases
Investigations
Breath sounds abnormal
Abnormal chest sounds
Investigations
Breath sounds abnormal
Abnormal chest sounds NOS
Investigations
Blood gases abnormal
Blood gases abnormal
Investigations
Blood gases abnormal
Blood gases NOS abnormal
Investigations
Blood pH abnormal
Blood pH abnormal
Investigations
Blood pH decreased
Blood pH decreased
Investigations
Breath sounds abnormal
Breath sounds decreased
Investigations
Respiratory rate decreased
Breathing rate slowed
Investigations
Respiratory rate decreased
Breathing slowed
Investigations
Breath sounds abnormal
Diminished lung sounds
Investigations
Blood pH decreased
Low pH
Investigations
Oxygen saturation abnormal
Oxygen saturation abnormal
Investigations
Oxygen saturation decreased
Oxygen saturation decreased
Investigations
Oxygen saturation decreased
Oxygen saturation low
Investigations
PO2 abnormal
Oxygen tension abnormal NOS
Investigations
PO2 decreased
Oxygen tension decreased
Investigations
PCO2 decreased
Partial pressure CO2 decreased
Investigations
PO2 abnormal
Partial pressure O2 abnormal NOS
Investigations
PO2 decreased
Partial pressure O2 decreased
Investigations
PCO2 decreased
PCO2 decreased
Investigations
Blood pH decreased
pH decreased
Investigations
Blood pH decreased
pH reduced
Investigations
Blood pH decreased
Plasma pH decreased
Investigations
PO2 abnormal
PO2 abnormal NOS
Investigations
PO2 decreased
PO2 decreased
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         37
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
Investigations
PCO2 decreased
Reduced CO2 tension
Investigations
Respiratory rate decreased
Respiration rate decreased
Investigations
Respiratory rate decreased
Respiratory rate decreased
Investigations
Respiratory rate decreased
Respiratory rate low
Investigations
Breath sounds abnormal
Respiratory sounds decreased
Investigations
Blood pH decreased
Serum pH decreased
Investigations
Oxygen saturation abnormal
Oximetry abnormal
Investigations
Oxygen saturation decreased
Oximetry decreased
Investigations
Blood pH decreased
Arterial blood pH decreased
Investigations
Blood pH decreased
Venous blood pH decreased
Investigations
PCO2 abnormal
PCO2 abnormal
Investigations
Breath sounds abnormal
Abnormal chest sound
Investigations
PO2 abnormal
PO2 abnormal
Investigations
Breath sounds absent
Breath sounds absent
Investigations
Breath sounds abnormal
Breath sounds abnormal
Investigations
Breath sounds abnormal
Vesicular breathing abnormal
Investigations
Venous oxygen saturation decreased
Mixed venous blood saturation 
decreased
Investigations
Venous oxygen saturation abnormal
Mixed venous blood saturation 
abnormal
Investigations
Venous oxygen saturation decreased
SvO2 decreased
Investigations
Venous oxygen saturation abnormal
SvO2 abnormal
Investigations
Capnogram abnormal
Capnogram abnormal
Investigations
End-tidal CO2 abnormal
End-tidal CO2 abnormal
Investigations
End-tidal CO2 decreased
End-tidal CO2 decreased
Investigations
Alveolar oxygen partial pressure 
decreased
Alveolar oxygen partial pressure
decreased
Investigations
Alveolar oxygen partial pressure 
abnormal
Alveolar oxygen partial pressure 
abnormal
Investigations
Venous oxygen partial pressure 
decreased
Venous oxygen partial pressure 
decreased
Investigations
Venous oxygen partial pressure 
abnormal
Venous oxygen partial pressure 
abnormal
Investigations
Venous oxygen saturation decreased
Venous oxygen saturation decreased
Investigations
Venous oxygen saturation abnormal
Venous oxygen saturation abnormal
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         38
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
Investigations
Oxygen saturation decreased
Arterial oxygen saturation decreased
Investigations
Oxygen saturation abnormal
Arterial oxygen saturation abnormal
Investigations
PO2 decreased
Arterial oxygen partial pressure 
decreased
Investigations
PO2 abnormal
Arterial oxygen partial pressure 
abnormal
Investigations
PO2 decreased
PaO2 decreased
Investigations
PO2 abnormal
PaO2 abnormal
Investigations
Breath sounds abnormal
Coarse breath sounds
Nervous system disorders
Central-alveolar hypoventilation
Central-alveolar hypoventilation
Nervous system disorders
Hypercapnic coma
Hypercapnic coma
Psychiatric disorders
Breath holding
Breath holding
Psychiatric disorders
Breath holding
Breath holding attack
Psychiatric disorders
Breath holding
Breath holding spells
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
A.R.D.S.
Respiratory, thoracic and 
mediastinal disorders
Respiratory acidosis
Acidosis respiratory
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory failure
Acute on chronic respiratory failure
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Acute respiratory distress syndrome
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory failure
Acute respiratory failure
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Adult RDS
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Adult respiratory distress syndrome
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Adult respiratory stress syndrome
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Air hunger
Respiratory, thoracic and 
mediastinal disorders
Anoxia
Anoxia
Respiratory, thoracic and 
mediastinal disorders
Apnoea
Apnea
Respiratory, thoracic and 
mediastinal disorders
Apnoea
Apnoea
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         39
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
Respiratory, thoracic and 
mediastinal disorders
Apnoeic attack
Apnoea attack
Respiratory, thoracic and 
mediastinal disorders
Apnoeic attack
Apnoeic attack
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
ARDS
Respiratory, thoracic and 
mediastinal disorders
Respiratory arrest
Arrest pulmonary
Respiratory, thoracic and 
mediastinal disorders
Respiratory arrest
Arrest respiratory
Respiratory, thoracic and 
mediastinal disorders
Asphyxia
Asphyxia
Respiratory, thoracic and 
mediastinal disorders
Asphyxia
Asphyxiation
Respiratory, thoracic and 
mediastinal disorders
Bradypnoea
Bradypnea
Respiratory, thoracic and 
mediastinal disorders
Bradypnoea
Bradypnoea
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Breath shortness
Respiratory, thoracic and 
mediastinal disorders
Hypopnoea
Breathing abnormally shallow
Respiratory, thoracic and 
mediastinal disorders
Respiratory arrest
Breathing arrested
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Breathing difficult
Respiratory, thoracic and 
mediastinal disorders
Hypopnoea
Breathing shallow
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Breathlessness
Respiratory, thoracic and 
mediastinal disorders
Hypercapnia
Carbon dioxide narcosis
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Central sleep apnoea syndrome
Respiratory, thoracic and 
mediastinal disorders
Cheyne-Stokes respiration
Cheyne-Stokes respiration
Respiratory, thoracic and 
mediastinal disorders
Cyanosis central
Cyanosis central
Respiratory, thoracic and 
mediastinal disorders
Respiratory depression
Depression respiratory
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         40
6\VWHP2UJDQ&ODVV
3UHIHUUHG7HUP
/RZHVW/HYHO7HUP
$FXWHFHQWUDOUHVSLUDWRU\GHSUHVVLRQ604
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Difficulty breathing
Respiratory, thoracic and 
mediastinal disorders
Respiratory distress
Distress respiratory
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Dyspnea
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Dyspnea exacerbated
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Dyspnoea
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Dyspnoea exacerbated
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Dyspnoea NOS
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Failure respiratory
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Gasping
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Hunger air
Respiratory, thoracic and 
mediastinal disorders
Hypercapnia
Hypercapnia
Respiratory, thoracic and 
mediastinal disorders
Hypercapnia
Hypercapnic
Respiratory, thoracic and 
mediastinal disorders
Hypercapnia
Hypercarbia
Respiratory, thoracic and 
mediastinal disorders
Hypopnoea
Hypopnea
Respiratory, thoracic and 
mediastinal disorders
Hypopnoea
Hypopnoea
Respiratory, thoracic and 
mediastinal disorders
Hypoventilation
Hypoventilation
Respiratory, thoracic and 
mediastinal disorders
Hypoxia
Hypoxaemia
Respiratory, thoracic and 
mediastinal disorders
Hypoxia
Hypoxemia
Respiratory, thoracic and 
mediastinal disorders
Hypoxia
Hypoxia
Respiratory, thoracic and 
mediastinal disorders
Hypoxia
Hypoxic
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         41
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Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Increased shortness of breath
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Increased work of breathing
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Labored breathing
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Laboured breathing
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Laboured respiration
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Marked inactivity of chest wall on 
inspiratory effort
Respiratory, thoracic and 
mediastinal disorders
Hypercapnia
Narcosis carbon dioxide
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Obstructive sleep apnoea syndrome
Respiratory, thoracic and 
mediastinal disorders
Orthopnoea
Orthopnea
Respiratory, thoracic and 
mediastinal disorders
Orthopnoea
Orthopnoea
Respiratory, thoracic and 
mediastinal disorders
Respiratory arrest
Pulmonary arrest
Respiratory, thoracic and 
mediastinal disorders
Respiratory gas exchange disorder
Resp gas exchange disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Respiration abnormal
Respiration abnormal
Respiratory, thoracic and 
mediastinal disorders
Cheyne-Stokes respiration
Respiration biot-type
Respiratory, thoracic and 
mediastinal disorders
Cheyne-Stokes respiration
Respiration Cheyne-Stokes-type
Respiratory, thoracic and 
mediastinal disorders
Respiratory depression
Respiration depressed
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Respiration failure
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiration irregularity
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Respiration labored
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Respiration labored
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         42
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Respiratory, thoracic and 
mediastinal disorders
Hypopnoea
Respiration spontaneous decreased
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiratory abnormality, unspecified
Respiratory, thoracic and 
mediastinal disorders
Respiratory acidosis
Respiratory acidosis
Respiratory, thoracic and 
mediastinal disorders
Respiratory arrest
Respiratory arrest
Respiratory, thoracic and 
mediastinal disorders
Respiratory depression
Respiratory depression
Respiratory, thoracic and 
mediastinal disorders
Respiratory depth decreased
Respiratory depth decreased
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiratory disorder
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiratory disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Respiratory distress
Respiratory distress
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Respiratory distress syndrome adult
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiratory dysfunction NOS
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Respiratory failure
Respiratory, thoracic and 
mediastinal disorders
Respiratory gas exchange disorder
Respiratory gas exchange disorder 
NOS
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Respiratory insufficiency
Respiratory, thoracic and 
mediastinal disorders
Respiratory paralysis
Respiratory paralysis
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiratory rhythm disorder
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Respiratory system disorder
Respiratory, thoracic and 
mediastinal disorders
Hypercapnia
Retention carbon dioxide
Respiratory, thoracic and 
mediastinal disorders
Hypopnoea
Shallow breathing
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Shock lung
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         43
6\VWHP2UJDQ&ODVV
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Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Short of breath
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Shortness of breath
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Sleep apnea
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Sleep apnea syndrome
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Sleep apnoea
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Sleep apnoea syndrome
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Sleep apnoea syndromes
Respiratory, thoracic and 
mediastinal disorders
Asphyxia
Strangulation
Respiratory, thoracic and 
mediastinal disorders
Asphyxia
Suffocation
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Surfactant deficiency syndrome adult
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Syndrome adult respiratory distress
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory distress syndrome
Syndrome respiratory distress adult
Respiratory, thoracic and 
mediastinal disorders
Respiratory disorder
Unspecified disease of respiratory 
system
Respiratory, thoracic and 
mediastinal disorders
Hypoventilation
Ventilation difficult
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Ventilatory failure
Respiratory, thoracic and 
mediastinal disorders
Respiration abnormal
Respiratory sighs
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory failure
Acute respiratory decompensation
Respiratory, thoracic and 
mediastinal disorders
Respiration abnormal
Respiration abnormal NOS
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Pulmonary failure
Respiratory, thoracic and 
mediastinal disorders
Asphyxia
Injury asphyxiation
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         44
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Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Apnoea syndrome
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Labored respiration
Respiratory, thoracic and 
mediastinal disorders
Apnoeic attack
Apnea attack
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Apnea syndrome
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Central sleep apnea syndrome
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Obstructive sleep apnea syndrome
Respiratory, thoracic and 
mediastinal disorders
Orthopnoea
Supine dyspnea
Respiratory, thoracic and 
mediastinal disorders
Orthopnoea
Supine dyspnea
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Hypercapnic respiratory failure
Respiratory, thoracic and 
mediastinal disorders
Respiratory gas exchange disorder
Respiratory gas exchange disorder
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Restrictive respiratory insufficiency
Respiratory, thoracic and 
mediastinal disorders
Apnoeic attack
Apneic attack
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Acute dyspnea
Respiratory, thoracic and 
mediastinal disorders
Dyspnoea
Acute dyspnea
Respiratory, thoracic and 
mediastinal disorders
Cyanosis central
Cyanosis central aggravated
Respiratory, thoracic and 
mediastinal disorders
Respiratory failure
Respiratory failure aggravated
Respiratory, thoracic and 
mediastinal disorders
Acute respiratory failure
Acute respiratory insufficiency
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Hypopnea syndrome
Respiratory, thoracic and 
mediastinal disorders
Sleep apnoea syndrome
Hypopnoea syndrome
Respiratory, thoracic and 
mediastinal disorders
Hypoventilation
Alveolar hypoventilation
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         45
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Surgical and medical procedures
Oxygen supplementation
Oxygen supplementation
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Gastrointestinal disorders
Angina bullosa haemorrhagica
Angina bullosa haemorrhagica
Gastrointestinal disorders
Angina bullosa haemorrhagica
Angina bullosa hemorrhagica
Gastrointestinal disorders
Aphthous stomatitis
Aphthous stoma
Gastrointestinal disorders
Aphthous stomatitis
Aphthous stomatitis
Gastrointestinal disorders
Aphthous stomatitis
Aphthous ulcer
Gastrointestinal disorders
Aphthous stomatitis
Buccal mucosa aphthous ulceration
Gastrointestinal disorders
Aphthous stomatitis
Canker sores oral
Gastrointestinal disorders
Aphthous stomatitis
Oral aphthae
Gastrointestinal disorders
Aphthous stomatitis
Stomatitis aphthous
Gastrointestinal disorders
Aphthous stomatitis
Stomatitis ulcerative aphthous
Gastrointestinal disorders
Aphthous stomatitis
Ulcer aphthous
Gastrointestinal disorders
Aphthous stomatitis
Ulcer aphthous oral
Gastrointestinal disorders
Aphthous stomatitis
Ulcers aphthous oral
Gastrointestinal disorders
Aphthous stomatitis
Canker sore lip
Gastrointestinal disorders
Aphthous stomatitis
Aphthous ulcer recurrent
Gastrointestinal disorders
Aphthous stomatitis
Aphtha
Gastrointestinal disorders
Buccal mucosal roughening
Roughness oral
Gastrointestinal disorders
Buccal mucosal roughening
Buccal mucosal roughening
Gastrointestinal disorders
Buccal mucosal roughening
Rough mouth
Gastrointestinal disorders
Burning mouth syndrome
Burning mouth syndrome
Gastrointestinal disorders
Chapped lips
Lip rough
Gastrointestinal disorders
Chapped lips
Chapped lips
Gastrointestinal disorders
Chapped lips
Cracked lips
Gastrointestinal disorders
Cheilitis
Angular cheilitis
Gastrointestinal disorders
Cheilitis
Angular stomatitis
Gastrointestinal disorders
Cheilitis
Cheilitis
Gastrointestinal disorders
Cheilitis
Lip redness
Gastrointestinal disorders
Cheilitis
Desquamative cheilitis
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         46
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Gastrointestinal disorders
Cheilitis
Rash lips
Gastrointestinal disorders
Cheilitis
Irritation lips
Gastrointestinal disorders
Cheilitis
Raw lips
Gastrointestinal disorders
Cheilitis
Redness corner of mouth
Gastrointestinal disorders
Cheilitis
Inflammation lips
Gastrointestinal disorders
Cheilitis
Soreness corner mouth
Gastrointestinal disorders
Cheilitis
Sores lip
Gastrointestinal disorders
Cheilitis
Perleche
Gastrointestinal disorders
Cheilitis
Angular cheilosis
Gastrointestinal disorders
Cheilitis granulomatosa
Cheilitis granulomatosa
Gastrointestinal disorders
Cheilosis
Cheilosis
Gastrointestinal disorders
Contact stomatitis
Contact stomatitis
Gastrointestinal disorders
Enlarged uvula
Enlarged uvula
Gastrointestinal disorders
Gingival blister
Gingival blister
Gastrointestinal disorders
Gingival blister
Blisters gum
Gastrointestinal disorders
Gingival oedema
Gingival oedema
Gastrointestinal disorders
Gingival oedema
Oedema gum
Gastrointestinal disorders
Gingival oedema
Gingival edema
Gastrointestinal disorders
Gingival oedema
Edema gum
Gastrointestinal disorders
Gingival pruritus
Gingival pruritus
Gastrointestinal disorders
Gingival pruritus
Itching gum
Gastrointestinal disorders
Gingival swelling
Gingival swelling
Gastrointestinal disorders
Gingival swelling
Gum swelling
Gastrointestinal disorders
Hypoaesthesia oral
Anaesthesia lip
Gastrointestinal disorders
Hypoaesthesia oral
Anaesthesia mouth
Gastrointestinal disorders
Hypoaesthesia oral
Anaesthesia oral mucosa
Gastrointestinal disorders
Hypoaesthesia oral
Anaesthesia tongue
Gastrointestinal disorders
Hypoaesthesia oral
Hypoaesthesia oral NOS
Gastrointestinal disorders
Hypoaesthesia oral
Hypoaesthesia tongue
Gastrointestinal disorders
Hypoaesthesia oral
Numbness circumoral
Gastrointestinal disorders
Hypoaesthesia oral
Numbness of mouth angular
Gastrointestinal disorders
Hypoaesthesia oral
Numbness of tongue
Gastrointestinal disorders
Hypoaesthesia oral
Numbness oral
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         47
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Gastrointestinal disorders
Hypoaesthesia oral
Numbness perioral
Gastrointestinal disorders
Hypoaesthesia oral
Oral mucosal anaesthesia
Gastrointestinal disorders
Hypoaesthesia oral
Perioral numbness
Gastrointestinal disorders
Hypoaesthesia oral
Tongue sensation loss of
Gastrointestinal disorders
Hypoaesthesia oral
Tongue tip numbness of
Gastrointestinal disorders
Hypoaesthesia oral
Hypoaesthesia lips
Gastrointestinal disorders
Hypoaesthesia oral
Hypoaesthesia gingival
Gastrointestinal disorders
Hypoaesthesia oral
Numbness mouth
Gastrointestinal disorders
Hypoaesthesia oral
Numb mouth
Gastrointestinal disorders
Hypoaesthesia oral
Numb lips
Gastrointestinal disorders
Hypoaesthesia oral
Numbness lips
Gastrointestinal disorders
Hypoaesthesia oral
Hypoaesthesia gum
Gastrointestinal disorders
Hypoaesthesia oral
Numbness gum
Gastrointestinal disorders
Hypoaesthesia oral
Numbness gingival
Gastrointestinal disorders
Hypoaesthesia oral
Hypoesthesia gingival
Gastrointestinal disorders
Hypoaesthesia oral
Hypoesthesia lips
Gastrointestinal disorders
Hypoaesthesia oral
Hypoesthesia oral
Gastrointestinal disorders
Hypoaesthesia oral
Hypoesthesia tongue
Gastrointestinal disorders
Hypoaesthesia oral
Hypoaesthesia oral
Gastrointestinal disorders
Hypoaesthesia oral
Hypoesthesia gum
Gastrointestinal disorders
Hypoaesthesia oral
Anesthesia lip
Gastrointestinal disorders
Hypoaesthesia oral
Anesthesia mouth
Gastrointestinal disorders
Hypoaesthesia oral
Anesthesia oral mucosa
Gastrointestinal disorders
Hypoaesthesia oral
Anesthesia tongue
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia of mouth
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia of oral mucosa, 
including tongue
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia oral
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia oral NOS
Gastrointestinal disorders
Leukoplakia oral
Oral leukoplakia NOS
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia buccalis
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia labialis
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia lingualis
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         48
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Gastrointestinal disorders
Leukoplakia oral
Leukoplakia of oral mucosa, incl 
tongue
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia tongue
Gastrointestinal disorders
Lip blister
Blister of lip
Gastrointestinal disorders
Lip blister
Lip blister
Gastrointestinal disorders
Lip blister
Blister lip
Gastrointestinal disorders
Lip discolouration
Lip colour altered
Gastrointestinal disorders
Lip discolouration
Lip discolouration
Gastrointestinal disorders
Lip discolouration
Lip color altered
Gastrointestinal disorders
Lip discolouration
Lip discoloration
Gastrointestinal disorders
Lip disorder
Lip disorder NOS
Gastrointestinal disorders
Lip disorder
Lip disorder
Gastrointestinal disorders
Lip disorder
Bumps lip
Gastrointestinal disorders
Lip erosion
Lip erosion
Gastrointestinal disorders
Lip exfoliation
Lip sloughing
Gastrointestinal disorders
Lip exfoliation
Peeling lips
Gastrointestinal disorders
Lip exfoliation
Lip exfoliation
Gastrointestinal disorders
Lip haematoma
Lip haematoma
Gastrointestinal disorders 
Lip haematoma
Lip hematoma
Gastrointestinal disorders
Lip haemorrhage
Lip haemorrhage
Gastrointestinal disorders
Lip haemorrhage
Hemorrhage lips
Gastrointestinal disorders
Lip haemorrhage
Bleeding lips
Gastrointestinal disorders
Lip haemorrhage
Lip hemorrhage
Gastrointestinal disorders
Lip haemorrhage
Haemorrhage lips
Gastrointestinal disorders
Lip haemorrhage
Lip bleeding
Gastrointestinal disorders
Lip oedema
Edema lip
Gastrointestinal disorders
Lip oedema
Lip edema
Gastrointestinal disorders
Lip oedema
Lip oedema
Gastrointestinal disorders
Lip oedema
Oedema lip
Gastrointestinal disorders
Lip pain
Lip pain
Gastrointestinal disorders
Lip pain
Lip sore
Gastrointestinal disorders
Lip pain
Lip soreness
Gastrointestinal disorders
Lip pain
Tender lips
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         49
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Gastrointestinal disorders
Lip pain
Stinging lips
Gastrointestinal disorders
Lip pain
Sensitive lips
Gastrointestinal disorders
Lip pruritus
Lip pruritus
Gastrointestinal disorders
Lip swelling
Lip swelling
Gastrointestinal disorders
Lip swelling
Lips swelling non-specific
Gastrointestinal disorders
Lip swelling
Swelling lips
Gastrointestinal disorders
Lip swelling
Swelling of lips
Gastrointestinal disorders
Lip swelling
Swollen lips
Gastrointestinal disorders
Lip ulceration
Lip ulcer
Gastrointestinal disorders
Lip ulceration
Lip ulceration
Gastrointestinal disorders
Lip ulceration
Ulcer lip
Gastrointestinal disorders
Melanoplakia oral
Melanoplakia oral
Gastrointestinal disorders
Mouth haemorrhage
Hemorrhage mouth
Gastrointestinal disorders
Mouth haemorrhage
Hemorrhage of mouth
Gastrointestinal disorders
Mouth haemorrhage
Hemorrhage oral
Gastrointestinal disorders
Mouth haemorrhage
Mouth haemorrhage
Gastrointestinal disorders
Mouth haemorrhage
Mouth hemorrhage
Gastrointestinal disorders
Mouth haemorrhage
Oral haemorrhage
Gastrointestinal disorders
Mouth haemorrhage
Oral hemorrhage
Gastrointestinal disorders
Mouth haemorrhage
Oral mucosa bleeding
Gastrointestinal disorders
Mouth haemorrhage
Oral mucosa ecchymosis
Gastrointestinal disorders
Mouth haemorrhage
Oral mucosal petechiae
Gastrointestinal disorders
Mouth haemorrhage
Petechiae oral mucosa
Gastrointestinal disorders
Mouth haemorrhage
Bleeding mouth
Gastrointestinal disorders
Mouth haemorrhage
Haemorrhage mouth
Gastrointestinal disorders
Mouth haemorrhage
Haemorrhage of mouth
Gastrointestinal disorders
Mouth haemorrhage
Haemorrhage oral
Gastrointestinal disorders
Mouth haemorrhage
Mouth bleeding
Gastrointestinal disorders
Mouth ulceration
Buccal mucosa ulceration
Gastrointestinal disorders
Mouth ulceration
Buccal ulceration
Gastrointestinal disorders
Mouth ulceration
Mouth ulcer
Gastrointestinal disorders
Mouth ulceration
Mouth ulceration
Gastrointestinal disorders
Mouth ulceration
Oral ulceration
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         50
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Gastrointestinal disorders
Mouth ulceration
Stomatitis ulcerative
Gastrointestinal disorders
Mouth ulceration
Ulcer buccal
Gastrointestinal disorders
Mouth ulceration
Ulcer mouth
Gastrointestinal disorders
Mouth ulceration
Ulceration mouth
Gastrointestinal disorders
Mouth ulceration
Ulceration of mouth
Gastrointestinal disorders
Mouth ulceration
Ulcerative stomatitis
Gastrointestinal disorders
Mouth ulceration
Ulcerative stomatitis, acute
Gastrointestinal disorders
Mouth ulceration
Mouth ulceration aggravated
Gastrointestinal disorders
Odynophagia
Odynophagia
Gastrointestinal disorders
Odynophagia
Swallowing painful
Gastrointestinal disorders
Oedema mouth
Edema of mouth
Gastrointestinal disorders
Oedema mouth
Oedema mouth
Gastrointestinal disorders
Oedema mouth
Oral mucosa swollen
Gastrointestinal disorders
Oedema mouth
Swollen mouth
Gastrointestinal disorders
Oedema mouth
Edema mouth
Gastrointestinal disorders
Oedema mouth
Oedema of mouth
Gastrointestinal disorders
Oral discharge
Oral discharge
Gastrointestinal disorders
Oral discomfort
Burning oral sensation
Gastrointestinal disorders
Oral discomfort
Discomfort in mouth
Gastrointestinal disorders
Oral discomfort
Lip burning sensation of
Gastrointestinal disorders
Oral discomfort
Oral cavity discomfort
Gastrointestinal disorders
Oral discomfort
Oral discomfort
Gastrointestinal disorders
Oral discomfort
Oral hot feeling
Gastrointestinal disorders
Oral discomfort
Burning corner of mouth
Gastrointestinal disorders
Oral discomfort
Burning lips
Gastrointestinal disorders
Oral discomfort
Burning mouth
Gastrointestinal disorders
Oral disorder
Oral soft tissue disorder NOS
Gastrointestinal disorders
Oral disorder
Oral mucosal disorder
Gastrointestinal disorders
Oral disorder
Oral lesion
Gastrointestinal disorders
Oral disorder
Oral soft tissue disorder
Gastrointestinal disorders
Oral disorder
Oral disorder
Gastrointestinal disorders
Oral disorder
Mouth bump
Gastrointestinal disorders
Oral dysaesthesia
Dysesthesia of lips
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         51
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Gastrointestinal disorders
Oral dysaesthesia
Dysesthesia of tongue
Gastrointestinal disorders
Oral dysaesthesia
Oral dysaesthesia
Gastrointestinal disorders
Oral dysaesthesia
Oral dysesthesia
Gastrointestinal disorders
Oral dysaesthesia
Dysaesthesia of lips
Gastrointestinal disorders
Oral dysaesthesia
Dysaesthesia of tongue
Gastrointestinal disorders
Oral dysaesthesia
Vincent's symptom
Gastrointestinal disorders
Oral leukoedema
Oral leukoedema
Gastrointestinal disorders
Oral lichen planus
Oral lichen planus
Gastrointestinal disorders
Oral mucosa atrophy
Oral mucosa atrophy
Gastrointestinal disorders
Oral mucosa erosion
Oral mucosa erosion
Gastrointestinal disorders
Oral mucosal blistering
Blistering of mouth
Gastrointestinal disorders
Oral mucosal blistering
Oral mucosa blister
Gastrointestinal disorders
Oral mucosal blistering
Oral mucosa blistering
Gastrointestinal disorders
Oral mucosal blistering
Oral mucosal blistering
Gastrointestinal disorders
Oral mucosal discolouration
Oral mucosa discolouration
Gastrointestinal disorders
Oral mucosal discolouration
Oral mucosal discolouration
Gastrointestinal disorders
Oral mucosal discolouration
Oral mucosal discoloration
Gastrointestinal disorders
Oral mucosal eruption
Oral mucosal eruption
Gastrointestinal disorders
Oral mucosal erythema
Oral mucosa redness
Gastrointestinal disorders
Oral mucosal erythema
Oral redness
Gastrointestinal disorders
Oral mucosal erythema
Redness mouth
Gastrointestinal disorders
Oral mucosal erythema
Oral mucosal erythema
Gastrointestinal disorders
Oral mucosal erythema
Palatal erythema
Gastrointestinal disorders
Oral mucosal exfoliation
Oral mucosal sloughing
Gastrointestinal disorders
Oral mucosal exfoliation
Sloughing of buccal mucosa
Gastrointestinal disorders
Oral mucosal exfoliation
Sloughing of mouth
Gastrointestinal disorders
Oral mucosal exfoliation
Gingival sloughing
Gastrointestinal disorders
Oral mucosal exfoliation
Peeling mouth
Gastrointestinal disorders
Oral mucosal exfoliation
Desquamation mouth
Gastrointestinal disorders
Oral mucosal exfoliation
Sloughing gums
Gastrointestinal disorders
Oral mucosal exfoliation
Sloughing gingival
Gastrointestinal disorders
Oral mucosal exfoliation
Peeling gingival
Gastrointestinal disorders
Oral mucosal exfoliation
Peeling gum
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         52
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Gastrointestinal disorders
Oral mucosal exfoliation
Desquamation gum
Gastrointestinal disorders
Oral mucosal exfoliation
Desquamation gingival
Gastrointestinal disorders
Oral mucosal exfoliation
Oral mucosal exfoliation
Gastrointestinal disorders
Oral mucosal hypertrophy
Oral mucosal hypertrophy
Gastrointestinal disorders
Oral pain
Mouth pain
Gastrointestinal disorders
Oral pain
Oral angular pain
Gastrointestinal disorders
Oral pain
Oral mucosa pain
Gastrointestinal disorders
Oral pain
Oral pain
Gastrointestinal disorders
Oral pain
Pain mouth
Gastrointestinal disorders
Oral pain
Pain oral
Gastrointestinal disorders
Oral pain
Sore mouth
Gastrointestinal disorders
Oral pain
Sensitive mouth
Gastrointestinal disorders
Oral pain
Tender mouth
Gastrointestinal disorders
Oral pain
Stinging mouth
Gastrointestinal disorders
Oral pain
Soreness roof of mouth
Gastrointestinal disorders
Oral papule
Oral papule
Gastrointestinal disorders
Oral pruritus
Intraoral pruritus
Gastrointestinal disorders
Oral pruritus
Itching mouth
Gastrointestinal disorders
Oral pruritus
Oral pruritus
Gastrointestinal disorders
Oral submucosal fibrosis
Oral submucosal fibrosis
Gastrointestinal disorders
Oral submucosal fibrosis
Oral submucous fibrosis, including 
of tongue
Gastrointestinal disorders
Oral submucosal fibrosis
Oral submucous fibrosis, incl of 
tongue
Gastrointestinal disorders
Oral toxicity
Oral toxicity
Gastrointestinal disorders
Palatal disorder
Palatal disorder
Gastrointestinal disorders
Palatal disorder
Palatal lesion
Gastrointestinal disorders
Palatal disorder
Palatal nodule
Gastrointestinal disorders
Palatal disorder
Soft palate disorder
Gastrointestinal disorders
Palatal dysplasia
Palatal dysplasia
Gastrointestinal disorders
Palatal oedema
Palatine arch swollen
Gastrointestinal disorders
Palatal oedema
Oedema uvula
Gastrointestinal disorders
Palatal oedema
Edema uvula
Gastrointestinal disorders
Palatal oedema
Palatal oedema
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         53
6\VWHP2UJDQ&ODVV
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Gastrointestinal disorders
Palatal oedema
Palatal edema
Gastrointestinal disorders
Palatitis
Palatitis
Gastrointestinal disorders
Paraesthesia oral
Circumoral paresthesia
Gastrointestinal disorders
Paraesthesia oral
Mouth paresthesia
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia circumoral
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia mouth
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia oral NOS
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia tongue
Gastrointestinal disorders
Paraesthesia oral
Paresthesia circumoral
Gastrointestinal disorders
Paraesthesia oral
Paresthesia mouth
Gastrointestinal disorders
Paraesthesia oral
Tongue abnormal feeling of
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia lips
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia gingival
Gastrointestinal disorders
Paraesthesia oral
Tingling mouth
Gastrointestinal disorders
Paraesthesia oral
Tingling lips
Gastrointestinal disorders
Paraesthesia oral
Paresthesia lips
Gastrointestinal disorders
Paraesthesia oral
Tingling tongue
Gastrointestinal disorders
Paraesthesia oral
Tingling gum
Gastrointestinal disorders
Paraesthesia oral
Tingling gingival
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia gum
Gastrointestinal disorders
Paraesthesia oral
Paresthesia gingival
Gastrointestinal disorders
Paraesthesia oral
Paresthesia gum
Gastrointestinal disorders
Paraesthesia oral
Paresthesia oral
Gastrointestinal disorders
Paraesthesia oral
Paresthesia tongue
Gastrointestinal disorders
Paraesthesia oral
Paraesthesia oral
Gastrointestinal disorders
Paraesthesia oral
Perioral tingling
Gastrointestinal disorders
Paraesthesia oral
Perioral paraesthesia
Gastrointestinal disorders
Paraesthesia oral
Perioral paresthesia
Gastrointestinal disorders
Pigmentation buccal
Pigmentation buccal
Gastrointestinal disorders
Pigmentation lip
Lip pigmental spot
Gastrointestinal disorders
Pigmentation lip
Lip pigmentation
Gastrointestinal disorders
Pigmentation lip
Pigmentation lip
Gastrointestinal disorders
Pyostomatitis vegetans
Pyostomatitis vegetans
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         54
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Gastrointestinal disorders
Stomatitis
Buccal inflammation
Gastrointestinal disorders
Stomatitis
Mouth irritation
Gastrointestinal disorders
Stomatitis
Mucositis oral
Gastrointestinal disorders
Stomatitis
Stomatitis
Gastrointestinal disorders
Stomatitis
Sores mouth
Gastrointestinal disorders
Stomatitis
Sores roof of mouth
Gastrointestinal disorders
Stomatitis
Raw mouth
Gastrointestinal disorders
Stomatitis
Irritation roof of mouth
Gastrointestinal disorders
Stomatitis
Chapped mouth
Gastrointestinal disorders
Stomatitis
Inflammation of mouth
Gastrointestinal disorders
Stomatitis
Mouth broke out
Gastrointestinal disorders
Stomatitis
Inflammation under tongue
Gastrointestinal disorders
Stomatitis
Oral mucosal irritation
Gastrointestinal disorders
Stomatitis
Vesicular stomatitis
Gastrointestinal disorders
Stomatitis
Gingivostomatitis
Gastrointestinal disorders
Stomatitis
Pseudomembranous stomatitis
Gastrointestinal disorders
Stomatitis haemorrhagic
Stomatitis haemorrhagic
Gastrointestinal disorders
Stomatitis haemorrhagic
Stomatitis hemorrhagic
Gastrointestinal disorders
Stomatitis necrotising
Cancrum oris
Gastrointestinal disorders
Stomatitis necrotising
Mouth necrosis
Gastrointestinal disorders
Stomatitis necrotising
Necrosis mouth
Gastrointestinal disorders
Stomatitis necrotising
Noma
Gastrointestinal disorders
Stomatitis necrotising
Stomatitis necrotising
Gastrointestinal disorders
Stomatitis necrotising
Stomatitis necrotizing
Gastrointestinal disorders
Uvulitis
Uvulitis
 
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Respiratory, thoracic and 
mediastinal disorders
Allergic cough
Allergic cough
Respiratory, thoracic and 
mediastinal disorders
Choking
Choked on food
Respiratory, thoracic and 
mediastinal disorders
Choking
Choking
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         55
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Respiratory, thoracic and 
mediastinal disorders
Choking
Choke on medication
Respiratory, thoracic and 
mediastinal disorders
Choking sensation
Choking sensation
Respiratory, thoracic and 
mediastinal disorders
Choking sensation
Choking sensation (excl psychogenic 
and dysphagia)
Respiratory, thoracic and 
mediastinal disorders
Choking sensation
Pharynx closed sensation of
Respiratory, thoracic and 
mediastinal disorders
Choking sensation
Pharynx strangled sensation of
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough increased
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough nonproductive
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough resembling asthma
Respiratory, thoracic and 
mediastinal disorders
Cough
Coughing
Respiratory, thoracic and 
mediastinal disorders
Cough
Dry cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Irritant cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Irritative cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Nocturnal cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Persistent dry cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Persistent non-productive cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough aggravated
Respiratory, thoracic and 
mediastinal disorders
Cough
Coughing after drug inhalation
Respiratory, thoracic and 
mediastinal disorders
Cough
Drug-induced cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Smoker's cough
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         56
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Respiratory, thoracic and 
mediastinal disorders
Cough
Paroxysmal cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Acute cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Chronic cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Persistent cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Painful cough
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough ineffective
Respiratory, thoracic and 
mediastinal disorders
Cough
Cough weak
Respiratory, thoracic and 
mediastinal disorders
Cough decreased
Cough decreased
Respiratory, thoracic and 
mediastinal disorders
Dry throat
Dry throat
Respiratory, thoracic and 
mediastinal disorders
Dry throat
Pharynx dry
Respiratory, thoracic and 
mediastinal disorders
Dry throat
Throat dry
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Distorted voice
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Disturbance in loudness
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Dysphonia
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Hoarse voice
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Hoarseness
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Hoarseness of voice
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Phonation difficulty
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Resonance disorder
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Vocal tone disorder
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         57
6\VWHP2UJDQ&ODVV
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Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Vocal volume disorder
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Voice alteration
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Voice disturbance
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Voice disturbance, unspecified
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Voice lowered
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Hypophonia
Respiratory, thoracic and 
mediastinal disorders
Dysphonia
Rhinolalia
Respiratory, thoracic and 
mediastinal disorders
Haemoptysis
Blood streaked sputum
Respiratory, thoracic and 
mediastinal disorders
Haemoptysis
Coughing blood
Respiratory, thoracic and 
mediastinal disorders
Haemoptysis
Haemoptysis
Respiratory, thoracic and 
mediastinal disorders
Haemoptysis
Hemoptysis
Respiratory, thoracic and 
mediastinal disorders
Haemoptysis
Sputum bloody
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Hiccough
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Hiccup
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Hiccups
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Singultation
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Singultous
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Singultus
Respiratory, thoracic and 
mediastinal disorders
Hiccups
Intractable hiccups
Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Airway secretion excessive
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         58
6\VWHP2UJDQ&ODVV
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Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Bronchial secretion excessive
Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Bronchorrhea
Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Bronchorrhoea
Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Excessive bronchial secretion
Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Tracheo-bronchial secretion excess
Respiratory, thoracic and 
mediastinal disorders
Increased bronchial secretion
Increased bronchial secretion
Respiratory, thoracic and 
mediastinal disorders
Increased upper airway secretion
Throat secretion increased
Respiratory, thoracic and 
mediastinal disorders
Increased upper airway secretion
Phlegm
Respiratory, thoracic and 
mediastinal disorders
Increased upper airway secretion
Increased upper airway secretion
Respiratory, thoracic and 
mediastinal disorders
Increased viscosity of bronchial 
secretion
Sputum viscosity increased
Respiratory, thoracic and 
mediastinal disorders
Increased viscosity of bronchial 
secretion
Increased viscosity of bronchial 
secretion
Respiratory, thoracic and 
mediastinal disorders
Increased viscosity of nasal secretion
Increased viscosity of nasal secretion
Respiratory, thoracic and 
mediastinal disorders
Increased viscosity of nasal secretion
Thick nasal mucus
Respiratory, thoracic and 
mediastinal disorders
Laryngeal discomfort
Laryngeal discomfort
Respiratory, thoracic and 
mediastinal disorders
Laryngeal discomfort
Pharyngolaryngeal discomfort
Respiratory, thoracic and 
mediastinal disorders
Laryngeal pain
Laryngeal pain
Respiratory, thoracic and 
mediastinal disorders
Laryngeal pain
Larynx burning pain of
Respiratory, thoracic and 
mediastinal disorders
Laryngeal pain
Larynx pain
Respiratory, thoracic and 
mediastinal disorders
Laryngeal pain
Pharyngolaryngeal pain
Respiratory, thoracic and 
mediastinal disorders
Mouth breathing
Jaw breathing
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         59
6\VWHP2UJDQ&ODVV
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Respiratory, thoracic and 
mediastinal disorders
Mouth breathing
Mouth breathing
Respiratory, thoracic and 
mediastinal disorders
Nasal discharge discolouration
Nasal discharge discolouration
Respiratory, thoracic and 
mediastinal disorders
Nasal discharge discolouration
Nasal discharge discoloration
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Discomfort in nose
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal burning
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal cavity strange sensation of
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal irritation
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal itching
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal passage irritation
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal soreness
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Sore nose
Respiratory, thoracic and 
mediastinal disorders
Nasal discomfort
Nasal discomfort
Respiratory, thoracic and 
mediastinal disorders
Nasal flaring
Nasal flaring
Respiratory, thoracic and 
mediastinal disorders
Nasal obstruction
Nasal obstruction
Respiratory, thoracic and 
mediastinal disorders
Nasal obstruction
Nasal obstruction increased
Respiratory, thoracic and 
mediastinal disorders
Nasopharyngeal reflux
Nasopharyngeal reflux
Respiratory, thoracic and 
mediastinal disorders
Nocturnal dyspnoea
Nocturnal dyspnoea
Respiratory, thoracic and 
mediastinal disorders
Nocturnal dyspnoea
Nocturnal dyspnea
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal blistering
Oropharyngeal blistering
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal discomfort
Pharynx discomfort
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         60
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Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal discomfort
Pharynx ill sensation of
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal discomfort
Pharynx strange sensation of
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal discomfort
Oropharyngeal discomfort
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Pain pharynx
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Pain throat
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Sore throat
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Sore throat NOS
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Throat pain
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Throat sore
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Chronic sore throat
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal pain
Oropharyngeal pain
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal plaque
Mouth plaque
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal plaque
Plaque mouth
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal plaque
Oropharyngeal plaque
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal scar
Oropharyngeal scar
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus discomfort
Paranasal sinus discomfort
Respiratory, thoracic and 
mediastinal disorders
Productive cough
Productive cough
Respiratory, thoracic and 
mediastinal disorders
Productive cough
Sputum
Respiratory, thoracic and 
mediastinal disorders
Productive cough
Expectoration
Respiratory, thoracic and 
mediastinal disorders
Respiratory tract oedema
Respiratory tract oedema
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         61
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mediastinal disorders
Respiratory tract oedema
Airway oedema
Respiratory, thoracic and 
mediastinal disorders
Respiratory tract oedema
Airway edema
Respiratory, thoracic and 
mediastinal disorders
Respiratory tract oedema
Respiratory tract edema
Respiratory, thoracic and 
mediastinal disorders
Rhinalgia
Nasal stinging
Respiratory, thoracic and 
mediastinal disorders
Rhinalgia
Stinging of nose
Respiratory, thoracic and 
mediastinal disorders
Rhinalgia
Rhinalgia
Respiratory, thoracic and 
mediastinal disorders
Rhinalgia
Nasal pain
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Nasal discharge
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Nasal discharge watery excessive
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Rhinorrhea
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Rhinorrhoea
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Runny nose
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Nasal mucus increased
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Mucus nasal increased
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Gustatory rhinorrhoea
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Sniffles
Respiratory, thoracic and 
mediastinal disorders
Rhinorrhoea
Gustatory rhinorrhea
Respiratory, thoracic and 
mediastinal disorders
Sneezing
Paroxysmal sneeze
Respiratory, thoracic and 
mediastinal disorders
Sneezing
Sneezing
Respiratory, thoracic and 
mediastinal disorders
Sneezing
Sneezing excessive
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         62
6\VWHP2UJDQ&ODVV
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Respiratory, thoracic and 
mediastinal disorders
Snoring
Snore
Respiratory, thoracic and 
mediastinal disorders
Snoring
Snoring
Respiratory, thoracic and 
mediastinal disorders
Sputum decreased
Sputum decreased
Respiratory, thoracic and 
mediastinal disorders
Sputum discoloured
Sputum discolored
Respiratory, thoracic and 
mediastinal disorders
Sputum discoloured
Sputum discoloured
Respiratory, thoracic and 
mediastinal disorders
Sputum increased
Sputum excretion increased
Respiratory, thoracic and 
mediastinal disorders
Sputum increased
Sputum increased
Respiratory, thoracic and 
mediastinal disorders
Sputum retention
Sputum excretion difficulty
Respiratory, thoracic and 
mediastinal disorders
Sputum retention
Sputum expectoration difficult
Respiratory, thoracic and 
mediastinal disorders
Sputum retention
Sputum sticking sensation of
Respiratory, thoracic and 
mediastinal disorders
Sputum retention
Sputum retention
Respiratory, thoracic and 
mediastinal disorders
Suffocation feeling
Suffocation feeling
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Burning in throat
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Local throat irritation
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Pharyngo-oral irritation
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Pharynx burning sensation of
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Pharynx irritated sensation of
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Pharynx itchy sensation of
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Throat burning sensation of
Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Throat irritation
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         63
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Respiratory, thoracic and 
mediastinal disorders
Throat irritation
Itchy throat
Respiratory, thoracic and 
mediastinal disorders
Throat lesion
Throat lesion
Respiratory, thoracic and 
mediastinal disorders
Throat tightness
Constriction throat
Respiratory, thoracic and 
mediastinal disorders
Throat tightness
Throat constriction
Respiratory, thoracic and
mediastinal disorders
Throat tightness
Throat tightness
Respiratory, thoracic and 
mediastinal disorders
Upper airway necrosis
Upper airway necrosis
Respiratory, thoracic and 
mediastinal disorders
Upper airway obstruction
Upper airway obstruction
Respiratory, thoracic and 
mediastinal disorders
Upper airway resistance syndrome
Upper airway resistance syndrome
Respiratory, thoracic and 
mediastinal disorders
Upper respiratory tract congestion
Upper respiratory tract congestion
Respiratory, thoracic and 
mediastinal disorders
Upper respiratory tract inflammation
Upper respiratory tract inflammation
Respiratory, thoracic and 
mediastinal disorders
Upper respiratory tract inflammation
Acute upper respiratory tract 
inflammation
Respiratory, thoracic and 
mediastinal disorders
Upper respiratory tract irritation
Upper respiratory tract irritation
Respiratory, thoracic and 
mediastinal disorders
Upper-airway cough syndrome
Posterior nasal drip
Respiratory, thoracic and 
mediastinal disorders
Upper-airway cough syndrome
Postnasal drip
Respiratory, thoracic and 
mediastinal disorders
Upper-airway cough syndrome
Chronic post nasal drip
Respiratory, thoracic and 
mediastinal disorders
Upper-airway cough syndrome
Upper-airway cough syndrome
Respiratory, thoracic and 
mediastinal disorders
Yawning
Yawn
Respiratory, thoracic and 
mediastinal disorders
Yawning
Yawning
Respiratory, thoracic and 
mediastinal disorders
Yawning
Yawning excessive
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         64
5RXWHRI$GPLQLVWUDWLRQ8SSHU5HVSLUDWRU\7UDFW'LVRUGHUV+/7([FOXGH,QIHFWLRQV
Respiratory, thoracic and 
mediastinal disorders
Adductor vocal cord weakness
Adductor vocal cord weakness
Respiratory, thoracic and 
mediastinal disorders
Adenoidal disorder
Adenoidal disorder
Respiratory, thoracic and 
mediastinal disorders
Adenoidal hypertrophy
Adenoid vegetations
Respiratory, thoracic and 
mediastinal disorders
Adenoidal hypertrophy
Adenoidal hypertrophy
Respiratory, thoracic and 
mediastinal disorders
Allergic pharyngitis
Allergic pharyngitis
Respiratory, thoracic and 
mediastinal disorders
Allergic sinusitis
Allergic sinusitis
Respiratory, thoracic and 
mediastinal disorders
Allergic sinusitis
Seasonal sinusitis
Respiratory, thoracic and 
mediastinal disorders
Chronic eosinophilic rhinosinusitis
Chronic eosinophilic rhinosinusitis
Respiratory, thoracic and 
mediastinal disorders
Chronic hyperplastic eosinophilic 
sinusitis
Chronic hyperplastic eosinophilic 
sinusitis
Respiratory, thoracic and
mediastinal disorders
Croup noninfectious
Croup noninfectious
Respiratory, thoracic and 
mediastinal disorders
Dysaesthesia pharynx
Dysaesthesia pharynx
Respiratory, thoracic and 
mediastinal disorders
Dysaesthesia pharynx
Dysesthesia pharynx
Respiratory, thoracic and 
mediastinal disorders
Dysaesthesia pharynx
Laryngopharyngeal dysesthesia
Respiratory, thoracic and 
mediastinal disorders
Dysaesthesia pharynx
Laryngopharyngeal dysaesthesia
Respiratory, thoracic and 
mediastinal disorders
Eosinophilic rhinitis
Eosinophilic rhinitis
Respiratory, thoracic and 
mediastinal disorders
Epiglottic cyst
Epiglottic cyst
Respiratory, thoracic and 
mediastinal disorders
Epiglottic erythema
Epiglottic erythema
Respiratory, thoracic and 
mediastinal disorders
Epiglottic mass
Epiglottic mass
Respiratory, thoracic and 
mediastinal disorders
Epiglottic oedema
Epiglottic oedema
Respiratory, thoracic and 
mediastinal disorders
Epiglottic oedema
Epiglottic edema
Respiratory, thoracic and 
Epiglottis ulcer
Epiglottis ulcer
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         65
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Bleeding nose
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Epistaxis
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Haemorrhage nasal
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Hemorrhage nasal
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Nasal bleeding
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Nasal mucus blood tinged
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Nose bleed
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Nose bleeds
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Nosebleed
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
Chronic epistaxis
Respiratory, thoracic and 
mediastinal disorders
Intranasal hypoaesthesia
Intranasal numbness
Respiratory, thoracic and 
mediastinal disorders
Intranasal hypoaesthesia
Intranasal hypoaesthesia
Respiratory, thoracic and 
mediastinal disorders
Intranasal hypoaesthesia
Intranasal hypoesthesia
Respiratory, thoracic and 
mediastinal disorders
Intranasal paraesthesia
Intranasal paraesthesia
Respiratory, thoracic and 
mediastinal disorders
Intranasal paraesthesia
Intranasal paresthesia
Respiratory, thoracic and 
mediastinal disorders
Laryngeal cyst
Laryngeal cyst
Respiratory, thoracic and 
mediastinal disorders
Laryngeal disorder
Laryngeal disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Laryngeal disorder
Unspecified disease of larynx
Respiratory, thoracic and 
mediastinal disorders
Laryngeal disorder
Laryngeal disorder
Respiratory, thoracic and 
Laryngeal dyspnoea
Laryngeal dyspnoea
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         66
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Laryngeal dyspnoea
Laryngeal dyspnea
Respiratory, thoracic and 
mediastinal disorders
Laryngeal erythema
Laryngeal erythema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haematoma
Laryngeal haematoma
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haematoma
Laryngeal hematoma
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haematoma
Glottic haematoma
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haematoma
Glottic hematoma
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haemorrhage
Laryngeal haemorrhage
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haemorrhage
Laryngeal hemorrhage
Respiratory, thoracic and 
mediastinal disorders
Laryngeal haemorrhage
Laryngeal bleeding
Respiratory, thoracic and 
mediastinal disorders
Laryngeal hypertrophy
Laryngeal hypertrophy
Respiratory, thoracic and 
mediastinal disorders
Laryngeal infiltration
Laryngeal infiltration NOS
Respiratory, thoracic and 
mediastinal disorders
Laryngeal infiltration
Laryngeal infiltration
Respiratory, thoracic and 
mediastinal disorders
Laryngeal inflammation
Laryngeal inflammation
Respiratory, thoracic and 
mediastinal disorders
Laryngeal inflammation
Laryngeal mucositis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal leukoplakia
Laryngeal leukoplakia
Respiratory, thoracic and 
mediastinal disorders
Laryngeal leukoplakia
Laryngeal leucoplakia
Respiratory, thoracic and 
mediastinal disorders
Laryngeal mass
Laryngeal mass
Respiratory, thoracic and 
mediastinal disorders
Laryngeal necrosis
Laryngeal necrosis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal necrosis
Laryngeal chondronecrosis
Respiratory, thoracic and 
Laryngeal obstruction
Laryngeal obstruction
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         67
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Laryngeal obstruction
Subglottic obstruction
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Edema glottis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Edema larynx
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Edema of larynx
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Edema vocal cord
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Glottic edema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Glottic oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Laryngeal edema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Laryngeal oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Larynx edema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Larynx oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Oedema of larynx
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Subglottic edema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Subglottic oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Vocal cord edema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Vocal cord oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Oedema glottis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Oedema larynx
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Oedema vocal cord
Respiratory, thoracic and 
Laryngeal oedema
Aryepiglottis edema
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         68
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Aryepiglottis oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Acute laryngeal edema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal oedema
Acute laryngeal oedema
Respiratory, thoracic and 
mediastinal disorders
Laryngeal polyp
Laryngeal polyp
Respiratory, thoracic and 
mediastinal disorders
Laryngeal stenosis
Laryngeal stenosis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal stenosis
Laryngeal stricture
Respiratory, thoracic and 
mediastinal disorders
Laryngeal stenosis
Stenosis of larynx
Respiratory, thoracic and 
mediastinal disorders
Laryngeal stenosis
Subglottic stenosis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal stenosis
Supraglottic stenosis
Respiratory, thoracic and 
mediastinal disorders
Laryngeal ulceration
Laryngeal ulceration
Respiratory, thoracic and 
mediastinal disorders
Laryngeal ulceration
Larynx ulcer
Respiratory, thoracic and 
mediastinal disorders
Laryngeal ulceration
Larynx ulceration
Respiratory, thoracic and 
mediastinal disorders
Laryngeal ventricle prolapse
Laryngeal ventricle prolapse
Respiratory, thoracic and 
mediastinal disorders
Laryngitis allergic
Laryngitis allergic
Respiratory, thoracic and 
mediastinal disorders
Laryngospasm
Glottic spasm
Respiratory, thoracic and 
mediastinal disorders
Laryngospasm
Laryngeal spasm
Respiratory, thoracic and 
mediastinal disorders
Laryngospasm
Laryngismus
Respiratory, thoracic and 
mediastinal disorders
Laryngospasm
Laryngospasm
Respiratory, thoracic and 
mediastinal disorders
Laryngospasm
Larynx muscle hypersensitive
Respiratory, thoracic and 
Laryngospasm
Spasm glottis
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         69
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Laryngospasm
Spasm larynx
Respiratory, thoracic and 
mediastinal disorders
Larynx irritation
Larynx irritation
Respiratory, thoracic and 
mediastinal disorders
Larynx irritation
Larynx itching
Respiratory, thoracic and 
mediastinal disorders
Maxillary sinus pseudocyst
Maxillary sinus pseudocyst
Respiratory, thoracic and 
mediastinal disorders
Nasal cavity mass
Nasal cavity mass
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Congestion nasal
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Nasal congestion
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Nasal stuffiness
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Nose congestion
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Rhinitis medicamentosa
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Rhinitis medicamentous
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Nasal mucosal swelling
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Chronic nasal congestion
Respiratory, thoracic and 
mediastinal disorders
Nasal congestion
Acute nasal congestion
Respiratory, thoracic and 
mediastinal disorders
Nasal cyst
Nasal cyst
Respiratory, thoracic and 
mediastinal disorders
Nasal cyst
Intranasal cyst
Respiratory, thoracic and 
mediastinal disorders
Nasal disorder
Nasal disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Nasal disorder
Nasal disorder
Respiratory, thoracic and 
mediastinal disorders
Nasal dryness
Dry nose
Respiratory, thoracic and 
Nasal dryness
Nasal dryness
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         70
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Nasal dryness
Nose dry feeling of
Respiratory, thoracic and 
mediastinal disorders
Nasal dryness
Nose dryness
Respiratory, thoracic and 
mediastinal disorders
Nasal inflammation
Nasal inflammation
Respiratory, thoracic and 
mediastinal disorders
Nasal inflammation
Nasal septal inflammation
Respiratory, thoracic and 
mediastinal disorders
Nasal inflammation
Nasal mucosal inflammation
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosa atrophy
Nasal mucosa atrophy
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal discolouration
Nasal mucosal discolouration
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal discolouration
Nasal mucosal discoloration
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal discolouration
Nasal mucosal pallor
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal disorder
Nasal mucosal disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal disorder
Nasal mucosal disorder
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal disorder
Nasal mucosal erythema
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal disorder
Nasal mucosal hyperaemia
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal disorder
Nasal mucosal ulcer
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal disorder
Nasal mucosal hyperemia
Respiratory, thoracic and 
mediastinal disorders
Nasal mucosal hypertrophy
Nasal mucosal hypertrophy
Respiratory, thoracic and 
mediastinal disorders
Nasal necrosis
Nasal mucosal necrosis
Respiratory, thoracic and 
mediastinal disorders
Nasal necrosis
Nasal necrosis
Respiratory, thoracic and 
mediastinal disorders
Nasal necrosis
Necrosis nasal
Respiratory, thoracic and 
Nasal necrosis
Nasal septal mucosa necrosis
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         71
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Nasal odour
Nasal odour
Respiratory, thoracic and 
mediastinal disorders
Nasal odour
Nasal odor
Respiratory, thoracic and 
mediastinal disorders
Nasal oedema
Nasal oedema
Respiratory, thoracic and 
mediastinal disorders
Nasal oedema
Nose edema
Respiratory, thoracic and 
mediastinal disorders
Nasal oedema
Nose oedema
Respiratory, thoracic and 
mediastinal disorders
Nasal oedema
Nasal turbinate edema
Respiratory, thoracic and 
mediastinal disorders
Nasal oedema
Nasal edema
Respiratory, thoracic and 
mediastinal disorders
Nasal oedema
Nasal turbinate oedema
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Nasal polyp
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Nasal polyps
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Polyp of nasal cavity
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Polyps nasal
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Unspecified nasal polyp
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Hyperplastic nasal polyp
Respiratory, thoracic and 
mediastinal disorders
Nasal polyps
Choanal polyp
Respiratory, thoracic and 
mediastinal disorders
Nasal septum disorder
Nasal septum disorder
Respiratory, thoracic and 
mediastinal disorders
Nasal septum disorder
Nasal septum disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Nasal septum disorder
Nasal septal erythema
Respiratory, thoracic and 
mediastinal disorders
Nasal septum perforation
Nasal septum perforation
Respiratory, thoracic and 
Nasal septum perforation
Perforation nasal septum
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         72 
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Nasal septum ulceration
Nasal septum ulceration
Respiratory, thoracic and 
mediastinal disorders
Nasal turbinate abnormality
Nasal turbinate abnormality
Respiratory, thoracic and 
mediastinal disorders
Nasal turbinate hypertrophy
Hypertrophy of nasal turbinates
Respiratory, thoracic and 
mediastinal disorders
Nasal turbinate hypertrophy
Nasal turbinate hypertrophy
Respiratory, thoracic and 
mediastinal disorders
Nasal turbinate hypertrophy
Concha bullosa
Respiratory, thoracic and 
mediastinal disorders
Nasal ulcer
Nasal ulcer
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal spasm
Oropharyngeal spasm
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal spasm
Spasm oropharyngeal
Respiratory, thoracic and 
mediastinal disorders
Oropharyngeal swelling
Oropharyngeal swelling
Respiratory, thoracic and 
mediastinal disorders
Paranasal cyst
Paranasal sinus mucocoele
Respiratory, thoracic and 
mediastinal disorders
Paranasal cyst
Paranasal cyst
Respiratory, thoracic and 
mediastinal disorders
Paranasal cyst
Paranasal sinus mucocele
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus haematoma
Maxillary sinus haematoma
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus haematoma
Maxillary sinus hematoma
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus haematoma
Paranasal sinus haematoma
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus haematoma
Paranasal sinus hematoma
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus hypersecretion
Paranasal sinus hypersecretion
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus hypersecretion
Nasal sinus discharge
Respiratory, thoracic and 
mediastinal disorders
Paranasal sinus mucosal hypertrophy
Paranasal sinus mucosal hypertrophy
Respiratory, thoracic and 
Paranasal sinus necrosis
Paranasal sinus necrosis
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         73
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal cyst
Pharyngeal cyst
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal disorder
Pharyngeal disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal disorder
Unspecified disease of pharynx
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal disorder
Nasopharyngeal disorder
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal disorder
Pharyngeal disorder
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal dyskinesia
Pharyngeal dyskinesia
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal enanthema
Pharyngeal enanthema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal erosion
Pharyngeal erosion
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal erythema
Pharynx redness of
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal erythema
Red throat
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal erythema
Pharyngeal erythema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal erythema
Uvular erythema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal exudate
Pharyngeal exudate
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal fistula
Pharyngeal fistula
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haematoma
Pharyngeal haematoma
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haematoma
Pharyngeal hematoma
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Haemorrhage from throat
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Haemorrhage pharyngeal
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Hemorrhage from throat
Respiratory, thoracic and 
Pharyngeal haemorrhage
Pharyngeal haemorrhage
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         74
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Hemorrhage pharyngeal
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Pharyngeal hemorrhage
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Oropharyngeal hemorrhage
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Oropharyngeal haemorrhage
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal haemorrhage
Pharyngeal bleeding
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal hypertrophy
Pharyngeal hypertrophy
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal hypoaesthesia
Pharyngeal hypoaesthesia
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal hypoaesthesia
Numbness throat
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal hypoaesthesia
Pharyngeal hypoesthesia
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal inflammation
Pharyngeal inflammation
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal inflammation
Pharyngeal mucositis
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal lesion
Pharyngeal lesion
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal leukoplakia
Pharyngeal leukoplakia
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal mass
Pharyngeal mass
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal mucosa atrophy
Pharyngeal mucosa atrophy
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal necrosis
Pharyngeal necrosis
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Edema pharynx
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Oedema pharynx
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Pharyngeal oedema
Respiratory, thoracic and 
Pharyngeal oedema
Pharynx edema
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         75
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Throat edema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Throat oedema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Throat swelling
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Throat swelling non-specific
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Throat swelling NOS
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Pharyngeal edema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal oedema
Pharynx oedema
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal polyp
Pharyngeal polyp
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal stenosis
Pharyngeal stenosis
Respiratory, thoracic and 
mediastinal disorders
Pharyngeal ulceration
Pharyngeal ulceration
Respiratory, thoracic and 
mediastinal disorders
Reflux laryngitis
Laryngopharyngeal reflux
Respiratory, thoracic and 
mediastinal disorders
Reflux laryngitis
Reflux laryngitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis allergic
Allergic rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis allergic
Allergic rhinitis (excl hay fever)
Respiratory, thoracic and 
mediastinal disorders
Rhinitis allergic
Atopic rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis allergic
Rhinitis allergic
Respiratory, thoracic and 
mediastinal disorders
Rhinitis allergic
Rhinitis allergic atopic
Respiratory, thoracic and 
mediastinal disorders
Rhinitis allergic
Rhinitis allergic NOS
Respiratory, thoracic and 
mediastinal disorders
Rhinitis atrophic
Atrophic rhinitis
Respiratory, thoracic and 
Rhinitis atrophic
Ozena
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         76
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Rhinitis atrophic
Rhinitis atrophic
Respiratory, thoracic and 
mediastinal disorders
Rhinitis atrophic
Dry rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis hypertrophic
Rhinitis hypertrophic
Respiratory, thoracic and 
mediastinal disorders
Rhinitis perennial
Perennial allergic rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis perennial
Perennial rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis perennial
Rhinitis perennial
Respiratory, thoracic and 
mediastinal disorders
Rhinitis seasonal
Allergic rhinitis due to pollen
Respiratory, thoracic and 
mediastinal disorders
Rhinitis seasonal
Rhinitis seasonal
Respiratory, thoracic and 
mediastinal disorders
Rhinitis seasonal
Seasonal allergic rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis seasonal
Seasonal rhinitis
Respiratory, thoracic and 
mediastinal disorders
Rhinitis ulcerative
Rhinitis ulcerative
Respiratory, thoracic and 
mediastinal disorders
Rhinolithiasis
Rhinolithiasis
Respiratory, thoracic and 
mediastinal disorders
Rhinolithiasis
Nasal calculus
Respiratory, thoracic and 
mediastinal disorders
Sinus congestion
Nasal sinus congestion
Respiratory, thoracic and 
mediastinal disorders
Sinus congestion
Sinus congestion
Respiratory, thoracic and 
mediastinal disorders
Sinus disorder
Sinus disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Sinus disorder
Sinus disorder
Respiratory, thoracic and 
mediastinal disorders
Sinus perforation
Perforation of sinus
Respiratory, thoracic and 
mediastinal disorders
Sinus perforation
Sinus perforation
Respiratory, thoracic and 
Sinus polyp
Antral polyp (of maxillary sinus)
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         77
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Sinus polyp
Maxillary sinus polyp
Respiratory, thoracic and 
mediastinal disorders
Sinus polyp
Sinus polyp
Respiratory, thoracic and 
mediastinal disorders
Sinus polyp degeneration
Polypoid sinus degeneration
Respiratory, thoracic and 
mediastinal disorders
Sinus polyp degeneration
Sinus polyp degeneration
Respiratory, thoracic and 
mediastinal disorders
Sinusitis noninfective
Sinusitis noninfective
Respiratory, thoracic and 
mediastinal disorders
Stridor
Stridor
Respiratory, thoracic and 
mediastinal disorders
Stridor
Stridor inspiratory
Respiratory, thoracic and 
mediastinal disorders
Tonsillar atrophy
Tonsillar atrophy
Respiratory, thoracic and 
mediastinal disorders
Tonsillar atrophy
Submerged tonsil
Respiratory, thoracic and 
mediastinal disorders
Tonsillar disorder
Chronic tonsillar disease
Respiratory, thoracic and 
mediastinal disorders
Tonsillar disorder
Tonsillar disorder
Respiratory, thoracic and 
mediastinal disorders
Tonsillar disorder
Cryptic tonsil
Respiratory, thoracic and 
mediastinal disorders
Tonsillar haemorrhage
Tonsillar haemorrhage
Respiratory, thoracic and 
mediastinal disorders
Tonsillar haemorrhage
Tonsillar hemorrhage
Respiratory, thoracic and 
mediastinal disorders 
Tonsillar haemorrhage
Tonsillar bleeding
Respiratory, thoracic and 
mediastinal disorders
Tonsillar hypertrophy
Tonsillar hypertrophy
Respiratory, thoracic and 
mediastinal disorders
Tonsillar hypertrophy
Enlarged tonsils
Respiratory, thoracic and 
mediastinal disorders
Tonsillar inflammation
Tonsillar inflammation
Respiratory, thoracic and 
mediastinal disorders
Tonsillar ulcer
Tonsillar ulcer
Respiratory, thoracic and 
Tonsillolith
Tonsillolith
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         78
6\VWHP2UJDQ&ODVV
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mediastinal disorders
Respiratory, thoracic and 
mediastinal disorders
Vasomotor rhinitis
Vasomotor rhinitis
Respiratory, thoracic and 
mediastinal disorders
Velopharyngeal incompetence
Velopharyngeal incompetence
Respiratory, thoracic and 
mediastinal disorders
Vocal cord atrophy
Vocal cord atrophy
Respiratory, thoracic and 
mediastinal disorders
Vocal cord cyst
Vocal cord cyst
Respiratory, thoracic and 
mediastinal disorders
Vocal cord disorder
Vocal cord disorder NOS
Respiratory, thoracic and 
mediastinal disorders
Vocal cord disorder
Vocal cord dysfunction
Respiratory, thoracic and 
mediastinal disorders
Vocal cord disorder
Vocal cord disorder
Respiratory, thoracic and 
mediastinal disorders
Vocal cord inflammation
Vocal cord inflammation
Respiratory, thoracic and 
mediastinal disorders
Vocal cord leukoplakia
Vocal cord leukoplakia
Respiratory, thoracic and 
mediastinal disorders
Vocal cord polyp
Polyp of vocal cord
Respiratory, thoracic and 
mediastinal disorders
Vocal cord polyp
Vocal cord polyp
Respiratory, thoracic and 
mediastinal disorders
Vocal cord thickening
Singers nodules
Respiratory, thoracic and 
mediastinal disorders
Vocal cord thickening
Vocal cord thickening
Respiratory, thoracic and 
mediastinal disorders
Vocal cord thickening
Vocal cord nodule
(4)AEs related to taste and smell disorders: 
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Nervous system disorders
Dysgeusia
After taste
Nervous system disorders
Ageusia
Ageusia
Nervous system disorders
Parosmia
Altered smell sensation
Nervous system disorders
Anosmia
Anosmia
Nervous system disorders
Dysgeusia
Dysgeusia
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         79
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Nervous system disorders
Parosmia
Dysosmia
Nervous system disorders
Parosmia
Dysosmia NOS
Nervous system disorders
Parosmia
Faint odor of sulfur
Nervous system disorders
Hypogeusia
Gustatory sense diminished
Psychiatric disorders
Hallucination, gustatory
Hallucination gustatory
Psychiatric disorders
Hallucination, olfactory
Hallucination olfactory
Psychiatric disorders
Hallucination, gustatory
Hallucination, gustatory
Psychiatric disorders
Hallucination, olfactory
Hallucination, olfactory
Nervous system disorders
Parosmia
Hyperosmia
Nervous system disorders
Hypogeusia
Hypogeusia
Nervous system disorders
Anosmia
Loss of smell
Nervous system disorders
Ageusia
Loss of taste
Psychiatric disorders
Hallucination, olfactory
Olfactory hallucination
Nervous system disorders
Dysgeusia
Parageusia
Nervous system disorders
Parosmia
Parosmia
Nervous system disorders
Parosmia
Perversion olfactory
Nervous system disorders
Parosmia
Smell alteration
Nervous system disorders
Parosmia
Smell change
Nervous system disorders
Anosmia
Smell loss
Nervous system disorders
Parosmia
Smell perversion
Nervous system disorders
Parosmia
Smelly sensation
Nervous system disorders
Parosmia
Strange smell sensation
Nervous system disorders
Dysgeusia
Taste abnormality
Nervous system disorders
Ageusia
Taste absent
Nervous system disorders
Dysgeusia
Taste alteration
Nervous system disorders
Dysgeusia
Taste altered
Nervous system disorders
Dysgeusia
Taste bitter
Nervous system disorders
Dysgeusia
Taste bitter-salty
Nervous system disorders
Dysgeusia
Taste changed
Nervous system disorders
Hypogeusia
Taste diminished
Nervous system disorders
Dysgeusia
Taste disturbance
Nervous system disorders
Dysgeusia
Taste garlic
Nervous system disorders
Ageusia
Taste loss
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         80
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Nervous system disorders
Dysgeusia
Taste metallic
Nervous system disorders
Dysgeusia
Taste peculiar
Nervous system disorders
Dysgeusia
Taste perversion
Nervous system disorders
Dysgeusia
Taste salty
Nervous system disorders
Dysgeusia
Taste sour
Nervous system disorders
Dysgeusia
Taste sweet
Nervous system disorders
Dysgeusia
Bilious taste
Nervous system disorders
Parosmia
Cacosmia
Nervous system disorders
Hyposmia
Hyposmia
Nervous system disorders
Parosmia
Faint odour of sulfur
Nervous system disorders
Olfactory nerve disorder
Olfactory nerve disorder
Investigations
Olfactory test abnormal
Olfactory test abnormal
Investigations
Olfactory test abnormal
Olfactory acuity test abnormal
Nervous system disorders
Hyposmia
Diminished sense of smell
Investigations
Gustometry abnormal
Gustometry abnormal
General disorders and 
administration site conditions
Product taste abnormal
Medication after taste
Nervous system disorders
Parosmia
Phantosmia
Nervous system disorders
Parosmia
Olfactism
Nervous system disorders
Hypergeusia
Hypergeusia
Nervous system disorders
Dysgeusia
Chalky taste
(5)AEs related to depression and suicidality/self-injury: 
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Activation syndrome
Activation syndrome
Adjustment disorder with depressed mood
Adjustment disorder with depressed mood
Adjustment disorder with depressed mood
Adjustment reaction with brief depressive reaction
Adjustment disorder with depressed mood
Adjustment reaction with prolonged depressive reaction
Adjustment disorder with mixed anxiety and depressed 
mood
Adjustment disorder with mixed anxiety and depressed 
mood
Agitated depression
Agitated depression
Agitated depression
Depression agitated
Anhedonia
Anhedonia
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         81
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Anhedonia
Loss of all pleasure
Antidepressant therapy
Antidepressant therapy
Childhood depression
Childhood depression
Decreased interest
Decreased interest
Decreased interest
Loss of all interest
Decreased interest
Loss of interest
Decreased interest
Reduced interest in usual activities
Depressed mood
Chronic depressive mood
Depressed mood
Dejection emotional
Depressed mood
Depressed mood
Depressed mood
Emotional dejection
Depressed mood
Feeling blue
Depressed mood
Feeling down
Depressed mood
Feeling sad
Depressed mood
Low mood
Depressed mood
Mood depression
Depressed mood
Mood depressions
Depressed mood
Unhappiness
Depression
Acute depression
Depression
Anxiety depression
Depression
Anxiodepressive syndrome
Depression
Anxious depression
Depression
Atypical depressive disorder
Depression
Brief depressive reaction
Depression
Chronic depression
Depression
Depressed reaction
Depression
Depressed state
Depression
Depression
Depression
Depression aggravated
Depression
Depression functional
Depression
Depression mental
Depression
Depression NOS
Depression
Depression reactive
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         82
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Depression
Depression worsened
Depression
Depressive disorder
Depression
Depressive episode
Depression
Depressive illness
Depression
Depressive reaction
Depression
Depressive state
Depression
Depressive stupor
Depression
Exogenous depression
Depression
Mixed anxiety & depressive
Depression
Reactive depression
Depression
Recurrent depressive disorder
Depression
Unipolar depression
Depression
Unipolar depressive illness
Depression postoperative
Depression postoperative
Depression postoperative
Postoperative depression
Depressive symptoms
Depressive symptoms
Depressive symptoms
Depressive symptoms aggravvated 
Dysphoria
Dysphoria
Dysthymic disorder
Chronic depressive personality disorder
Dysthymic disorder
Depression neurotic
Dysthymic disorder
Depressive neurosis
Dysthymic disorder
Depressive personality disorder
Dysthymic disorder
Dysthymia
Dysthymic disorder
Dysthymic disorder
Dysthymic disorder
Neurotic depression
Electroconvulsive therapy
Bilateral ECT
Electroconvulsive therapy
ECT
Electroconvulsive therapy
ECT (electro-convulsive therapy)
Electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy
Modified ECT
Electroconvulsive therapy
Unilateral ECT
Electroconvulsive therapy
Unmodified ECT
Feeling guilty
Feeling guilty
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         83
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Feeling guilty
Feeling remorse
Feeling of despair
Feeling of despair
Feelings of worthlessness
Feelings of worthlessness
Major depression
Depression endogenous
Major depression
Depression psychotic
Major depression
Depressive type psychosis
Major depression
Endogenous depression
Major depression
Involutional depression
Major depression
Involutional melancholia
Major depression
Major depression
Major depression
Major depressive disorder aggravated
Major depression
Major depressive disorder NOS
Major depression
Major depressive disorder with melancholic features
Major depression
Major depressive disorder, recurrent episode
Major depression
Major depressive disorder, recurrent episode, in full 
remission
Major depression
Major depressive disorder, single episode
Major depression
Major depressive disorder, single episode in full 
remission
Major depression
Major depressive illness
Major depression
Melancholia
Major depression
Melancholic depression
Major depression
Psychosis depressive
Major depression
Psychotic depression
Menopausal depression
Depression perimenopausal
Menopausal depression
Depression postmenopausal
Menopausal depression
Menopausal depression
Menopausal depression
Postmenopausal depression
Post stroke depression
Post stroke depression
Postictal depression
Postictal depression
Postpartum depression
Baby blues
Postpartum depression
Depression puerperal
Postpartum depression
Postnatal blues
Postpartum depression
Postnatal depression (excl psychosis)
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         84
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Postpartum depression
Postpartum depression
Postpartum depression
Puerperal depression
Postpartum depression
Transitory postpartum mood disturbance
Affect lability
Affect lability
Affect lability
Affective incontinence
Affect lability
Emotional incontinence
Affect lability
Emotional instability
Affect lability
Emotional lability
Affect lability
Instability emotional
Affect lability
Labile affect
Affect lability
Lability emotional
Affect lability
Mental lability symptom
Affect lability
Pseudobulbar affect
Alcohol abuse
Alcohol abuse
Alcohol abuse
Alcohol abuse chronic
Alcohol abuse
Alcohol abuse, continuous drinking behavior
Alcohol abuse
Alcohol abuse, continuous drinking behaviour
Alcohol abuse
Alcohol abuse, episodic drinking behavior
Alcohol abuse
Alcohol abuse, episodic drinking behaviour
Alcohol abuse
Alcohol abuse, in remission
Alcohol abuse
Alcohol abuse, unspecified drinking behavior
Alcohol abuse
Alcohol abuse, unspecified drinking behaviour
Alcohol abuse
Nondependent abuse of alcohol
Alcohol poisoning
Acute alcoholic intoxication
Alcohol poisoning
Acute alcoholic intoxication in alcoholism, continuous 
drinking behavior
Alcohol poisoning
Acute alcoholic intoxication in alcoholism, continuous 
drinking behaviour
Alcohol poisoning
Acute alcoholic intoxication in alcoholism, episodic 
drinking behavior
Alcohol poisoning
Acute alcoholic intoxication in alcoholism, episodic 
drinking behaviour
Alcohol poisoning
Acute alcoholic intoxication in alcoholism, in remission
Alcohol poisoning
Acute alcoholic intoxication in alcoholism, unspecified 
drinking behavior
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         85
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Alcohol poisoning
Acute alcoholic intoxication in alcoholism, unspecified 
drinking behaviour
Alcohol poisoning
Alcohol intoxication
Alcohol poisoning
Alcohol intoxication acute
Alcohol poisoning
Alcohol intoxication, acute
Alcohol poisoning
Alcohol poisoning
Alcohol poisoning
Drunkenness
Alcohol poisoning
Toxic effect of alcohol
Alcohol poisoning
Toxic effect of ethyl alcohol
Alcohol poisoning
Toxic effect of fusel oil
Alcohol poisoning
Toxic effect of isopropyl alcohol
Alcohol poisoning
Toxic effect of methyl alcohol
Alcohol poisoning
Toxic effect of unspecified alcohol
Alcohol problem
Alcohol problem
Alcohol problem
Alcohol problem NOS
Alcohol rehabilitation
Alcohol rehabilitation
Alcoholism
Alcohol addiction
Alcoholism
Alcohol craving
Alcoholism
Alcohol dependence syndrome
Alcoholism
Alcoholic relapse
Alcoholism
Alcoholism
Alcoholism
Alcoholism (excl psychosis)
Alcoholism
Chronic alcoholism
Alcoholism
Dipsomania
Apathy
Ambition loss of
Apathy
Apathy
Apathy
Avolition
Apathy
Initiative loss of
Apathy
Lack of motivation
Apathy
Loss of ambition
Apathy
Loss of initiative
Blunted affect
Affective blunting
Blunted affect
Blunted affect
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         86
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Constricted affect
Constricted affect
Constricted affect
Restricted affect
Crying
Crying
Crying
Crying abnormal
Crying
Crying uncontrollable
Crying
High-pitched crying
Crying
Inconsolable crying
Crying
Persistent crying
Crying
Uncontrollable crying
Crying
Weeping
Crying
Weepy
Disturbance in attention
Attention concentration difficulty
Disturbance in attention
Attention impaired
Disturbance in attention
Attentiveness decreased
Disturbance in attention
Concentration (mental) abnormal
Disturbance in attention
Concentration ability impaired
Disturbance in attention
Concentration impaired
Disturbance in attention
Concentration impairment
Disturbance in attention
Concentration loss
Disturbance in attention
Disturbance in attention
Disturbance in attention
Impairment of attention
Disturbance in attention
Mental concentration decreased
Disturbance in attention
Mental concentration difficult
Disturbance in attention
Mental concentration difficulty
Disturbance in attention 
Mental concentration impaired
Disturbance in attention
Poor concentration
Disturbance in attention
Simple disturbance of activity and attention
Disturbance in attention
Vigilance decreased
Dyssomnia
Dysfunctions associated with sleep stages or arousal 
from sleep
Dyssomnia
Dyssomnia
Dyssomnia
Dyssomnia NOS
Emotional distress
Embarrassment
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         87
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Emotional distress
Emotional distress
Emotional distress
Humiliation
Emotional distress
Mental distress
Emotional distress
Suffering
Emotional poverty
Emotional poverty
Emotional poverty
Emotional withdrawal
Emotional poverty
Lack of feeling emotions
Emotional poverty
Poverty emotional
Emotional poverty
Withdrawal emotional
Hypersomnia
Hypersomnia
Hypersomnia
Idiopathic hypersomnia
Hypersomnia
Persistent disorder of initiating or maintaining 
wakefulness
Hypersomnia
Primary hypersomnia
Hypersomnia
Sleep excessive
Hypersomnia
Transient disorder of initiating or maintaining 
wakefulness
Hyposomnia
Hyposomnia
Impaired self-care
Impaired self-care
Initial insomnia
Initial insomnia
Initial insomnia
Trouble falling asleep
Intentional product misuse
Intentional drug misuse
Intentional product misuse
Intentional misuse
Intentional product misuse
Intentional misuse by dose change
Intentional product misuse
Intentional misuse in dosing frequency
Intentional product misuse
Intentional product misuse
Intentional product use issue
Intentional dose decrease
Intentional product use issue
Intentional dose increase
Intentional product use issue
Intentional product use issue
Intentional product use issue
Intentional use beyond labeled administration duration
Intentional product use issue
Intentional use beyond labeled duration
Intentional product use issue
Intentional use beyond labelled administration duration
Intentional product use issue
Intentional use beyond labelled duration
Intentional product use issue
Intentional use by incorrect route
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         88
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Intentional product use issue
Intentional use for unlabeled indication
Intentional product use issue
Intentional use for unlabelled indication
Listless
Listless
Listless
Listlessness
Maternal use of illicit drugs
Maternal use of illicit drugs
Memory impairment
Forgetfulness
Memory impairment
Hypomnesia
Memory impairment
Memory deficit
Memory impairment
Memory disturbance
Memory impairment
Memory disturbance (excl dementia)
Memory impairment
Memory impaired
Memory impairment
Memory impairment
Memory impairment
Short-term memory impairment
Middle insomnia
Arousal night
Middle insomnia
Middle insomnia
Middle insomnia
Nocturnal awakening
Middle insomnia
Sleep maintenance insomnia
Mood altered
Affect alteration
Mood altered
Affect altered
Mood altered
Altered mood
Mood altered
Bad mood
Mood altered
Mood alteration NOS
Mood altered
Mood altered
Mood altered
Mood change
Mood swings
Mood swings
Mood swings
Mood variable
Morose
Morose
Morose
Moroseness
Negative thoughts
Negative thoughts
Neglect of personal appearance
Appearance personal neglect of
Neglect of personal appearance
Neglect of person appearance
Neglect of personal appearance
Neglect of personal appearance
Neglect of personal appearance
Personal appearance neglect of
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         89
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Poor quality sleep
Light sleep
Poor quality sleep
Poor quality sleep
Poor quality sleep
Poor sleep
Poor quality sleep
Sleep restless
Poor quality sleep
Sleep unwell
Poor quality sleep
Wakefulness
Psychomotor hyperactivity
Activity motor exaggerated
Psychomotor hyperactivity
Behavior hyperactive
Psychomotor hyperactivity
Behaviour hyperactive
Psychomotor hyperactivity
Hyperactive
Psychomotor hyperactivity
Hyperactivity
Psychomotor hyperactivity
Increased activity
Psychomotor hyperactivity
Irritable hyperkinesis
Psychomotor hyperactivity
Motor activity exaggerated
Psychomotor hyperactivity
Muscular hyperactivity
Psychomotor hyperactivity
Overactive
Psychomotor hyperactivity
Overactivity
Psychomotor hyperactivity
Psychomotor agitation
Psychomotor hyperactivity
Psychomotor excitability
Psychomotor hyperactivity
Psychomotor hyperactivity
Psychomotor retardation
Psychomotor retardation
Psychosocial support
Psychosocial counseling
Psychosocial support
Psychosocial support
Psychotherapy
Art therapy
Psychotherapy
Cognitive psychotherapy
Psychotherapy
Couples psychotherapy
Psychotherapy
Family psychotherapy
Psychotherapy
Group psychotherapy
Psychotherapy
Hippotherapy
Psychotherapy
Interpersonal psychotherapy
Psychotherapy
Play therapy
Psychotherapy
Psychotherapy
Psychotherapy
Supportive psychotherapy
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         90
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Self esteem decreased
Self esteem decreased
Substance-induced mood disorder
Stimulant-induced mood disorder
Substance-induced mood disorder
Substance-induced mood disorder
Tearfulness
Tearfulness
Terminal insomnia
Awakening early
Terminal insomnia
Early morning awakening
Terminal insomnia
Terminal insomnia
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Columbia suicide severity rating scale abnormal
Columbia suicide severity rating scale abnormal
Completed suicide
Accomplished suicide
Completed suicide
Completed suicide
Completed suicide
Suicide
Completed suicide
Suicide (accomplished)
Depression suicidal
Depression suicidal
Depression suicidal
Suicidal depression
Intentional overdose
Deliberate overdose
Intentional overdose
Drug overdose deliberate self-inflicted
Intentional overdose
Intentional overdose
Intentional overdose
Multiple drug overdose intentional
Intentional overdose
Non-accidental overdose
Intentional overdose
Overdose deliberate self-inflicted
Intentional overdose
Overdose intentional
Intentional self-injury
Deliberate self-harm
Intentional self-injury
Deliberate self-injury
Intentional self-injury
Intentional self-injury
Intentional self-injury
Parasuicide
Intentional self-injury
Repeated parasuicide
Intentional self-injury
Self inflicted laceration
Intentional self-injury
Self mutilation
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Upsher-Smith Laboratories, Inc.
  
Statistical Analysis Plan for Protocol No.: P261-402
15May2017                                                                                                                                                         91
3UHIHUUHG7HUP
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Attempted suicide  
Deliberate poisoning
Attempted suicide  
Poisoning deliberate
Poisoning deliberate
Poisoning deliberate
Poisoning deliberate
Poisoning deliberate self-inflicted
Self injurious behaviour
Self injurious behavior
Self injurious behaviour
Self injurious behavior without suicidal intent
Self injurious behaviour
Self injurious behaviour
Self injurious behaviour
Self injurious behaviour without suicidal intent
Self-injurious ideation
Self-injurious ideation
Self-injurious ideation
Thoughts of self harm
Suicidal behaviour
Preparatory actions toward imminent suicidal behavior
Suicidal behaviour
Preparatory actions toward imminent suicidal behaviour
Suicidal behaviour
Suicidal behavior
Suicidal behaviour
Suicidal behaviour
Suicidal behaviour
Suicide gesture
Suicidal ideation
Active suicidal ideation
Suicidal ideation
Death wishes
Suicidal ideation
Life weariness
Suicidal ideation
Passive suicidal ideation
Suicidal ideation
Suicidal ideation
Suicidal ideation
Suicidal intention
Suicidal ideation
Suicidal plans
Suicidal ideation
Suicidal tendency
Suicide attempt
Attempted suicide
Suicide attempt
Suicide attempt
Suicide attempt
Suicide attempt other than overdose
Suicide attempt
Unsuccessful suicide
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