Clinical trial NCT01390220
Conditions: Epilepsy
Keywords: Epilepsy seizure clusters acute repetitive seizures rescue treatment ARTEMIS
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2011-06-01; Completion date: 2017-03-01
Enrollment: 292 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the safety and effectiveness of USL261 for the outpatient treatment of seizure clusters.

Detailed description:
Qualifying participants underwent an in-clinic administration (Test Dose Phase \[TDP\]) of two doses of USL261 (intranasal midazolam 5 mg), separated by 10 minutes, in the absence of seizures. Eligible participants were then randomized to USL261 versus Placebo in an outpatient Comparative Phase (CP). When the participant had a qualifying seizure cluster episode, as described in an individualized patient management plan, the participant's caregiver administered the double-blind dose. An open-label USL261 dose could be administered after 10 minutes and up to 6 hours after the double-blind dose, if the participant had persistent or recurrent seizures. Initial participants could not proceed to CP until an independent data safety monitoring board (DSMB) reviewed safety data from at least the first 25 participants in TDP; the DSMB performed additional safety reviews at pre-set intervals based on enrollment.

Arms: arm 1: intranasal midazolam 5mg arm 2: Intranasal placebo
Interventions: intervention 1: USL261 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Confidential 
Protocol P261-401
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Confidentiality Statement:  The confidential information in the following document is 
provided to you as an Investigator, potential Investigator, or consultant for review by you, your 
staff, and applicable Institutional Review Board.  The information contained herein should not 
be disclosed to others, without written authorization from Upsher-Smith Laboratories, Inc., 
except to the extent necessary to obtain informed consent from those persons to whom the drug 
will be administered.
Upsher-Smith Laboratories, Inc.
6701 Evenstad Drive
Maple Grove, MN 55369
Clinical Research Protocol
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety and Efficacy of Intranasal Midazolam (USL261) 
in the Outpatient Treatment of Subjects with Seizure 
Clusters
ARTEMIS-1: Acute Rescue Therapy in Epilepsy with 
Midazolam Intranasal Spray-1
Protocol Number:
P261-401
EudraCT Number:
2011-001318-32
Protocol Version:
Fifth Issue, Amendment 4
Amendment is only applicable to the United Sttaes
Issue Date:
20 May 2015
Clinical Phase:
Phase III
US IND Number:
77,421
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Protocol P261-401
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SYNOPSIS
Sponsor: Upsher-Smith Laboratories, Inc. (USL)
Name of Development Product:  USL261 (intranasal midazolam; formerly ITI-111)
Study Title: A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of 
Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects with Seizure Clusters
Study Number: P261-401
Study Phase: III
Efficacy Objective(s):  
Primary Efficacy Objective: 
To evaluate the efficacy of USL261 compared with that of intranasal (IN) placebo for the outpatient 
treatment of seizure clusters based on Treatment Success, which is defined as achieving both of the 
following:

Termination of seizure(s) within 10 minutes after study drug administration, and

No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 hours
after study drug administration
Secondary Efficacy Objective(s):  
To evaluate the efficacy of USL261 compared with that of IN placebo for the outpatient treatment of 
seizure clusters using the following: 

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
Safety Objective:
To evaluate the safety and tolerability of USL261 for the treatment of seizure clusters using the 
following assessments:

Adverse events (AEs)

Caregiver-recorded respiration rate at 15 minutes, 30 minutes, 1 hour, 2 hours and 4 hours after
study drug administration in the Comparative Phase

Clinical laboratory tests

Vital signs measurements (systolic and diastolic blood pressure, pulse rate, respiration rate and
temperature) as recorded by the study center personnel

Physical, nasal and neurological examinations

Brief Smell Identification Test (B-SIT)

Columbia-Suicide Severity Rating Scale (C-SSRS)

Requirement for unscheduled emergency room (ER) or emergency medical service (EMS) visit
within 24 hours after study drug administration
Study Design: 
This is a phase III multicenter study, with 2 distinct phases and 4 study center visits. The first phase is 
the Test-Dose Phase where subjects will receive 2 doses of open-label 5.0 mg USL261 administered 10 
minutes apart at the study center. The Test-Dose Phase is designed to assess the safety, tolerability, and 
pharmacokinetics (PK) of USL261 in a monitored setting and provide the caregivers with training on the 
study procedures. The Test-Dose Phase will be followed by the Comparative Phase, an outpatient, 
double-blind, placebo-controlled, parallel-group phase. In the Comparative Phase, all subjects will be 
randomized 2:1 to receive 5.0 mg USL261 or placebo. During the Comparative Phase, the subject’s 
caregiver will administer the double-blind study drug when the subject experiences a seizure cluster that 
meets the study criteria, as described in the subject’s individualized Patient Management Plan (PMP). If 
the treated seizure cluster 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 < 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 Patient Management Plan), the double-blind dose of study medication may be 
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Protocol P261-401
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followed by a single dose of 5.0 mg USL261. Any time between 24 to 120 hours after study drug 
administration, subjects and caregivers will return to the study center for a post-dose study visit. 
A maximum of approximately 350 subjects, aged 12 years or older, with a documented history of seizure 
clusters and on a stable antiepileptic drug (AED) regimen will be enrolled in the Test-Dose Phase. 
Before any subject continues to the Comparative Phase, safety data from at least 25 subjects in the Test-
Dose Phase will be reviewed by an independent Data and Safety Monitoring Board (DSMB). 
Enrollment will temporarily halt once approximately 25 subjects complete the Test-Dose Phase, to allow 
the DSMB to review the safety data. If the safety data from this initial cohort supports continuation of 
the trial according to the DSMB, enrollment into the Test-Dose Phase will resume and the initial 25 
subjects will proceed to the Comparative Phase. All subsequent subjects will progress directly from 
Test-Dose Phase to the Comparative Phase.
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/Independent Ethics Committee policy
2.
Subject has a competent, adult (age ≥ 18) caregiver(s) who is able to recognize and observe the
subject’s seizure cluster episodes, 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 is not likely to conceive, as indicated by a “yes” answer to at least 1 of the following
questions:

Is the subject a male?

Is the subject a postmenopausal female with greater than 1 year since last menses and a
follicular stimulating hormone value greater than 40 mIU/mL?

Is the subject a female who has written medical documentation of being permanently
sterilized (e.g. hysterectomy, double oophorectomy, bilateral salpingectomy)?

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:
o
A diaphragm and a condom with spermicide,
o
An intrauterine device (IUD) used in combination with a barrier method (e.g. condom,
diaphragm, or cervical cap with spermicide),
o
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.
Subject has an established diagnosis of partial or generalized epilepsy that includes all of the
following:

A documented history of seizure clusters lasting a minimum of 10 minutes from the time
the seizure cluster is recognized

The 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

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
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
In the investigator’s opinion, it would be safe for the subject to receive placebo as a first
dose of study drug followed by active treatment (USL261) as the second dose of study
drug no earlier than 10 minutes after the first dose

The subject’s stereotyped seizure cluster pattern is composed of multiple (≥ 2) partial or
generalized seizures

The subject’s stereotyped seizure cluster pattern was established > 3 months before Visit 1

A frequency of ≥ 3 stereotyped seizure clusters during the year before Visit 1

At least 1 stereotyped seizure cluster occurring ≤ 4 months before Visit 1

The seizure cluster pattern described above is confirmed by a central reviewer
6.
Subject is receiving a regimen of AED(s) that has been stable (i.e., no changes in the type of
AED) since Visit 1 and for ≥ 7 days before Visit 2. Changes in dose of an AED are allowed
during the study; however, the new dose level must be kept stable for at least 7 days before the
subject receives study drug. Benzodiazepines that are used for rescue therapy of seizures or for
non-epilepsy indications are allowed provided they are typically used ≤ 3 days within a 7-day
period on average and always at the same dose. Daily use of a benzodiazepine as a chronic
AED is not permitted.
7.
Subject has had a documented brain computerized tomography or magnetic resonance imaging
review, performed after diagnosis of epilepsy and before Visit 1, that confirms the absence of a
progressive neurological disorder
8.
Subject weight is 40 kg to 125 kg (inclusive)
9.
Subject must have a screening (Visit 1) 12-lead electrocardiogram (ECG) that meets the
following criteria:

QTcF interval ≤ 450 msec for males and ≤ 470 msec for females

Consistent sinus rhythm as determined by the investigator

No left bundle branch block (LBBB)

No other clinically significant conduction disorders as determined by the investigator
10. Subject must have screening (Visit 1) vital sign values that meet the following criteria:

Systolic blood pressure of ≤ 160 mm Hg

Diastolic blood pressure of ≤ 90 mm Hg

Pulse rate of 50 to 115 bpm, inclusive

No clinically significant vital sign values as determined by the investigator
Note: At the discretion of the investigator, out-of-range blood pressure or heart rate
measurements may be repeated once, and the repeat measurement used in relation to this
inclusion.
Exclusions
At Visit 1 (Screening)
1.
Subject has a neurological disorder that is likely to progress in the next year
2.
Subject has acute narrow-angle glaucoma
3.
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
4.
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
5.
Subject has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit 1
6.
Subject has suicidality, defined as any of the following: a) active suicidal plan/intent or active
suicidal thoughts in the 6 months before Visit 1 as defined by a Columbia-Suicide Severity
Rating Scale (C-SSRS) suicidal ideation score ≥ 3, b) any suicide attempt in the past 5 years as
determined by the C-SSRS or medical history, or c) other clinically significant suicidality as
determined by the investigator
7.
Subject, in the investigator’s opinion, has met the criteria for a major depressive episode at any
time within 6 months before Visit 1 (criteria defined by the current edition of the Diagnostic
and Statistical Manual of Mental Disorders)
8.
Subject has or has had psychosis in the 12 months before Visit 1, excluding postictal psychosis
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Protocol P261-401
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9.
Subject has a history of their stereotypical seizure cluster (for which they are being enrolled in
the study) progressing to status epilepticus (as determined by the investigator) within the 2
years before Visit 1
10. Subject has a history of drug or alcohol abuse within 1 year before Visit 1
11. Subject has a positive pregnancy test at Visit 1 or is currently pregnant or breastfeeding
(females only)
12. Subject has a history of allergy or any significant adverse reaction (including rash) to
midazolam
13. Subject is currently using an investigational drug or device or has used such within 30 days
before Visit 1
14. Subject is currently using a vagal nerve stimulator (VNS) unless the device has been implanted
for at least 6 months and the settings have not changed within 4 weeks before Visit 1
15. 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)
16. Subject has any clinically significant laboratory abnormality as determined by the investigator
and as confirmed by repeat testing, or has any of the following laboratory abnormalities at Visit
1 as confirmed by repeat testing:

Alanine transaminase (ALT) and/or aspartate transaminase (AST) results > 2 times the
upper limit of normal

White blood cell count < 2.5x109/L

Sodium < 128 mEq/L

Creatinine > 2.0 mg/dL
17. Subject is not appropriate for the study for any other reason as determined by the investigator
At Visit 2
18. Subject has developed a new medical condition, suffered a change in status of an established
medical condition, developed a laboratory abnormality, or required a new treatment or
medication which meets any previously described study exclusion criteria.
19. Subject has a positive pregnancy test (females only)
20. Subject has active suicidal plan/intent or suicidal thoughts as defined by a C-SSRS suicidal
ideation score ≥ 3 or has had a suicide attempt since the last visit
21. Subject has consumed any clinically significant CYP450 3A inhibitor/inducer, opioid, other
respiratory depressant (excluding antiepileptic drugs) within the required washout period before
Visit 2
22. Subject has any of the following during the observation period after administration of the USL261
test dose at Visit 2:

Blood pressure (BP)
o
Systolic blood pressure (SBP) < 85 mm Hg and the change from baseline (pre-dose
evaluation) in SBP is deemed clinically significant by the investigator
o
A ≥ 40 mm Hg decrease from baseline (pre-dose evaluation) in SBP
o
Diastolic blood pressure (DBP) < 50 mm Hg and the change from baseline (pre-dose
evaluation) in DBP is deemed clinically significant by the investigator
o
A ≥ 30 mm Hg decrease from baseline (pre-dose evaluation) in DBP

Heart rate (HR)
o
HR > 120 or < 50 beats per minute (bpm) and change from baseline (pre-dose
evaluation) in HR is deemed clinically significant by the investigator
o
A ≥ 40 bpm change from baseline (pre-dose evaluation) in HR

Respiratory rate (RR)
o
RR > 24 breaths per minute and change from baseline (pre-dose evaluation) in RR is
deemed clinically significant by the investigator
o
RR < 8 breaths per minute while awake or after arousing

Sedation to the degree that the subject does not respond to mild prodding or shaking

Oxygen saturation < 90% for > 30 seconds or requires oxygen at anytime

Clinically-significant ECG findings as determined by the investigator
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Note: At the discretion of the investigator, out-of-range BP or HR measurements may be 
repeated once, and the repeat measurement used in relation to exclusion criteria, as long as the 
rules outlined in Section 6.2.2.3 are followed.
At Visit 3
23. Subject has developed a new medical condition, suffered a change in status of an established 
medical condition, developed a laboratory abnormality, or required a new treatment or 
medication which meets any previously described study exclusion criteria
24. Subject has a positive pregnancy test
25. Subject has active suicidal plan/intent or suicidal thoughts as defined by a C-SSRS suicidal 
ideation score ≥ 3 or has had a suicide attempt since the last visit.
Study Population: A maximum of approximately 350 subjects enrolled in the Test-Dose Phase in order 
to achieve 240 subjects completing the Comparative Phase. This assumes that approximately 32% of 
subjects enrolled in the Test-Dose Phase do not complete the Comparative Phase.
Test/Reference Product, Dose, and Mode of Administration:
Test Product: USL261 (intranasal midazolam; formerly ITI-111)
Test-Dose Phase: Two (2) open-label 5.0 mg doses (1 actuation each), separated by 10 minutes (total 
dose 10 mg)
Comparative Phase: One (1) double-blind 5.0 mg dose (1 actuation); One (1) 5.0 mg dose (1 actuation) 
administered for persistent or recurrent seizure activity
Reference Product: Placebo nasal spray
Comparative Phase only: One (1) double-blind dose (1 actuation)
Duration of Treatment: 10 minutes for Test-Dose Phase, variable for Comparative Phase
Duration of Subject Participation:
Screening: Up to 28 days; can be longer during the time of DSMB review
Test-Dose Phase: Up to 28 days; can be longer during the time of DSMB review
Comparative Phase: The duration of each subject’s participation in the Comparative Phase will be 
variable and will be determined by the frequency of observed seizure events. Assuming an average of 3
seizure clusters per year, approximately half of the study subjects complete the study within ~4 months 
after randomization to treatment. Subjects may remain in the Comparative Phase for up to 6 months. 
Any subject who has not treated a seizure cluster meeting the study criteria within 6 months of Visit 3 
(Randomization) will be discontinued from the study.
Efficacy Assessment(s): 
Efficacy will be determined using the following information at a minimum:

Date and time of study drug administration

Date, start, and stop time of each seizure within 24 hours after any study drug administration 

Date and time when subject has returned to full baseline functionality after the treated seizure 
cluster, as determined by the caregiver
Safety Assessments:  
Collection of AEs, physical and neurological examinations, clinical laboratory evaluations, vital signs, 
caregiver-recorded respiration rate, 12-Lead ECG, pulse oximetry, sedation (determined by the OAA/S),
C-SSRS, the need for second dose of medication or emergency treatment, and B-SIT.
Pharmacokinetic Assessments: 
Blood samples will be collected before and at 5, 10, 20, 30 minutes and 1, 2, and 4 hours after 
administration of the first 5.0 mg test dose of USL261 at Visit 2. After 132 subjects have completed the 
Comparative Phase, for all new test dosed subjects, blood samples will be collected before and at 5, 10, 
20, 30 minutes and 1hour after administration of the first 5.0 mg test dose of USL261 at Visit 2.
Statistical Methods:
Efficacy
Efficacy variables will be analyzed using the modified Intent-to-Treat (mITT) Population, which 
consists of all subjects who are randomized to receive double-blind treatment, who receive at least 1 
dose of study drug during the Comparative Phase, and who have any post-treatment efficacy 
assessments.
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Primary Efficacy Endpoint and Analysis:
The primary efficacy endpoint is the proportion of subjects who meet the criteria for Treatment Success. 
Treatment Success is a composite measure of efficacy that will be assessed based upon the first seizure 
cluster treated with study drug during the Comparative Phase. Treatment Success is defined as 
achieving the following:

Termination of seizure(s) within 10 minutes after administration of study drug and

No recurrence of seizure(s) beginning 10 minutes after administration of study drug to 6 hours
after administration of study drug
The primary efficacy endpoint will be analyzed by Fisher’s Exact Test. Chi-squared test will be 
performed as a sensitivity analysis.
The trial utilizes a group sequential design with 3 interim analyses and a maximum of approximately 
240 subjects who have completed the Comparative Phase.  Subjects who receive at least 1 dose of study 
drug during the Comparative Phase and who complete Visit 4 will have completed the Comparative 
Phase.  The interim analyses will occur at N=132, 165, and 204 subjects complete the Comparative 
Phase with a final analysis (if needed) at N=240 subjects completing the Comparative Phase.  At each 
interim analysis the trial may be stopped for efficacy or futility.  Interim analyses for efficacy are 
evaluated using a Lan-DeMets alpha spending function approximating the Pocock boundary to preserve 
type I error at 2.5%.  Futility monitoring is based on Bayesian predictive probabilities.  At each interim 
analysis the trial is stopped for futility if the predictive probability of success at the maximal sample size 
is less than 10%.  Assuming treatment rates of 0.40 for the placebo arm and Odds Ratio of 2.9, the 
power of this design is approximately 90%.  These analyses will be conducted using the mITT 
population and a one-sided test comparing two populations.  Interim analyses for efficacy and futility 
will be performed by an unblinded interim monitoring committee separate from the Sponsor.
Secondary Efficacy Endpoints and Analyses:
The secondary efficacy variables include the following:

Proportion of subjects with recurrence of a seizure(s) beginning 10 minutes after administration
of study drug to 4 hours after administration of study drug, by Fisher’s Exact Test. In addition,
Chi-squared test will be performed as a sensitivity analysis.

Time to next seizure with a start time > 10 minutes after study drug administration, analyzed by
a log-rank test, and presented with Kaplan-Meier estimates for time to event at specific
percentiles
Safety
Safety analyses will be performed using the Safety Population, which includes all subjects that receive at 
least 1 dose of study drug. Safety data from both the Test-Dose Phase and the Comparative Phase will be 
summarized. 
Safety Endpoints

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 treatment received and visit

Vital sign measurements (SBP, DBP, HR, respiration rate and temperature) and oxygen
saturation performed by study center staff  will be summarized at each visit and time point

Caregiver-recorded respiration rate from the Comparative Phase will be presented using
descriptive statistics at each time point. 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.

Changes from baseline in 12-lead ECG parameters in the Test Dose Phase will be summarized.

The number of subjects requiring an unscheduled ER or EMS visit within 24 hours after study
drug administration in the Comparative Phase will be analyzed by Fisher’s Exact Test.

Suicidal behavior and ideation using the C-SSRS will be summarized at each visit.

OAA/S sum and composite scores after the study drug administration in the Test-Dose Phase
will be presented by time point.
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
Physical, nasal, and neurological examination results will be presented by treatment group and 
visit.

Olfactory assessment results and changes from baseline will be presented by treatment group 
and visit.
Pharmacokinetic 
Pharmacokinetic Endpoints
Pharmacokinetic (PK) profile of midazolam and 1-hydroxymidazolam will be assessed at the Test Dose 
Visit after administration USL261. The following PK parameters will be calculated:
•
AUC0-t – the area under the plasma concentration-time curve from time 0 to last measurable 
concentration estimated by the linear trapezoidal method
•
AUC0-∞ – the area under the plasma concentration-time curve from time zero extrapolated to 
infinity
•
Cmax – the maximum plasma concentration
•
tmax – the time to maximum plasma concentration
•
λz – the terminal elimination rate constant
•
t1/2 – the terminal elimination half-life
•
tlag – the time before the first measurable plasma concentration
•
CL/F – apparent clearance*
•
Vβ/F  - volume of distribution*
* calculate for Midazolam only and not for 1-OH-midazolam.
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Table 1.   Procedure Schedule
Phase
Screening
Test-
Dose 
Phase
Comparative Phase
Visit Number
1
2[a]
3[b]
Treatment[c]
4 or 
ET[d]
Study Assessments
Informed consent[e]
X
Register subject with IRT
X
Inclusion/Exclusion evaluation
X
X
X
Caregiver training[f]
X
X
X
Demographics
X
Medical/surgical history[g]
X
Concomitant medication review
X
X
X
X
ER and EMS Visit Review [h]
X
X
Physical exam[i]
X
X
X
X
Neurological exam[j]
X
X
X
X
B-SIT
X
X
X
Clinical laboratory testing[k]
X
X
FSH level (females only)
X
Pregnancy testing[l]  (all females)
X
X
X
X
Drug screen[m]
X
Patient Management Plan (PMP)[n]
X
X
X
Central review of seizure cluster 
description[o]
X
Treatment administration
X[p]
X
Call central study nurse hotline [q]
X
Pharmacokinetic blood  sampling[r]
X
Observer’s  Assessment of 
Alertness/Sedation (OAA/S)[s]
X
12-lead ECG
X
X[t]
Body weight
X
X
X
X
Height
X
X
Vital signs[u]
X
X
X
X
Caregiver-recorded respiration 
rate[v]
X
X
Pulse oximetry[u]
X
Report test dose information on IRT
X
Columbia- Suicide Severity Rating 
Scale [w]
X
X
X
X
Outcome Assessments
X
X
Randomization using IRT
X
Dispense study materials kit [x]
X
Record seizure activity in Subject 
Workbook
X
Evaluate subject’s return to baseline 
functionality [y]
X
Adverse event collection
X
X
X
X
X
Collect study drug containers, used 
and unused
X
Review/collect Subject Workbook 
X
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Telephone follow-up
X[z]
[a] Visit 2 assessments occurring at the same time should be completed in the following order: ECG, OAA/S, vitals, pulse
oximetry, PK blood draw, and second dose; Visit 2 will occur within 28 days of Visit 1. If necessary, assessments may be
performed up to 1 minute before or 1 minute after the scheduled time.
[b] For patients enrolled in the study after the initial DSMB review, Visit 3 will occur a minimum of 24 hours and a 
maximum of 28 days after Visit 2.
[c] These assessments will be performed by the caregiver.
[d] Visit 4 will occur between 24 and 120 hours after double-blind study drug administration. Any subject who has not
treated a seizure cluster meeting the study criteria within 6 months of Visit 3 (Randomization) will return to the study
center for Visit 4 (Early Termination)..
[e] Informed consent provided by subject (or subject’s LAR) and caregiver before any other study-specific procedures;
assent may also be required for some subjects (see Section 5)
[f] Caregiver training includes, but is not limited to, providing self-study training to the caregiver and review of that
training by the study center personnel. It also includes CPR and airway management training for caregivers. For details on
caregiver training, see Section 9.3.3.
[g] Includes seizure history and current/past medication use; complete at Visit 1 (see Section 6.2.2.1).
[h] At Visit 1, collect number of calls to EMS and ER visits for a seizure cluster or other seizure emergency in the year
prior to screening. At Visit 4, 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. Number of calls to EMS and ER visits for a seizure cluster or other seizure
emergency since last visit or follow-up phone call will also be collected on each monthly telephone follow up call between
Visit 3 and Visit 4 or ET.
[i] Physical examination includes assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart,
abdomen, lymph nodes, and extremities, and a nasal cavity examination using a nasal speculum (see Section 6.2.2.2).
[j] A complete neurological examination will be performed at Visits 1 and 4/ET. A partial neurological examination will
be performed at Visits 2 and 3 (see Section 6.2.2.2).
[k] Includes hematology, serum chemistry, and urinalysis; phenobarbital levels will be assessed at Visit 1 for subjects
taking phenobarbital and in subjects for which the investigator deems it necessary (see Section 6.2.2.7).
[l] Serum pregnancy test at Visit 1, urine pregnancy tests at Visits 2, 3, and 4/ET (see Section 6.2.2.7).
[m] Includes barbiturates, benzodiazepines, cocaine, marijuana, methamphetamine, opiates, and phencyclidine (all in
urine) and alcohol (blood) (see Section 6.2.2.7).
[n] PMP preparation begins at Visit 1. PMP should be completed before a subject receives the first test dose of USL261
at Visit 2. PMP provided to and reviewed with subject and caregiver at Visit 3 (see Section 9.3.1).
[o] Approval of each subject’s seizure cluster pattern by central reviewer is required  for study inclusion (see Section 9.3.1)
[p] At Visit 2, subjects will receive a test dose of 5.0 mg USL261 administered by a member of the study center
personnel followed by a second dose of 5.0 mg USL261 10 minutes later administered by the caregiver under the
supervision of study center personnel (see Section 6.1.7).
[q] Caregivers to call the central study nurse hotline as soon as possible after administering study drug.
[r] Blood samples for PK assessment will be collected before and at 5, 10, 20, 30 minutes and 1, 2, and 4 hours after the
first test dose. After 132 subjects have completed the Comparative Phase, for all new test dosed subjects, blood samples
will be collected before and at 5, 10, 20, 30 minutes and 1hour after administration of the first 5.0 mg test dose of USL261
at Visit 2.
[s] At Visit 2, the OAA/S will be administered before and at 5, 10, 20, 30 minutes and 1, 2, and 4 hours after the first test
dose by a trained member of the study center personnel (see Section 6.2.2.5). After 132 subjects have completed the
Comparative Phase, for all new test dosed subjects, the OAA/S will be administered before and at 5, 10, 20, 30 minutes
and 1 hour after the first test dose by a trained member of the study center personnel.
[t] ECG will be performed twice at Visit 2: once before and once 15 minutes after the first test dose (see Section 6.2.2.4)
[u] Vital signs include blood pressure (BP), heart rate (HR), respiration rate (RR), and temperature. At Visit 2, BP, HR,
RR, and pulse oximetry are recorded before and at 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3 and 4 hours after the first
test dose. After 132 subjects have completed the Comparative Phase, for all new test dosed subjects, BP, HR, RR, and
pulse oximetry will be recorded before and at 5, 10, 15, 20, 30, 45 minutes and 1 hour after the first test dose. Temperature
will be measured only at the pre-dose time point.
[v] Caregiver counts the number of breaths taken by the subject during a 30-second interval. At Visit 2, caregivers will
measure respiration rate before and at 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3 and 4 hours after the first test dose.
After 132 subjects have completed the Comparative Phase, for all new test dosed subjects, caregivers will measure
respiration rate before and at 5, 10, 15, 20, 30, 45 minutes and 1 hour after the first test dose. On the day of treatment,
caregivers will measure respiration rate at approximately 15 and 30 minutes and 1, 2, and 4 hours after study drug
administration (see Section 6.2.2.3).
[w] Baseline/Screening version of the C-SSRS is administered at Visit 1. The Since Last Visit version is administered at
Visits 2, 3 and 4/ET.
[x] 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.
[y] Caregiver will 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.
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[z] After Visit 3, telephone follow-up calls with the subject, subject’s LAR, or subject’s caregiver are to occur monthly
until Visit 4 or ET.
Abbreviations: BP = blood pressure; ECG = electrocardiogram; ET = early termination; FSH = follicle stimulating
hormone; HR = heart rate; IRT = Interactive Response Technology System; LAR = legally acceptable representative;
OAA/S = Observer’s Assessment of Alertness/Sedation; PMP = patient management plan; QOL = quality of life; RR =
respiration rate
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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:
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
LIST OF TABLES .......................................................................................................... 18
LIST OF ABBREVIATIONS ......................................................................................... 20
1
INTRODUCTION ........................................................................................... 22
1.1
Background Information ......................................................................... 22
1.2
Non-Clinical Information......................................................................... 24
1.3
Clinical Studies......................................................................................... 25
1.3.1
Results of Completed Studies................................................................. 29
2
STUDY OBJECTIVES.................................................................................... 32
2.1
Efficacy Objectives................................................................................... 32
2.1.1
Primary Efficacy Objective .................................................................... 32
2.1.2
Secondary Efficacy Objectives ............................................................... 33
2.1.3
Exploratory Efficacy Objectives............................................................. 33
2.2
Safety Objective........................................................................................ 33
2.3
Pharmacokinetic Objective...................................................................... 34
3
DESCRIPTION OF STUDY ........................................................................... 34
3.1
Overview................................................................................................... 34
3.2
Screening .................................................................................................. 36
3.3
Test-Dose Phase........................................................................................ 36
3.4
Comparative Phase .................................................................................. 37
4
RATIONALE................................................................................................... 39
4.1
Rationale for the Study ............................................................................ 39
4.2
Rationale for the Study Design ................................................................ 39
4.3
Rationale for Dosing Regimen ................................................................. 40
5
SUBJECT SELECTION.................................................................................. 42
5.1
Number of Subjects Required.................................................................. 42
5.2
Inclusion Criteria ..................................................................................... 42
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5.3
Exclusion Criteria .................................................................................... 45
5.4
Informed Consent..................................................................................... 48
5.5
Authorization to Use and Disclose Medical Information........................ 50
6
STUDY METHODOLOGY ............................................................................ 51
6.1
Study Procedures ..................................................................................... 51
6.1.1
Visit 1 (Screening Visit)......................................................................... 51
6.1.2
Visit 2 (Test-Dose)................................................................................. 53
6.1.3
DSMB Assessment (After 25 Subjects Complete Visit 2)....................... 56
6.1.4
Visit 3 (Randomization) ......................................................................... 57
6.1.5
Treatment............................................................................................... 58
6.1.6
Visit 4 (Post-Dose Assessment or Early Termination) ............................ 61
6.1.7
Dosing Instructions ................................................................................ 63
6.2
Methods of Assessment ............................................................................ 64
6.2.1
Efficacy Assessments............................................................................. 64
6.2.2
Safety Assessments ................................................................................ 64
6.2.3
Pharmacokinetic Assessments ................................................................ 71
6.2.4
Treatment Compliance ........................................................................... 72
6.2.5
Subject and Caregiver Outcome Assessments......................................... 72
6.3
Prior and Concomitant Therapy ............................................................. 73
6.3.1
Permitted Medications............................................................................ 73
6.3.2
Prohibited Medications........................................................................... 74
6.3.3
Use of Benzodiazepines.......................................................................... 74
6.4
Restrictions during the Study .................................................................. 75
6.4.1
Activity Restrictions............................................................................... 75
6.4.2
Food and Fluid Intake............................................................................. 75
6.5
Subject Withdrawal or Discontinuation.................................................. 75
6.6
Treating Overdose.................................................................................... 77
6.7
Pregnancy ................................................................................................. 78
7
ADVERSE EVENT MANAGEMENT............................................................ 78
7.1
Definitions:  Adverse Events and Serious Adverse Events ..................... 78
7.2
Reporting of Adverse Events and Serious Adverse Events .................... 82
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7.3
Clinical Laboratory Abnormalities and Other Abnormal Assessments 85
8
RANDOMIZATION AND BLINDING METHODS ..................................... 85
8.1
Randomization ......................................................................................... 85
8.2
Blinding..................................................................................................... 86
9
MATERIALS AND SUPPLIES ...................................................................... 87
9.1
Study Drug ............................................................................................... 87
9.1.1
Controlled Substance Documentation..................................................... 87
9.2
Study Drug Labeling................................................................................ 87
9.3
Additional Study Supplies........................................................................ 88
9.3.1
Patient Management Plan ....................................................................... 88
9.3.2
Subject Workbook.................................................................................. 89
9.3.3
Caregiver Training Materials.................................................................. 91
9.4
Study Drug Inventory and Storage.......................................................... 92
9.4.1
Drug Storage at Research Centers........................................................... 93
9.4.2
Dispensing of Study Drug ...................................................................... 93
9.4.3
Return or Destruction of Study Drug ...................................................... 94
10
DATA ANALYSIS AND STATISTICAL PROCEDURES ........................... 94
10.1
Populations for Analysis .......................................................................... 95
10.2
Disposition, Demographics, and Other Baseline Characteristics........... 95
10.3
Medical and Surgical History .................................................................. 96
10.4
Prior and Concomitant Medications ....................................................... 96
10.5
Efficacy Analyses...................................................................................... 96
10.5.1 Primary Efficacy Endpoint and Analysis ................................................ 97
10.5.2 Secondary Efficacy Endpoints and Analyses .......................................... 98
10.5.3 Exploratory Efficacy Variables and Analyses ......................................... 99
10.5.4 Safety Analyses.................................................................................... 100
10.5.5 Data and Safety Monitoring Board ....................................................... 103
10.6
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses. 103
10.6.1 Pharmacokinetic Variables and Analyses.............................................. 103
10.6.2 Pharmacokinetic/Pharmacodynamic Variables and Analyses................ 104
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10.7
Sample Size Justification........................................................................ 104
10.8
Interim Analyses for Success ................................................................. 106
10.9
Interim Analyses for Futility.................................................................. 106
11
ADMINISTRATIVE PROCEDURES .......................................................... 107
11.1
Regulatory Approval.............................................................................. 107
11.2
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval....................................................................................... 107
11.3
Study Personnel...................................................................................... 108
11.4
Ongoing Information for Independent Ethics Committee.................... 108
11.5
Completion of Electronic Case Report Forms ...................................... 108
11.6
Study Monitoring ................................................................................... 109
11.6.1 Data and Safety Monitoring Board ....................................................... 110
11.7
Quality Assurance Procedures............................................................... 111
11.7.1 Access to Source Documentation.......................................................... 111
11.7.2 Auditing Procedures............................................................................. 112
11.8
USL Policy on Fraud in Clinical Studies............................................... 112
11.9
Use of Information and Publication....................................................... 112
11.10
Amendment to Protocol ......................................................................... 113
11.11
Deviations from Protocol ....................................................................... 113
11.12
Records of Study .................................................................................... 114
11.13
Completion of Study............................................................................... 115
11.14
Study Funding........................................................................................ 115
11.15
Financial Disclosure ............................................................................... 115
12
REFERENCE LIST....................................................................................... 116
APPENDIX 1
PROHIBITED CONCOMITANT SUBSTANCES........................... 120
APPENDIX 2
MIDAZOLAM INJECTION, USP, PACKAGE INSERT 
(HOSPIRA)
............................................................................................................. 124
APPENDIX 3
AMENDMENT 4................................................................................ 144
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PROTOCOL SIGNATURE PAGE .............................................................................. 158
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LIST OF TABLES
Table 1.   Procedure Schedule........................................................................................... 9
Table 2.   USL261 Animal Toxicity Studies.................................................................... 24
Table 3.  Summary of Completed and Ongoing Clinical Studies with USL261............ 26
Table 4.   Clinical Laboratory Tests ............................................................................... 69
Table 5.   Serious Adverse Event Reporting Requirements........................................... 84
Table 6.   Well Controlled Trials Reported in the Literature...................................... 105
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LIST OF FIGURES
Figure 1.   Study Design .................................................................................................. 36
Figure 2.   Flow of Informed Consent............................................................................. 50
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LIST OF ABBREVIATIONS
Abbreviation
Definition
ACLS
Advanced Cardiac Life Support
AE
Adverse Event
AED
Antiepileptic drug
ALT
Alanine aminotransferase (same as SGPT)
AST
Aspartate aminotransferase (same as SGOT)
AUC0-t
Area under the plasma concentration-time curve from time 0 to time of 
last measureable concentration
AUC0-∞
Area under the plasma concentration-time
curve from time 0 
extrapolated to infinity
-hCG
Beta-human chorionic gonadotropin
bid
Twice daily dosing
BLQ
Below lower limit of quantification
BP
Blood pressure
bpm
Beats per minute
B-SIT
Brief Smell Identification Test
CFR
Code of Federal Regulations
CI
Confidence interval
Cmax
Maximum plasma concentration
CPR
Cardiopulmonary resuscitation
CRO
Clinical research organization
DBP
Diastolic blood pressure
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
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
GLP
Good Laboratory Practice
HR
Heart rate
ICH
International Conference on Harmonization 
ICF
Informed consent form
IEC
Independent ethics committee
IM
Intramuscular 
IN
Intranasal 
Inc
Incorporated
IND
Investigational new drug
IRB
Institutional Review Board
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Abbreviation
Definition
ITI
Ikano Therapeutics, Inc., study initiator
IV 
Intravenous 
IRT
Interactive Response Technology System
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intent-to-treat 
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
PR
Rectal
RR
Respiratory rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Standard deviation
SOC
System organ class
TEAE
Treatment-emergent adverse event
Tlag
Time before the first measurable plasma concentration
Tmax
Time to reach the maximum plasma concentration
T1/2
Terminal half-life
US
United States
USL
Upsher-Smith Laboratories, Inc., study sponsor
USL261
Intranasal midazolam, study drug (formally ITI-111)
USP
United States Pharmacopeia
VNS
Vagal nerve stimulator
WBC
White blood cell 
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1
INTRODUCTION
1.1
Background Information
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]
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 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.[6] The development of an easily administered 
outpatient treatment of seizure clusters may reduce emergency medical intervention and 
decrease seizure cluster duration. While rectal diazepam gel (Diastat®, Valeant 
Pharmaceuticals International) is currently available in the United States (US), a portion of 
the population does not respond adequately to this treatment, and/or for some, the rectal 
route of administration is inappropriate or unacceptable.[7] As such, a treatment that is 
effective in interrupting seizure activity, has a rapid onset of action, and is easily 
administered in the outpatient setting is currently an unmet medical need.
Midazolam is a benzodiazepine with potent inhibitory activity at the GABA-A receptor and 
demonstrates anticonvulsant properties.[8] In adults, midazolam is usually administered via 
IV or intramuscularly (IM) at doses of 1 mg to10 mg; pediatric patients are dosed by weight 
(mg/kg) and usually require higher doses than adults.[9] Like other benzodiazepines,
midazolam administration may cause sedation, anxiolysis, and amnesia.[10, 11] Sedative 
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effects usually occur within 5 minutes of IV administration and within 15 minutes of 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 IN midazolam was originally described in the late 
1980s,[10] and over the past 15 years, approximately 20 publications have described it as a 
safe and efficacious treatment for seizure control in a variety of populations, including adult 
and pediatric.[7, 10, 13-31] Publications such as these demonstrate the desire of patients, 
caregivers, and physicians to have this type of product available for acute intermittent 
treatment of seizure clusters. Furthermore, use of IN midazolam for treatment of seizures 
has been advocated by numerous 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 mg/mL) approved for IV delivery 
administered IN with a needleless 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 Food and Drug Administration (FDA). In fact, the volume of midazolam 
sterile injection solution usually ranges from 1 ml-2 mL,[11] which exceeds the 
recommended volume for optimal IN delivery (≤200 μL).[34] Despite the sub-optimal 
formulation and delivery system, IN delivery of midazolam sterile injection solution has 
been very effective in some 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
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 of
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USL261 delivers adequate drug concentrations in a small volume (100 μL), and preliminary 
human studies show positive pharmacokinetic (PK) and bioavailability properties with good 
safety and tolerability. The present study is designed to establish the efficacy and safety of 
USL261 for the outpatient treatment of seizure clusters.
1.2
Non-Clinical 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).
Table 2.  USL261 Animal Toxicity Studies
Study
Species 
and 
Duration
n[a]
Doses
mg/day
Sex
Daily Dose
(NOAEL)
Cmax
ng/ml [b]
AUC
ng*h/L
[c]
mg/
day
mg/kg/
day
WIL-
637002
Rat –
14 Days
10-15
0, 1, 3, 6
M
6
16.7
1473
330
F
6
24.5
1747
832
WIL-
637001
Dog – 14 
Days
4-6
0, 10, 15, 
30
M
30
3.3
1226
519
F
30
4.3
1915
724
WIL-
637003
Dog – 90 
Days
4-6
0, 20, 30, 
60 [d]
M
60
4.9
Daily dose 1: 814
914
Daily dose 2: 749
F
60
6.5
Daily dose 1: 770
803
Daily dose 2: 918
Experimur 
10-610
Rat –
6 Months 
(3-month 
interim 
sacrifice)
20
(10 for the 
3-month
group)
0, 1, 3, 6 
[d]
M
6
19
235
126
F
6
10
363
270
Abbreviations: AUC, area under the curve; Cmax, maximum plasma concentration; NOAEL, no-observable-adverse-effect 
level.
[a]Number of animals/sex/group varied by treatment.
[b] Cmax at Day 13 is presented for WIL-637002 and WIL-637001; Cmax at Day 88 is presented for WIL-637003
[c] AUClast at Day 13 is presented for WIL-637002 and WIL-637001; Total AUC0-24 at Day 88 is presented for WIL-637003
[d] Dosing for WIL-637003 and Experimur 10-610 was twice daily
USL261 was well tolerated after IN administration to rats (14-day and 6-month dosing) and 
dogs (14- and 90-day dosing). Acute transient hypoactivity, impaired equilibrium, partial 
closure of one or both eyes, swaying, and/or transient ataxia (e.g., impaired equilibrium) 
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occurred shortly after dosing in most midazolam-treated groups, and these observations are 
consistent with the known pharmacological properties of midazolam.
No significant effects on the nasal cavity were observed, and the no-observable-adverse-
effect levels (NOAEL) were the maximum doses that could be administered based on 
midazolam solubility and the maximum volumes that could be ethically administered IN to 
the animals. The safety of systemic exposure of midazolam has been established via a 
complete set of animal studies as well as clinical experience with midazolam since its 
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 10-160).  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.
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.
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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Table 3.  Summary of Completed and Ongoing Clinical Studies with USL261
Protocol 
No.
Objective(s) of the 
Study
Study Design and 
Type of Control
Test Product(s); Dosage 
regimen; Route of 
Administration
Number of 
Subjects; 
Age Range
Type of 
Subjects
Duration of 
Study
PD and Safety 
Assessments
Completed Studies
MZ0714
Evaluate BA, PK, and 
safety of single doses 
of USL261; Compare 
PK and PD of 
USL261, midazolam 
IV infusion, and 
midazolam IV 
administered IN via 
needleless syringe. 
Open-Label, 
Five-Way 
Crossover, 
Randomized 
Subjects received 5 different 
MZ treatments in random 
sequence:  2.5, 5.0, or 7.5 mg 
USL261; 2.5 mg IV MZ 
infused over 15 min; and 5.0 
mg MZ (from IV 
formulation) administered IN 
via a needleless syringe 
25 Subjects
18 – 45 y
Healthy 
human 
volunteers
5 visits in 
approximately 
5-6 weeks,
preceded by a
screen visit
(-1 to -21
days)
SSS, DSST, 
OAA/S, 
physical exam, 
nasal exam,
vital signs, 
TEAEs, oxygen 
saturation, 
subject sensory 
perception
MZ0815
Determine the safety, 
tolerability, PK and 
PD of ascending 
single- and two-dose 
regimens of USL261 
Open-Label 
Subjects received IN USL261 
at 2 visits. At Visit 1 they 
received a single dose; at 
Visit 2 they received 2 doses 
separated by 15 minutes. 
A: 2.5 mg/2.5 mg+2.5 mg
B:5.0 mg /5.0 mg +2.5 mg
C: 5.0 mg /5.0 mg +5.0 mg
D. 7.5 mg /7.5 mg +5.0 mg
E: 7.5 mg /7.5 mg +7.5 mg
An overall 
total of 90 
subjects (60 
adults 18-65 
y; 30 
adolescents 
12-17 y)
Subjects 
with 
epilepsy 
taking 
stable 
doses of 
AEDs
4 visits for a 
total study 
duration of 
approximately 
1 ½ to 6 
weeks for 
each subject
SSS, DSST, 
OAA/S, 
physical 
(including nasal) 
and neurological 
exams, vital 
signs, TEAEs, 
oxygen 
saturation, 
subject sensory 
perception
P261-201
Evaluate the safety, 
tolerability, PK, and 
PD of ascending 
single- and two-dose 
regimens of USL261 
compared with that of 
placebo 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Dose Escalation 
Subjects received a single 10, 
15, 17.5, or 20 mg dose of IN 
USL261 or placebo, followed 
≥3 days later by the same 
total dose or placebo, 
administered as 2 divided 
doses 10 minutes apart. Four 
dose cohorts were completed 
in ascending order, and dose 
60 adult 
subjects;
18 – 65 y
Subjects 
with 
epilepsy 
taking 
stable 
doses of 
AEDs
4 visits 
(screening, 2 
evaluation 
visits, and 
follow-up) 
over a 7 to 58 
day time 
frame 
TEAEs, vital 
signs, oxygen 
saturation; SSS, 
OAA/S, and 
Coding subtest 
of Wechsler 
Adult 
Intelligence 
Scale-IV 
(WAIS-IV)
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Protocol 
No.
Objective(s) of the 
Study
Study Design and 
Type of Control
Test Product(s); Dosage 
regimen; Route of 
Administration
Number of 
Subjects; 
Age Range
Type of 
Subjects
Duration of 
Study
PD and Safety 
Assessments
escalation occurred only after 
review of safety data.
P261-102
Evaluate the safety, 
tolerability, PK and 
PD of USL261 in 
geriatric and non-
geriatric subjects
Randomized, 
Investigator and 
subject blind, 
Sponsor open
Subjects were randomized to 
receive a single dose of 2.5 
and 5.0 mg USL261 at 2 
study visits in a crossover 
fashion.
A total of 30 
subjects (12 
adult 18-40 y; 
18 geriatrics 
≥65 y)
Generally 
healthy 
geriatric 
and non-
geriatric 
subjects.
4 visits 
(screening, 2 
evaluation 
visits, and 
follow-up) 
over a 9 to 50 
day time 
frame 
TEAEs, vital 
signs, oxygen 
saturation; SSS, 
OAA/S, and 
DSST
Ongoing Studies
P261-401
Evaluate the efficacy, 
safety, and 
tolerability of 
USL261 compared 
with IN placebo for 
the outpatient 
treatment of seizure 
clusters; Evaluate the 
PK profile of USL261 
after administration of 
10 mg open-label 
USL261 (2 single, 
5 mg test doses 
administered 10 min 
apart)
Randomized, 
Double-Blind, 
Placebo-Controlled 
Test-Dose Phase:  2 doses of 
open-label 5.0 mg IN 
USL261 administered 
10 minutes apart.
Comparative Phase: subjects 
are randomized 2:1 to receive 
5.0 mg IN USL261 or 
placebo to be administered 
during a seizure cluster event, 
with the possibility of 
administration of an open-
label 5.0 mg IN USL261 dose 
10 min to 6 hrs after the 
double-blind dose.
Planned: a 
maximum of 
approximately 
240
subjects; 
≥12y
Subjects 
with 
epilepsy 
who have 
seizure 
clusters
A test-dose 
phase of up to 
28 days,
followed by a 
comparative 
phase which 
will be 
variable, 
dependent on 
when the 
subject 
experiences a 
seizure cluster
OAA/S, C-
SSRS, physical 
and neurological 
exam, vital 
signs, TEAEs, 
clinical 
laboratory 
evaluations, 
ECG, pulse 
oximetry, and 
need for 2nd 
dose or 
emergency 
treatment
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Protocol 
No.
Objective(s) of the 
Study
Study Design and 
Type of Control
Test Product(s); Dosage 
regimen; Route of 
Administration
Number of 
Subjects; 
Age Range
Type of 
Subjects
Duration of 
Study
PD and Safety 
Assessments
P261-301
Evaluate the efficacy, 
safety, and 
tolerability of 
USL261 compared 
with IN placebo for 
the treatment of 
intermittent bouts of 
increased seizure 
activity in subjects 
admitted to the EMU
Randomized, 
Double-Blind, 
Placebo-Controlled 
Eligible subjects will be 
randomized 1:1 to receive 5.0 
mg IN USL261 or placebo.  
Planned: 
approximately 
62 subjects; 
≥12 y
Subjects 
with 
epilepsy 
admitted 
to the 
EMU who 
present 
seizure 
activity 
that meets 
defined 
Treatment 
Criteria
Screening 
may occur at 
EMU 
admission or 
up to 28 days
prior; 
Treatment 
may occur 
any time 
during EMU 
admission 
with 
monitoring 
for up to 6 hrs 
post-dose; 
Exit 
Assessment 
may occur up 
to 48 hrs after 
treatment
TEAEs, clinical 
laboratory 
evaluations, 
vital signs, 
ECGs (screening 
only), physical, 
nasal, and 
neurological 
exams, C-SSRS
AED indicates anti-epileptic drugs; BA, bioavailability; C-SSRS, Columbia-Suicide Severity Rating Scale; DSST, Digit Symbol Substitution Test; ECG, electrocardiogram; EMU, 
epilepsy monitoring unit; IN,  intranasal; IV, intravenous; MZ, midazolam; OAA/S, Observer’s Assessment of Alertness/Sedation; PD, pharmacodynamic; PK, pharmacokinetic; 
SSS, Stanford Sleepiness Scale; TEAE, treatment-emergent adverse event.
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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 
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majority of TEAEs (95.7%) were considered related to study drug.  No serious adverse 
events (SAEs) or 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; 
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however, the event was transient and not associated with sedation, hypoventilation, or 
changes in vital signs.
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 
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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.  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. 
2
STUDY OBJECTIVES
2.1
Efficacy Objectives
2.1.1
Primary Efficacy Objective
To evaluate the efficacy of USL261 compared with that of IN placebo for the outpatient 
treatment of seizure clusters based on Treatment Success, which is defined as achieving
both of the following:
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
Termination of seizure(s) within 10 minutes after study drug administration, and

No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6
hours after study drug administration
2.1.2
Secondary Efficacy Objectives
To evaluate the efficacy of USL261 compared with that of IN placebo for the outpatient 
treatment of seizure clusters using the following: 

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
2.1.3
Exploratory Efficacy Objectives
To evaluate the efficacy of USL261 for the outpatient treatment of seizure clusters using the 
following:

Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study
drug administration to 24 hours after study drug administration

Time to return to full baseline functionality (as determined by the caregiver)

Analyses for subjects receiving 2 doses of USL261 (see Section 10.5.3.1)

Subject and caregiver outcome assessments
2.2
Safety Objective
To evaluate the safety and tolerability of USL261 for the treatment of seizure clusters using 
the following assessments:

AEs

Caregiver-recorded respiration rate at 15 minutes, 30 minutes, 1 hour, 2 hours and 4
hours after study drug administration in the Comparative Phase

Clinical laboratory tests
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
Vital sign measurements (systolic and diastolic BP, HR, RR and temperature) as
recorded by the study center personnel

Physical, nasal and neurological examinations

Brief Smell Identification Test (B-SIT)

Columbia-Suicide Severity Rating Scale (C-SSRS)

Requirement for unscheduled ER or EMS visit within 24 hours after study drug
administration
2.3
Pharmacokinetic Objective
To evaluate the PK profile of USL261 after administration of USL261 using the following 
PK parameters:
•
AUC0-t – the area under the plasma concentration-time curve from time 0 to last
measurable concentration estimated by the linear trapezoidal method
•
AUC0-∞ – the AUC from time zero extrapolated to infinity
•
Cmax – the maximum plasma concentration
•
tmax – the time to maximum plasma concentration
•
t1/2 – the terminal elimination half-life
•
λz – the terminal elimination rate constant
•
tlag – the time before the first measurable plasma concentration
•
CL/F – apparent clearance
•
Vβ/F – volume of distribution
3
DESCRIPTION OF STUDY
3.1
Overview
This is a phase III multicenter study, with 2 distinct phases and 4 study center visits as 
depicted in Figure 1. The first phase is the Test-Dose Phase where subjects will receive 2
doses of open-label 5.0 mg USL261 administered 10 minutes apart at the study center. The 
Test-Dose Phase is designed to assess the safety, tolerability, and PK of USL261 in a 
monitored setting and provide the caregivers with training on the study procedures. 
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The Test-Dose Phase will be followed by the Comparative Phase, an outpatient, double-
blind, placebo-controlled, parallel-group phase. In the Comparative Phase, all subjects will 
be randomized 2:1 to receive 5.0 mg USL261 or placebo. During the Comparative Phase, 
the subject’s caregiver will administer the double-blind study drug when the subject 
experiences a seizure cluster that meets the study criteria, as described in the subject’s 
individualized Patient Management Plan (PMP). If the treated seizure cluster 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 < 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 double-blind dose of study medication may be 
followed by a single dose of 5.0 mg USL261. Any time between 24 to 120 hours after study 
drug administration, subjects and caregivers will return to the study center for a post-dose 
study visit (Visit 4). 
After Visit 3, the study coordinator or designee will call the caregiver or subject at least once 
each month until the subject has completed Visit 4 or has prematurely discontinued from the 
study.
After Visit 4, the subject will have completed the study and will be considered for 
enrollment in an open-label extension study, if one is offered at that time.
A maximum of approximately 350 subjects, aged 12 years or older, with a documented 
history of seizure clusters and on a stable AED regimen (no change in type[s] of drug) will 
be enrolled in the Test-Dose Phase. Before any subject continues to the Comparative Phase, 
safety data from at least 25 subjects in the Test-Dose Phase will be reviewed by an 
independent Data and Safety Monitoring Board (DSMB). Enrollment will temporarily halt 
once approximately 25 subjects complete the Test-Dose Phase, to allow the DSMB to 
review the safety data. If the safety data from this initial cohort supports continuation of the 
trial according to the DSMB, enrollment into the Test-Dose Phase will resume and the 
initial 25 subjects will proceed to the Comparative Phase. All subsequent subjects will 
progress directly from Test-Dose Phase to the Comparative Phase.
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Figure 1.   Study Design 
3.2
Screening
After subjects and caregivers have provided informed consent (and assent, where 
appropriate), subjects will undergo screening procedures at Visit 1 (see Table 1, Procedure 
Schedule). At Visit 1, training will be provided to the caregivers for self-study, which will 
be completed at or before Visit 2 (see Section 9.3.3). The screening period (time between 
Visit 1 and 2) will be a maximum of 28 days. The screening period may be extended in 
certain cases; however, the extension of the screening period must be approved by the 
Sponsor or CRO designee. If a screening period extension is granted for a given subject, that 
subject will have to undergo repeat screening laboratory and ECG assessments within 28 
days before Visit 2.
3.3
Test-Dose Phase
The Test-Dose Phase, which occurs at Visit 2, will take place at the study center under the 
supervision of the study investigator within 28 days of Visit 1. The investigator, or other 
qualified study personnel, will review, assess, and (if needed) re-instruct subjects and 
caregivers on the information provided in the self-study training (see Section 9.3.3). 
Caregivers must pass the CPR exam and demonstrate airway management techniques before 
subjects are given a test dose. 
Subjects who meet eligibility criteria at Visit 2 will receive a test dose of 5.0 mg USL261 
administered by a member of the study center personnel followed by a second dose of 5.0 
mg USL261 10 minutes later administered by the caregiver under the supervision of study 
center personnel. Caregivers and study center personnel will monitor the subject during the 
observation period for at least 4 hours after the test doses are administered and the 
Visit 1
Screening
Visit 2
Test-Dose
Visit 3
Randomization
Seizure 
Cluster 
Treatment
Visit 4
Post-Dose 
Visit
24-120 hours
after dose
DSMB 
Review
1
st 25 subjects
Test-Dose Phase
Comparative Phase
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assessments outlined in Table 1 will be performed. After 132 subjects have completed the 
Comparative Phase, for all new test dosed subjects, caregivers and study center personnel 
will monitor the subject during the observation period for at least 1 hour after test dose 
administration. A subject who experiences signs or symptoms at Visit 2 that are concerning 
in the investigator’s judgment or are exclusionary per exclusion criterion #22 must be 
monitored until resolved or longer as deemed appropriate by the investigator.
At least one person who is trained and qualified to perform airway assessment and 
management, including endotracheal intubation (or local country/site equivalent) and 
Advanced Cardiac Life Support (ACLS) (or local country/site equivalent), will be available 
at the site for the entire observation period following the administration of the first test dose.
3.4
Comparative Phase
Subjects and caregivers will return to the study center for Visit 3 within 24 hours to 28 days 
of Visit 2 (unless DSMB review is not yet completed). The time between Visit 2 and Visit 3 
may be extended in certain cases; however, the extension must be approved by the Sponsor 
or CRO designee. At Visit 3, the investigator, or other qualified study personnel, will 
review, assess, and (if needed) re-instruct caregivers on the information provided in the self-
study training. Before subjects are randomized, caregivers must have demonstrated hands-
on competence in administering the study drug, performing timed respiration rate 
measurements and recording them in the practice Subject Worksheet, as well as demonstrate 
airway management techniques (see Section 9.3.3).
If the subject continues to meet eligibility criteria at Visit 3, he/she will be randomized to 
receive either USL261 5-mg or placebo. Caregivers will receive a study materials kit, 
which includes the Subject Workbook, the subject’s PMP, and the study drug kit. The PMP 
will specify the criteria for seizure cluster recognition, the procedure for contacting the 
central study nurse hotline after study drug administration, the requirements for 
administering a second dose of study drug (USL261), and a rescue protocol individualized 
for the subject. 
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During the Comparative Phase, caregivers will administer the double-blind study 
medication at the time of recognition of a seizure cluster that meets study criteria (according 
to the subject’s individualized PMP) and call the central study nurse hotline as soon as 
possible following study drug administration. If the treated seizure cluster has not 
terminated within 10 minutes after the initial drug administration OR another seizure occurs 
between10 minutes and 6 hours after administration of the study drug, AND the subject 
does not have < 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 second dose of study drug (i.e., 5.0 mg dose of 
USL261) may be administered. If the second dose of study drug (i.e., 5.0 mg dose of 
USL261) is administered, the caregiver will again call the central study nurse hotline as 
soon as possible after its administration. The caregiver will monitor the subject after study 
drug administration to record safety and efficacy measurements (see Section 6.1.4). 
If the subject encounters persistent seizure cluster activity or seizure recurrence (as defined 
in the subject’s PMP), has less than 8 breaths per minute, or is excessively and 
uncharacteristically sedated, caregivers will follow the rescue protocol in the subject’s PMP. 
The subject’s rescue protocol will outline rescue instructions individualized for the subject, 
including when and how to contact EMS (or local equivalent).
Subjects and caregivers will return to the study center 24 to 120 hours after study drug 
administration for Visit 4. Subjects who are prematurely discontinued from study 
participation or terminate their participation should return to the study center for Visit 4 
(Early Termination). The subject or caregiver will 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 (Visit 4 [Post-
Dose Assessment or ET]) or 7 days after last administration of study drug , whichever is 
later. The subject or caregiver may also call the central study nurse hotline at any time 
during the study for help or advice regarding study procedures.
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This study will be conducted in accordance with International Conference on Harmonization 
(ICH) E6, Guidelines 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 and 56 concerning informed consent and 
Institutional Review Board [IRB] regulations, respectively).
4
RATIONALE
4.1
Rationale for the Study
Although a substantial number of AEDs are currently marketed, a significant unmet need 
still exists in the treatment of epilepsy.  Current AED therapies do not adequately control 
seizures (ie, seizure-freedom) in as many as 30% of epilepsy patients.[37, 38] Breakthrough 
seizures can occur in subjects with previously controlled epilepsy and may result from 
problems with treatment compliance (e.g., forgetting to take medication) or waning efficacy 
of current regimen. This study seeks to evaluate the treatment success rate and safety of 
USL261 compared with IN placebo for the outpatient treatment of seizure clusters in 
subjects with partial or generalized epilepsy with a documented history of seizure clusters 
on a stable regimen of antiepilepsy treatment(s).
4.2
Rationale for the Study Design
The Test-Dose Phase was included to assess the safety, tolerability, and PK of USL261 in a 
monitored setting before subjects receive it as an outpatient during a seizure cluster. It will 
also allow study center personnel to effectively train the caregivers on study procedures, 
including study drug administration.  
The Comparative Phase, consisting of a double-blind dose followed by a second dose of 
study drug (i.e., 5.0 mg dose of USL261), which is administered only if the subject 
experiences treatment failure, was designed to study the efficacy of 5.0 mg USL261 versus 
placebo, while allowing for the possibility that some subjects may require a higher dose to 
terminate the seizure cluster. Since caregivers and subjects will be aware that the second 
dose is active, there may be a “progression bias” prompting some to declare treatment 
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failure and administer the second dose. To reduce this possibility, and to increase the safety 
exposure in this study, subjects will be randomized 2:1, USL261:placebo.
The duration of each subject’s participation will be determined by the frequency of observed 
seizure events. Assuming an average of 3 seizure clusters per year, approximately half of the 
study subjects will complete the study within ~4 months after randomization to treatment.
Subjects may remain in the Comparative Phase for up to 6 months. Any subject who has not 
treated a seizure cluster meeting the study criteria within 6 months of Visit 3 (Randomization) 
will be discontinued from the study.
4.3
Rationale for Dosing Regimen
The 5.0 mg dose of USL261 used for this phase III trial is based on safety data reported in 2 
ITI-sponsored 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 min 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, the
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 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 patients diagnosed with epilepsy (MZ0815) who 
were taking concomitant medications, including AEDs known to induce CYP450 3A4. 
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 demonstrate that 0.1 to 0.3 mg/kg of IV-approved midazolam administered 
intranasally (5 mg to > 20 mg fixed-dose per subject) effectively terminates seizure activity 
in most subjects.[21, 25, 39] These doses have seldom caused excessive sedation or 
respiratory depression.[40]
The 5.0 mg midazolam dose proposed for the Comparative Phase of this study is expected to 
be safe and efficacious. The 10 mg dose of midazolam provided by USL261 is well within 
the range of doses correlated with efficacy and has been found to be safe. [18, 31]
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 GABA-A receptor binding characteristics of midazolam 
as well as the drug’s complex distribution and metabolism. Therefore, for subjects who do 
not respond by 10 minutes after administration of 5.0 mg USL261, a second 5.0 mg dose 
may be administered.
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5
SUBJECT SELECTION
5.1
Number of Subjects Required
A maximum of approximately 350 subjects are expected to be enrolled in the Test Dose 
Phase of the study in order to have a maximum of approximately 240 subjects who have 
completed the Comparative Phase.
5.2
Inclusion Criteria
A subject will be eligible for enrollment in the study if all of the following criteria apply:
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 IRB/Independent ethics committee (IEC) policy
2. Subject has a competent, adult (age ≥ 18) caregiver(s) who is able to recognize and
observe the subject’s seizure cluster episodes, 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 is not likely to conceive, as indicated by a “yes” answer to at least 1 of the
following questions:

Is the subject is a male?

Is the subject a postmenopausal female with greater than 1 year since last
menses and a follicular stimulating hormone value greater than 40 mIU/mL?

Is the subject a female who has written medical documentation of being
permanently sterilized (e.g., hysterectomy, double oophorectomy, bilateral
salpingectomy)?

Has the subject agreed to use two effective methods of contraception during
the entire study if she is sexually active or becomes sexually active during
the study (Except where local law or regulation differs; approval by USL or
designee is required in such cases)?
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Examples of two effective methods of contraception include the following:
o
A diaphragm and a condom with spermicide,
o
An intrauterine device (IUD) used in combination with a barrier
method (e.g. condom, diaphragm, or cervical cap with spermicide),
o
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. Subject has an established diagnosis of partial or generalized epilepsy that includes
all of the following:

A documented history of seizure clusters lasting a minimum of 10 minutes
from the time the seizure cluster is recognized

The 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

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

In the investigator’s opinion, it would be safe for the subject to receive
placebo as a first dose of study drug followed by active treatment (USL261)
as the second dose of study drug no earlier than 10 minutes after the first
dose

The subject’s stereotyped seizure cluster pattern is composed of multiple (≥
2) partial or generalized seizures

The subject’s stereotyped seizure cluster pattern was established > 3 months
before Visit 1

A frequency of ≥3 stereotyped seizure clusters during the year before Visit 1

At least 1 stereotyped seizure cluster occurring ≤ 4 months before Visit 1
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
The seizure cluster pattern described above is confirmed by a central
reviewer (see Section 9.3.1)
6. Subject is receiving a regimen of AED(s) that has been stable (i.e., no changes in the
type of AED) since Visit 1 and for ≥7 days before Visit 2. Changes in dose of an
AED are allowed during the study; however, the new dose level must be kept stable
for at least 7 days before the subject receives study drug. 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 and always at
the same dose. Daily use of a benzodiazepine as a chronic AED is not permitted.
7. Subject has had a documented brain computerized tomography or magnetic
resonance imaging review, performed after diagnosis of epilepsy and before Visit 1,
that confirms the absence of a progressive neurological disorder
8. Subject weight is 40 kg to 125 kg (inclusive)
9. Subject must have a screening (Visit 1) 12-lead electrocardiogram (ECG) that meets
the following criteria:

QTcF interval ≤450 msec for males and ≤470 msec for females

Consistent sinus rhythm as determined by the investigator

No left bundle branch block (LBBB)

No other clinically significant conduction disorders as determined by the
investigator
10. Subject must have screening (Visit 1) vital sign values that meet the following
criteria:

Systolic blood pressure of ≤ 160 mm Hg

Diastolic blood pressure of ≤ 90 mm Hg

Pulse rate of 50 to 115 bpm, inclusive

No clinically significant vital sign values as determined by the investigator
Note: At the discretion of the investigator, out-of-range BP or HR measurements 
may be repeated once, and the repeat measurement used in relation to this inclusion 
criterion.
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5.3
Exclusion Criteria
A subject will not be eligible for this study if any of the following criteria apply:
At Visit 1 (Screening)
1. Subject has a neurological disorder that is likely to progress in the next year
2. Subject has acute narrow-angle glaucoma
3. 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
4. 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
5. Subject has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit
1
6. Subject has suicidality, defined as any of the following: a) active suicidal plan/intent
or active suicidal thoughts in the 6 months before Visit 1 as defined by a Columbia-
Suicide Severity Rating Scale (C-SSRS) suicidal ideation score ≥ 3, b) any suicide
attempt in the past 5 years as determined by the C-SSRS or medical history, or c)
other clinically significant suicidality as determined by the investigator
7. Subject, in the investigator’s opinion, has met the criteria for a major depressive
episode at any time within 6 months before Visit 1 (criteria defined by the current
edition of the Diagnostic and Statistical Manual of Mental Disorders)
8. Subject has or has had psychosis in the 12 months before Visit 1, excluding postictal
psychosis
9. Subject   has  a  history of their stereotypical seizure cluster (for which they are
being enrolled in the study) progressing to status epilepticus (as determined by the
investigator) within the 2 years before Visit 1
10. Subject has a history of drug or alcohol abuse within 1 year before Visit 1
11. Subject has a positive pregnancy test at Visit 1 or is currently pregnant or
breastfeeding (females only)
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12. Subject has a history of allergy or any significant adverse reaction (including rash) to
midazolam
13. Subject is currently using an investigational drug or device or has used such within
30 days before Visit 1
14. Subject is currently using a vagal nerve stimulator (VNS) unless the device has been
implanted for at least 6 months and the settings have not changed within 4 weeks
before Visit 1
15. Subject has plasma phenobarbital concentrations > 35 μg/mL at Visit 1
(phenobarbital concentrations will be measured in subjects taking phenobarbital and
in subjects for which the investigator deems it necessary)
16. Subject has any clinically significant laboratory abnormality as determined by the
investigator and as confirmed by repeat testing (see Section 6.2.2.7.2), or has any of
the following laboratory abnormalities at Visit 1 as confirmed by repeat testing:

Alanine transaminase (ALT) and/or aspartate transaminase (AST) results > 2
times the upper limit of normal

White blood cell count (WBC) < 2.5x109/L

Sodium < 128 mEq/L

Creatinine > 2.0 mg/dL
17. Subject is not appropriate for the study for any other reason as determined by the
investigator
At Visit 2
18. Subject has developed a new medical condition, suffered a change in status of an
established medical condition, developed a laboratory abnormality, or required a
new treatment or medication which meets any previously described study exclusion
criteria
19. Subject has a positive pregnancy test (females only)
20. Subject has active suicidal plan/intent or suicidal thoughts as defined by a C-SSRS
suicidal ideation score ≥ 3 or has had a suicide attempt since the last visit
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21. Subject has consumed any clinically significant CYP450 3A inhibitor/inducer,
opioid, or other respiratory depressant (excluding antiepileptic drugs) within the
required washout period before Visit 2 (see Appendix 1)
22. Subject has any of the following during the observation period after administration
of the USL261 test dose at Visit 2:

Blood pressure (BP)
o
Systolic blood pressure (SBP) < 85 mm Hg and the change from baseline
(pre-dose evaluation) in SBP is deemed clinically significant by the
investigator
o
A ≥40 mm Hg decrease from baseline (pre-dose evaluation) in SBP
o
Diastolic blood pressure (DBP) < 50 mm Hg and the change from
baseline (pre-dose evaluation) in DBP is deemed clinically significant by
the investigator
o
A ≥30 mm Hg decrease from baseline (pre-dose evaluation) in DBP

Heart Rate (HR)
o
HR > 120 or < 50 bpm and change from baseline (pre-dose evaluation) in
HR is deemed clinically significant by the investigator
o
A ≥40 bpm change from baseline (pre-dose evaluation) in HR

Respiratory rate (RR)
o
RR > 24 breaths per minute and change from baseline (pre-dose
evaluation) in RR is deemed clinically significant by the investigator
o
RR < 8 breaths per minute while awake or after arousing

Sedation to the degree that the subject does not respond to mild prodding or
shaking

Oxygen saturation < 90% for > 30 seconds or requires oxygen at any time

Clinically-significant ECG findings as determined by the investigator
Note: At the discretion of the investigator, out-of-range BP or HR measurements 
may be repeated once, and the repeat measurement used in relation to exclusion 
criteria, as long as the rules outlined in Section 6.2.2.3 are followed.
At Visit 3
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23. Subject has developed a new medical condition, suffered a change in status of an
established medical condition, developed a laboratory abnormality, or required a
new treatment or medication which meets any previously described study exclusion
criteria
24. Subject has a positive pregnancy test
25. Subject has active suicidal plan/intent or suicidal thoughts as defined by a C-SSRS
suicidal ideation score ≥ 3 or has had a suicide attempt since the last visit
5.4
Informed Consent
Each prospective subject or the subject’s LAR will provide written informed consent before 
any 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.
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 
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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/EC policy. In these cases, the ICF will be signed by the subject’s LAR. The assent 
form will provide similar information as the informed consent form, and the same 
procedures will be followed as described above for the informed consent form. 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 informed consent 
form with the study protocol for IRB/IEC approval. All proposed informed consent forms 
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 only applies to study centers in the United 
States.
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 legally acceptable representative the purpose of the subject 
authorization and the disclosures agreed to by signing the authorization document. Subjects 
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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 LAR will voluntarily sign and date an authorization document.  Prior to 
participation in the study, the subject or 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 
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.
6.1.1
Visit 1 (Screening Visit)
Before any study procedure is performed, the subject (or subject’s LAR) will provide 
written informed consent (see Section 5.4). At Visit 1, subjects will undergo screening 
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assessments to determine if they are eligible to participate in the study according to the 
inclusion/exclusion criteria.  The following evaluations will be performed during Visit 1:
At Visit 1 (Screening)

Obtain informed consent of subject (or subject’s LAR) (see Section 5.4)

Obtain assent of subject, if applicable (see Section 5.4)

Obtain informed consent of caregiver(s) (see Section 5.4)

Register subject with Interactive Response Technology System (IRT)

Assessment of inclusion/exclusion criteria (see Section 5)

Provide training to caregiver for self-study (see Section 9.3.3)

Collect demographic information (e.g., date of birth, gender, ethnic origin, race)

Collect medical and surgical history, including current disease (see Section 6.2.2.1)

Collect prior and concomitant medication information (see Section 6.3)

Collect number of calls to EMS and ER visits for a seizure cluster or other seizure
emergency in the year prior to screening.

Complete physical, nasal, and neurological examinations (see Section 6.2.2.2)

Collect blood and urine samples for clinical laboratory testing (serum chemistry,
hematology, urinalysis and phenobarbital level [if necessary]) and FSH level
(females only); (see Section 6.2.2.7)

Collect blood sample for serum pregnancy test (all females) (see Section 6.2.2.7)

Collect urine sample for urine drug screen and blood sample for alcohol test (see
Section 6.2.2.7)

Begin preparation of PMP (see Section 9.3.1)

Submit PMP, including seizure cluster descriptions, to Central Reviewer (see
Section 9.3.1)

Perform 12-lead ECG (see Section 6.2.2.4)

Measure height and weight

Measure vital signs (BP, HR, RR, and temperature) (see Section 6.2.2.3)

Perform the Baseline/Screening C-SSRS (see Section 6.2.2.8)

Collect any adverse events occurring after written informed consent is obtained
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6.1.2
Visit 2 (Test-Dose)
Once initial eligibility is confirmed but no later than 28 days from Visit 1, subjects and 
caregivers will enter the Test-Dose Phase to assess the safety, tolerability, and PK of
USL261 and provide the caregivers training on study procedures, including study drug 
administration.  All caregivers must be present at Visit 2 for this training, except for new 
caregivers who are assigned after Visit 2. At least 1 person who is trained and qualified to 
perform airway assessment and management, including endotracheal intubation (or local 
country/site equivalent) and ACLS (or local country/site equivalent), must be available at 
the site for the entire observation period. Prior to 132 subjects completing the Comparative 
Phase the observation period will be at least 4 hours following test dose administration.
After 132 subjects have completed the Comparative Phase, for all new test dosed subjects, 
the observation period will be defined as at least 1 hour following test dose administration.
6.1.2.1
Before Administration of Test Dose at Visit 2
The investigator or other qualified study center personnel will perform the following before 
administration of the USL261 test dose at Visit 2:

Review of inclusion/exclusion criteria (see Section 5)

Caregiver training (see Section 9.3.3)
o
Review, assess, and re-instruct (when needed) caregivers on the information
provided in the self-study training
o
Ensure caregiver has passed the CPR exam and can demonstrate the correct
technique for airway management (including neck extension, chin lift, and jaw
thrust maneuvers)

Collect concomitant medication information (see Section 6.3)

Complete physical, nasal and brief neurological examinations (see Section 6.2.2.2)

Administer B-SIT (see Section 6.2.2.9)

Perform a urine pregnancy test (all females) (see Section 6.2.2.7)
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
Ensure that the PMP is finalized before a subject receives a test dose of USL261 (see
Section 9.3.1)

Collect blood sample for PK analysis (see Section 6.2.3)

Perform baseline OAA/S (see Section 6.2.2.5)

Perform baseline 12-lead ECG (see Section 6.2.2.4)

Measure body weight

Measure baseline vital signs (BP, HR, respiration rate, temperature) (see Section
6.2.2.3)

Measure baseline oxygen saturation with pulse oximetry (see Section 6.2.2.6)

Perform C-SSRS (see Section 6.2.2.8)

Administer the subject outcome assessments (see Section 6.2.5)
Caregivers will perform the following assessments before administration of the USL261 test 
dose at Visit 2:

Demonstrate the correct technique for airway management (including neck
extension, chin lift, and jaw thrust maneuvers)

Monitor and record the baseline respiration rate of the subject (see Section 6.2.2.3)

Complete the caregiver outcome assessments (see Section 6.2.5)
6.1.2.2
Administration of Test Dose at Visit 2
Subjects who continue to meet all eligibility criteria will receive 2 doses of 5.0 mg USL261
10 minutes apart.

Study center personnel will administer the first dose

Subject’s primary caregiver will administer the second dose under supervision of
qualified study personnel
6.1.2.3
Post-Administration of Test Dose at Visit 2
Study personnel and the caregiver will monitor the subject for the entire observation period. 
Prior to 132 subjects completing the Comparative Phase, the observation period will be 4 
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hours. After 132 subjects have completed the Comparative Phase, for all new test dosed 
subjects, the observation period will be at least 1 hour following test dose administration.
Assessments occurring at the same time should be completed in the following order: ECG,
OAA/S, measurement of vital signs (including respiration rate), pulse oximetry, blood draw
for PK analysis and second test dose.
Study center personnel will perform the following:

Perform 12-lead ECG approximately 15 minutes after the first test dose (see Section
6.2.2.4)

Perform OAA/S at approximately 5, 10, 20, 30 minutes and 1, 2 and 4 hours after the
first test dose. After 132 subjects have completed the Comparative Phase, for all new
test dosed subjects, perform OAA/S at approximately 5, 10, 20, 30 minutes and 1
hour after the first test dose (see Section 6.2.2.5)

Record vital signs (BP, HR, and respiration rate at approximately 5, 10, 15, 20, 30,
45 minutes and 1, 1.5, 2, 3, and 4 hours after administration of the first dose. After
132 subjects have completed the Comparative Phase, for all new test dosed subjects,
record vital signs (BP, HR, and respiration rate at approximately 5, 10, 15, 20, 30, 45
minutes and 1 hour after administration of the first dose (see Section 6.2.2.3)

Record pulse oximetry at approximately 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2,
3, and 4 hours after administration of the first dose. After 132 subjects have
completed the Comparative Phase, for all new test dosed subjects, record pulse
oximetry at approximately 5, 10, 15, 20, 30, 45 minutes and 1 hour after
administration of the first dose (see Section 6.2.2.6)

Collect blood samples for PK analysis at approximately 5, 10, 20, 30 minutes, and 1,
2, and 4 hours after administration of the first dose. After 132 subjects have
completed the Comparative Phase, for all new test dosed subjects, collect blood
samples for PK analysis at approximately 5, 10, 20, 30 minutes, and 1 hour after
administration of the first dose (see Section 6.2.3)

Collect and record AEs
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
Call the Interactive Response Technology System (IRT) to report test-dose
information
Caregivers will perform the following and record the assessments into a practice Subject
Worksheet:

Under the supervision of study center personnel, the caregiver will monitor and
record respiration rate of the subject at approximately 5, 10, 15, 20, 30, 45 minutes
and 1, 1.5, 2, 3, and 4 hours after the first test dose. After 132 subjects have
completed the Comparative Phase, for all new test dosed subjects, the caregiver will
monitor and record respiration rate of the subject at approximately 5, 10, 15, 20, 30,
45 minutes and 1 hour after the first test dose. To determine respiration rate, the
caregiver will count the number of breaths taken by the subject during a 30-second
interval (see Section 6.2.2.3).
A subject who experiences signs or symptoms at Visit 2 that are concerning in the 
investigator’s judgment or are exclusionary per exclusion criterion #22 must be monitored 
until resolved or longer as deemed appropriate by the investigator. Subjects who no longer 
meet eligibility criteria after the Test-Dose Phase (see Section 5.3, Exclusion Criteria) 
and/or have decided not to participate further in the trial will proceed to the Early 
Termination (ET) visit and complete the Visit 4 procedures (see Section 6.1.6).
6.1.3
DSMB Assessment (After 25 Subjects Complete Visit 2)
Before any subject is enrolled in the Comparative Phase, safety data from at least 25 
subjects in the Test-Dose Phase will be reviewed by the DSMB. Enrollment will 
temporarily halt once approximately 25 subjects complete the test dose visit, to allow the 
DSMB to review the safety data.  If the DSMB findings indicate that administering 2 doses 
of USL261 5.0 mg (total 10 mg) meets safety requirements, the study will continue as 
planned. Subjects from the Test-Dose Phase whose data were analyzed by the DSMB will 
be randomized at Visit 3, and all subsequent subjects will proceed from Visit 2 to Visit 3 as 
outlined below.
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6.1.4
Visit 3 (Randomization)
For subjects enrolled in the study after the initial DSMB review, Visit 3 will take place 
between 24 hours and 28 days after Visit 2. The time between Visit 2 and Visit 3 may be 
extended in certain cases; however, the extension must be approved by the Sponsor or CRO 
designee. At Visit 3, the subject will be randomized to receive either USL261 or placebo, if 
he or she continues to meet the eligibility criteria (Section 5). At Visit 3, the investigator or 
other qualified study personnel will perform the following:

Review of inclusion/exclusion criteria (see Section 5)

Caregiver training
o
Review, assess, and re-instruct (when needed) caregivers on the information
provided in the self-study training

Ensure caregiver has demonstrated hands-on competence in administering the study
drug, measuring timed respiration rate, recording information in a practice Subject
Worksheet and performing the correct technique for airway management (including
neck extension, chin lift, and jaw thrust maneuvers)

Collect concomitant medication information

Complete physical , nasal and brief neurological examinations (see Section 6.2.2.2)

Administer B-SIT (see Section 6.2.2.9)

Perform a urine pregnancy test (all females)

Review the PMP with the subject and caregiver

Measure body weight

Measure vital signs (BP, HR, respiration rate, temperature) (see Section 6.2.2.3)

Perform C-SSRS, Since Last Visit version (see Section 6.2.2.8)

Call the Interactive Response Technology System (IRT) to obtain the study drug kit
identification number to be dispensed

Provide subjects/caregivers with study kit, which includes at a minimum:
o
Individualized PMP
o
Individualized Summary of the PMP (i.e., laminated card for convenient
reference)
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o
Subject Workbook
o
Study drug kit
o
Dosing instructions

Collect and record AEs
The investigator or his/her designee will confirm that the subject and caregiver clearly 
understand the study procedures (e.g., requirements for documenting seizure activity, timing 
for respiration rate monitoring, etc.) before leaving the study center. Caregivers will again 
be reminded to call the central study nurse hotline as soon as study drug is administered. If 
caregivers give the second dose, a call to the central study nurse is required as well. 
6.1.5
Treatment
The caregiver will document in the Subject Workbook all seizure activity that occurs from 
the time the subject and caregiver receive the study materials kit at Visit 3 until Visit 4 or 
Early Termination (ET). Seizure activity 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 and untreated seizures should also be 
recorded, with the information estimated to the best of the subject’s or caregiver’s ability.
When a seizure cluster that meets study criteria (per the subject’s individualized PMP) is 
identified, the caregiver will: 

Note the time of recognition of the seizure cluster onset

Administer the double-blind study drug intranasally

Note the time of study drug administration

Call the central study nurse hotline as soon as possible after administering the study
drug; a central study nurse will assist the caregiver in making study-related efficacy
and safety assessments, if needed, and will be responsible for safety monitoring
following administration of study drug
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
Measure and record subject’s respiration rate by counting the number of breaths
taken in a 30-second interval at approximately 15 and 30 minutes, and 1, 2, and 4
hours after study drug administration (respiration rate will be measured at these
times whether or not the seizure cluster has ended, unless, for reasons of subject
safety, it cannot be performed)

Ensure the rescue protocol in the PMP is followed if the subject has less than 8
breaths per minute, is excessively and uncharacteristically sedated or other criteria
outlined in the rescue protocol are met

Administer the second dose of study drug (i.e., 5.0 mg dose of USL261) if (see
Section 6.1.7.2.2):
o
The initial seizure cluster episode has not terminated within 10 minutes after the
initial drug administration
OR
o
Another seizure occurs between 10 minutes and 6 hours after administration of
the study drug
AND
o
There is no evidence of excessive, uncharacteristic marked sedation (as defined
by the investigator in the PMP), the subject does not have a respiratory rate less
than 8 breaths per minute, and the subject does not require emergency rescue
treatment with assisted breathing or intubation
If the second dose of study drug (i.e., 5.0 mg dose of USL261) is administered, the caregiver 
will do the following:

Call the central study nurse hotline as soon as possible after the second dose is
administered

Ensure the rescue protocol in the PMP is followed if the subject has less than 8
breaths per minute, is excessively and uncharacteristically sedated, or seizure cluster
activity persists or recurs following the administration of the second dose; the
subject’s rescue protocol will outline what is considered to be persistent or recurrent
seizure activity and uncharacteristic sedation for the particular subject
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After the seizure cluster has ended, the caregiver will do the following:

Evaluate 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 following information is recorded in the Subject Workbook
o
Date and start time when the treated seizure cluster was recognized
o
All seizure activity
o
Date and time of study drug administration(s)
o
Respiration rate measurements and the date(s) and times they were collected (see
Section 6.2.2.3)
o
Any changes in the subject’s overall health for 24 hours after receiving study
drug
o
Medications that the subject received and device use by the subject in the 24
hours following study drug administration

Continue to record all seizure activity until Visit 4 in the Subject Workbook

Re-package the study drug (used and unused) for return
Upon receiving a call from the caregiver stating the study drug (first, double-blind dose 
and/or second dose [ie, 5.0 mg dose of USL261]) had been administered, a central study 
nurse may do the following:

Assist the caregiver in completing study assessments accurately and on time
according to the protocol, if needed; a central study nurse will have access to all
individualized PMPs so they are aware of each subject’s seizure morphology

Help the caregiver to determine if the rescue protocol in the PMP needs to be
activated, if necessary

Notify the investigator within 24 hours that the subject received drug and will need
to schedule follow-up visit; site personnel will then contact both caregiver and
subject to schedule Visit 4
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6.1.6
Visit 4 (Post-Dose Assessment or Early Termination)
Subjects and caregivers will return to the study center for Visit 4 between 24 and 120 hours 
(i.e., 1 to 5 days) after study drug administration. Subjects who are prematurely 
discontinued from study participation or terminate their participation should return to the 
study center for Visit 4 (Early Termination). Any subject who has not treated a seizure 
cluster meeting the study criteria within 6 months of Visit 3 (Randomization) will be 
discontinued from the study and will return to the study center for Visit 4 (Early 
Termination).
At Visit 4 (Post-Dose or Early Termination [ET]), the investigator or other qualified study 
personnel will do the following:

Collect concomitant medication information

Collect number of calls to EMS and ER visits for a seizure cluster or other seizure
emergency since Visit 3 or the most recent follow-up phone call.

Complete physical, nasal and neurological examinations (see Section 6.2.2.2)

Collect blood and urine samples for clinical laboratory testing (serum chemistry,
hematology, and urinalysis) (see Section 6.2.2.7)

Perform urine pregnancy test (all females)

Measure body weight and height

Measure vital signs (BP, HR, respiration rate, temperature) (see Section 6.2.2.3)

Administer B-SIT (see Section 6.2.2.9)

Perform C-SSRS, Since Last Visit version (see Section 6.2.2.8)

Administer the subject and caregiver outcome assessments (see Section 6.2.5)Collect
and record AEs

Collect study drug and container(s) (used and unused)

Review and collect the Subject Workbook
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6.1.6.1
Telephone Follow-Up and Support
6.1.6.1.1
Telephone Follow-up
After Visit 3, the study coordinator or designee will call the caregiver or subject at least 
once each month until the subject has completed Visit 4 or has prematurely discontinued 
from the study. On these telephone calls, a member of the study center personnel will do the 
following:

Verify that at least 1 trained caregiver is still available

Ask about any seizure clusters that occurred

Ask about whether the study materials kit is still accessible and available

Review study procedures

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 Visit 3 or the most recent follow-up phone call.
6.1.6.1.2
Central study nurse hotline
A toll-free hotline with access to a central study nurse(s) will be available 24 hours a day, 7 
days a week to assist subjects and caregivers who need additional information on study 
procedures or general advice and support. It is a requirement for caregivers to call the 
central study nurse hotline as soon as possible after administering study treatment, including 
the second dose if needed, for the subject’s seizure cluster episode. A central study nurse 
will assist the caregiver in making study-related efficacy and safety measurements, if 
needed, and will be responsible for safety monitoring following the administration of study 
drug. A central study nurse(s) will have access to all subject’s individualized PMPs so they 
are aware of each subject’s seizure morphology and can help the caregiver determine if the 
rescue protocol needs to be activated. 
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A member of the study center staff will be notified by either a central study nurse or the 
CRO [inVentiv Health Clinical] that a subject has received study drug. The study 
coordinator at the study center (or designee) will contact the caregiver and/or subject to 
schedule Visit 4, which will occur in the 24 to 120 hours after study drug administration. 
6.1.7
Dosing Instructions
6.1.7.1
Test-Dose Phase Dosing
The test dose administered at Visit 2 is an open-label dose of USL261 administered in 2 
parts: a single 5.0 mg dose (1 actuation) into either nostril, followed 10 minutes later by a 
second 5.0 mg dose (1 actuation), administered in the opposite nostril. 
The first dose will be administered by study personnel and the second dose by the primary 
caregiver under the supervision of qualified study personnel.
6.1.7.2
Comparative Phase Dosing
6.1.7.2.1
Dosing Double-Blind Study Medication 
During the Comparative Phase, the caregiver will administer to the subject 1 actuation of the 
double-blind study drug, to which they have been randomized (5.0 mg USL261 or a 
matching placebo nasal spray), into either nostril upon occurrence of a qualifying seizure 
cluster. 
6.1.7.2.2
Dosing of Second Dose (i.e., 5.0 mg dose of USL261)
The caregiver may administer a second dose of study drug (i.e., 5.0 mg dose of USL261)
into the subject’s opposite nostril if the following criteria are met:

The initial seizure cluster has not terminated within 10 minutes after the initial drug
administration, provided that the subject does not have < 8 breaths per minute, does not
require emergency rescue treatment with assisted breathing or intubation and does not
have or excessive, uncharacteristic, marked sedation (as defined by the investigator in
the PMP),
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OR

Another seizure occurs between 10 minutes and 6 hours after administration of the
double-blind study drug, provided that the subject does not have < 8 breaths per minute,
does not require requiring emergency rescue treatment with assisted breathing or
intubation and does not have excessive, uncharacteristic, marked 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).
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

Date, start, and stop time of each seizure within 24 hours after any study drug
administration

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
A complete medical history will be collected by qualified medical personnel participating in 
the study for each subject, including seizure history. Medical history will be taken and 
recorded at Visit 1. Changes to medical history will be reviewed by the Investigator and 
noted if appropriate as an AE.
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6.2.2.2
Physical and Neurological Examinations
Physical 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, and a nasal cavity examination using a nasal speculum.
During the nasal exam, special attention will be paid to signs of nasal congestion and signs 
of abrasion or trauma. Complete physical examinations will be conducted at Visits 1, 2, 3,
and 4 / ET. Height will be measured at Visits 1 and 4/ET. 
Complete neurological examinations will be conducted at Visits 1 and 4 / ET. The complete 
neurological exam will consist of evaluations of the following: Mental status (including 
orientation, memory and quality/fluency of speech), cranial nerves II-XII, motor strength of 
the upper and lower limbs, deep tendon and plantar reflexes, sensory exam, station and gait, 
hopping, Romberg test, finger-to-nose test, heel-to-shin test, rapid alternating movements, 
nystagmus, and tremor or other abnormal movements. A partial neurological examination 
will be conducted at Visits 2 and 3 and will consist of evaluations of the following: Mental 
status (including orientation, memory and quality/fluency of speech), station and gait, 
finger-to-nose test, heel-to-shin test, rapid alternating movements, nystagmus, and tremor or 
other abnormal movements. Neurological examinations will be conducted by a qualified 
investigator or sub-investigator.
Any clinically-significant abnormality identified during the physical or neurological 
examination at Visit 1 will be recorded in the subject’s medical history. 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. 
Vital signs to be collected include the following:
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
Systolic and diastolic BP

HR

Respiration rate

Temperature
At Visits 1, 3, and 4 or ET, the vital signs listed above will be measured while subjects are 
seated and at rest for a minimum of 5 minutes.
At Visit 2, qualified study personnel will review and record in source documents the 
subject’s BP, respiration rate, and HR before and at 5, 10, 15, 20, 30, 45, and 1, 1.5, 2, 3,
and 4 hours after the administration of the first test dose. After 132 subjects have completed 
the Comparative Phase, for all new test dosed subjects, study personnel will review and 
record in source documents the subject’s BP, respiration rate, and HR before and at 5, 10, 
15, 20, 30, 45, and 1 hour after the administration of the first test dose. Temperature will be 
measured only at the pre-dose time point at Visit 2. 
As part of their training, caregivers will measure the subject’s respiration rate at these same 
time points and record the findings in a practice worksheet under the supervision of study 
personnel. To determine respiration rate, the caregiver will count the number of breaths 
taken by the subject during a 30-second interval.
During the Comparative Phase of the study, caregivers will measure respiration rate at 
approximately 15 and 30 minutes, and 1, 2, and 4 hours after study drug administration. 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.
At the discretion of the investigator, out-of-range BP or HR measurements may be repeated 
and the repeat measurement used in relation to inclusion / exclusion criteria, as long as the 
following are rules are followed:

The repeat measurement must be made within 15 minutes after the out-of-range
measurement
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
The repeat measurement must be made before the next designated time point

For each individual vital sign parameter (e.g. SBP), only one repeat measurement is
allowed at each time point

There cannot be more than three repeat measurements for an individual vital sign
parameter (e.g. SBP) in total over the entire observation period at Visit 2
6.2.2.4
Electrocardiogram (ECG)
A 12-lead ECG will be performed at Visit 1. In order to eligible for the study, a subject 
must have a screening (Visit 1) 12-lead ECG that meets the criteria outlined in Section 5.2.
During Visit 2, a 12-lead ECG will be performed before and at 15 minutes after the first 5.0 
mg test dose. Subjects with clinically significant ECG findings at Visit 2, as determined by 
the investigator, will be discontinued from the study.
ECGs will be centrally reviewed by a cardiologist and by the investigator or designee. An 
ECG report will be sent to the study center by the central ECG vendor; the investigator will 
review the ECG report and indicate the clinical significance of all abnormal findings, and 
then sign and file the ECG report in the subject’s study file.  ECG procedures will be 
provided to all study centers by the central ECG vendor study initiation.
6.2.2.5
Observer’s Assessment of Alertness/Sedation Scale (OAA/S)
The OAA/S scale is a validated qualitative categorical measure of sedation.[41] The 
OAA/S scale is composed of the following assessment categories: responsiveness, speech, 
facial expression, and eyes. 
The OAA/S scale will be scored in 2 ways; a composite score, defined as the lowest score in
any one of the 4 assessment categories and a sum score, which is calculated as the total of 
the scores in the 4 assessment categories. 
The OAA/S will be administered at Visit 2 before and at 5, 10, 20, 30 minutes and 1, 2, and 
4 hours after the first test dose by a qualified member of the study center personnel. After 
132 subjects have completed the Comparative Phase, for all new test dosed subjects, the 
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OAA/S will be administered at Visit 2 before and at 5, 10, 20, 30 minutes and 1 hour after 
the first test dose.
6.2.2.6
Pulse Oximetry
At Visit 2, O2 saturation will be measured using pulse oximetry.  Oxygen saturation will be 
recorded in the source document before and at 5, 10, 15, 20, 30, 45 minutes, and at 1, 1.5, 2, 
3, and 4 hours after administration of the first 5.0 mg test dose. After 132 subjects have 
completed the Comparative Phase, for all new test dosed subjects, oxygen saturation will be 
recorded in the source document before and at 5, 10, 15, 20, 30, 45 minutes, and at 1 hour 
after administration of the first 5.0 mg test dose.
An observation of O2 saturation < 90% will be recorded as an AE, if O2 saturation remains 
below 90% for > 30 seconds. The pulse oximetry device placement and function will be
confirmed by qualified study center personnel, and subjects will be clinically assessed to 
determine the validity of the recording.
6.2.2.7
Clinical Laboratory Assessments
All subjects will have the clinical laboratory tests performed as listed in Table 4. The total 
volume of blood collected for clinical laboratory assessments will be approximately 20 mL 
(1.5 tablespoons) per subject. Subject fasting is not required before collection of clinical 
laboratory blood or urine samples.
All females will undergo a serum pregnancy test at Visit 1 and urine pregnancy tests for
beta-human chorionic gonadotropin (β-hCG) at Visits 2, 3, and 4. Test results must be 
negative at these visits for a subject to be enrolled or continue in the 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.  
Procedures regarding the acquisition of these specimens and necessary supplies will be 
provided to all study centers by the central laboratory prior to study initiation.
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Table 4.   Clinical Laboratory Tests
Hematology
(Visits 1 and 4 / ET)
Serum Chemistry
(Visits 1 and 4 / ET)
CBC with differential
A/G ratio
Hgb
Albumin
Hct
AP
MCV
ALT (SGPT)
MCH
AST (SGOT)
MCHC
Bicarbonate
Platelets
BUN
             RBC
BUN/Creatinine ratio
             WBC           
Calcium
Pregnancy Test[a] (Visits 1, 2, 3, 4/ET)
(Females only)
Cholesterol (total)
β-hCG
Cholesterol/HDL ratio
Drug Screen
(Visit 1 only)
Cholesterol/LDL ratio
Amphetamines
Chloride
Barbiturates
Creatinine
Benzodiazepines
GGT
Cannabinoids
Globulin
Cocaine metabolites
Glucose
Ethyl alcohol[b]
HDL cholesterol
Opiates
Iron 
Phencyclidine
LDH
Plasma phenobarbital[c]
(Visit 1 only)
LDL cholesterol
Urinalysis
(Visits 1 and 4 / ET)
Phosphorus
Bilirubin
Potassium
Blood
Sodium
Glucose
Total/direct bilirubin
            Cells (WBC, RBC, epithelial)
Total protein
Ketones
Triglycerides
Leukocytes
Uric acid
Nitrites
Additional Screening Test
(Visit 1 only)
pH
FSH (females only)
Protein
Specific gravity
Urobilinogen
Abbreviations:  β-hCG, beta-human chorionic gonadotropin; ALT (same as SGPT), alanine aminotransferase; AP, alkaline 
phosphatase; AST (same as SGOT), aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; 
GGT, gamma-glutamyl transpeptidase; Hct, hematocrit; HDL, high-density lipoprotein; Hgb, hemoglobin; LDH, lactate 
dehydrogenase; LDL, low-density lipoprotein; MCH, mean corpuscular hemoglobin; MCHC,  mean corpuscular hemoglobin 
concentration; MCV, mean corpuscular volume; pH, hydrogen ion concentration; SGOT, serum glutamic oxaloacetic 
transaminase; SGPT, serum glutamic pyruvic transaminase.
[a]Serum β-hCG levels measured at Visit 1, urine β-hCG levels measured at Visits 2, 3, 4
[b]Blood alcohol screen
[c] Only for subjects taking phenobarbital and for subjects for which the investigator deems it necessary.
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6.2.2.7.1
Sample Collection, Storage, and Shipping
Blood and urine specimens will be collected by qualified study center personnel and sent to 
and analyzed by a central laboratory for the hematology, urinalysis, serum chemistry, urine 
drug screen, and blood alcohol analyses. Laboratory test results will be flagged by the 
central laboratory if they meet protocol specified inclusion/exclusion criteria (e.g., WBC <
2.5x109/L). Detailed instructions of sample collection, storage, and shipping will be 
provided by the central laboratory.
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.
6.2.2.7.2
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.
6.2.2.8
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinician-rated scale that assesses suicidal behavior and ideation. The 
Baseline/Screening version will be administered at Visit 1 and the Since Last Visit version 
will be administered at Visits 2, 3, and 4/ET. 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).
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6.2.2.9
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 (pre-dose only), Visit 3, 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.
6.2.3
Pharmacokinetic Assessments
Plasma concentrations of midazolam and 1-hydroxymidazolam will be determined using a 
bioanalytical assay in a GLP analytical laboratory contracted by the study sponsor. Blood 
samples for PK analyses will be collected from each subject before and at 5, 10, 20, 30 
minutes, and 1, 2, and 4 hours after administration of the first test dose at Visit 2. After 132 
subjects have completed the Comparative Phase, for all new test dosed subjects, blood 
samples for PK analyses will be collected from each subject before and at 5, 10, 20, 30 
minutes, and 1 hour after administration of the first test dose at Visit 2.
Blood samples will be collected through a saline flush catheter or by direct venipuncture 
using Vacutainer® or Monovette® 6 mL tubes containing EDTA K2 anticoagulant and will 
immediately be placed in an ice bath. The clock times of all blood draws will be recorded 
and reported for each subject. All tubes will be labeled with the subject number, protocol,
visit number, and planned blood draw time point. A maximum of 50 mL of blood will be 
collected for PK analysis during the entire course of the study. Following collection
(maximum 110 minutes), the blood samples will be centrifuged at 4°C with a centrifugal 
speed of approximately 3000 rpm for 10 minutes. Plasma will be split into 2 aliquots of at 
least 1.0 mL each and placed in labeled, screw-cap, polypropylene tubes.  Labels will be
affixed to the tubes in a manner that will prevent detachment after freezing. All plasma PK 
samples will be stored frozen at -20°C (±5°C), within 120 minutes from the start of 
centrifugation until they are shipped to the analytical laboratory.
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Bioanalytical samples will be transported to the analytical laboratory in 2 separate 
shipments, with each set of aliquots in separate shipments. Once the analytical laboratory 
confirms receipt of the first shipment, the second set of aliquots may be sent. The samples 
should be packed on sufficient dry ice to be kept frozen for at least 72 hours. 
Detailed instructions for PK sample collection, storage, and shipping will be provided by the 
analytical laboratory.
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.
6.2.5
Subject and Caregiver Outcome Assessments
The subject and caregiver outcome assessments should be completed at each visit as 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.
6.2.5.1
SF-12v2 Health Survey (SF-12)
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 the primary caregiver individually at Visits 2 and 4.
6.2.5.2
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 Visits 2 and 4.
6.2.5.3
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 primary caregiver 
individually at Visit 4.
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6.2.5.4
Caregiver Questionnaire
The Caregiver Questionnaire is self-administered by the primary caregiver and consists of 2 
main sections as follows: 1) Caregiver demographics (completed at Visit 2 or if there is a 
change in primary caregiver during the study), and 2) Resource utilization (completed at Visit 
4). The purpose of the resource utilization questions is to capture any unscheduled healthcare 
use that occurred as a result of the seizure activity for which the study drug was administered.
6.3
Prior and Concomitant Therapy
Prior therapy is defined as any medication (prescription or non-prescription), nutritional 
supplement, herbal preparation or device (e.g. VNS magnet) taken or used within 30 days
prior to the first dose of study drug at Visit 2.
If the subject is using or has recently used any of the food, beverage, or medicinal products 
listed in Appendix 1, Prohibited Concomitant Substances, 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 2 through Visit 4 or ET.
6.3.1
Permitted Medications
A subject’s AED regimen (with or without intermittent use of benzodiazepines at a constant 
dose [see Section 6.3.3]) must be stable (no changes in drug type) from Visit 1 through Visit 
4 or ET and for ≥ 7 days before Visit 2. Changes in dose of an AED are allowed during the 
study; however, the new dose level must be kept stable for at least 7 days before the subject 
receives study drug in both the Test Dose and Comparative Phases. VNS settings must be 
kept stable throughout the study period and the use of a magnet with the VNS must 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 
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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.
6.3.2
Prohibited Medications
The medications listed in Appendix 1, Prohibited Concomitant Substances are prohibited 
from Visit 1 through Visit 4 / ET. These medications include CYP450 3A
inhibitors/inducers, opioids, and other respiratory depressants (except antiepileptic drugs). 
If a subject was taking any of these medications at or before Visit 1, the time between the 
last dose of that substance and Visit 2 must be equal to or greater than the minimum 
washout time shown in Appendix 1, Prohibited Concomitant Substances.
If a subject takes any of these medications after V2 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 and 
always at the same dose. 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; this will be outlined in the subject’s PMP.  
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
Food and beverage substances that are restricted during this study are detailed in Appendix 
1, Prohibited Concomitant Substances. Foods and beverages not permitted during the study 
(from Visit 1 to Visit 4) include grapefruit, grapefruit juice, Seville oranges, and star fruit. 
Consuming these substances during the study may alter the subjects’ response to treatment 
with USL261. 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 their future medical care. The 
investigator will also discontinue a subject’s study participation if the subject has not treated
a seizure cluster meeting the study criteria within 6 months after randomization. A subject 
who prematurely discontinues from the study should return to the clinic within 7 days to 
undergo the ET visit (Visit 4) 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: The subject findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (e.g., change in AED drug during 
the study, 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 randomization

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
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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 Visit 4 evaluations. In 
the event that a subject elects not to return to the study site for the ET Visit, the investigator 
must make 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. 
Replacement of Subjects:
Subjects who prematurely discontinue from the study after receiving double-blind study 
drug will not be replaced.
6.6
Treating Overdose
Refer to the Hospira Midazolam Injection, USP, Package Insert for full details on 
midazolam overdose (see Appendix 2).  In the case of suspected overdose, respiration, pulse 
rate, 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 access should be obtained. Should hypotension 
develop, treatment may include intravenous 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 
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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 AE(s) and attributed to the overdose of 
study drug.
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 (Visit 4) evaluations. The investigator 
must notify USL or its designee within 24 hours of learning about the pregnancy.  The 
investigator must complete the Pregnancy Notification Form provided by USL or its 
designee. The investigator 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 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.
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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
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:
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:
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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
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 serious AE 
(SAE).
Seriousness: As provided in FDA Title 21 CFR Part 312 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 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. 
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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 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.
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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.
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 (Visit 4 [Post-
Dose Assessment or ET]) or7 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 or SAE 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 (Visit 4 [Post-Dose Assessment or ET]) 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 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 as 
described below.  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 the Medical Monitor.
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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 serious event.  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
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
Fatal or 
Life-Threatening
SAEs
Immediate
Telephone
or E-
mail[b]
North and South America: 
(e-
mail)
Rest of World: 
(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] Email 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/EC. 
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 clinically significant.  Supplemental measurements and/or evaluations may be 
necessary to fully investigate the nature and/or causality of an AE or SAE.  This may 
include additional laboratory tests, diagnostic procedures, or consultation with other 
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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 preexisting 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
At Visit 1, the investigator, or designee, will contact the Interactive Response Technology 
System (IRT) to register the subject. At Visit 2, the investigator, or designee, will contact 
IRT to confirm the administration of the test dose. At Visit 3, subjects meeting the 
eligibility criteria will be randomized (2:1) to receive USL261 or matching placebo using
the IRT; the Investigator, or designee, will obtain a drug kit number via IRT at Visit 3. 
Instruction on access and use of the IRT service will be detailed in the IRT manual provided 
by the IRT vendor.
The randomization code will be generated by an unblinded statistician at the CRO [inVentiv 
Health Clinical] who is not otherwise involved in study activities. The randomization will 
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be generated using fixed blocks and will be stratified by age (< 18 vs. ≥18). USL will not 
have access to the randomization code.
8.2
Blinding 
USL261 will not be blinded for the Test-Dose Phase or for the second dose provided to 
some subjects during the Comparative Phase; however, blinding is considered important for 
safety and efficacy assessments for the first dose of the Comparative Phase. Therefore, drug 
supplies for the first dose in the Comparative Phase will be labeled in double-blind fashion 
with information including the protocol number, kit identification number, and instructions 
for use. The drug name will not appear on the label, and neither the investigator/study 
center staff nor the subject/caregiver will know the identity of the randomized medication.
The interim analyses will be conducted by an unblinded statistician and reviewed by an 
unblinded interim monitoring committee, both independent of the sponsor. The sponsor, 
USL, will remain blinded throughout the trial until database lock has occurred. Once 
database lock has occurred, the final statistical analysis of this trial will be performed by a 
CRO under the direction of USL.
If it is medically imperative to know what study treatment the subject is receiving, the
investigator or designee will contact the IRT and select the option for exposing the blinded
information. The individual who breaks the blind must record the date and rationale in the
subject’s medical records and on the eCRF. In such cases, the investigator or designee 
should contact the Medical Monitor before the blind is broken (if possible). Every effort 
should be made to collect complete efficacy and safety data on these subjects. Furthermore, 
inVentiv Health Clinical will also have the capability to unblind individual subject data for 
the purposes of fulfilling regulatory reporting requirements for unexpected AEs, which is in 
compliance with ICH guidelines. 
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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 
USP. 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.
Midazolam, the active ingredient in USL261, is designated as a Schedule IV controlled 
substance with abuse potential by the US Controlled Substances Act (21 CFR §1308).
The placebo nasal spray will consist of the same inactive ingredients as found in the 
USL261:
 
 Each actuation of the unit dose pump will deliver 0.1 mL of this 
solution.
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 and placebo nasal spray containers will be provided as ready-to-use assemblies 
packaged to prevent accidental actuation. Both active and placebo drug utilize 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 
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vial holder is pushed into the nasal actuator, which sprays the dose out of the nasal spray 
actuator tip.
Study drug (active and placebo) 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, distributed, and destroyed in compliance with US Drug Enforcement 
Administration (DEA) regulations.
The study drug supplies will be labeled appropriate to their use. USL261 5.0 mg containers 
for the Test Dose Phase and the second dose of the Comparative Phase will be identified as 
open-label treatments. The label for the double-blind, first dose of the Comparative Phase 
will contain at a minimum the following information for the US (additional items will be 
added as required for other study countries):

Protocol number

Kit identification number from the randomization scheme

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
An individualized PMP will be prepared by the investigator or designee for each subject
based on information provided by the subject (when able) and caregiver(s). 
The individualized PMP will describe, at a minimum, the type of seizure cluster eligible for 
treatment with study drug, the criteria for seizure cluster recognition, when to administer the 
study drug, when to call the central study nurse hotline, requirements for when to give the 
second dose of study drug (ie, 5.0 mg dose of USL261), and a rescue protocol for persistent 
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or recurrent seizure activity or other safety concern. Contact information for study center 
personnel, the central study nurse hotline and emergency medical service(s) will also be 
listed in the PMP.
The following steps will be followed for PMP preparation:
1. At Visit 1, the subject and caregiver each provide the investigator (or designee) a 
description of both the seizure clusters and the typical, non-clustering seizures (if 
any) in their own words.
2. The investigator (or designee) will add his/her notes to the subject and caregiver 
descriptions, specifying what type of seizures each description refers to and any 
other relevant information.
3. The PMP is drafted by the investigator and qualified study center personnel
using the template provided by the Sponsor or CRO.
4. The PMP, including the seizure cluster descriptions from the subject, caregiver, 
and investigator, are then provided to an expert Central Reviewer for a final 
determination of whether or not the subject qualifies for study inclusion and 
input on whether further information is needed.
5. The PMP is finalized by the investigator and qualified study center personnel
before the subject receives the first test dose at Visit 2. The PMP will be 
discussed and agreed upon by the subject, caregiver, and investigator.
6. Subjects and caregivers will receive a copy of the PMP at Visit 3.  A summary of 
the PMP (i.e., laminated card for convenient reference) will also be provided.
If the Central Reviewer does not approve the subject for study participation, the subject will 
be screen failed.
9.3.2
Subject Workbook
Caregivers will receive a Subject Workbook for the Comparative Phase of the trial. In this 
study, the Subject Workbook is a critical source document for collecting and recording 
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outpatient information during the Comparative Phase of this study. The Subject Workbook
will be used to record:

Seizure activity (Seizure activity 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 [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 subject’s or caregiver’s ability. The caregiver will document in the Subject 
Workbook all seizure activity that occurs from the time the subject and caregiver 
receive the study materials kit at Visit 3 until Visit 4 or ET).

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)

Medications that the subject received and device use by the subject within 24 hours 
after study drug administration

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 Visit 4 or ET.
At Visit 2, the caregiver will enter timed respiration rate measurements into a practice 
Subject Worksheet for training purposes (see Section 9.3.3).
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9.3.3
Caregiver Training Materials
Caregivers will be trained in study procedures by qualified study personnel beginning as 
early as Visit 1 and retrained, if necessary, at Visits 2 and 3. Training will be provided to 
the caregiver(s) at Visit 1 for self-study on the following topics:

Overview of the study

Understanding the subject’s individualized PMP

Recognizing a cluster seizure episode

Procedures for study drug administration

Mandatory requirement for contacting the central study nurse after subject is treated
with double-blind study drug and the second dose of study drug (i.e., 5.0 mg dose of
USL261), if needed

Performing study-related measurements (e.g., measuring respiration rate, completing
the Subject Workbook)

Procedures for safety monitoring

Cardiopulmonary resuscitation (CPR) including airway management

Contact information for help and advice from study center personnel and a toll-free
telephone hotline to a central study nurse (available 24 hours a day, 7 days a week)
The training provided at Visit 1 for self-study will be completed at or before Visit 2. 
Completion of the self-study training will be certified by qualified study staff and/or by 
web-based or paper-based questionnaire. The investigator, or other qualified study 
personnel, will review, assess, and (if needed) re-instruct subjects and caregivers on the 
information provided in the self-study training at Visits 2 and 3. Before subjects are given 
the test dose at Visit 2, caregivers must pass the CPR exam, which addresses airway 
management, breathing, and circulation and must demonstrate airway management 
techniques including neck extension, chin lift, and jaw thrust maneuvers. During Visit 2, 
the primary caregiver will administer the second test dose and monitor the subject by 
performing timed respiration rate measurements. Respiration rate assessed by the caregiver
will be recorded in a practice Subject Worksheet at Visit 2. 
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Before the subject is randomized, caregivers must have demonstrated hands-on competence 
in administering the study drug, performing the timed respiration rate measurements, 
recording information in the practice Subject Worksheet, and performing the correct 
technique for airway management. The investigator or his/her designee will confirm that the 
subject and caregiver clearly understand the study procedures (e.g., requirements for 
documenting seizure activity, timing for respiration rate monitoring, etc.) before leaving the 
study center at Visit 3.
Caregivers that are added during the study will have to complete similar training 
requirements as those noted above.
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 site receives, and document any damaged or 
unusable study drug in the inventory log.
Only after receipt of all required documentation from a clinical site 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 and forward 
the original to the drug distribution center. 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 code) on the drug accountability log. The 
investigator/designee will also document any subsequent returns or losses of study drug on 
the drug accountability log.
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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
securely locked, substantially constructed enclosure with limited access (e.g., locked
cabinet). The investigator will take adequate precautions to prevent theft or diversion of the 
study medication, consistent with 21 CFR § 312.69. Within the locked storage area, study 
drug will be stored at a controlled room temperature (with excursions between 15° and 30°C
[59° and 86°F]) until used. 
Before an investigator is allowed to participate in this study, the drug storage area at his/her 
site 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 medication will be dispensed by the study center pharmacist or other qualified 
individual, and each test dose or study drug kit dispensed will be documented in the drug 
accountability log.
The USL261 test doses (2 USL261 5.0 mg containers) will be dispensed to study personnel 
at Visit 2.
If the subject continues to meet all eligibility criteria at Visit 3, the pharmacist or other 
qualified individual at the study center will call the IRT to obtain the kit identification 
number. The appropriate study drug kit, which contains blinded study drug and the second 
dose of study drug (i.e., 5.0 mg dose of USL261), will then be documented and dispensed to 
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the subject or caregiver. When dispensing the study drug kit at Visit 3, qualified site 
personnel will also tell or remind subjects/caregivers to:

Store study drug at controlled room temperature (see Section 9.4.1), and

Return study drug containers, both used and unused, to clinic staff at the next visit
9.4.3
Return or Destruction of Study Drug
At Visit 4 or ET, 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, a final inventory of study drug shipped to the site, dispensed, 
and remaining at the site will be performed by the Study Monitor (or designee) and the 
investigator (or designee). This reconciliation will be logged on the drug accountability 
form, signed, and dated. If any supplies are missing, this must be indicated on the drug 
accountability/return forms along with an explanation of the discrepancy. Any 
discrepancies noted will be investigated, resolved, and documented before 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 or designee, 
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 
drugs will be returned to USL or designee for destruction.
10 DATA ANALYSIS AND STATISTICAL PROCEDURES
All statistical analyses will be performed using appropriate procedures in SAS version 9.2 or 
higher. Additional software may be used for the production of graphics or specific 
statistical methodology as appropriate. 
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Data will be listed and tabulated by treatment group. Continuous variables will be 
summarized using descriptive statistics (n, mean, standard deviation, minimum, median, and 
maximum). Categorical data will be presented using counts and percentages.
Statistical significance will be determined by two-sided tests with p-value <0.05, unless 
otherwise specified.
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 and unblinding.
10.1
Populations for Analysis
Screened Population: The Screened Population includes all subjects who signed an ICF or 
assent form.
Safety Population: The Safety Population includes all subjects who received at least 1
dose of study drug. Therefore, this population includes all treated subjects, including those
who terminate before randomization, as well as all subjects who are randomized.
Randomized Population: The Randomized Population contains all subjects who are 
randomized to receive double-blind treatment.
Modified Intent-to-Treat Population (mITT): The mITT Population will consist of all 
subjects in the Randomized Population who receive at least 1 dose of study drug during the 
Comparative Phase and who have any post-treatment efficacy assessments. 
PK Population: The PK population contains all subjects who receive both test doses of 
USL261 in the Test-Dose Phase with sufficient blood samples for PK analysis.
10.2
Disposition, Demographics, and Other Baseline Characteristics
A summary of subject disposition will be prepared that displays the number of subjects 
screened, and the number of subjects who received a test dose, were randomized, who 
received double-blind study drug in the Comparative Phase (first dose), who received the 
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second dose of study drug (i.e., 5.0 mg dose of USL261) in the Comparative Phase, and who 
completed the study.  The number of subjects who did not complete the study will be 
summarized according to the primary reason for withdrawal. The number of subjects in 
each analysis population will also be tabulated.
Descriptive statistics of the demographic profile and baseline characteristics will be 
summarized for the Safety Population, and repeated for the Randomized, Randomized 
Safety and mITT Populations. No formal statistical analyses of these data are planned.  
10.3
Medical and Surgical History
Medical and surgical history will be classified according to the Medical Dictionary for 
Regulatory Activities (MedDRA®) and the incidences will be tabulated for the Safety 
Population.
10.4
Prior and Concomitant Medications
All medications will be classified according to the World Health Organization Drug 
Dictionary and the incidences will be tabulated by drug class and/or generic name for the 
Safety Population during the Test Dose Phase and for the Randomized and Randomized 
Safety population during the Comparative Phase. Prior medications will include all 
medications taken 30 days prior to the first dose of study drug. Prior medications will be 
summarized for the Randomized and Randomized Safety populations. Concomitant drug 
therapy will include all medications (prescription or non-prescription), nutritional 
supplement, or herbal preparation taken from Visit 2 through Visit 4 or ET.  Concomitant
AEDs will be summarized separately.
10.5
Efficacy Analyses
The data to assess the efficacy endpoints will be obtained from the Subject Workbooks and 
entered into the Electronic Data Capture (EDC) system. All efficacy analyses will be 
conducted using the mITT Population, and analyzed according to the randomized treatment 
assignment.
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10.5.1
Primary Efficacy Endpoint and Analysis
The primary efficacy endpoint is the proportion of subjects who meet the criteria for
Treatment Success. Treatment Success is a composite measure of efficacy that will be 
assessed based upon the first seizure cluster treated with study drug during the Comparative 
Phase.  Treatment Success is defined as achieving the following:

Termination of seizure(s) within 10 minutes after study drug administration, and

No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6
hours after study drug administration
Subjects who receive the second dose of study drug within 6 hours of the first dose during 
the Comparative Phase (i.e., USL261 5.0 mg) will not meet the definition of Treatment 
Success.
The null hypothesis is that there is no difference in the proportion of subjects with 
Treatment Success in the USL261 and placebo groups. The alternative hypothesis is that 
the Treatment Success rate will be different between the USL261 and placebo groups.
The primary efficacy endpoint will be analyzed by Fisher’s Exact Test using the mITT 
Population.  The 95% confidence intervals (CIs) around the proportions will be reported. 
Chi-squared test will be performed as a sensitivity analysis.
The components of the primary endpoint (seizure termination and recurrence) will also be 
analyzed separately using Fisher’s Exact Test.
Additional exploratory analyses may be conducted; details will be provided in the SAP.
10.5.1.1
Missing Data and Sensitivity analysis for Primary Outcome
Subjects who do not have sufficient available data to confirm whether they can be classified 
either as “Treatment Success” or as “Not a Treatment Success” are considered to have missing 
data. Subjects with missing data impacting determination of Treatment Success will be 
assumed to have had an unfavorable outcome and will be treated as not a Treatment Success. 
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Sensitivity analysis will be conducted for the Treatment Success endpoint in order to assess 
robustness of study conclusions to missing data using a tipping point approach.
10.5.2
Secondary Efficacy Endpoints and Analyses
The secondary efficacy analyses will be performed on the mITT population. The secondary 
efficacy endpoints include the following:

Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after
administration of double-blind study drug to 4 hours after administration of double-blind
study drug
o
Subjects who have been administered the second dose of study drug (i.e., 5.0 mg
dose of USL261) within 4 hours of double-blind study drug administration will
be assumed to have had a seizure.
o
The proportion of subjects with occurrence of seizure(s) within 4 hours after
administration of study drug will be analyzed using Fisher’s Exact Test. The
95% CIs will be presented for the proportion. In addition, Chi-squared test will
be performed as a sensitivity analysis.

Time to next seizure with a start time > 10 minutes after study drug administration
o
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 study
drug (i.e., 5.0 mg dose of USL261) will be censored at the end of the observation
period.
o
Subjects administered the second dose of study drug (i.e., 5.0 mg dose of
USL261) that did not have a seizure before the administration of second dose of
study drug (i.e., 5.0 mg dose of USL261) will be censored at the time of the
second dose (USL261) administration.
o
This variable will be analyzed by a log-rank test, and presented with Kaplan-
Meier estimates for time-to-event at specific percentiles with associated standard
error and 95% CI. The Kaplan-Meier curve will be displayed by treatment arm.
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In addition, the hazard ratio for treatment (USL261: placebo) and its 95% CI will 
be calculated from a Cox proportional hazards model.
10.5.3
Exploratory Efficacy Variables and Analyses
Exploratory efficacy variables and analyses are detailed below and will be analyzed using 
the mITT population.

Proportion of subjects with recurrence of seizure(s) beginning 10  minutes after double-
blind study drug administration to 24 hours after double-blind study drug administration 
o
Subjects who have been administered the second dose of study drug (i.e., 5.0 
mg dose of USL261) within 24 hours of double-blind study drug 
administration will be assumed to have had a seizure.
o
The proportion of subjects with occurrence of seizure(s) within 24 hours after 
administration of study drug will be analyzed using Fisher’s Exact Test.  The 
95% CIs will be presented for the proportion. In addition, Chi-squared test 
will be performed as a sensitivity analysis.

Return to full baseline functionality within 24 hours after study drug administration (as 
determined by the caregiver)
o
Subjects who do not return to full baseline functionality by the end of the 24-
hour observation period, and have not been administered the second dose of 
study drug (i.e., 5.0 mg dose of USL261), will be censored at the end of the 
observation period. 
o
Subjects who were administered the second dose of study drug (i.e. 5.0 mg 
dose of USL261) will be censored at the time that the second dose of study 
drug (i.e., 5.0 mg dose of USL261) was administered.
o
The proportion of subjects who have documented return to full baseline 
functionality will be analyzed by Fisher’s Exact Test.  The 95% CIs will be 
presented for the proportion. In addition, Chi-squared test will be performed 
as a sensitivity analysis. 
o
This variable will be analyzed by a log-rank test, and presented with Kaplan-
Meier estimates for time to event at specific percentiles with associated 
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standard error and 95% CI. The Kaplan-Meier curve will be displayed by 
treatment arm. In addition, the hazard ratio for treatment (USL261: placebo) 
and its 95% CI will be calculated from a Cox proportional hazards model.

Analyses for subjects receiving 2 doses of study drug (see Section 10.5.3.1)

Subject and caregiver outcome assessments
10.5.3.1
Analyses for Subjects Receiving 2 Doses of Study Drug
It is important to assess the subject’s response to the second dose of study drug (i.e., 5.0 mg 
dose of USL261) in order to evaluate the usefulness of the split-dose strategy. Data from 
subjects randomized to receive double-blind USL261 and who subsequently received the 
second dose of study drug (i.e., 5.0 mg dose of USL261) will be analyzed to determine:

The proportion of subjects who satisfy the Treatment Success criteria relative to the
timing of the second dose of study drug (i.e., 5.0 mg dose of USL261); the analysis and
definition of Treatment Success will be similar to the primary efficacy variable
described in Section 10.5.1.
10.5.4
Safety Analyses
Safety will be assessed through the collection of AE reports, OAA/S (Sum and Composite 
scores), requirements for unscheduled ER or EMS visit(s), vital signs, caregiver-recorded 
respiration rates, laboratory evaluations, ECGs, physical, nasal and neurological 
examinations, and C-SSRS scores. All safety analyses will be presented by phase of the 
study based on the Safety Population and Randomized Safety Population, unless otherwise 
specified.
Safety data from both the Test-Dose Phase and the Comparative Phase will be summarized. 
Adverse Events: AE verbatim text will be coded using MedDRA and summarized by 
System Organ Class (SOC) and preferred term. AEs with onset on or after the start of study 
drug and up to 7 days after the last dose of study drug are considered treatment emergent
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adverse events (TEAEs); AEs reported prior to treatment administration in the Test-Dose 
Phase will be included in subject listings but not included in summaries. 
Patients who experience at least 1 TEAE or SAE will be presented for each SOC and 
preferred term by treatment received. 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).  SAEs and AEs leading to 
discontinuation will be summarized. In addition, listings of all TEAEs, SAEs, and AEs 
leading to discontinuation will be presented.
Clinical Laboratory Data: Clinical laboratory results for serum chemistry, hematology, 
and urinalysis will be presented by treatment received and visit using summary statistics.  
Changes from baseline will also be displayed. Normal range shift tables will be generated 
for each parameter.  In addition, clinically significant abnormalities, as predefined in the 
SAP, will be tabulated.
Vital Signs Measurements: Vital signs measurements performed by study site staff will be 
presented using descriptive statistics. Systolic and diastolic BP (mmHg), HR (bpm), RR
(breaths per minute), and temperature (degrees Celsius) will be summarized at each visit and 
time point.  Changes from baseline will also be displayed. 
Caregiver-recorded respiration rate: Caregiver-recorded respiration rates will be 
presented using descriptive statistics at each time point by treatment group and overall total 
for Randomized safety population. 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, 
treatment group, and overall total.
ECG Measurements: For 12-lead ECG parameters, changes from baseline (Visit 2; pre-
dose) to post-administration of first test dose (Visit 2; 15 minutes post-dose) for all subjects 
will be summarized descriptively at each scheduled visit and time point collected for the 
Safety Population. Mean and mean change from baseline values at Visit 2 will be presented. 
In addition, counts and percentages for ECG diagnosis (normal or abnormal) at each study 
visit and time point will also be presented. If the diagnosis was abnormal, counts and 
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percentages for clinical significance will be presented. The number of subjects meeting the 
criteria specified in SAP will be presented by treatment group for the Safety Population.
OAA/S Composite and Sum Score: Both the Sum and Composite scores for the OAA/S
will be presented by time point at Visit 2. The OAA/S Sum score is calculated as the sum of 
the scores in the 4 assessment categories. The Sum score will be set to missing if 1 or more 
of the 4 assessment categories are missing. The OAA/S Composite score is the lowest score 
among the 4 assessment categories. The Composite score will be set to missing if all 4 of the 
assessment categories are missing. Descriptive statistics and graphical presentations will be 
used to present results by time point at Visit 2 for the Safety Population. Number of subjects 
with an OAAS composite score of 1 at Visit 2 will be presented by time point and overall.
Requirement for Unscheduled ER or EMS Visit: The number of subjects requiring an
unscheduled EMS or ER visit within 24 hours after study drug administration during the 
Comparative Phase will be compared between treatment groups for the Randomized Safety 
Population using Fisher’s Exact Test. In addition, Chi-squared test will be performed as a 
sensitivity analysis. 
C-SSRS: C-SSRS results will be summarized at each visit. The number and percent of
patients with each suicidal behavior and ideation will be displayed. The number and percent
of patients with any suicidal behavior and any suicidal ideation, along with the number and
percent of patients 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.
Physical, nasal and neurological examinations: For physical, nasal and neurological 
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 by treatment group and visit.
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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.
10.5.5
Data and Safety Monitoring Board
The DSMB will meet to review safety data for the first 25 subjects who have completed the 
Test-Dose Phase and when approximately 33, 66, 99, 132, 165, and 204 subjects have 
Comparative Phase data available. The DSMB may also decide to meet and review safety 
data at other time points deemed necessary.
All analyses that are required to support the DSMB will be performed by an unblinded 
statistician not otherwise involved in the study. The DSMB will notify the Sponsor’s Senior 
Management of the results only if they recommend discontinuing the trial due to safety-
related reasons. Even then, the Sponsor will not have access to individual subject data until 
after the database is locked. 
Details of the DSMB membership, meeting schedule, and data review and analysis will be 
documented in the DSMB Charter.
10.6
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses
10.6.1
Pharmacokinetic Variables and Analyses
Pharmacokinetic parameters for individual plasma concentrations will be calculated using a 
standard non-compartmental approach using appropriate validated pharmacokinetic software 
(WinNonlin Enterprise version 5.2 or higher).The following PK parameters of midazolam 
and 1-hydroxymidazolam will be calculated from data obtained for the PK Population:
•
AUC0-t – the area under the plasma concentration-time curve (AUC) from time 0 to time
t, where t is the last measurable concentration, estimated using the linear trapezoidal rule
•
AUC0-inf – the AUC from time 0 extrapolated to infinity, calculated by adding Ct/λz to
AUC0-t, where Ct  is the last quantifiable concentration and λz is the elimination rate
constant
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•
Cmax – the maximum plasma concentration
•
tmax – the time to reach the maximum plasma concentration
•
λz – the terminal elimination rate constant
•
t1/2 – the terminal elimination half-life
•
tlag – the time before the first measurable plasma concentration
•
CL/F – apparent clearance*
•
Vβ/F – volume of distribution*
* calculate for Midazolam only and not for 1-OH-midazolam.
Concentrations values reported as below the limit of quantification (BLQ) will be treated as 
“0” and listed as BLQ. For the calculation of PK parameters, BLQ values will be set to zero 
(“0”). Actual sampling times will be used in the calculations of pharmacokinetic parameters.
Descriptive statistics will include the number of observations, mean, geometric mean, 
standard deviation (SD), and coefficient of variation, as well as median, minimum, and 
maximum for the PK variables. Additional descriptive statistics will be provided by sub-
group such age group, gender, race, etc. Exploratory analysis assessing the relationship 
between PK parameters and selected baseline characteristics may be conducted if 
applicable.  
10.6.2
Pharmacokinetic/Pharmacodynamic Variables and Analyses
The PK/PD analysis of data from the test dose will consist of correlating the plasma 
midazolam plus 1-hydroxymidazolam concentrations to respiratory rate, BP, HR, O2
saturation, and sedation based on OAA/S scores. Regression analysis will describe the 
PK/PD relationship, if one exists. If appropriate, for those PD measurements found to 
correlate to plasma concentrations, the influence of covariates such as gender, AED inducer 
status, weight, BMI, race, and age group will be explored.
10.7
Sample Size Justification
Recently, a well-controlled study of IM diazepam (DZP) for the treatment of acute repetitive 
seizures was reported in the literature (See Table 6 below).[42]  A meta-analysis based on 
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Odds Ratio was conducted on the pooled data from this recent study and the two well-
controlled studies of rectal (PR) Diazepam-Diastat that were used as the basis for the 
original design of this protocol (see Table 6 below).[43, 44]   
Table 6.   Well Controlled Trials Reported in the Literature
Reference Study
Treatment
Placebo 
Response
Treatment 
Response
Abou-Khalil
et al. 
2013 [42]
IM Diazepam
0.50
0.72
Cereghino e al., 1998
[43]
PR Diazepam-
Diastatb
0.40
0.63
Dreifuss et al, 1998a
[44]
PR Diazepam-
Diastatb
0.28
0.64
a)
In this study sequential doses were administered at the onset of seizure, 4 hours (children and adults) and 12 hours (adults only) 
post first dose. Therefore, only the data out to 4 hours post first dose was used.
b)
Response rates were extracted from Kaplan-Meier curves.
In this meta-analysis the outcomes from the three different studies are relatively consistent
with an estimated pooled common Odds Ratio of 2.90, which is significantly lower than 3.5 
assumed Odds Ratio in the original protocol.  With the originally planned sample size of 
132 subjects who have completed the Comparative Phase the power is estimated to be 75%, 
much lower than the targeted 90% power.  Therefore, a classic group sequential design, with 
3 interim analyses and a maximum sample size of 240 subjects who have completed the 
Comparative Phase is proposed in order to reach sufficient overall power (approximately 
90%) for this study with possible study stopping at interims for efficacy or futility.
In this group sequential design, interim analyses will occur after 132, 165, and 204 subjects 
have completed the Comparative Phase.  At any interim analysis the trial may stop early for 
either efficacy or futility.  Assuming a 0.40 placebo rate with the updated odds ratio of 2.9, 
the overall power of this design is approximately 90%, while maintaining 2.5% type I error.  
All interim analyses will be performed using the mITT population and a one-sided test 
comparing two proportions.  Interim analyses will be conducted by an unblinded statistician 
and reviewed by an unblinded Interim Analysis Monitoring Committee (IAMC), both 
independent of the sponsor.  IAMC membership, responsibilities, timelines, and 
communication channels will be clearly specified in a charter.  In particular, the IAMC 
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communication channels with the sponsor will be limited to maintain the blind of the 
sponsor study team in order to minimize the chance of operational bias.   To this end, the 
IAMC will inform senior management first of the decision to continue the trial or stop 
according to the statistical analysis plan.  Senior management will in turn inform the team to 
continue or not to continue the study only with no further information on the interim 
analysis.
In order to achieve the maximum sample size of 240 subjects who have completed the 
Comparative Phase, 350 subjects will be enrolled in the Test-Dose Phase to account for the 
approximate 32% of subjects test dosed that do not complete the requirements for efficacy 
evaluation (receive at least 1 dose of study drug during the Comparative Phase and who 
complete Visit 4).
10.8
Interim Analyses for Success
At the sample sizes of N=132, 165, 204, and 240 subjects completing the Comparative 
Phase, a one-sided test of two proportions is performed to determine the test value to 
compare to the critical value obtained from a Lan-DeMets alpha spending function 
approximating a Pocock boundary.  Complete details for the critical values at each interim 
analysis and simulation results are provided in the SAP.
10.9
Interim Analyses for Futility
At each of the prespecified interim analyses (N=132, 165, 204, futility is not applicable at 
the N=240 final analysis) the predictive probability of success at the maximum sample size 
is computed.  This calculation begins by assuming uniform prior distributions Beta (1,1) on 
probability of treatment success in the control arm (pC) and the probability of treatment 
success in the treatment arm (pT) and computing the posterior distribution with the currently 
available data. The predictive distribution of the final data assuming the maximal sample 
size of N=240 is then computed.  The number of future treatment successes for each arm has 
a Beta-Binomial distribution which is then added the fixed number of current treatment 
successes in each arm.  We may then compute the predictive probability that a trial success 
is reached at N=240 subjects completing the Comparative Phase.  If this predictive 
probability is less than 10%, the trial will be stopped for futility.  Note that the success 
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boundaries are computed assuming no futility stopping, and thus controls type I error 
regardless of the method used for futility stopping.  Complete details and simulation results
are found in the SAP.
11 ADMINISTRATIVE PROCEDURES
11.1
Regulatory Approval
This study requires application to the appropriate regulatory body 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 bodies 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 (IRB) or Independent Ethics Committee 
(IEC) Approval
USL or its designee must receive signed and dated written confirmation that the study 
protocol and ICF and assent forms 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 before 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 
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with GCP. If any such changes are made to the informed consent or assent forms, subjects 
and/or caregivers that 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 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 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 
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notebook will be eligible to enter or make edits to the data. Qualified research personnel 
will accurately enter data from both clinic- 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 
represents 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) has therefore 
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., hospital and general practice 
charts, appointment books, original laboratory records).  The investigator must exercise 
judgment regarding information in a subject’s chart that is not relevant to the performance, 
observations, or conduct of this study.  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.
11.6.1
Data and Safety Monitoring Board
The study will be conducted under the supervision of an independent DSMB (see Section 
10.5.5, Data and Safety Monitoring Board). All DSMB members have extensive experience 
in either clinical trials and/or management of seizures. The DSMB is responsible for the 
ongoing review of a clinical trial and for making recommendations concerning the 
continuation, modification, and termination of the trial.
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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: 

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.
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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 representatives 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 of the request.
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, formulae, 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 
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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 or permission granted by USL. In accordance with generally 
recognized principles of scientific collaboration, coauthorship 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 
publications of this study, refer to the signed agreement between USL and the investigator.
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.
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.  Minor deviations may appear to be of 
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little or no consequence, but nonetheless they should be reported so that they can be 
assessed for their effect on the 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 
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
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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 investigators 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 
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 disclosure statements 
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 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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12 REFERENCE LIST
1.
Cereghino JJ. Identification and treatment of acute repetitive seizures in children and
adults. Curr Treat Options Neurol. 2007;9:249-255.
2.
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338:970-976.
3.
Sankar R, Rho JM. Do seizures affect the developing brain? Lessons from the
laboratory. J Child Neurol. 2007;22:21S-9S.
4.
Bergen DC. Do seizures harm the brain? Epilepsy Curr. 2006;6:117-118.
5.
Lowe MN, Palmer KJ, Wilde MI. Management of acute repetitive seizures: defining
the role of rectal diazepam gel. Dis Manage Health Outcomes. 2000;8:355-368.
6.
Glauser TA. Designing practical evidence-based treatment plans for children with
prolonged seizures and status epilepticus. J Child Neurol. 2007;22:38S-46S.
7.
Fisgin T, Gurer Y, Tezic T, et al. Effects of intranasal midazolam and rectal diazepam
on acute convulsions in children: prospective randomized study. J Child Neurol.
2002;17:123-126.
8.
Charney DS, Mihic SJ, Harris RA. Goodman & Gilman's The Pharmacological Basis
of Therapeutics. 11th ed. New York: McGraw-Hill; 2006.
9.
Versed [Prescribing Information]. Bedford, OH: Ben Venue Laboratories, Inc.; 2001.
10.
Wilton NC, Leigh J, Rosen DR, Pandit UA. Preanesthetic sedation of preschool
children using intranasal midazolam. Anesthesiology. 1988;69:972-975.
11.
Griffith N, Howell S, Mason DG. Intranasal midazolam for premedication of children
undergoing day-case anaesthesia: comparison of two delivery systems with
assessment of intra-observer variability. Br J Anaesth. 1998;81:865-869.
12.
Bell DM, Richards G, Dhillon S, et al. A comparative pharmacokinetic study of
intravenous and intramuscular midazolam in patients with epilepsy. Epilepsy Res.
1991;10:183-1890.
13.
Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectal diazepam for the
home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr
Adolesc Med. 2010;164:747-753.
14.
Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute
childhood seizures. Pediatr Neurol. 2006;34:355-359.
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15.
Fisgin T, Gurer Y, Senbil N, et al. Nasal midazolam effects on childhood acute 
seizures. J Child Neurol. 2000;15:833-835.
16.
Holsti M, Sill BL, Firth SD, Filloux FM, Joyce SM, Furnival RA. Prehospital 
intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care.
2007;23:148-153.
17.
Jeannet PY, Roulet E, Maeder-Ingvar M, Gehri M, Jutzi A, Deonna T. Home and 
hospital treatment of acute seizures in children with nasal midazolam. Eur J Paediatr 
Neurol. 1999;3:73-77.
18.
Kendall JL, Reynolds M, Goldberg R. Intranasal midazolam in patients with status 
epilepticus. Ann Emerg Med. 1997;29:415-417.
19.
Kutlu NO, Yakinci C, Dogrul M, Durmaz Y. Intranasal midazolam for prolonged 
convulsive seizures. Brain Dev. 2000;22:359-361.
20.
Mittal P, Manohar R, Rawat AK. Comparative study of intranasal midazolam and 
intravenous diazepam sedation for procedures and seizures. Indian J Pediatr.
2006;73:975-978.
21.
Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal 
midazolam with intravenous diazepam for treating febrile seizures in children: 
prospective randomised study. BMJ. 2000;321:83-86.
22.
Lahat E, Goldman M, Barr J, Eshel G, Berkovitch M. Intranasal midazolam for 
childhood seizures. Lancet. 1998;352:620.
23.
O'Regan ME, Brown JK, Clarke M. Nasal rather than rectal benzodiazepines in the 
management of acute childhood seizures? Dev Med Child Neurol. 1996;38:1037-
1045.
24.
Kyrkou M, Harbord M, Kyrkou N, Kay D, Coulthard K. Community use of intranasal 
midazolam for managing prolonged seizures. J Intellect Dev Disabil. 2006;31:131-
138.
25.
Mahmoudian T, Zadeh MM. Comparison of intranasal midazolam with intravenous 
diazepam for treating acute seizures in children. Epilepsy Behav. 2004;5:253-255.
26.
McGlone R, Smith M. Intranasal midazolam. An alternative in childhood seizures. 
Emerg Med J. 2001;18:234.
27.
Scheepers M, Comish S, Cordes L, Clough P, Scheepers B. Buccal midazolam and 
rectal diazepam for epilepsy. Lancet. 1999;353:1797-1798.
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28.
Scheepers M, Scheepers B, Clarke M, Comish S, Ibitoye M. Is intranasal midazolam 
an effective rescue medication in adolescents and adults with severe epilepsy? Seizure.
2000;9:417-422.
29.
Scheepers M, Scheepers B, Clough P. Midazolam via the intranasal route: an effective 
rescue medication for severe epilepsy in adults with learning disability. Seizure.
1998;7:509-512.
30.
Segal DC, Vofsi O, Katz Y. An alternative route of drug administration in acute 
convulsions. Isr Med Assoc J. 2000;2:629.
31.
Wilson MT, Macleod S, O'Regan ME. Nasal/buccal midazolam use in the community. 
Arch Dis Child. 2004;89:50-51.
32.
Koren G. Intranasal midazolam for febrile seizures. A step forward in treating a 
common and distressing condition. BMJ. 2000;321:64-65.
33.
Smith M, Carley S. Best evidence topic report. Intranasal midazolam in patients with 
fits. Emerg Med J. 2005;22:436-437.
34.
Rey E, Treluyer JM, Pons G. Pharmacokinetic optimization of benzodiazepine therapy 
for acute seizures. Focus on delivery routes. Clin Pharmacokinet. 1999;36:409-424.
35.
Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status 
epilepticus. Am J Emerg Med. 2006;24:343-346.
36.
Pieri L, Schaffner R, Scherschlicht R, et al. Pharmacology of midazolam. 
Arzneimittelforschung. 1981;31:2180-2201.
37.
Lyseng-Williamson KA, Yang LP. Topiramate: a review of its use in the treatment of 
epilepsy. Drugs. 2007;67:2231-2256.
38.
French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new 
antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS 
Subcommittees of the American Academy of Neurology and the American Epilepsy 
Society. Epilepsia. 2004;45:410-423.
39.
Wermeling DP. Intranasal delivery of antiepileptic medications for treatment of 
seizures. Neurotherapeutics. 2009;6:352-358.
40.
End-of-Phase-2 Briefing Document for FDA, Appendix 3a. Intranasal Therapeutics, 
Inc.;
2008 Oct 21. Report No.: SN 0016.
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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.
Abou-Khalil B, Wheless J, Rogin J et al. A double-blind, randomized, placebo-
controlled trial of a diazepam auto-injector administered by caregivers to patients with
epilepsy who require intermittent intervention for acute repetitive seizures. Epilepsia
2013;54;1968-1976.
43.
Cereghino JJ, Mitchell WG, Murphy J et al. Treating repetitive seizures with a rectal
diazepam formulation. Neurology 1998;51;1274-1282.
44.
Dreifuss FE, Rosman NP, Cloyd JC et al. A Comparison of Rectal Diazepam Gel and
Placebo for Acute Repetitive Seizures. NEJM 1998;338;1869-1875.
45.
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.
46.
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.
47.
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.
48.
Thakker A, Shanbag P. A randomized controlled trial of intranasal-midazolam versus
intravenous-diazepam for acute childhood seizures. J Neurol 2012.
49.
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 Visit 4 / ET. If the subject 
was taking any of these medications at or before Visit 1, the time between the last dose of that 
substance and Visit 2 must be equal to or greater than the minimum washout time shown 
below. 
The first listing 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 of substances represents opioids, or 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 the usage is unlikely 
to achieve meaningful systemic levels. These lists may not be all-inclusive; direct any 
questions to the Medical Monitor.
Listing 1:
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
Bergamottin (a 
constituent of 
grapefruit juice)
----
7
C
Chloramphenicol
Alficetyn, Amphicol, Biomicin, Chlornitromycin, 
Chlora, Phenicol, Medicom, Nevimycin Vernacetin, 
Veticol
7
Cimetidine
Tagamet
7
Cyclosporine
Gengraf, Neoral, Sandimmune
7
Cisapride
Propulsid
7
Clarithromycin
Biaxin, Biaxin XL
7
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D
Danazol
Danocrine
7
Delavirdine 
Rescriptor
7
Diethyldithiocarbamate
(diethyldione,
diethyldithiocarbamic 
acid)
—
7
Diltiazem
Cardizem, Tiazac, Dilacor XR
7
E
Echinacea 
—
7
Efavirenz 
Efavirenz
11
Ergotamine 
Cafergot
7
Erythromycin
Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, 
E.E.S.-400, Filmtab, Erymax, Ery-Tab, Eryc,Ranbaxy, 
Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin 
Stearate Filmtab, Erythrocot, E-Base, Erythroped, 
Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, 
Abboticin-ES, Erycin, PCE Dispertab, Stiemycine, 
Acnasol, Tiloryth
7
F
Fluoxetine 
Prozac, Fontex, Ladose, Sarafem, Solax, Lovan 
30
Fluvoxamine 
Luvox
7
G
Gestodene
Minesse 
7
Grapefruit
—
7
Grapefruit juice
—
7
I 
Imatinib
Gleevec 
7
Indinavir
Crixiban 
7
Itraconazole
Sporanox 
7
K 
Ketoconazole
Nizoral 
7
L 
Lovastatin 
Mevacor
7
M 
Metronidazole[a]
Flagyl
7
Mibefradil 
Posicor (withdrawn from US market) 
7
Miconazole[a]
Monistat 
7
Mifepristone 
Mifeprex 
7
N
Nefazodone 
Serzone
7
Nelfinavir 
Viracept 
7
Nevirapine 
Viramune
9
Nisoldipine 
Sular
7
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Nitrendipine 
Bayotensin, Baypress, Bylotensin, Deiten, Nidrel, 
Nitrepin
7
Norfluoxetine
( metabolite of 
fluoxetine)
—
30
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
Seville oranges
—
7
Star fruit
—
7
St. John’s Wort
—
30
T
Tacrolimus
FK506, Prograf
8
Telithromycin
Ketek
7
Thalidomide
Thalomid
7
Troleandomycin
Tao
7
V
Verapamil
Calan, Isoptin
7
Voriconazole
VFEND
7
Z
Zafirlukast
Accolate
7
[a] Topical and vaginal metronidazole and miconazole are allowed.
— indicates no other name was available at the time this protocol was prepared.
Listing 2
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
7
H
Hydrocodone  
Lorcet
1
Hydromorphone  
Dilaudid
1
L
Levorphanol 
Levo-Dromoran
2
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Generic or 
Substance Name
Other Name
(US Brand Name or Research Designation)
Minimum Washout
Period
(days)
M
Methadone   
Dolophine
2
Meperidine  
Demerol
1
Morphine
Duramorph 
7
O
Oxycodone  
Oxycontine 
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 or Substances
B
Buspirone
Ansial, Ansiced, Anxiron, Axoren, Bespar, BuSpar, 
Buspimen, Buspinol, Buspisal, Narol, Spitomin, Sorbon
7
P
Pimozide
Orap 15
15
Propofol
Diprivan
7
T
Tetrahydrocannabinol
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: P261-401
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of 
Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects with Seizure 
Clusters
ARTEMIS-1: Acute Rescue Therapy in Epilepsy with Midazolam Intranasal Spray-1
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 effects of USL261 on olfaction.
Change 2
The procedures to be completed at Visits 1, 4, and on the monthly telephone follow-up calls
between Visit 3 and Visit 4 have been updated to add collection of the number of calls to 
EMS and ER visits for a seizure cluster or other seizure emergency prior to Visit 1 and 
during the study. This change has been made to allow for collection of number of calls to 
EMS and ER visits due to seizure emergencies prior to and during the study beyond use of 
EMS, ER, or the Rescue Protocol in the 24 hours after study drug administration. This will 
allow for assessment of healthcare utilization while USL261 is available to the caregiver 
and subject for the entire duration of the study. 
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Change 3
The introduction section was updated to reflect current study status.
Change 4
The time between Visit 2 (Test Dose) and Visit 3 (Randomization was clarified. Visit 3 is to 
occur within 24 hours to 28 days of Visit 2. The time between Visit 2 and Visit 3 may be 
extended, the extension must be approved by the Sponsor or CRO designee.
SECTIONS OF PROTOCOL AFFECTED BY CHANGE
Change 1
Synopsis – Safety Objective and 2.2 Safety Objective:

Brief Smell Identification Test (B-SIT)
Synopsis – Safety Assessments:
Collection of AEs, physical and neurological examinations, clinical laboratory evaluations, 
vital signs, caregiver-recorded respiration rate, 12-Lead ECG, pulse oximetry, sedation 
(determined by the OAA/S), C-SSRS, and the need for second dose of medication or 
emergency treatment, and B-SIT.
Synopsis – Statistical Methods, Safety:

Olfactory assessment results and changes from baseline will be presented by 
treatment group and visit.
Table 1 – Procedure Schedule:
Phase
Screening
Test-Dose 
Phase
Comparative Phase
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Visit Number
1
2[a]
3[b]
Treatment[c]
4 or 
ET[d]
Study Assessments
B-SIT
X
X
X
6.1.2.1 Before Administration of Test Dose at Visit 2

Administer B-SIT (see Section 6.2.2.9)
6.1.4 Visit 3 (Randomization)

Administer B-SIT (see Section 6.2.2.9)
6.1.6
Visit 4 (Post Dose Assessment or Early Termination)

Administer B-SIT (see Section 6.2.2.9)
6.2.2.9 Brief Smell Identification Test
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 (pre-dose only), Visit 3, 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.
10.5.4 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
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Table 1 – Procedure Schedule:
Phase
Screening
Test-Dose 
Phase
Comparative Phase
Visit Number
1
2[a]
3[b]
Treatment[c]
4 or 
ET[d]
Study Assessments
ER and EMS Visit Review [h]
X
X
[h] At Visit 1, collect number of calls to EMS and ER visits for a seizure cluster or other seizure emergency in the year prior 
to screening. At Visit 4, 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. Number of calls to EMS and ER visits for a seizure cluster or other seizure emergency since 
last visit or follow-up phone call will also be collected on each monthly telephone follow up call between Visit 3 and Visit 4 
or ET. 
6.1.1 Visit 1 (Screening Visit)

Collect number of calls to EMS and ER visits for a seizure cluster or other seizure 
emergency in the year prior to screening.
6.1.6
Visit 4 (Post Dose Assessment or Early Termination)

Collect number of calls to EMS and ER visits for a seizure cluster or other seizure 
emergency since Visit 3 or the most recent follow-up phone call.
6.1.6.1 Telephone Follow Up and Support

Collect number of calls to EMS and ER visits for a seizure cluster or other seizure 
emergency since Visit 3 or the most recent follow-up phone call.
Change 3
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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Table 3.  Summary of Completed and Ongoing Clinical Studies with USL261
Protocol 
No.
Objective(s) of the 
Study
Study Design and 
Type of Control
Test Product(s); Dosage 
regimen; Route of 
Administration
Number of 
Subjects; Age 
Range
Type of 
Subjects
Duration of 
Study
PD and Safety 
Assessments
Completed Studies
MZ0714
Evaluate BA, PK, 
and safety of single 
doses of USL261; 
Compare PK and 
PD of USL261, 
midazolam IV 
infusion, and 
midazolam IV 
administered IN via 
needleless syringe. 
Open-Label, 
Five-Way 
Crossover, 
Randomized 
Subjects received 
5 different MZ treatments 
in random sequence:  2.5, 
5.0, or 7.5 mg USL261; 2.5 
mg IV MZ infused over 
15 min; and 5.0 mg MZ 
(from IV formulation) 
administered IN via a 
needleless syringe 
25 Subjects
18 – 45 y
Healthy 
human 
volunteers
5 visits in 
approximately 
5-6 weeks, 
preceded by a 
screen visit 
(-1 to -21 
days) 
SSS, DSST, 
OAA/S, 
physical exam, 
nasal exam,
vital signs, 
TEAEs, oxygen 
saturation, 
subject sensory 
perception
MZ0815
Determine the 
safety, tolerability, 
PK and PD of 
ascending single-
and two-dose 
regimens of USL261 
Open-Label 
Subjects received IN 
USL261 at 2 visits. At Visit 
1 they received a single 
dose; at Visit 2 they 
received 2 doses separated 
by 15 minutes. 
A: 2.5 mg/2.5 mg+2.5 mg
B:5.0 mg /5.0 mg +2.5 mg
C: 5.0 mg /5.0 mg +5.0 mg
D. 7.5 mg /7.5 mg +5.0 mg
E: 7.5 mg /7.5 mg +7.5 mg
An overall 
total of 90 
subjects (60 
adults 18-65 
y; 30 
adolescents 
12-17 y) 
Subjects 
with 
epilepsy 
taking 
stable 
doses of 
AEDs
4 visits for a 
total study 
duration of 
approximately 
1 ½ to 6 weeks 
for each 
subject
SSS, DSST, 
OAA/S, 
physical 
(including 
nasal) and 
neurological 
exams, vital 
signs, TEAEs, 
oxygen 
saturation, 
subject sensory 
perception
P261-201
Evaluate the safety, 
tolerability, PK, and 
PD of ascending 
single- and two-dose 
regimens of USL261 
compared with that 
of placebo 
Randomized, 
Double-Blind, 
Placebo-
Controlled, Dose 
Escalation 
Subjects received a single 
10, 15, 17.5, or 20 mg dose 
of IN USL261 or placebo, 
followed ≥3 days later by 
the same total dose or 
placebo, administered as 2 
divided doses 10 minutes 
apart. Four dose cohorts 
were completed in 
ascending order, and dose 
60 adult 
subjects;
18 – 65 y
Subjects 
with 
epilepsy 
taking 
stable 
doses of 
AEDs
4 visits 
(screening, 2 
evaluation 
visits, and 
follow-up) 
over a 7 to 58 
day time 
frame 
TEAEs, vital 
signs, oxygen 
saturation; 
SSS, OAA/S, 
and Coding 
subtest of 
Wechsler 
Adult 
Intelligence 
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Protocol 
No.
Objective(s) of the 
Study
Study Design and 
Type of Control
Test Product(s); Dosage 
regimen; Route of 
Administration
Number of 
Subjects; Age 
Range
Type of 
Subjects
Duration of 
Study
PD and Safety 
Assessments
escalation occurred only 
after review of safety data.
Scale-IV 
(WAIS-IV)
P261-102
Evaluate the safety, 
tolerability, PK and 
PD of USL261 in 
geriatric and non-
geriatric subjects
Randomized, 
Investigator and 
subject blind, 
Sponsor open
Subjects were randomized 
to receive a single dose of 
2.5 and 5.0 mg USL261 at 2 
study visits in a crossover 
fashion.
A total of 30 
subjects (12 
adult 18-40 y; 
18 geriatrics 
≥65 y)
Generally 
healthy 
geriatric 
and non-
geriatric 
subjects.
4 visits 
(screening, 2 
evaluation 
visits, and 
follow-up) 
over a 9 to 50 
day time 
frame 
TEAEs, vital 
signs, oxygen 
saturation; 
SSS, OAA/S, 
and DSST
Ongoing Studies
P261-401
Evaluate the 
efficacy, safety, and 
tolerability of 
USL261 compared 
with IN placebo for 
the outpatient 
treatment of seizure 
clusters; Evaluate 
the PK profile of 
USL261 after 
administration of 
10 mg open-label 
USL261 (2 single, 
5 mg test doses 
administered 
10 min apart)
Randomized, 
Double-Blind, 
Placebo-
Controlled 
Test-Dose Phase:  2 doses 
of open-label 5.0 mg IN 
USL261 administered 
10 minutes apart.
Comparative Phase: 
subjects are randomized 
2:1 to receive 5.0 mg IN 
USL261 or placebo to be 
administered during a 
seizure cluster event, with 
the possibility of 
administration of an open-
label 5.0 mg IN USL261 
dose 10 min to 6 hrs after 
the double-blind dose.
Planned: a 
maximum of 
approximately 
240
subjects; 
≥12y
Subjects 
with 
epilepsy 
who have 
seizure 
clusters
A test-dose 
phase of up to 
28 days, 
followed by a 
comparative 
phase which 
will be 
variable, 
dependent on 
when the 
subject 
experiences a 
seizure cluster
OAA/S, C-
SSRS, physical 
and 
neurological 
exam, vital 
signs, TEAEs, 
clinical 
laboratory 
evaluations, 
ECG, pulse 
oximetry, and 
need for 2nd 
dose or 
emergency 
treatment
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Protocol 
No.
Objective(s) of the 
Study
Study Design and 
Type of Control
Test Product(s); Dosage 
regimen; Route of 
Administration
Number of 
Subjects; Age 
Range
Type of 
Subjects
Duration of 
Study
PD and Safety 
Assessments
P261-301
Evaluate the 
efficacy, safety, and 
tolerability of 
USL261 compared 
with IN placebo for 
the treatment of 
intermittent bouts 
of increased seizure 
activity in subjects 
admitted to the 
EMU
Randomized, 
Double-Blind, 
Placebo-
Controlled 
Eligible subjects will be 
randomized 1:1 to receive 
5.0 mg IN USL261 or 
placebo.  
Planned: 
approximately 
62 subjects; 
≥12 y
Subjects 
with 
epilepsy 
admitted 
to the 
EMU who 
present 
seizure 
activity 
that meets 
defined 
Treatment 
Criteria
Screening 
may occur at 
EMU 
admission or 
up to 28 days
prior; 
Treatment 
may occur 
any time 
during EMU 
admission 
with 
monitoring 
for up to 6 hrs 
post-dose; 
Exit 
Assessment 
may occur up 
to 48 hrs after 
treatment
TEAEs, 
clinical 
laboratory 
evaluations, 
vital signs, 
ECGs 
(screening 
only), physical, 
nasal, and 
neurological 
exams, C-SSRS
AED indicates anti-epileptic drugs; BA, bioavailability; C-SSRS, Columbia-Suicide Severity Rating Scale; DSST, Digit Symbol Substitution Test; ECG, electrocardiogram; 
EMU, epilepsy monitoring unit; IN,  intranasal; IV, intravenous; MZ, midazolam; OAA/S, Observer’s Assessment of Alertness/Sedation; PD, pharmacodynamic; PK, 
pharmacokinetic; SSS, Stanford Sleepiness Scale; TEAE, treatment-emergent adverse event.
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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%) was considered related to study drug.  No serious adverse events 
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(SAEs) or 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 suggests that 
they were related to route of administration. 
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 to 20 minutes after 
a single dose; approximately 20 to 30 minutes after the 2-dose regimen) and the midazolam 
Cmax, AUC0-t, and AUC0-∞ general increased with total dose. Midazolam Cmax was lower 
in adolescents as compared to adults. The mean t1/2 following the 2-dose regimen of USL261 
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 antiepileptic drugs 
(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 
adverse events AEs.  Most TEAEs were mild to moderate in severity and deemed probably 
related to study drug.  The most frequently-reported TEAEs (reported by ≥10% of subjects) 
associated with the study drug were dysgeusia (86%), oropharyngeal pain (57%), rhinalgia 
(31%), and burning sensation (11%).  One subject, who was administered a total dose of 12.5 
mg USL261, 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.
USL has completed the clinical conduct of a third Phase I clinical trial (P261-201) entitled 
“A Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study to Determine the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intranasal Midazolam 
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(USL261) in Adult Subjects with Epilepsy on Stable Antiepileptic Drug Regimens”.  This 
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.
USL has completed the clinical conduct of a fourth Phase I clinical trial (P261-102) entitled 
“A Randomized, Investigator and Subject Blind, Sponsor Open, Phase 1 Study of the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Intranasal Midazolam (USL261) 
in Healthy Geriatric and Non-Geriatric Subjects”.  This 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.
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 
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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 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.
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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.
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 
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≥ 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.
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 
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Confidential 
Protocol P261-401
Approved Protocol Version: 
Amendment 4, 20 May 2015
157 of 158
Upsher-Smith Laboratories, Inc.
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.
Change 4
3.4 Comparative Phase
Subjects and caregivers will return to the study center for Visit 3 within 24 hours to 28 days of 
Visit 2 (unless DSMB review is not yet completed).  The time between Visit 2 and Visit 3 may 
be extended in certain cases; however, the extension must be approved by the Sponsor or 
CRO designee.
6.1.4 Visit 3 (Randomization)
For subjects enrolled in the study after the initial DSMB review, Visit 3 will take place between 
24 hours and 28 days after Visit 2.  The time between Visit 2 and Visit 3 may be extended in 
certain cases; however, the extension must be approved by the Sponsor or CRO designee.
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Confidential 
Protocol P261-401 
Protocol Signature Page 
Authorized Sponsor Representative Signature: 
, Pharm.D. 
Upsher-Smith Laboratories, Inc. 
6701 Evenstad Drive 
Maple Grove, MN 55369-6026 
Date 
Investigator Agreement: By my signature, I confirm that my staff and I have carefully read and 
understand this protocol or protocol amendment, and agree to comply with the conduct and terms 
of the study specified herein and with any other study conduct procedures provided by 
Upsher-Smith Laboratories, Inc. (USL). For protocol amendments, I agree not to implement the 
amendment without agreement from USL and prior submission to and written approval (where 
required) from the Institutional Review Board (IRB), except when necessary to eliminate an 
immediate hazard to the subjects, or for administrative aspects of the study (where permitted by 
all applicable regulatory requirements). 
I agree to conduct the study in accordance with 
International -Conference of Harmonisation E6, Guideline for Good Clinical Practice, and 
applicable regulatory requirements. 
Principal Investigator 
Name oflnvestigator (Print) 
Signature of Investigator 
Approved Protocol Version: 
Amendment 4, 20 May 2015 
Laboratories, Inc. 
Site Number 
Date 
158of158 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
A Randomized, Double-Blind, Placebo-Controlled Study of the 
Safety and Efficacy of Intranasal Midazolam (USL261) in the Outpatient 
Treatment of Subjects with Seizure Clusters 
ARTEMIS-1: Acute Rescue Therapy in Epilepsy with Midazolam 
Intranasal Spray-1
Protocol Number P261-401
Upsher-Smith Laboratories, Inc.
6701 Evenstad Drive
Maple Grove, MN 55369
Date of Plan:   April 14, 2017 (Final v2.9)
CONFIDENTIAL
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STATISTICAL ANALYSIS PLAN 
Final 2.9 
A Randomized, Double-Blind, Placebo-Controlled Study of the 
Safety and Efficacy oflntranasal M:idazolam (USL261) in the Outpatient 
Treatment of Subjects with Seizure Clusters 
ARTEMIS-1: Acute Rescue Therapy in Epilepsy with Midazolam Intranasal 
Spray-1 
APPROVAL SIGNATURES 
Development Program Leader 
Upsher-Smith Laboratories, Inc. 
Biostatistics 
H20 Clinical, LLC 
-
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Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
3
TABLE OF CONTENTS
LIST OF ABBREVIATIONS......................................................................................................7
1.
INTRODUCTION....................................................................................................8
2.
STUDY DESIGN.....................................................................................................8
2.1.
General Study Design and Plan.................................................................................8
2.1.1.
Screening..................................................................................................................9
2.1.2.
Test-Dose Phase .....................................................................................................10
2.1.3.
Comparative Phase .................................................................................................10
2.2.
Randomization and Method of Treatment Assignment............................................11
2.3.
Study Procedures....................................................................................................12
3.
STUDY OBJECTIVES...........................................................................................15
3.1.
Primary Efficacy Objective.....................................................................................15
3.2.
Secondary Efficacy Objectives ...............................................................................15
3.3.
Exploratory Efficacy Objectives .............................................................................15
3.4.
Safety Objectives....................................................................................................15
3.5.
Pharmacokinetic Objectives....................................................................................16
4.
ANALYSIS POPULATIONS.................................................................................16
4.1.
Screened Population ...............................................................................................16
4.2.
Safety Population....................................................................................................16
4.3.
Randomized Population..........................................................................................16
4.4.
Randomized Safety Population ...............................................................................17
4.5.
Modified Intent-to-Treat Population (mITT)...........................................................17
4.6.
Per Protocol Population ..........................................................................................17
4.7.
Pharmacokinetic Population....................................................................................17
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................18
5.1.
Level of Significance..............................................................................................18
5.2.
Handling of Missing Data.......................................................................................18
5.3.
Interim Analyses.....................................................................................................19
5.3.1.
Early Success..........................................................................................................19
5.3.2.
Early Futility ..........................................................................................................20
5.3.3.
Early Termination not related to Success or Futility................................................20
5.3.4.
Logistical details for interim analyses .....................................................................20
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Statistical Analysis Plan for Protocol No.: P261-401
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5.4.
Examination of Subgroups......................................................................................21
5.5.
Data Collected from Unscheduled Visits.................................................................21
6.
DESIGN OPERATING CHARACTERISTICS......................................................21
6.1.
Simulation Scenarios ..............................................................................................21
6.2.
Operating Characteristics........................................................................................22
7.
STATISTICAL ANALYSIS...................................................................................22
7.1.
Subject Disposition.................................................................................................23
7.2.
Protocol Deviations ................................................................................................23
7.3.
Demographics and Baseline Characteristics ............................................................24
7.4.
Medical and Surgical History..................................................................................24
7.5.
Prior and Concomitant Medications........................................................................25
7.6.
Analyses of Efficacy Endpoints ..............................................................................26
7.6.1.
Primary Efficacy Endpoint......................................................................................26
7.6.1.1.
Derivation of Treatment Success Endpoint .............................................................27
7.6.1.2.
Analysis of the Primary Endpoint ...........................................................................28
7.6.2.
Secondary Efficacy Endpoints ................................................................................29
7.6.2.1.
Proportion of Subjects with Recurrence of Seizure(s) Beginning 10 Minutes 
after Administration of Double-Blind Study Drug to 4 Hours after Double-
Blind Study Drug Administration ...........................................................................29
7.6.2.2.
Time to Next Seizure with a Start Time >10 Minutes after Double-Blind 
Study Drug Administration.....................................................................................30
7.6.3.
Exploratory Efficacy Analyses................................................................................30
7.6.3.1.
Proportion of Subjects with Recurrence of Seizure(s) Beginning 10 Minutes 
after Study Drug Administration to 24 Hours after Study Drug 
Administration........................................................................................................30
7.6.3.2.
Return to Full Baseline Functionality within 24 Hours after Study Drug 
Administration (as determined by the caregiver).....................................................31
7.6.3.3.
Analyses for Subjects Receiving 2 Doses of Study Drug.........................................31
7.6.3.4.
Treatment Success of all Dose of Study Drug .........................................................32
7.6.3.5.
Subject and Caregiver Outcome Assessments.........................................................33
7.7.
Safety Analyses ......................................................................................................34
7.7.1.
Adverse Events (AEs).............................................................................................34
7.7.1.1.
Pre-treatment AEs ..................................................................................................34
7.7.1.2.
Treatment-emergent AEs (TEAEs) .........................................................................34
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Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
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7.7.2.
Observer’s Assessment of Alertness/Sedation (OAA/S)..........................................37
7.7.2.1.
Composite Score.....................................................................................................37
7.7.2.2.
Sum Score ..............................................................................................................37
7.7.2.3.
Pharmacodynamic (PD) Parameters........................................................................37
7.7.3.
Requirement for Unscheduled ER or EMS Visit .....................................................38
7.7.4.
Brief Smell Identification Test (B-SIT; United States only) ....................................38
7.7.5.
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................38
7.7.5.1.
Suicidal Ideation.....................................................................................................39
7.7.5.2.
Suicidal Behavior ...................................................................................................39
7.7.6.
Physical, Nasal, and Complete Neurological Examinations.....................................40
7.7.7.
Laboratory Parameters............................................................................................40
7.7.8.
Vital Signs and Oxygen Saturation .........................................................................40
7.7.9.
Electrocardiogram (ECG) .......................................................................................41
8.
OTHER PLANNED ANALYSES ..........................................................................41
8.1.
Pharmacokinetic (PK) Analyses..............................................................................41
8.2.
Pharmacokinetic/Pharmacodynamic Variables and Analyses ..................................42
9.
CHANGES TO THE PLANNED ANALYSIS .......................................................42
10.
MOCK TABLES, FIGURES, AND DATA LISTINGS..........................................44
11.
REFERENCES.......................................................................................................44
APPENDIX 1.
POTENTIALLY CLINICALLY SIGNIFICANT LABORATORY 
VALUES................................................................................................................45
APPENDIX 2.
CLASSIFICATION OF ENZYME INDUCING AEDS..................................46
APPENDIX 3.
LIST OF AE TERMS OF SPECIAL INTEREST............................................49
LIST OF TABLES
Table 1:
Schedule of the Study Procedures...........................................................................12
Table 2:
Required p-values for declaring success according to Lan-DeMets Pocock 
Approximation Spending Function .........................................................................20
Table 3:
Study Phases Start and End.....................................................................................22
Table 4:
Classification of Prior and Concomitant Medications..............................................25
Table 5:
Search Strategy for AESI........................................................................................36
Table 6:
Pharmacodynamic Parameters ................................................................................38
Table 7:
Suicidal Ideation Scores..........................................................................................39
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Statistical Analysis Plan for Protocol No.: P261-401
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Table 8:
Potentially Clinically Significant Laboratory Values...............................................45
Table 9:
Listing of Non-Enzyme Inducing AEDs .................................................................46
Table 10:
List of Enzyme Inducing AEDs ..............................................................................46
Table 11:
Abuse-related AEs (MedDRA Preferred Term).......................................................49
Table 12:
AEs Related to Acute Central Respiratory Depression (SMQ) ................................51
Table 13:
AEs Related to Route of Administration-Oral Soft Tissue Conditions (HLT)..........60
Table 14:
AEs Related to Route of Administration-Respiratory Disorders NEC (HLT) ..........68
Table 15:
AEs Related to Route of Administration-Upper Respiratory Tract Disorders 
(HLT) (Exclude Infections).....................................................................................77
Table 16:
AEs Related to Taste and Smell Disorders (SMQ) ..................................................92
Table 17:
AEs Related to Depression and Suicidality/Self-Injury-Depression (SMQ) 
(Exclude Suicide/Self-Injury) .................................................................................93
Table 18:
AEs Related to Depression and Suicidality/Self-Injury-Suicide/Self-Injury 
(SMQ)..................................................................................................................102
LIST OF FIGURES
Figure 1:
Study Design ............................................................................................................9
Figure 2:
Disposition Flow Chart...........................................................................................23
Figure 3:
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) .....................................................................................................28
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Statistical Analysis Plan for Protocol No.: P261-401
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LIST OF ABBREVIATIONS
Abbreviation
Definition
µL
Microliter
ACLS
Advanced Cardiac Life Support
AE
Adverse event
AED
Antiepileptic Drugs
ATC
Anatomic Therapeutic Chemical
B-SIT
Brief Smell Identification Test
C-SSRS
Columbia-Suicide Severity Rating Scale
CFR
Code of Federal Regulations
CI
Confidence interval
CRO
Contract Research Organization
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
EMS
Emergency Medical Services
ER
Emergency Room
ET
End of Treatment
GCP
Good Clinical Practice
IAMC
Interim Analysis Monitoring Committee
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IN
Intranasal
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITI
Intranasal Therapeutics, Inc.
ITIQ
Intranasal Therapy Impact Questionnaire 
ITT
Intent-to-treat
LAR
Legally acceptable representative
MCS
Mental Health Component Score (SF-12v2)
MDZ
Midazolam
Mg
Milligram
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intent-to-treat
OAA/S
Observer’s Assessment of Alertness/Sedation
IV
Intravenous
PCS
Physical Health Component Score (SF-12v2)
PK
Pharmacokinetic
PMP
Patient Management Plan
PT
Preferred Term in MedDRA
RSAF
Randomized Safety Population 
SAS
Statistical Analysis Software
SD
Standard deviation
USL
Upsher-Smith Laboratories, Inc.
USL261
Midazolam Nasal Spray, study drug (formally ITI-111)
SOC
System Organ Class in MedDRA
TEAE
Treatment-emergent adverse event
TSQM
Treatment Satisfaction Questionnaire for Medication
WHO
World Health Organization
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Statistical Analysis Plan for Protocol No.: P261-401
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1.
INTRODUCTION
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 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 of the Phase 3 study Protocol P261-401 (Fifth Issue, 
Amendment 4, 20 May 2015).
2.
STUDY DESIGN
2.1.
General Study Design and Plan
This is a Phase 3 multicenter study, with 2 distinct phases and 4 study center visits as depicted in
Figure 1. The first phase is the Test-Dose Phase where subjects will receive 2 doses of open-
label 5.0 mg USL261 10 minutes apart at the study center. The Test-Dose Phase is designed to 
assess the safety, tolerability and pharmacokinetics of USL261 in a monitored setting and 
provide the caregivers with training on the study procedures. The Test-Dose Phase will be 
followed by an outpatient, double-blind, placebo-controlled, parallel-group phase, referred to as 
the Comparative Phase. In the Comparative Phase, all subjects will be randomized 2:1 to receive 
5.0 mg USL261 or placebo. The subject’s caregiver will administer the double-blind study drug 
at the time of a seizure cluster that meets the study criteria, according to the subject’s 
individualized Patient Management Plan (PMP). The double-blind dose of study medication may 
be followed by an open-label single dose of 5.0 mg USL261 if any of the following occurs:

The treated seizure cluster 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 <8 breaths per minute, does not require 
emergency rescue treatment and assisted breathing intubation, and does not have 
excessive uncharacteristic sedation 
Anytime between 24 to 120 hours after study drug administration, subjects and caregivers will 
return to the study center for a post-dose study visit (Visit 4). 
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Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
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A maximum of approximately 350 subjects, aged 12 years and older, with a documented history 
of seizure clusters and on a stable AED regimen (no change in type[s] of drug) will be enrolled 
in the Test-Dose Phase in order to achieve a maximum of 240 subjects completing the 
Comparative Phase. Before any subject continues to the Comparative Phase, safety data from at 
least 25 subjects in the Test-Dose Phase will be reviewed by an independent Data and Safety 
Monitoring Board (DSMB). Enrollment will temporarily halt once approximately 25 subjects 
complete the Test-Dose Phase, to allow the DSMB to review the safety data. If the safety data 
from this initial cohort supports continuation of the trial according to the DSMB, enrollment into 
the Test-Dose Phase will resume and the initial 25 subjects will proceed to the Comparative 
Phase. All subsequent subjects will progress directly from Test-Dose Phase to the Comparative 
Phase.
A classic group sequential design, with 3 interim analyses and a maximum sample size of 240 
subjects who have completed the Comparative Phase is utilized in order to reach sufficient 
overall power (approximately 90%) for this study with possible study stopping at interims for 
efficacy or futility. In this group sequential design, interim analyses will occur after 132, 165, 
and 204 subjects have completed the Comparative Phase.
Figure 1 shows the overall study scheme with regard to screening, Test-Dose Phase, and 
Comparative Phase. 
Figure 1:
Study Design
2.1.1.
Screening
After subjects and caregivers have provided informed consent (and assent, where appropriate), 
subjects will undergo screening procedures at Visit 1 (see Table 1). At Visit 1, training will be 
provided to the caregivers for self-study, which will be completed at or before Visit 2. The 
screening period (time between Visit 1 and 2) will be a maximum of 28 days. The screening 
period may be extended in certain cases; however, the extension of the screening period must be 
approved by the Sponsor or CRO designee. If a screening period extension is granted for a given 
subject, that subject will have to undergo repeat screening laboratory and ECG assessments 
within 28 days before Visit 2.
Visit 1
Screening
Visit 2
Test-Dose
Visit 3
Randomization
Seizure 
Cluster 
Treatment
Visit 4
Post-Dose 
Visit
24-120 hours 
after dose
Test-Dose 
Phase
Comparative 
Phase
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Statistical Analysis Plan for Protocol No.: P261-401
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2.1.2.
Test-Dose Phase
The Test-Dose Phase, which occurs at Visit 2, will take place at the study center under the 
supervision of the study investigator within 28 days of Visit 1. The investigator, or other 
qualified study personnel, will review, assess, and (if needed) re-instruct subjects and caregivers 
on the information provided in the self-study training. Caregivers must demonstrate hands-on 
competence in performing timed assessments and recording information in the Subject 
Workbook, as well as airway management techniques. 
Subjects who meet eligibility criteria at Visit 2 will receive a test dose of 5.0 mg USL261 
administered by a member of the study center personnel followed by a second dose of 5.0 mg 
USL261 10 minutes later administered by the caregiver under the supervision of a member of the 
study center personnel. Caregivers and study center personnel will monitor the subject during the 
observation period for at least 4 hours after the test doses are administered and the assessments 
outlined in Table 1 will be performed. After 132 subjects have completed the Comparative 
Phase, for all new test dosed subjects, caregivers and study center personnel will monitor the 
subject during the observation period for at least 1 hour after test dose administration. A subject 
who experiences signs or symptoms at Visit 2 that are concerning in the investigator’s judgment 
or are exclusionary per exclusion criterion number 22 must be monitored until resolved or longer 
as deemed appropriate by the investigator.
At least one study center personnel who is trained and qualified to perform airway assessment 
and management, including endotracheal intubation (or local country /site equivalent) and 
Advanced Cardiac Life Support (ACLS) (or local country/site equivalent), will be available at 
the site for the entire observation period following the administration of the first test dose.
2.1.3.
Comparative Phase
Subjects and caregivers will return to the study center for Visit 3 within 24 hours to 28 days of 
Visit 2 (unless DSMB review of first 25 subjects is not yet completed). At Visit 3, the 
investigator, or other qualified study personnel, will review, assess, and (if needed) re-instruct 
caregivers on the information provided in the self-study training. Before subjects are 
randomized, caregivers must have demonstrated hands-on competence in administering the study 
drug, performing timed respiration rate measurements and recording them in the practice Subject 
Worksheet, as well as airway management techniques.
If the subject continues to meet eligibility criteria at Visit 3, he/she will be randomized to receive 
either USL261 5.0 mg or placebo. Caregivers will receive a study materials kit, which includes 
the Subject Workbook, the subject’s Patient Management Plan (PMP), and the study drug kit. 
The PMP will specify the criteria for seizure cluster recognition, the procedure for contacting the 
central study nurse hotline after study drug administration, the requirements for administering a 
second dose of study drug (active USL261), and a rescue protocol individualized for the subject.
During the Comparative Phase, caregivers will administer the double-blind study medication at 
the time of a seizure cluster that meets study criteria (according to the subject’s individualized 
PMP) and call the central study nurse hotline as soon as possible following study drug 
administration. If the treated seizure 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 < 8 breaths per minute, does not require emergency 
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Statistical Analysis Plan for Protocol No.: P261-401
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rescue treatment with assisted breathing or intubation, and does not have excessive 
uncharacteristic sedation (as defined by the investigator in the PMP), the second dose of study 
drug (ie, 5.0 mg dose of USL261) may be administered. If the second dose of study drug is 
administered, the caregiver will again call the central study nurse hotline as soon as possible after 
its administration. The caregiver will monitor the subject after study drug administration to 
record safety and efficacy measurements.
If the subject encounters persistent seizure cluster activity or seizure recurrence (as defined in the 
subject’s PMP), has < 8 breaths per minute, or is excessively and uncharacteristically sedated, 
caregivers will follow the rescue protocol in the subject’s PMP. The subject’s rescue protocol 
will outline rescue instructions individualized for the subject, including when and how to contact 
EMS (or local equivalent).
Subjects and caregivers will return to the study center 24 to 120 hours after study drug 
administration for Visit 4. Subjects who are prematurely discontinued from study participation or 
terminate their participation should return to the study center for Visit 4 (Early Termination).
The subject or caregiver will 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 (Visit 4 [Post-Dose Assessment or ET]) or 7 days after last 
administration of study drug , whichever is later. The subject or caregiver may also call the 
central study nurse hotline at any time during the study for help or advice regarding study 
procedures.
This study will be conducted in accordance with International Conference on Harmonization 
(ICH) E6, Guidelines 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 and 56 concerning informed consent and Institutional Review 
Board [IRB] regulations, respectively).
2.2.
Randomization and Method of Treatment Assignment 
A stratified, blocked randomization schema will be generated by an unblinded statistician and 
used to assign subjects to treatment. Treatment assignments will be assigned and kept strictly 
confidential by the Interactive Response Technology (IRT) System. Randomization will be 
stratified by age (< 18 vs. ≥ 18). Within each stratum, subjects will be randomized in a 2:1 ratio 
of USL261 5.0 mg nasal spray (active) or matching placebo nasal spray using an appropriate 
randomly permuted block.
Subjects who meet eligibility requirements at Visit 3 will be randomized to treatment. At the 
time of randomization, subjects will be assigned unique subject identification numbers. Numbers 
will be assigned in consecutive increasing order without replacement or reuse of any assigned 
number. The study will be double-blinded to the treatment group assignment accessible only to 
authorized persons per sponsor’s (or designee’s) Standard Operating Procedures (SOPs) until the 
time of unblinding. 
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Statistical Analysis Plan for Protocol No.: P261-401
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2.3.
Study Procedures
The schedule of study procedures and evaluations is summarized in Table 1.
Table 1:
Schedule of the Study Procedures
Phase
Screening
Test-Dose 
Phase
Comparative Phase
Visit Number
1
2[a]
3[b]
Treatment[c]
4 or ET[d]
Study Assessments
Informed consent[e]
X
Register subject with IRT
X
Inclusion/Exclusion evaluation
X
X
X
Caregiver training[f]
X
X
X
Demographics
X
Medical/surgical history[g]
X
Concomitant medication review
X
X
X
X
ER and EMS Visit Review[h]
X
X
Physical exam[i]
X
X
X
X
Neurological exam[j]
X
X
X
X
B-SIT
X
X
X
Clinical laboratory testing[k]
X
X
FSH level (females only)
X
Pregnancy testing[l] (all females)
X
X
X
X
Drug screen[m]
X
Patient Management Plan (PMP)[n]
X
X
X
Central review of seizure cluster 
description[o]
X
Treatment administration
X[p]
X
Call central study nurse hotline [q]
X
Pharmacokinetic blood sampling[r]
X
Observer’s Assessment of 
Alertness/Sedation (OAA/S)[s]
X
12-lead ECG
X
X[t]
Body weight
X
X
X
X
Height
X
X
Vital signs[u]
X
X
X
X
Caregiver-recorded respiration rate[v] 
X
X
Pulse oximetry[u]
X
Report test dose information on IRT
X
Columbia- Suicide Severity Rating 
Scale [w]
X
X
X
X
Outcome Assessments
X
X
Randomization using IRT
X
Dispense study materials kit [x]
X
Record seizure activity in Subject 
Workbook
X
Evaluate subject’s return to baseline 
functionality [y]
X
Adverse event collection
X
X
X
X
X
Collect study drug containers, used and 
unused
X
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Review/collect Subject Workbook 
X
Telephone follow-up
X[z]
[a] Visit 2 assessments occurring at the same time should be completed in the following order: ECG, OAA/S, vitals, pulse 
oximetry, PK blood draw, and second dose; Visit 2 will occur within 28 days of Visit 1. If necessary, assessments may be 
performed up to 1 minute before or 1 minute after the scheduled time.
[b] For patients enrolled in the study after the initial DSMB review, Visit 3 will occur a minimum of 24 hours and a maximum 
of 28 days after Visit 2.
[c] These assessments will be performed by the caregiver.
[d] Visit 4 will occur between 24 and 120 hours after double-blind study drug administration. Any subject who has not treated 
a seizure cluster meeting the study criteria within 6 months of Visit 3 (Randomization) will return to the study center for Visit
4 (Early Termination).
[e] Informed consent provided by subject (or subject’s LAR) and caregiver before any other study-specific procedures; assent 
may also be required for some subjects
[f] Caregiver training includes, but is not limited to, providing self-study training to the caregiver and review of that training 
by the study center personnel. It also includes CPR and airway management training for caregivers. 
[g] Includes seizure history and current/past medication use; complete at Visit.
[h] At Visit 1, collect number of calls to EMS and ER visits for a seizure cluster or other seizure emergency in the year prior 
to screening. At Visit 4, 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. Number of calls to EMS and ER visits for a seizure cluster or other seizure emergency since 
last visit or follow-up phone call will also be collected on each monthly telephone follow-up call between Visit 3 and Visit 4 
or ET.
[i] Physical examination includes assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, 
lymph nodes, and extremities, and a nasal cavity examination using a nasal speculum.
[j] A complete neurological examination will be performed at Visits 1 and 4/ET. A partial neurological examination will be 
performed at Visits 2 and 3. 
[k] Includes hematology, serum chemistry, and urinalysis; phenobarbital levels will be assessed at Visit 1 for subjects taking 
phenobarbital and in subjects for which the investigator deems it necessary.
[l] Serum pregnancy test at Visit 1, urine pregnancy tests at Visits 2, 3, and 4/ET.
[m] Includes barbiturates, benzodiazepines, cocaine, marijuana, methamphetamine, opiates, and phencyclidine (all in urine) 
and alcohol (blood).
[n] PMP preparation begins at Visit 1. PMP should be completed before a subject receives the first test dose of USL261 at 
Visit 2. PMP provided to and reviewed with subject and caregiver at Visit 3.
[o] Approval of each subject’s seizure cluster pattern by central reviewer is required for study inclusion
[p] At Visit 2, subjects will receive a test dose of 5.0 mg USL261 administered by a member of the study center personnel 
followed by a second dose of 5.0 mg USL261 10 minutes later administered by the caregiver under the supervision of study 
center personnel.
[q] Caregivers to call the central study nurse hotline as soon as possible after administering study drug. 
[r] Blood samples for PK assessment will be collected before and at 5, 10, 20, 30 minutes and 1, 2, and 4 hours after the first
test dose. After 132 subjects have completed the Comparative Phase, for all new test dosed subjects, blood samples will be 
collected before and at 5, 10, 20, 30 minutes and 1hour after administration of the first 5.0 mg test dose of USL261 at Visit 2.
[s] At Visit 2, the OAA/S will be administered before and at 5, 10, 20, 30 minutes and 1, 2, and 4 hours after the first test dose 
by a trained member of the study center personnel. After 132 subjects have completed the Comparative Phase, for all new test 
dosed subjects, the OAA/S will be administered before and at 5, 10, 20, 30 minutes and 1 hour after the first test dose by a 
trained member of the study center personnel.
[t] ECG will be performed twice at Visit 2: once before and once 15 minutes after the first test dose 
[u] Vital signs include blood pressure (BP), heart rate (HR), respiration rate (RR), and temperature. At Visit 2, BP, HR, RR, 
and pulse oximetry are recorded before and at 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3 and 4 hours after the first test dose. 
After 132 subjects have completed the Comparative Phase, for all new test dosed subjects, BP, HR, RR, and pulse oximetry 
will be recorded before and at 5, 10, 15, 20, 30, 45 minutes and 1 hour after the first test dose. Temperature will be measured 
only at the pre-dose time point.
[v] Caregiver counts the number of breaths taken by the subject during a 30-second interval. At Visit 2, caregivers will 
measure respiration rate before and at 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3 and 4 hours after the first test dose. After 
132 subjects have completed the Comparative Phase, for all new test dosed subjects, caregivers will measure respiration rate 
before and at 5, 10, 15, 20, 30, 45 minutes and 1 hour after the first test dose. On the day of treatment, caregivers will measure 
respiration rate at approximately 15 and 30 minutes and 1, 2, and 4 hours after study drug administration. 
[w] Baseline/Screening version of the C-SSRS is administered at Visit 1. The Since Last Visit version is administered at Visits 
2, 3 and 4/ET. 
[x] 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. 
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[y] Caregiver will 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.
[z] After Visit 3, telephone follow-up calls with the subject, subject’s LAR, or subject’s caregiver are to occur monthly until 
Visit 4 or ET. Abbreviations: BP = blood pressure; ECG = electrocardiogram; ET = early termination; FSH = follicle 
stimulating hormone; HR = heart rate; IRT = Interactive Response Technology System; LAR = legally acceptable 
representative; OAA/S = Observer’s Assessment of Alertness/Sedation; PMP = patient management plan; QOL = quality of 
life; RR = respiration rate
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3.
STUDY OBJECTIVES
3.1.
Primary Efficacy Objective
The primary efficacy objective is to evaluate the efficacy of USL261 compared with placebo for 
the outpatient treatment of seizure clusters based on Treatment Success, which is defined as 
achieving both of the following:

Termination of seizure(s) within 10 minutes after study drug administration, and

No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 
hours after study drug administration.
3.2.
Secondary Efficacy Objectives
The secondary efficacy objectives of this study are to evaluate the efficacy of USL261 compared 
with placebo for the outpatient treatment of seizure clusters using the following:

Time to next seizure with a start time >10 minutes after the study drug administration

Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study 
drug administration to 4 hours after study drug administration
3.3.
Exploratory Efficacy Objectives
The exploratory efficacy objectives of this study are detailed for the comparison of USL261 and 
placebo for the outpatient treatment of seizure clusters.

Proportion of subjects with recurrence of seizure(s) beginning 10 minutes after study 
drug administration to 24 hours after study drug administration.

Time to return to full baseline functionality (as determined by the caregiver)

Analyses for subjects receiving 2 doses of study drug

Subject and caregiver outcome assessments

SF-12v2 for both subject and caregiver

Treatment Satisfaction Questionnaire for Medication (TSQM)

Intranasal Therapy Impact Questionnaire (ITIQ)
3.4.
Safety Objectives
The safety objectives are to evaluate the safety and tolerability of USL261 for the treatment of 
seizure clusters using the following assessments:

Adverse events (AEs)

Caregiver-recorded respiration rate at 15 minutes, 30 minutes, 1 hour, 2 hours and 4 
hours after study drug administration in the Comparative phase

Requirement for unscheduled emergency room (ER) or emergency medical service 
(EMS) visit within 24 hours after study drug administration
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
Brief Smell Identification Test (B-SIT; United States only)

Columbia-Suicide Severity Rating Scale (C-SSRS)

Observer’s Assessment of Alertness/Sedation Scale

Physical, nasal, and neurological examinations

Clinical laboratory tests

Vital signs (systolic and diastolic blood pressure, heart rate, respiration rate and 
temperature) as recorded by the study center personnel
3.5.
Pharmacokinetic Objectives
The Pharmacokinetic (PK) objective is to evaluate the PK profile of USL261 after administration 
of USL261 using the following PK parameters.

AUC0-last – the area under the plasma concentration-time curve from time 0 to the last 
measurable concentration. Estimation by the linear-up/log-down trapezoidal method
is preferred.

AUC0-x – the area under the plasma concentration-time curve from time 0 to time x, 
where x =1, 2 and 4 hours

Cmax – the maximum plasma concentration

tmax – the time to maximum plasma concentration

tlag – the time before the first measurable plasma concentration
4.
ANALYSIS POPULATIONS
4.1.
Screened Population
The Screened Population includes all subjects who signed an Informed Consent Form (ICF) or 
assent form.
4.2.
Safety Population
The Safety Population includes all subjects who received at least 1 dose of study drug even if 
they were not randomized. Therefore, this population includes all treated subjects, including 
those who terminate following the test dose (Visit 2), but before randomization (Visit 3), as well 
as subjects who are randomized.
4.3.
Randomized Population 
The Randomized Population includes all subjects who are randomized to receive double-blind 
treatment. The Randomized Population is also the Intent-to-treat (ITT) Population.
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4.4.
Randomized Safety Population
The Randomized Safety Population (RSAF) is the group of subjects who are randomized and 
receive at least one dose of double-blind study drug. If a subject received the wrong treatment in 
the double-blind period or until discontinuation, the safety data for that subject will be 
summarized under the actual treatment group received. The demographic, baseline 
characteristics and safety data will be summarized under the following treatment groups:

USL261 5 mg: USL261 group who received only the first dose of double-blind study 
drug

USL261 5 + 5 mg: USL261 group who received the first dose of double-blind study 
drug and the second dose of open-label USL261

Placebo: Placebo group who received only the first dose of double-blind study drug

Placebo + USL261 5 mg: Placebo group who received the first dose of double-blind 
study drug and the second dose of open-label USL261
4.5.
Modified Intent-to-Treat Population (mITT)
The mITT Population includes all subjects in the Randomized Population who received at least 1 
dose of study drug during the Comparative Phase, who had post-treatment efficacy assessment
(ie, with any seizure diary data). This mITT definition was chosen because Randomized subjects 
may be discontinued from the study prior to treatment in the Comparative Phase. Following the 
intent-to-treat principle, all efficacy analyses will be conducted using the mITT Population,
analyzed according to the randomized treatment assignment. The potential biases arising from 
excluding randomized subjects who did not receive study medication are negligible since 
exclusion is not influenced by knowledge of whether being assigned to USL261 or placebo.
4.6.
Per Protocol Population 
The Per Protocol Population includes all subjects in the mITT Population who did not 
discontinue study participation or have any excludable protocol deviations (see Section 7.2).
All protocol deviations will be reviewed in a blinded manor prior to DB lock and it will be 
determined prior to DB lock if a patient should be excluded from the Per Protocol population. 
The Per Protocol population will be used for supportive analysis to assess robustness of the 
primary analysis.
4.7.
Pharmacokinetic Population 
The PK Population includes all subjects who received a test dose of USL261 in the Test-Dose 
Phase, have at least one quantifiable post-dose concentration and have no excludable protocol 
deviations (see Section 7.2). All protocol deviations will be reviewed in a blinded manor prior to 
DB lock and it will be determined prior to DB lock if a patient should be excluded from the PK 
population.
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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Level of Significance
Statistical comparisons will be performed using two-sided tests at the =0.05 significance level
except as discussed in the interim analysis section.
To control Type I error for the primary and secondary efficacy endpoints, a statistical gate-
keeping procedure will be applied to control for multiplicity. The primary and secondary efficacy 
endpoints will be tested individually using the following hierarchical procedure:
First step: The proportion of subjects that are classified as Treatment Success during the 
Comparative Phase (two sided p-value) will be determined.
To proceed to the next step in the hierarchy, the previous step must be statistically significant (ie,
two sided p-value is significant favoring USL261).
Second step: Time to next seizure following first dose of study drug (p-value from the log-rank 
test) will be determined.
Third step: The proportion of subjects with recurrence of seizure(s) beginning at 10 minutes after 
to 4 hours following the first dose of study drug.
All null hypotheses will be defined as no treatment difference.
5.2.
Handling of Missing Data
Any specific imputation procedures for missing or incomplete data will be discussed in the 
section describing analytic methods for the efficacy/safety variable in question. Unless otherwise 
stated, observed data will be presented in tables and listings without imputation of missing 
values. 
AEs with non-complete start dates and complete stop dates after the first double-blind study drug 
administration will be considered TEAEs during the Test Dose Phase if:

Time is missing and the date is equal to or after the date of test-dose administration 
and is equal to or before the date of the first double-blind study drug administration;

Day and month are missing and the year is equal to or after the year of test-dose
administration but is equal to or before the year of the first double-blind study drug
administration;

Day is missing and the year is equal to or after the year of test-dose administration but 
is equal to or before the year of the first double-blind study drug administration;

Day is missing, the year is equal to the year of test-dose administration, and the 
month is equal to or after the month of test-dose administration but is equal to or 
before the month of the first double-blind study drug administration;

Year is missing;

Complete date is missing.
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AEs with partial start dates and complete stop dates after administration of the first double-blind 
study drug will be considered TEAEs during the Comparative Phase if:

Time is missing and the date is after the date of the first double-blind study drug 
administration;

Day and month are missing and the year is after the year of the first double-blind 
study drug administration;

Day is missing and the year is after the year of the first double-blind study drug 
administration;

Day is missing, the year is equal to the year of the first double-blind study drug
administration, and the month is after the month of the first double-blind study drug 
administration.
Missing AE relationships will be presented as ‘related’ in tables but missing in listings. Missing 
AE intensity will be considered as ‘severe’ in tables but will be reported as missing in listings.
Medications with non-complete dates will be considered concomitant if partial dates show that
medications were taken between the day of first dose of study drug at Visit 2 and the end of 
study. Medications will be considered prior if partial dates show that medications were taken 
within 30 days prior to the first dose of study drug at Visit 2. Medications can be categorized as 
both prior and concomitant.
5.3.
Interim Analyses
Three interim analyses will be conducted to evaluate the treatment success rate for possible early 
stopping for success or futility. The interim analyses will occur after 132, 165, and 204 subjects 
complete the Comparative Phase (ie, subjects have received at least 1 dose of study drug during 
the Comparative Phase). All interim analyses will be performed on the mITT population, ie,
subjects that are randomized and experience a cluster seizure event during the comparative 
phase. Subjects lost to follow-up or with missing primary outcome information will be 
considered treatment failures.
Treatment success is defined in Section 7.6.1.1.
5.3.1.
Early Success
Early success will be declared as shown in Table 2. A group sequential design is used to allow 
for multiple interim analyses for efficacy, yet control the type I error rate at 2.5%. The Lan-
DeMets spending function approximation of the Pocock boundary, is used for the efficacy 
boundary. The critical values for this efficacy boundary were obtained using R package gsDesign 
(version 2.8-8).
At each interim analysis, a one-sided Fisher’s Exact test on the two proportions will be 
performed and compared to the Lan-DeMets Pocock approximation boundary critical values. For 
the three planned interim analyses and the final analysis, the critical values are presented in
Table 2.
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Table 2:
Required p-values for declaring success according to Lan-DeMets Pocock 
Approximation Spending Function
Interim 
Analysis
P-value
132
0.0166
165
0.0094
204
0.0089
240
0.0085
5.3.2.
Early Futility
Also at each of the pre-specified interim analyses (N=132, 165, 204), the predictive probability 
of success at the maximum sample size is computed (futility is not applicable to the final analysis 
at 240 subjects). The predictive probability calculation begins by assuming non-informative 
uniform prior distributions, Beta(1,1), on the treatment success rates for the placebo/control arm 
(pC) and the probability of treatment success in the treatment arm (pT), and computing the 
posterior distribution with the currently available data. The predictive distribution of the final 
data assuming the maximal sample size of N=240 is then computed. The number of future 
treatment successes for each arm has a Beta-Binomial distribution which is then added to the 
fixed number of current treatment successes in each arm. We may then compute the predictive 
probability that a trial success is reached at N=240 subjects. If this predictive probability is less 
than 10%, the trial is stopped for futility. Note that the success boundaries are computed 
assuming no futility stopping, and thus controls type I error regardless of the method used for 
futility stopping.
5.3.3.
Early Termination not related to Success or Futility 
If the trial has not crossed a boundary for early success or early futility and yet is stopped early 
before reaching the pre-specified maximum sample size of 240 subjects, the final analysis will be 
conducted with the enrolled patients in the mITT population. The p-value required for study 
success will remain as the p-value required at the final analysis according to the pre-specified 
Lan-DeMets Pocock boundary as if the trial had performed all planned interim analyses and 
continued to the maximum sample size. Therefore the p-value required for success will be 
p=0.0085 as described in Table 2 (Section 5.3.1).
5.3.4.
Logistical details for interim analyses
The interim analyses will be conducted by an unblinded statistician and reviewed by an 
unblinded interim analysis monitoring committee (IAMC), both independent of the sponsor. The 
IAMC will consist of two individuals with adaptive design expertise to ensure the pre-specified 
adaptations are performed as planned, and to react to any unanticipated issues. The IAMC will 
be independent of the DSMB. IAMC membership, responsibilities, timelines, and 
communication channels will be clearly specified in a charter. In particular, the IAMC 
communication channels with the sponsor will be limited to maintain the blind of the sponsor 
study team in order to minimize the chance of operational bias. To this end, the IAMC will 
inform senior management first of the decision to continue the trial or stop according to the 
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statistical analysis plan. The senior management will in turn inform the team to continue or not 
to continue the study only with no further information on the interim analysis.
5.4.
Examination of Subgroups
Further analysis of the primary and secondary endpoints may be examined for consistency across
the subgroups listed below. Any subgroup analyses will be exploratory in nature.

Age (< 18 years, ≥18 - < 65 years, ≥65 years)

Sex (male/female)

Race (white/non-white)

Enzyme-inducing AEDs used within 14 days before the study drug administration 
(see Appendix 2) vs. others

Weight categories (</≥Median weight of the safety population)

Region (North America and similar [this includes USA, Canada, Australia and New 
Zealand], Eastern Europe [Hungary, Poland, Ukraine], and Western Europe [Spain, 
Germany, Italy, and Israel])

BMI standardized categories (underweight/normal [<25], overweight [≥25-<30], and 
obese 1-3 categories combined [≥30])
5.5.
Data Collected from Unscheduled Visits
The data collected from the unscheduled visits are excluded from the by visit summary analysis. 
However, when defining baseline for each assessment, the data collected from the unscheduled 
visits are still included.
6.
DESIGN OPERATING CHARACTERISTICS
6.1.
Simulation Scenarios
The estimated placebo treatment success rate is 0.40. The study is powered under the hypothesis 
that the USL261 treatment will lead to a clinically meaningful odds ratio of 2.9. With these 
assumptions, the sample size of 240 subjects who have completed the Comparative Phase (160 
USL261/80 placebo) is sufficient to obtain approximately 90% power.
We examined a range of odds ratios/treatment success rates for placebo treatment success rates 
of 40% and performed 10,000 simulations to determine the power and average sample size (type 
I error is controlled analytically through the group sequential design). Simulations were 
performed using R version 3.1.0. For a given set of data we computed the success and futility 
criteria analytically. To simulate an individual trial, placebo and treatment data were simulated 
from the appropriate Binomial distributions (using the required sample sizes and placebo and 
treatment rates) and compared to the success and futility bounds. Trials that continued at an 
interim had additional data simulated, and so on until the trial reached completion. After 
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simulating 10,000 trials, the overall power, expected sample size, and other operating 
characteristics were computed by taking the observed mean values throughout the simulations.
6.2.
Operating Characteristics
Assuming treatment success rates of 0.40 for the placebo arm, and Odds Ratio of 2.9, the power 
of this design is approximately 90% while maintaining at most 2.5% type I error. The expected 
(average) sample size will be approximately 150. 
7.
STATISTICAL ANALYSIS
Categorical variables will be summarized using counts and percentages. Continuous variables, 
including the change from baseline, will be summarized using descriptive statistics [n, mean, 
standard deviation (SD), minimum, median, maximum]. For modeling results, least squares 
means and standard errors will be presented.
Unless otherwise stated, all summaries will be presented by treatment group (USL261 or 
Placebo).
The Test Dose Phase is defined as the period of time from the date of first dose of study drug 
administration at Visit 2 up to, but not including, the date of randomization. The Comparative 
Phase is defined as the period of time from the date of randomization to the date of the last 
assessment in the study.
Table 3:
Study Phases Start and End
Epoch Name
Start Date 
End Date
Before Screening (BS)
Birth date
Date of Screening – 1 day
Screening (SC)
Date of screening
Date of Visit 2 – 1 day
Test-Dose (TD)
Visit 2 
Visit 3 (not including the date 
of randomization)
Double-blind (DB)
Visit 3 day
Visit 4
Post Treatment but in Study 
(PD)
Study drug discontinuation 
visit +1 day
Visit 4
Post Study Follow-up (PS)
If enter Double-blind: Visit 4
+1 day
If failed during TD: Visit 3 + 
1 day
Open ended
Baseline values are the last available values before Test-Dose administration. For rescreened 
subject who underwent two Test-Dose administration, the last available values before the later 
Test-Dose administration will be defined as Baseline values.
Data listings will include all subjects with at least one applicable value. Listings will be sorted by 
treatment group, site, subject number, and date (if applicable).
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All datasets and output will be produced using SAS® Version 9.1.3 or higher (SAS Institute, Inc., 
Cary, North Carolina, USA).
7.1.
Subject Disposition
All individual subject disposition data will be listed by clinic/investigator site for screen failures 
separately, and for subjects in the Safety Population separately.
The primary reason for screen failure will be listed for all screen failed subjects.
Subject disposition will be presented by the primary reason for early withdrawal for the Safety 
Population during the Test Dose Phase. The number and percent of subjects who completed the 
study and the number and percent of subjects who discontinued the study along with the 
distribution of the reasons for study discontinuation will be presented in total and by phases for 
all study populations wherever applicable (see Figure 2).
Figure 2:
Disposition Flow Chart
7.2.
Protocol Deviations
All instances of protocol non-compliance will be tracked during the study and CSR Reportable
protocol deviations will be finalized by a blinded Sponsor review prior to database lock. CSR 
Reportable deviations are deviations that materially affect the evaluation of efficacy or safety.
CSR Reportable deviations will be reviewed in a blinded manner to determine if the data should 
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be excluded from an analysis population. A subject with a CSR Reportable protocol deviation 
will not necessarily be excluded from the analysis populations. The excludable protocol 
deviations will be classified by the sponsor for each population. Protocol deviation categories 
will be presented in a data listing and summarized using counts and percentages by treatment 
group. Major protocol deviations may include, but are not limited to: 

Failure to obtain informed consent

Failure to report a Serious Adverse Event (SAE)

Enrolling patients outside of inclusion/exclusion criteria

Drug dispensing/dosing errors
7.3.
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be presented for the Safety Population and 
repeated for the Randomized Safety and mITT Populations. Subject demographics include age, 
gender, weight, height, BMI, race, clinical site region, and ethnicity. Weight recorded in pounds 
will be converted to kilograms, and height recorded in inches will be converted to centimeters.
Weight will also be categorized and summarized based on median for safety population
(<median weight and ≥ median weight).
Age (years) will be calculated as the integer number of years between date of birth and informed 
consent date. If the informed consent data is missing then the assent date will be used instead.
In addition subject age (years) will be categorized as follows:

< 18 years

≥18 - < 65 years

≥65 years
Subject baseline characteristics will include: IQ (if available), epilepsy type, 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. For 
seizure cluster episodes, if duration are collected in free-text which covers a period of time, 
average of the upper bound and the lower bound will be used for the analysis.
Subject demographics will additionally be presented for the mITT Population by the Treatment 
Success status of their first double-blind dose of study drug (see Section 7.6.1 for the definition 
of treatment success). These data presentations will include columns for “Treatment Success of 
first dose” and “Not Treatment Success of first dose” for each treatment group.
Comparability of treatment groups will be evaluated using descriptive statistics.
7.4.
Medical and Surgical History
Medical and surgical history will be coded using the MedDRA coding dictionary version 14.1.
Coded medical history terms will be summarized by MedDRA system organ class (SOC) and 
preferred term (PT) for the Safety, Randomized Safety and mITT Populations. SOC will be 
sorted alphabetically and then preferred term will be sorted in order of frequency of the total 
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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.
For subjects who were rescreened after study drug exposure and have two subject identifiers, all 
medical and surgical history data will be combined into one subject identifier.
7.5.
Prior and Concomitant Medications
Prior medications are defined as medications taken within 30 days prior to the first dose of study 
drug at Visit 2. Concomitant medication is defined as any medication taken between the day of 
first dose of study drug at Visit 2 and the end of study.
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. Medication start and end dates will be compared with the start date of study drug 
and classified as per Table 4. 
In case of partial or missing dates, comparisons will be made based on the level of detail 
available. For example, if start date of study drug administration is 04Jan2013, and a medication 
has a start date of Jan2013 but missing date the medication will be classified as concomitant. 
Table 4:
Classification of Prior and Concomitant Medications
End
date
Before start of 
study drug 
administration at 
Visit 2
On or after start of 
study drug 
administration at 
Visit 2
Missing
Start
date
Before start of study 
drug administration at 
Visit 2
Prior
Prior/Concomitant
Prior/Concomitant
On or after start of 
study drug 
administration at Visit 2
–
Concomitant
Concomitant
Missing
Prior
Prior/Concomitant
Prior/Concomitant
Prior medications will be summarized for the Safety, Randomized, and Randomized Safety 
Populations. Concomitant medications will be presented for the Safety Population during the 
Test Dose Phase and for the Randomized and Randomized Safety Populations during the 
Comparative Phase. 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 term.
At each level of summarization, a subject will be counted only once for each concomitant 
medication he/she has within that level. The percentage of subjects having had at least one 
medication at each level will be calculated.
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Prior/Concomitant medications excluding AEDs, prior/concomitant AEDs, prior/concomitant 
AEDs used for epilepsy, and prior/concomitant AEDs used for indications other than epilepsy 
will be summarized separately and similar to concomitant medications. AEDs will be further 
classified as enzyme-inducing and non-inducing AEDs.
Listings will be provided for prior/concomitant medications and prior/concomitant AEDs for all 
subjects. 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.
For subjects who were rescreened after study drug exposure and have two subject identifiers, all 
medication data will be combined into one subject identifier.
7.6.
Analyses of Efficacy Endpoints
Information recorded by the caregiver in the Subject Workbook will be used for analysis of the 
primary, secondary, and exploratory efficacy endpoints. Any seizures occurring within 24 hours 
after administration of study drug will be recorded. Subjects without any recurrent seizures 
recorded with a start time >10 minutes after administration of study drug will be considered 
seizure-free in all analyses.
The following covariates will be used in the analyses of efficacy endpoints, where specified:

Age (< 18 years, 18 - <65 years, ≥65 years)

Sex (male/female)

Weight (kg)

BMI standardized categories (underweight/normal [<25], overweight [≥25-<30], and 
obese 1-3 categories combined [≥30]) 

Geographic region of clinical site (North America and similar [this includes USA, 
Canada, Australia and New Zealand], Eastern Europe [Hungary, Poland, Ukraine], 
and Western Europe [Spain, Germany, Italy, and Israel])

Enzyme-inducing AEDs used within 14 days before the study drug administration 
(see Appendix 2) vs others
Additional covariates may also be explored.
7.6.1.
Primary Efficacy Endpoint
All statistical analyses of the primary efficacy endpoint will be conducted for the mITT 
Population and analyzed as described in Section 5.3. The primary efficacy endpoint analyses will 
also be conducted on the Per Protocol Population as supportive analyses. The following null (Ho) 
and alternative (Ha) hypotheses will be evaluated:

Ho: The proportion of subjects who meet the criteria for Treatment Success is not 
different between the USL261 and the placebo groups in the Comparative Phase;

Ha: The proportion of subjects who meet the criteria for Treatment Success is 
different between the USL261 and the placebo groups in the Comparative Phase.
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Treatment Success is a composite measure of efficacy that will be assessed based upon the first 
seizure cluster treated with study drug during the Comparative Phase. Treatment Success is 
defined as achieving the following:

Termination of seizure(s) within 10 minutes after the double-blind study drug 
administration, and

No recurrence of seizure(s) beginning 10 minutes after study drug administration to 6 
hours after the double-blind study drug administration
7.6.1.1.
Derivation of Treatment Success Endpoint
Treatment Success will be determined based on data reported in the CRFs and derived 
programmatically. An imputation will be conducted first for the seizure start time and end time. 
If the end time of a seizure is missing, impute the end time to the next subsequent seizure’s start 
time if the two aforementioned seizures occrurred within the same date; otherwise, the missing 
end time will be imputed as 23:59.
If the start time of a seizure is missing, impute the start time to the previous seizure’s end time if 
the two aforementioned seizures occurred within the same date; otherwise, the missing start time 
will be imputed as 00:00.
There are three components to be assessed in the programmatic derivation:
1. Termination of seizure(s) within 10 minutes: The initial seizure stopped within (≤) 10 
minutes from the time of dosing and any subsequent seizures also stopped within 10 
minutes of dosing. Data used in this derivation includes the time of first dose as recorded 
on the “Study Drug Administration (First Dose)” CRF, and seizure data recorded on the 
“Report All Seizures for 24 Hours” and the “Seizure Diary” CRFs. 
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 any seizures with start time from >10 minutes up to (≤) 6 hours after 
the first dose of study drug. Data used in this derivation includes seizure data recorded on 
the “Report All Seizures for 24 Hours” CRF.
3. No second dose given within 6 hours of the first dose of study drug administration as 
receiving the second dose within (≤) 6 hours confounds the efficacy evaluation of the first 
dose. Data used in this derivation include the time of second dose as recorded on the 
“Study Drug Administration (Second Dose)” CRF.
Subjects who meet all three of these components will be defined as a “Treatment Success.” 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.”
Possible scenarios for seizure data start and stop times within the 6 hour period following the 
first dose of study drug are displayed below in Figure 3, along with the treatment success 
endpoint derivation (assuming no second dose was given):
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Figure 3:
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)
7.6.1.2.
Analysis of the Primary Endpoint
Treatment Success will be analyzed by Fisher’s Exact test. The 95% confidence intervals (CIs), 
using normal approximation around the proportions, will be presented. In addition, each 
component (seizure termination and recurrence) of treatment success will be summarized by 
treatment group. Chi-squared test will be performed as a sensitivity analysis. Results from both 
tests (Fisher and Chi-squared) will be presented together. In addition, the Cochran-Mantel-
Haenszel (CMH) test, stratified by age (< 18 years, ≥18 - <65 years, ≥65 years) will be used to 
analyze Treatment Success.
Subjects who do not have sufficient available data to confirm whether they can be classified
either as “Treatment Success” or as “Not a Treatment Success” as described in Section 7.6.1.1
are considered to have missing data. For the primary analysis of Treatment Success, subjects 
with missing data impacting the Treatment Success endpoint described above will be considered 
as “Not a Treatment Success.” 
Similarly, for each component of the Treatment Success endpoint (seizure termination and 
recurrence), when available data do not allow to determine the classification, subjects with 
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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missing data will be considered as having an unfavorable outcome for the corresponding 
component. Sensitivity analysis will be conducted for the Treatment Success endpoint in order to 
assess robustness of study conclusions to missing data using a tipping point approach.4 This
approach will provide the results for the analysis of the primary endpoint under an exhaustive set 
of possible outcomes among subjects with missing data in the USL261 and Placebo treatment 
groups. Clinical interpretation of the plausibility of different combination of outcomes will be 
provided in the Clinical Study Report. The tipping point analysis will be conducted as follows. 
Let n1m and n2m be the number of subjects with missing data in the USL261 and Placebo 
treatment groups respectively.
Step 1: Let k1=0. 
Step 2: Let k2=0. 
Step 3: Repeat the analysis of the primary endpoint as described above by considering k1
subjects from the USL261 treatment group as “Not a Treatment Success” and (n1m - k1) subjects 
as “Treatment Success,” while considering k2 subjects from the Placebo treatment group as “Not 
a Treatment Success” and (n2m – k2) subjects as “Treatment Success.”
Step 4: Let k2= k2+1. Repeat Steps 3 - 4 while k2≤n2m.
Step 5: Let k1= k1+1. Repeat Steps 2 - 5 while k1≤n1m.
The results of the analysis for each possible combination of outcomes for subjects with missing 
data (k1 and k2) will be presented in a table. Additionally, a graph will be produced presenting 
the number of subjects with missing data considered as “Not a Treatment Success” on the X and 
Y axes for the USL261 and Placebo treatment groups respectively, and dots marking the 
combinations of X- and Y-axis values for which the null hypothesis was not rejected in favor of 
the USL261 treatment.
An additional exploratory logistic regression on Treatment Success will include the covariates 
specified in Section 7.6. A backward selection of covariates will be used to obtain the final 
model. All covariates with a p>0.10 will be dropped from the model. The covariates remaining in 
the final model that are identified as having significant association with the outcome (p<0.05) 
may be explored in a subgroup analysis. The odds ratio between USL261 and Placebo and its 
associated 95% confidence intervals will be reported. This analysis will be conducted 
considering all subjects with missing data as “Not a Treatment Success”, similar to the primary 
analysis.
7.6.2.
Secondary Efficacy Endpoints
All secondary efficacy analyses will be based on the mITT population. Multiplicity adjustments 
are described in Section 5.1).
7.6.2.1.
Proportion of Subjects with Recurrence of Seizure(s) Beginning 10 Minutes after 
Administration of Double-Blind Study Drug to 4 Hours after Double-Blind 
Study Drug Administration
The proportion of subjects with recurrence of seizure(s) recorded in the diary with start time >10 
minutes and ≤4 hours after the administration of double-blind study drug will be analyzed using 
Fisher’s Exact test. The 95% CIs will be presented for the proportion. In addition, Chi-squared 
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test will be performed as a sensitivity analysis. Subjects who have been administered the second 
dose of study drug (ie, 5.0 mg dose of USL261) within 4 hours of double-blind study drug 
administration will be derived as if they had a recurrence of seizure. Subjects who do not have a 
seizure recorded, or whose first seizure occurs >4 hours after study drug administration, will be 
counted as not having a seizure.
7.6.2.2.
Time to Next Seizure with a Start Time >10 Minutes after Double-Blind Study 
Drug Administration
Kaplan-Meier estimates will be used to summarize the time-to-next seizure after double-blind 
study drug administration. 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 study drug (ie, 5.0 
mg dose of USL261) will be censored at the end of the observation period. Subjects administered 
the second dose of study drug (ie, 5.0 mg dose of USL261) who did not have a seizure before the 
administration of the second dose will be censored at the time of the second dose (5.0 mg 
USL261) administration. The time-to-next seizure percentiles (defined based on the data) with 
associated 95% CIs will be displayed. The probabilities of experiencing the next seizure after 
double-blind study drug administration at each hour with associated standard error and 95% 
confidence intervals will be presented. The log-rank test will be used to compare the time to next 
seizure after double-blind study drug administration between treatment groups. In addition, the 
hazard ratio for treatment (USL261: placebo) and its 95% CI will be calculated from a Cox 
proportional hazards model. Kaplan-Meier curves by treatment group will also be presented.
Additional analysis will be conducted based on a different censoring method that subjects 
administered the second dose of study drug (ie, 5.0 mg dose of USL261) who did not have a 
seizure before the administration of the second dose will be considered as events (failure).
The Cox proportional hazards regression model will be used to evaluate the difference between
treatment groups adjusting for the covariates specified in Section 7.6. Interactions between 
treatment and each covariate will be evaluated at the 0.10 significance level; if not significant,
they will be removed from the final model.
7.6.3.
Exploratory Efficacy Analyses
Exploratory efficacy analyses will be conducted using the mITT population. All tests performed 
will test a two-sided hypothesis of no difference between groups at a significance level of 0.05
for all exploratory outcome measures.
7.6.3.1.
Proportion of Subjects with Recurrence of Seizure(s) Beginning 10 Minutes after 
Study Drug Administration to 24 Hours after Study Drug Administration
The proportion of subjects with recurrence of seizure(s) with a start time >10 minutes and ≤24 
hours after study drug administration will be analyzed using Fisher’s Exact Test. The 95% CIs 
will be presented for the proportion. In addition, Chi-squared test will be performed as a 
sensitivity analysis. Subjects who do not have a seizure recorded with a start time >10 minutes 
and ≤24 hours after the administration of double-blind study drug will be counted as not having a 
seizure. Subjects who have been administered the second dose of study drug (ie, 5.0 mg dose of 
USL261) within 24 hours will be assumed to have had a seizure.
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7.6.3.2.
Return to Full Baseline Functionality within 24 Hours after Study Drug 
Administration (as determined by the caregiver)
The proportion of subjects who have documented return to full baseline functionality will be 
analyzed using Fisher’s Exact Test. The 95% CIs will be presented for the proportion. In 
addition, Chi-squared test will be performed as a sensitivity analysis. Subjects who did not have 
a time of return to full baseline functionality recorded within 24 hours of study drug 
administration or who have been administered the second dose of study drug (ie, 5.0 mg dose of 
USL261) prior to returning to full functionality will be counted as not having returned to full 
baseline functionality.
Kaplan-Meier estimates will be used to summarize the time to return to full baseline 
functionality. Subjects who do not have a time of return to full baseline functionality recorded 
within 24 hours of study drug administration and have not been administered the second dose of 
study drug (ie, 5.0 mg dose of USL261) will be censored at the end of the observation period.
Subjects who were administered the second dose of study drug (ie, 5.0 mg dose of USL261) 
prior to returning to full functionality will be censored at the time that the second dose (USL261) 
was administered. The probabilities of return to full baseline functionality after double-blind 
study drug administration at each hour with associated standard error and 95% confidence 
intervals will be presented. The log-rank test will be used to compare the time to return to full 
baseline functionality between treatment groups. In addition, the hazard ratio for treatment 
(USL261: placebo) and its 95% CI will be calculated from a Cox proportional hazards model.
Kaplan-Meier curves by treatment group will also be presented.
The Cox proportional hazards regression model will be used to evaluate the difference between 
treatment groups adjusting for the covariates specified in Section 7.6. Interactions between 
treatment and each covariate will be evaluated at the 0.10 significance level; if not significant,
they will be removed from the final model.
7.6.3.3.
Analyses for Subjects Receiving 2 Doses of Study Drug
Data from subjects randomized to USL261 and placebo who received the first dose of double-
blind study drug and the second dose of open-label study drug (ie, 5.0 mg dose of USL261) will 
be used for the analyses of subjects receiving 2 doses of study drug.
7.6.3.3.1. Treatment Success of the Second Dose of Study Drug (5.0 mg of USL261)
Treatment Success of the second dose for subjects receiving the second dose of study drug (ie, 
5.0 mg of USL261) will be presented for each treatment group. For the active group, this 
represents two doses of 5.0 mg of USL261. The placebo group has received one dose of 5.0 mg 
of USL261 (preceded by a dose of placebo). Since the administration of the second dose is not a 
randomized treatment, the analysis includes only subjects whose seizure was not stopped by the 
first dose and were given the second dose of study drug (ie, 5.0 mg of USL261).
For this analysis, Treatment Success of the second dose is defined as achieving the following:

Termination of seizure(s) within 10 minutes after the second dose of study drug (5.0 
mg of USL261)
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
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 the primary 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.
7.6.3.3.2. Additional Second Dose Data Presentations / Analyses
A summary of subjects receiving the second dose of study drug by randomized treatment arm 
will be presented. In addition to the total number of subjects receiving the second dose, counts of 
subjects receiving the second dose in specific time categories post first dose (0 to <10 minutes, 
>=10 to ≤20 minutes, >20 minutes to ≤1 hr, >1 hr to 6 hrs, and >6 hrs) will also be presented.
Kaplan-Meier estimates will be used to summarize the time-to-second dose. Subjects who do not 
receive the second dose of study drug (ie, 5.0 mg dose of USL261) 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.
As an additional exploratory analysis, a logistic regression with response treatment success of the 
second dose will be examined including time from first dose to second dose as a continuous 
covariate with treatment as an effect.
Kaplan-Meier estimates will also be used to summarize the time-to-next seizure following the 
second dose. Subjects who do not have another seizure before the end of the 24-hour observation 
period following the second dose of study drug (ie, 5.0 mg dose of USL261) will be censored at 
the end of this observation period. The 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.
7.6.3.4.
Treatment Success of all Dose of Study Drug
Treatment Success of all doses will be assessed based upon the Treatment Success of the first 
dose and Treatment Success of the second dose taken within 6 hours after first dose during the 
Comparative Phase. If the second dose taken later than 6 hours after first dose, then treatment 
success of all doses will only be based on the result of treatment success for the first dose.
The same analysis as described in Section 7.6.3.3.1 (Treatment Success of the Second Dose of 
Study Drug) will be performed for treatment success of all doses.
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7.6.3.5.
Subject and Caregiver Outcome Assessments
7.6.3.5.1. SF-12v2
The SF-12v2 is a 12-item questionnaire which will be administered to both the subject and 
caregiver at Visits 2 and 4. All analyses 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 functioning, role-physical, bodily pain, and general health domains will be combined to 
obtain the Physical Health Component Score (PCS); the vitality, social functioning, role-
emotional, and mental health domains will be combined to obtain the Mental Health Component 
Score (MCS). The scores for each domain, the PCS 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.5
Summary scores for PCS and MCS for each patient 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.6 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. 
Summarization and analysis of SF-12v2 data will be performed for the mITT and the 
Randomized Safety population. The domain and component scores will be presented for Visit 2 
(baseline) and Visit 4/ET, including change from baseline. For each domain and component 
score a paired t-test will be used to assess the within-group mean change from baseline. An 
analysis of covariance (ANCOVA), with treatment and baseline as covariates, will be used for 
between-group comparison of change from baseline for the domain and component scores. 
7.6.3.5.2. Treatment Satisfaction Questionnaire for Medication (TSQM)
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.7
Effectiveness
([Q1 + Q2 + Q3) – 3]/18) * 100
If one item is missing then, ([Qx + Qy – 2]/12) * 100 where x and y = 1, 2, or 3, with 
x≠y.
Side-Effects
If Q4 is ‘No’ then score = 100
Else, ([Q5 + Q6 + Q7 + Q8 – 4]/16) * 100
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If one item is missing then, ([Qx + Qy + Qz – 3]/12) * 100 where x, y, and z = 5, 6, 7, or 
8, with x≠y≠z.
Convenience
([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.
Global Satisfaction
([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.
Summarization and analysis of TSQM data will be performed for the mITT population. The 4 
scale scores will be presented for Visit 2 (baseline) and Visit 4/ET, including change from 
baseline. For each score a paired t-test will be used to assess the within-group mean change from 
baseline. An analysis of covariance (ANCOVA), with treatment and baseline as covariates will 
be used for between-group comparison of change from baseline. 
7.6.3.5.3. Intranasal Therapy Impact Questionnaire (ITIQ)
The ITIQ is a two item questionnaire that is completed by both the subject and caregiver at Visit 
4/ET. 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 since subject received intranasal therapy 
will be compared between treatment groups using the t-test. The chi-square will be used to 
compare treatment groups for confidence about travelling having a spray the subject can take 
with them.
7.7.
Safety Analyses
All safety analyses will be presented by phase of the study based on the Safety Population and 
Randomized Safety Population, unless otherwise specified.
7.7.1.
Adverse Events (AEs)
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 16.1. Coding includes SOC and preferred term (PT). All verbatim descriptions and 
coded terms will be listed for all AEs.
For subjects who screen fail prior to the start of the Test Dose Phase for the reason of an adverse 
event, the event will be recorded on the Screening Failure Log.
7.7.1.1.
Pre-treatment AEs 
Pre-treatment AEs will be defined as any AE that started before the study drug administration at 
Visit 2. Pre-treatment AEs will be flagged out in a listing named as ‘Adverse Events’.
7.7.1.2.
Treatment-emergent AEs (TEAEs)
TEAEs will be categorized as TEAEs during the Test Dose Phase and TEAEs during the 
Comparative Phase based on the date and time of onset.
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The following AEs will be defined as TEAEs during the Test Dose Phase:

AEs with onset on or after study drug administration at Visit 2 and up to first dose of
study drug in Comparative Phase;

AEs that started prior to study drug administration at Visit 2, but worsened in severity 
following study drug administration at Visit 2 up to first dose of study drug in 
Comparative Phase.
The following AEs will be defined as TEAEs during the Comparative Phase:

AEs with onset on or after the first dose of study drug in Comparative Phase;

AEs that started prior to study drug administration at Visit 2, but worsened in severity 
following the first dose of study drug in Comparative Phase.
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 during the Test Dose Phase and for the Randomized 
Safety Population during the Comparative Phase. An overall summary of all AEs for Screened 
Population will also be presented. 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 
experiences 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 analysis 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 (< 18 years, ≥18 - <65 years, 
≥65 years), TEAEs by severity (mild, moderate, severe), TEAEs by relationship to study drug,
TEAEs of interests, serious TEAEs (SAEs) including SAEs leading to permanent discontinuation
or death, SAEs by severity, and SAEs by relationship to study drug. If there are any deaths while 
on 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, all TEAEs, SAEs, and AEs leading to discontinuation will be flagged out in the listing 
of Adverse Events. 
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 analysis, 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.
The following AEs of special interest (AESIs) will be summarized by AESI category:

Taste and smell disorders

Acute central respiratory depression

Route of administration
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
Depression and suicidality/self-injury

Abuse-related AEs
Abuse-related TEAEs will be further broken out by the following categories:

Drug Abuse, Dependence, Withdrawal and Substance-Related Disorders, Including 
Diversion

Euphoria-related Term

CNS Depressant Effects

Stimulation and Anxiety Symptoms

Perceptual Disturbances/Psychotomimetic Effects

Mood Disorders and Disturbances

Mental and Cognitive Impairment
Additional summaries will be made for abuse-related treatment-emergent SAEs and abuse-
related TEAEs resulted in discontinuation from study drug or the study.
SMQs and/or a USL-defined algorithm will be used to search AESIs. Search strategies are
described in Table 5.
Table 5:
Search Strategy for AESI
AESI category
Search Strategy
Taste and smell disorders
Modified Taste and Smell Disorders SMQ - broad 
Acute central respiratory depression
Modified Acute Central Respiratory Depression SMQ - broad 
Depression and suicidality/self-injury
Modified Depression and Suicidality/Self-Injury SMQ – broad
Route of administration
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 USL261’s nasal route 
of administration, e.g., terms for conditions in the respiratory 
tract below the larynx or terms with defined causes
Abuse-related AEs
USL-defined algorithm
Abbreviations: HLT=High Level Term; SMQ=Standardized MedDRA Queries; NEC=Not Elsewhere Classified.
Standard MedDRA Queries (SMQs) defined by the Council for International Organizations of 
Medical Sciences (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 AE terms in each category is presented in
Appendix 3. Summary tables will be presented by SOC and PT.
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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:

AE is a SAE

AE led to discontinuation

AE is severe in intensity and related to study drug 

AE required intervention and is related to study drug.
If action taken and other action taken of a AE are not “none”, ”not applicable”, “unknown” or 
“dose not changed”, then it will be considered requiring intervention. 
7.7.2.
Observer’s Assessment of Alertness/Sedation (OAA/S)
The OAA/S scale is a validated qualitative categorical measure of sedation.8 The OAA/S Scale is 
composed of four assessment categories: responsiveness, speech, facial expression, eyes.
Responsiveness has possible scores of 1, 2, 3, 4, or 5; speech has scores of 2, 3, 4, or 5; and 
facial expression and eyes have scores of 3, 4, or 5. The OAA/S Scale is scored in two ways as 
described below. Descriptive statistics and graphical presentations will be used to present results 
by time point at Visit 2 for the Safety Population.
7.7.2.1.
Composite Score
The composite score has a range between 1 (deep sleep) and 5 (alert); the lowest level checked 
by the study center personnel in any one of the four assessments will be analyzed. The composite 
score will be set to missing if all 4 of the assessment categories are missing.
Number of subjects with an OAA/S composite score of 1 at Visit 2 will be presented by time 
point and overall total.
7.7.2.2.
Sum Score
The sum score is the sum of the 4 assessments. If one of the assessment categories is missing, the 
sum score will be set to missing.
Summaries for the composite score and sum score will be based on the calculation specified 
above. However, an imputation approach on each domain score will be employed for the 
derivation of pharmacodynamic parameters described in the next section. Specifically, for each 
individual domain score, if a subject who has completely missing data at all timepoints for a 
single domain, the median domain score of all available data from all other subjects at each 
timepoint will be used as the domain score for this subject. For subjects with complete missing 
scores for two or more domains at all timepoints, each domain score will be treated as missing at 
all timepoints and OAA/S sum and composite scores will not be calculated.
7.7.2.3.
Pharmacodynamic (PD) Parameters
The following PD parameters will be calculated by subject using non-compartmental methods 
for the OAA/S composite score and sum score following midazolam dosing:
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Table 6:
Pharmacodynamic Parameters
Parameter
Definition
AUEC0-t
Area under the effect (AUEC) versus time curve, from time 0 to the time of last 
measurable value. Calculated using the linear trapezoidal method.
AUEC0-x
Area under the effect (AUEC) versus time curve, calculated using the linear 
trapezoidal method from time 0 to the x time, where x =1, 2 and 4 hours.
Emax
Maximum observed PD effect. Note – For OAA/S sum and composite scores, 
this will represent the lowest observed score (as lower scores indicate greater 
sedation)
Teffect
Time to Peak “Emax“ Effect
Among these parameters, the calculated OAA/S sum score and composite score will be used for 
calculating the unadjusted Emax. The Emax will also be adjusted by using change from baseline 
values of OAA/S composite score and sum score. For parameters AUEC0-t , AUEC0-x (x=1, 2, 4), 
the calculation will be based on the change from baseline values of OAA/S composite score and 
sum score.
Actual time will be used for AUEC calculation. If actual time for pre-dose values is before the 
Test dose, 0 will be used for time point calculation. If equal to or greater than 50% domain data 
for a subject is missing, then all their AUEC values (including AUEC0-last, AUEC0-1hr, AUEC0-2hr 
and AUEC0-4hr) will be treated as missing. If less than 50% domain data for a subject is missing, 
then last observation carried forward approach will be used to impute all missing time points 
after the last non-missing time point.
Individual PD parameter values will be listed and descriptive statistics will be used to present PD 
parameters at Visit 2 for the Safety Population.
7.7.3.
Requirement for Unscheduled ER or EMS Visit
The number and percent of subjects requiring an unscheduled ER or EMS visit within 24 hours 
after study drug administration in the Comparative Phase will be compared between treatment 
groups for the Randomized Safety Population using Fisher’s Exact Test. In addition, Chi-squared 
test will be performed as a sensitivity analysis.
7.7.4.
Brief Smell Identification Test (B-SIT; United States only)
For olfactory examination, the B-SIT final scores and changes from baseline will be presented 
and plotted by visits. Baseline value is defined as the Visit 2 (pre-dose) value. An analysis of 
covariance (ANCOVA), with treatment and baseline as covariates, will be used for between-
group comparison of change from baseline for the B-SIT final scores.
7.7.5.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is collected referencing two time points for suicidal ideation (lifetime, past 6 
months) and two time points for suicidal behavior (lifetime, past 5 years) at Visit 1 (screening).
For all analyses the ‘lifetime’ time point will be used for Visit 1 assessments. In addition, a 
‘Since Last Visit’ version will be administered at Visits 2, 3 and 4/ET.
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7.7.5.1.
Suicidal Ideation
The number and percent of subjects with each of the following suicidal ideation scores will be 
summarized for each visit by treatment group (See Table 7). The highest score for suicide 
ideation will be used for each subject by visit.
Table 7:
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 by treatment group. 
Descriptive statistics will also be presented for suicidal ideation intensity at each visit by 
treatment group. 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.
7.7.5.2.
Suicidal Behavior
The number and percent of the following suicidal behaviors will be summarized for each visit by 
treatment group.

Actual attempt

Engaged in non-suicidal self-injurious behavior

Aborted attempt

Interrupted attempts

Preparatory acts or behavior

Suicidal behavior

Any suicidal behavior regardless of type

Completed suicide
Descriptive statistics will be presented for the following suicidal behaviors for each visit by
treatment group.

Number of attempts

Aborted attempts
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
Interrupted attempts
The number and percent of subjects with any suicidal ideation or behavior will be presented for 
each visit by treatment group.
7.7.6.
Physical, Nasal, and Complete Neurological Examinations
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 and 
treatment group for the Safety and Randomized Safety Populations.
7.7.7.
Laboratory Parameters
Clinical laboratory parameters for serum chemistry, hematology, and urinalysis will be 
summarized descriptively for each study visit. Mean and mean change from baseline values will 
be presented for each study visit. Change from baseline will be calculated as the Visit 4/ET 
measurement minus the baseline measurement. If either the baseline or Visit 4/ET value is 
missing, the observation will not be included in the change from baseline summary. The last 
value at post-baseline visits will be used for summaries.
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 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 by for each 
treatment group. Additional displays of PCS may be presented.
Baseline values are the last available values collected prior to the test-dose.
7.7.8.
Vital Signs and Oxygen Saturation
Vital signs (systolic and diastolic blood pressure, pulse, respiration rate, temperature) will be 
summarized descriptively for each study visit and time point and presented graphically 
(excluding temperature) for each Visit 2 time point. Mean and mean change from baseline values 
will be presented for each study visit and time point, excluding temperature. 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. Baseline values are the last available values before Test-Dose 
administration.
Descriptive statistics and graphical presentations will be used to present results by visit and time 
point for oxygen saturation for the Safety Population.
The number of subjects meeting the following criteria will be presented by treatment group, by 
visit, and by time point:

< 8 breaths per minute after study drug administration

> 24 breaths per minute after study drug administration

systolic blood pressure < 85 mm Hg

a change from baseline in systolic pressure ≥ 40 mm Hg
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
diastolic blood pressure < 50 mm Hg

a change from baseline in diastolic pressure ≥ 30 mm Hg

Pulse rate > 120 beats per minute

Pulse rate < 50 beats per minute

a change from baseline in heart rate ≥ 40 beats per minute

oxygen saturation < 90%
The caregiver-recorded respiration rate from the Comparative Phase will be presented using 
descriptive statistics at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours by treatment group 
and overall total for the Randomized Safety Population. The number of subjects who have < 8 
and > 24 breaths per minute will be presented by time point, treatment group, and overall total.
7.7.9.
Electrocardiogram (ECG)
Electrocardiogram (ECG) parameters (heart rate, PR interval, RR interval, QRS interval, QT 
interval, and QTc interval) will be summarized descriptively for each scheduled visit and time 
point collected for the Safety Population. Mean and mean change from baseline values at Visit 2
will be presented. 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. In addition, counts and percentages 
for ECG diagnosis (normal or abnormal) at each study visit and time point will also be presented.
If the diagnosis was abnormal, counts and percentages for clinical significance will be presented.
Baseline values are the last available values before Test-Dose administration.
The number of subjects meeting the following criteria will be presented by treatment group for 
the Safety Population:

QTcF interval > 450 msec for males and > 470 msec for females
8.
OTHER PLANNED ANALYSES
8.1.
Pharmacokinetic (PK) Analyses
Pharmacokinetic parameters for individual plasma concentrations will be calculated using a 
standard non-compartmental approach using appropriate validated PK software (WinNonlin 
Enterprise version 5.2 or higher). The following PK parameters of midazolam and 1-
hydroxymidazolam will be calculated from data obtained for the PK Population:

AUC0-last – the area under the plasma concentration-time curve from time 0 to the last 
measurable concentration. Estimation by the linear-up/log-down trapezoidal method 
is preferred.

AUC0-x – the area under the plasma concentration-time curve from time 0 to time x, 
where x =1, 2 and 4 hours.

Cmax – the maximum plasma concentration

tmax – the time to reach the maximum plasma concentration
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
tlag – the time before the first measurable plasma concentration
Due to the limited length of the PK sampling schedule (out to a maximum of 4 hrs post dose), it 
is unlikely that sufficient samples will be available for estimation of the terminal rate constant 
(λz). Thus, λz and associated PK parameters (viz. terminal half-life, AUC0-∞, CL/F and Vz/F) will 
not be calculated a priori. If supported by the data, additional PK parameters may be calculated 
after discussion with the Sponsor.
Pre-dose concentration values reported as below the limit of quantification (BLQ) and missing 
pre-dose values will be treated as “0” and listed as BLQ. A series of BLQ values that includes 
the pre-dose time point will also be treated as “0” and listed as BLQ. All other BLQ values will 
be set to missing. Actual sampling times will be used in the calculations of PK parameters.
With the exception of tmax and tlag, descriptive statistics by treatment group will include the 
number of observations (N), mean, standard deviation (SD), coefficient of variation (CV%),
geometric mean, and geometric CV%, as well as median, minimum, and maximum for the PK
variables. Summary statistics for tmax and tlag will be limited to N, minimum, maximum and 
median. In addition, summary of PK variables stratified by AED inducer status as well as figures 
of Midazolam and 1-OH Midazolam concentrations on linear and semi-log scales will also be 
presented.
A covariate analysis that examines the effect of continuous (age, weight) and, if supported, 
categorical (gender, race, and age group [adult vs adolescent]) demographic variables on the PK 
parameters may be conducted.
8.2.
Pharmacokinetic/Pharmacodynamic Variables and Analyses
Correlations between PK/PD data from the test dose may be evaluated. If conducted, the PK/PD 
analysis may include correlating the plasma midazolam plus 1-hydroxymidazolam 
concentrations to respiratory rate, BP, HR, O2 saturation, and/or sedation based on OAA/S
scores. Regression analysis may be used describe the PK/PD relationship, if one exists. For those 
PD measurements found to correlate to plasma concentrations, the influence of covariates such 
as gender, AED inducer status, weight, BMI, race, and age group may be explored.
9.
CHANGES TO THE PLANNED ANALYSIS
Since the last submission of the P261-401 Statistical Analysis Plan (v2.4) to the FDA (S-0150, 
03 March 2015), the following changes were made to the plan (v2.5-v2.9):

The Brief Smell Identification Test (B-SIT) was added to the list of safety objectives. 
The plan for analysis of B-SIT data was also added. These changes were made to 
reflect the changes implemented in Protocol Amendment 4, 20 May 2015.

The procedures to be completed at Visits 1, 4, and on the monthly telephone follow-
up calls between Visit 3 and Visit 4 were updated to add collection of the number of 
calls to EMS and ER visits for a seizure cluster or other seizure emergency prior to 
Visit 1 and during the study. This change was made to reflect the changes 
implemented in Protocol Amendment 4, 20 May 2015.
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
The process for reviewing CSR Reportable protocol deviations and exclusions prior 
to database lock was clarified to determine if any subject should be excluded from 
specific analysis populations. 

The subgroup analyses of the primary and secondary endpoints were further clarified 
to examine consistency as follows:

The time-frame around the use of enzyme-inducing AEDs was defined as within 
14 days before study drug administration. Population PK modeling of deinduction 
times for strong CYP3A4 inducers, including carbamazepine, indicates a 
deinduction half-life following discontinuation of approximately 3 – 4 days with 
return to baseline function occurring within approximately 14 days following 
discontinuation of dosing. Based on these estimates, a subject should be classified 
as “induced” if they have received an enzyme-inducing AED ≤ 14 days prior to 
administration of USL261.

The weight will be categorized based on the median weight for the safety 
population (< median weight and ≥ median weight). This categorization based on 
the median weight was chosen to be representative of the population studied.

The BMI will be categorized as underweight/normal (< 25), overweight (≥25 to 
<30), and obese 1-3 categories combined (≥30). This categorization was based on 
standard BMI categories.

The subgroups frequency of seizure clusters and benzodiazepine use was removed 
as these subgroups are based on historic data and may not represent the seizure 
cluster frequency or benzodiazepine use relative to administration of study drug in 
the Comparative Phase.

The subgroups seizure types (generalized and focal) and seizure etiology were 
removed.

For subjects who were rescreened and underwent two Test Dose Visits, baseline will 
be defined as the last available values before the later Test Dose administration. This 
clarification was provided to prespecify how baseline is defined in a unique situation.

An additional exploratory efficacy analysis, “treatment success of all doses of study 
drug,” was included in the plan. This exploratory analysis was added to assess the 
Treatment Success of the first dose and Treatment Success of the second dose (taken 
within 6 hours) during the Comparative Phase.

The definition of a treatment-emergent adverse event (TEAE) in the Test Dose Phase 
and in the Comparative Phase was clarified. This clarification was made to clearly 
define the phase in which TEAEs will be reported. However, it does not impact the 
definition of a TEAE or the total TEAEs reported.

The AEs of special interest (AESI) and abuse-related AEs were defined.

Additional detail for the calculation of the following PD parameters: OAA/S sum 
score, AUEC0-t, AUEC0-x, and Emax was added.
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
An early study termination analysis unrelated to study success or futility was added in 
the event that the trial has not crossed a boundary for early success or early futility 
and yet is stopped early before reaching the pre-specified maximum sample size of 
240 subjects.
10.
MOCK TABLES, FIGURES, AND DATA LISTINGS
The mock TLGs will be provided in a separate document.
11.
REFERENCES 
1. Cereghino JJ. Identification and treatment of acute repetitive seizures in children and 
adults. Curr Treat Options Neurol. 2007;9:249-255.
2. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1988;338:970-976.
3. Glauser TA. Designing practical evidence-based treatment plans for children with 
prolonged seizures and status epilepticus. J Child Neurol. 2007;22:38S-46S.
4. Westat. Mental Health Treatment Study. Appendices. July 2011
5. Utah Department of Health. Interpreting the SF12. 2001 Utah Health Status Survey.
2001: 1-17.
6. Web. < http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434659/>
7. Web. <www.qualitymeasures.ahrq.gov>.
8. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, 
Siegel JL. Validity and Reliability of the Observer’s Assessment of Alertness/Sedation 
Scale: Study with Intravenous Midazolam. J of Clin Psychopharmacology. 1990; 10; 
4:244-251.
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APPENDIX 1.
POTENTIALLY CLINICALLY SIGNIFICANT 
LABORATORY VALUES
Table 8:
Potentially Clinically Significant Laboratory Values
Variable
Units
Values
Low
High
Haematology
Haemoglobin
g/L
< 100
Not applicable
g/L
> 20 decrease 
from baseline
> 20 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
Serum Chemistry
Albumin 
g/L
< 30
Not applicable
Alkaline phosphotase (AP)
U/L
Not applicable
> 2.5xULN
Alanine aminotransferase (ALT) Grade 1
U/L
Not applicable
> ULN & ≤ 3xULN
Alanine aminotransferase (ALT) Grade 2
U/L
Not applicable
> 3xULN & ≤ 5xULN
Alanine aminotransferase (ALT) Grade 3
U/L
Not applicable
> 5xULN & ≤ 20xULN
Alanine aminotransferase (ALT) Grade 4
U/L
Not applicable
> 20xULN
Aspartate aminotransferase (AST) Grade 1
U/L
Not applicable
> ULN & ≤ 3xULN
Aspartate aminotransferase (AST) Grade 2
U/L
Not applicable
> 3xULN & ≤ 5xULN
Aspartate aminotransferase (AST) Grade 3
U/L
Not applicable
> 5xULN & ≤ 20xULN
Aspartate aminotransferase (AST) Grade 4
U/L
Not applicable
> 20xULN
Bicarbonate 
mmol/L
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
Abbreviation: ULN=Upper Limit of Normal
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APPENDIX 2.
CLASSIFICATION OF ENZYME INDUCING AEDS
Note – The AEDs represented in Table 9 and Table 10 do not represent an exhaustive list.
Additional AEDs not listed need to be reviewed and assigned.
Table 9:
Listing of Non-Enzyme Inducing AEDs
AED name
Reference
Acetazolamide
[1]
Chloral Hydrate
[2]
Chlorazepate
[3]
Clonazepam
[4]
Diazepam
[5]
Ethosuximide
[6]
Gabapentin
[7]
Lacosamide
[8]
Lamotrigine
[9]
Levetiracetam
[10]
Lorazepam
[11]
Midazolam
[12]
Oxazepam
[13]
Perampanel
[14]
Pregabalin
[15]
Retigabine (ezogabine)
[16]
Tiagabine
[17]
Valproic Acid, 
Valproate, Divalproex 
Sodium
[18]
Vigabatrin
[6]
Zonisamide
[19]
Table 10:
List of Enzyme Inducing AEDs
AED name
Strength of inducera
Reference
Carbamazepine
Strong
[20]
Clobazam
Weak
[21]
Eslicarbazepine
Weak (borderline moderate)
[22]
Ethotoin
Strong (assumed from in vitro induction vs. phenytoin) 
[23]
Felbamate
Weak
[24]
Mephenytoin
Strong (assumed from in vitro induction vs. phenytoin) 
[23]
Oxcarbazepine
Weak (borderline moderate)
[25]
Phenobarbital
Strong
[26, 27]
Phenytoin
Strong
[20]
Primidone
Strong (via phenobarbital major metabolite)
[26, 27]
Rufinamide
Weak
[20]
Topiramate
Weak (only at doses > 200 mg/day)
[28]
a Based on decrease in AUC of CYP3A4 substrate [20]: Weak = 20 – 50% decrease, Moderate = 50 – 80% decrease,  
Strong = ≥ 80% decrease 
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Washout period required for deinduction following discontinuation of inducing AEDs.
Population PK modeling of deinduction times for strong CYP3A4 inducers, including 
carbamazepine, indicates a deinduction half-life following discontinuation of approximately 
3-4 days with return to baseline function occurring within approximately 14 days following 
discontinuation of dosing [29-32]. Based on these estimates, a subject should be classified as 
“induced” if they have received an enzyme-inducing AED ≤ 14 days prior to administration of 
USL261.
References
1. Spina, E., F. Pisani, and E. Perucca, Clinically significant pharmacokinetic drug interactions 
with carbamazepine. An update. Clin Pharmacokinet, 1996. 31(3): p. 198-214.
2. Perrigo, Chloral Hydrate Mixture. 2006.
3. Lundbeck, Tranxene T-Tab (clorazepate dipotassium) [Prescribing Information]. 2009.
4. Roche, Klonopin (clonazepam) [Prescribing Information]. 2009.
5. Valeant Pharmaceuticals, Diastat Accudial (diazepam) [Prescribing Information]. 2006.
6. Riva, R., et al., Pharmacokinetic interactions between antiepileptic drugs. Clinical 
considerations. Clin Pharmacokinet, 1996. 31(6): p. 470-93.
7. Pfizer, Neurontin (gabapentin) [Prescribing Information]. 2014.
8. UCB, Vimpat (lacosamide) [Prescribing Information]. 2011.
9. GlaxoSmithKline, Lamictal (lamotrigine) [Prescribing Information]. 2012.
10. UCB, Keppra (levetiracetam) [Prescribing Information]. 2013.
11. West-Ward Pharmaceuticals, Ativan (lorazepam) [Prescribing Information]. 2011.
12. Hospira, Midazolam Injection, USP [Prescribing Information]. 2009.
13. Alphapharm, Alepam (oxazepam) [Prescribing Information]. 2013.
14. Eisai, Fycompa (perampanel) [Prescribing Information]. 2013.
15. Pfizer, Lyrica (pregabalin) [Prescribing Information]. 2013.
16. GlaxoSmithKline, Potiga (ezogabine) [Prescribing Information]. 2013.
17. Cephalon, Gabitril (tiagabine hydrochloride) [Prescribing Information]. 2012.
18. AbbVie, Depakote (divalproex sodium) [Prescribing Information]. 2015.
19. Eisai, Zonegran (zonisamide) [Prescribing Information]. 2012.
20. U.S. Food and Drug Administration, Draft Guidance: Drug Interaction Studies — Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 2012.
21. Lundbeck, ONFI (clobazam) [Prescribing Information]. 2013.
22. Sunovion Pharmaceuticals, Aptiom (eslicarbazepine acetate) [Prescribing Information]. 
2013.
23. Kobayashi, K., et al., Key structural features of ligands for activation of human pregnane X 
receptor. Drug Metab Dispos, 2004. 32(4): p. 468-72.
24. Meda Pharmaceuticals, Felbatol (felbamate) [Prescribing Information]. 2011.
25. Novartis, Trileptal (oxcarbazepine) [Prescribing Information]. 2013.
26. Back, D.J., et al., The interaction of phenobarbital and other anticonvulsants with oral 
contraceptive steroid therapy. Contraception, 1980. 22(5): p. 495-503.
27. Ripp, S.L., et al., Use of immortalized human hepatocytes to predict the magnitude of clinical 
drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos, 2006. 34(10): p. 
1742-8.
28. Janssen Pharmaceuticals, Topamax (topiramate) [Prescribing Information]. 2012.
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29. Baneyx, G., et al., Physiologically based pharmacokinetic modeling of CYP3A4 induction by 
rifampicin in human: influence of time between substrate and inducer administration. Eur J 
Pharm Sci, 2014. 56: p. 1-15.
30. Brodie, M.J., et al., Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia, 
2013. 54(1): p. 11-27.
31. Punyawudho, B., et al., Characterization of the time course of carbamazepine deinduction by 
an enzyme turnover model. Clin Pharmacokinet, 2009. 48(5): p. 313-20.
32. Schaffler, L., B.F. Bourgeois, and H.O. Luders, Rapid reversibility of autoinduction of 
carbamazepine metabolism after temporary discontinuation. Epilepsia, 1994. 35(1): p. 195-8.
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APPENDIX 3.
LIST OF AE TERMS OF SPECIAL INTEREST
Table 11:
Abuse-related AEs (MedDRA Preferred Term)
Drug Abuse, Dependence, Withdrawal and Substance-Related Disorders, Including Diversion 
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
Euphoria-related Terms
Dizziness
Feeling drunk
Elevated mood
Feeling of relaxation
Euphoric mood
Inappropriate affect
Feeling abnormal
CNS Depressant Effects
Fatigue
Sluggishness
Lethargy
Somnolence
Sedation
Stupor
Stimulation and Anxiety Symptoms
Agitation
Hypervigilance
Anxiety
Nervousness
Energy increased
Psychomotor hyperactivity
Feeling jittery
Restlessness
Perceptual Disturbances/Psychotomimetic Effects
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
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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
Hallucination, tactile
Transient psychosis
Hallucination, visual
Mood Disorders and Disturbances
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
Mental and Cognitive Impairment
Amnesia
Mental disorder
Cognitive disorder
Mental status changes
Disturbance in attention
Paramnesia
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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
Table 12:
AEs Related to Acute Central Respiratory Depression (SMQ) 
System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
Cardiac disorders
Cyanosis
Acrocyanosis
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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 
complications
Respiratory fume inhalation 
disorder
Upper respiratory inflammation due 
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
Investigations
PO2 abnormal
PO2 abnormal NOS
Investigations
PO2 decreased
PO2 decreased
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
Investigations
Oxygen saturation decreased
Arterial oxygen saturation 
decreased
Investigations
Oxygen saturation abnormal
Arterial oxygen saturation abnormal
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
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
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System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
60
System Organ Class
Preferred Term
Lowest Level Term
Acute central respiratory depression (SMQ)
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
Surgical and medical procedures
Oxygen supplementation
Oxygen supplementation
Table 13:
AEs Related to Route of Administration-Oral Soft Tissue Conditions (HLT)
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
61
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
62
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
Gastrointestinal disorders
Hypoaesthesia oral
Numbness of mouth angular
Gastrointestinal disorders
Hypoaesthesia oral
Numbness of tongue
Gastrointestinal disorders
Hypoaesthesia oral
Numbness oral
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
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia of oral mucosa, incl 
tongue
Gastrointestinal disorders
Leukoplakia oral
Leukoplakia tongue
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
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System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
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System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
65
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
66
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
67
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
68
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration : Oral Soft Tissue Conditions (HLT)
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
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
Table 14:
AEs Related to Route of Administration-Respiratory Disorders NEC (HLT)
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
Respiratory, thoracic and 
mediastinal disorders
Allergic cough
Allergic cough
Respiratory, thoracic and 
mediastinal disorders
Choking
Choked on food
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
69
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
Respiratory, thoracic and 
mediastinal disorders
Choking
Choking
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
Respiratory, thoracic and 
mediastinal disorders
Cough
Paroxysmal cough
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
70
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
71
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
72
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
73
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
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
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
74
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
Respiratory, thoracic and 
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
75
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
76
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
77
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Respiratory Disorders NEC (HLT)
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
Table 15:
AEs Related to Route of Administration-Upper Respiratory Tract Disorders 
(HLT) (Exclude Infections)
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
78
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Epiglottis ulcer
Epiglottis ulcer
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
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
79
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Laryngeal dyspnoea
Laryngeal dyspnoea
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
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
80
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Laryngeal obstruction
Laryngeal obstruction
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
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
81
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Laryngeal oedema
Aryepiglottis edema
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
REDACTED COPY 
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
82
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Laryngospasm
Spasm glottis
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
83
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Nasal dryness
Nasal dryness
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
84
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Nasal necrosis
Nasal septal mucosa necrosis
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
85
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Nasal septum perforation
Perforation nasal septum
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
86
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Paranasal sinus necrosis
Paranasal sinus necrosis
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
87
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Pharyngeal haemorrhage
Pharyngeal haemorrhage
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
88
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Pharyngeal oedema
Pharynx edema
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
89
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Rhinitis atrophic
Ozena
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
90
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Sinus polyp
Antral polyp (of maxillary sinus)
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
91
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
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 
mediastinal disorders
Tonsillolith
Tonsillolith
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
92
System Organ Class
Preferred Term
Lowest Level Term
Route of Administration: Upper Respiratory Tract Disorders (HLT) (Exclude Infections)
Respiratory, thoracic and 
mediastinal disorders
Vocal cord thickening
Vocal cord thickening
Respiratory, thoracic and 
mediastinal disorders
Vocal cord thickening
Vocal cord nodule
Table 16:
AEs Related to Taste and Smell Disorders (SMQ)
System Organ Class
Preferred Term
Lowest Level Term
Taste and Smell Disorders (SMQ)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
93
System Organ Class
Preferred Term
Lowest Level Term
Taste and Smell Disorders (SMQ)
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
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
Table 17:
AEs Related to Depression and Suicidality/Self-Injury-Depression (SMQ) 
(Exclude Suicide/Self-Injury)
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
Activation syndrome
Activation syndrome
Adjustment disorder with depressed mood
Adjustment disorder with depressed mood
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
94
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
95
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
Depression
Depression NOS
Depression
Depression reactive
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
Feeling guilty
Feeling remorse
Feeling of despair
Feeling of despair
Feelings of worthlessness
Feelings of worthlessness
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
96
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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)
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
97
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
98
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
99
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
100
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
101
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
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
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
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
102
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Depression (SMQ) (Exclude Suicide/Self-Injury)
Psychotherapy
Supportive psychotherapy
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
Table 18:
AEs Related to Depression and Suicidality/Self-Injury-Suicide/Self-Injury 
(SMQ)
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Suicide/Self-Injury (SMQ)
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
Attempted suicide
Deliberate poisoning
Attempted suicide
Poisoning deliberate
Poisoning deliberate
Poisoning deliberate
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Upsher-Smith Laboratories, Inc.
Statistical Analysis Plan for Protocol No.: P261-401
14 April 2017
103
Preferred Term
Lowest Level Term
Depression and Suicide/Self-Injury: Suicide/Self-Injury (SMQ)
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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