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
Phase: PHASE3
Conditions: Epilepsy
Sponsor: UCB Biopharma S.P.R.L.

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Protocol P261-401
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except to the extent necessary to obtain informed consent from those persons to whom the drug 
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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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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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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.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or 
ations thereof. 

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