Public Disclosure Synopsis
Protocol B3541002 – 03 April 2017 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME: Lorazepam
PROTOCOL NO.: B3541002
PROTOCOL TITLE:
A Multi-Center, Open-Label, Non-Controlled Study to Evaluate the Efficacy and Safety ofLorazepam Intravenously Administered in Subjects With Status Epilepticus or Repetitive
Status Epilepticus
Study Centers:
Fifteen (15) centers in Japan took part in this study and enrolled subjects.
Study Initiation and Final Completion Dates:
25 November 2014 and 22 August 2016
Phase of Development:
Phase 3
Study Objective:
The primary objective was to evaluate the efficacy and safety of lorazepam
intravenously (IV) administered in subjects with status epilepticus (SE).
METHODS
Study Design:This was a multi-center, open-label, non-controlled study in Japanese subjects with SE orrepetitive SE. The target number of subjects with SE or repetitive SE/cluster seizures who
had seizures that could be evaluated by the investigator’s visual observations based on motor
symptoms was approximately 25 (including at least 3 adult subjects). At least 3 subjects
were to be enrolled in the category of nursing infants with the lower age limits 3 months to<1 year. In addition, at least 3 subjects were to be enrolled in the combined categories of
infants (1 year to <7 years) and children (7 years to <16 years). At least 5 adult subjects(including at least 3 with motor symptoms) with SE or repetitive SE/cluster seizures who had
seizures that could be evaluated by electroencephalogram (EEG) were to be enrolled. The
subjects were classified based on age at the initial administration of the study drug (Table 1).

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Table 1.

Target Number of Subjects With Status Epilepticus or Repetitive Status
Epilepticus/Cluster Seizures Who Had the Seizures With Motor Symptoms

Category
Pediatrics
Nursing infants
Infants
Children
AdultsTotal

Age(At the Initial Administration)

Target Number

3 months to <1 year
1 year to <7 years
7 years to <16 years
16 years--

At least 3
At least 3 in total for bothcategories (infants and children)
At least 3
25This study had up to a 6-month screening period, up to a 2-day treatment period andfollow-up visit 7 days after the last administration.
The schedule of activities is presented in Table 2.

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Table 2.

Schedule of Activities

Observation/Assessment

Treatment Periodb

Screening
PeriodaBeforeInitial
Dose

Allowable Period

Informed consent
Inclusion/exclusion
criteria
Medical history
WeightPregnancy testd
Physical examination(interview)
Vital signs (bloodpressure and pulse rate)e
SpO2e
Clinical laboratory tests
Assessment on epileptic
seizureAdverse events
Concomitant drugs andtherapy

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Up to
6 Months
BeforeInitialDoseX
X

10 Minutes
After Dose30 Minutes
After Dose2 Hours
After Dose

10 –15 Minutes
After Dose30 –40 Minutes
After Dose

1.75 2.25 Hours
After Dose

Follow-Up
Period12 Hours–
24 Hours
After
Dose

24 Hours–
48 Hours
After
Dose

Termination

7 Days After
Last
Administration
3 DaysWithin3 Days

X

X
X

X
X

X

X

X

X
Xf

X
X

X
X

Xa

X
(X)
(X)
(X)

Xc
X
X

X

X

(X)

X

X

X

X

X

X
X

X

X

X

X

(X)

X
X

(X)

X
X

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Table 2.

Schedule of Activities

Abbreviation: SpO2=arterial oxygen saturation measured by transcutaneous pulse oximetry.
a. In case informed consent was not obtained from the subject during the screening period, the emergency informed consent form was used and informed
consent was obtained from a legally acceptable representative/parent(s)/legal guardian before the initial dose. In this case, observations/assessments thatwere indicated on (X) were only performed before the initial dose of the study drug.
b. The day for the initial dose of the investigational treatment was on Day 1. If a second dose was to be given, the evaluation based on the initial dose were
performed before the second dose, and observation/test items “10 minutes after dose” and those after that in the above schedule were performed after thesecond dose.
c. In the case that the weight could not be measured, the most accurate estimate of the subject’s current weight was used.
d. A pregnancy test was performed only in female subjects of childbearing potential.
e. As for vital signs and SpO2, those continuously monitored by biological information monitors, etc could be used.
f. Only in the case that termination was before the clinical laboratory tests on “24 hours to 48 hours after dose”.

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Number of Subjects (Planned and Analyzed):
This study planned to enroll approximately 25 subjects with SE or repetitive SE/cluster
seizures who had evaluable motor symptoms by investigator’s visual observation. A total of
26 subjects were enrolled in the study and treated. All subjects completed the study. A totalof 25 subjects were analyzed for efficacy. A total of 26 subjects were analyzed for safety.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Subjects (either gender) 3 months of age with SE or repetitive SE/cluster seizures who had
seizures that could have been evaluated by investigator’s visual observations based on motor
symptoms or who had seizures that could be evaluated by EEG were enrolled in this study.
Main Exclusion Criteria: Subjects with known or suspected recurrent seizures due to illegal
drug or alcohol withdrawal, hypersensitivity to lorazepam or benzodiazepine, or
benzodiazepine abuse were excluded from the study.
Study Treatment:
For adult subjects (16 years), lorazepam 4 mg was IV administered at a slow injection rateof approximately 2 mg/minute. While for pediatric subjects (3 months to <16 years),lorazepam 0.05 mg/kg (but not exceeding 4 mg) was IV administered at a slow injection rateof approximately 2 mg/minute.
For subjects whose seizure did not stop or stopped but recurred within 10 minutes after the
initial dose, the second dose could be administered at the same dose and injection rate as theinitial dose, at least 10 minutes after the initial dose. For subjects whose seizure stopped but
recurred >10 minutes after the initial dose (but within 12 hours of the initial dose), an
additional dose could be administered at the same dose and injection rate as the initial dose.
A total of 2 doses were permitted in this study.
Efficacy Endpoints:
Primary Efficacy Endpoint:Proportion of subjects whose seizures stopped within 10 minutes after initial dose andwho continued seizure-free for at least 30 minutes after the completion of initial dose
(efficacy rate).

Key Secondary Efficacy Endpoint:Proportion of subjects whose seizures stopped within 10 minutes after the administrationof study drug (either initial or second dose [in 10 to 30 minutes from the initial dose]) and
who continued seizure-free for at least 30 minutes.

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Other Secondary Efficacy Endpoints:(1-1) Proportion of subjects whose seizures stopped within 10 minutes after theadministration of study drug (only the initial dose) and who continued seizure-free for atleast 12 hours postdose;(1-2) Proportion of subjects whose seizures stopped within 10 minutes after theadministration of study drug (either initial or second dose [in 10 to 30 minutes from theinitial dose]) and who continued seizure-free for at least 12 hours post-dose;(2-1) Proportion of subjects whose seizures stopped within 10 minutes after theadministration of study drug (only the initial dose) and who continued seizure-free for atleast 24 hours postdose;(2-2) Proportion of subjects whose seizures stopped within 10 minutes after theadministration of study drug (either initial or second dose [in 10 to 30 minutes from theinitial dose]) and who continued seizure-free for at least 24 hours postdose;(3-1) Time to resolution of seizures from the administration of study drug (only the initial
dose);

(3-2) Time to resolution of seizures from the administration of study drug (either initial orsecond dose);(4-1) Time to relapse from the resolution of seizures following the administration of
study drug (only the initial dose, within 24 hours);(4-2) Time to relapse from the resolution of seizures following the administration of
study drug (either initial or second dose, within 24 hours).

Safety Evaluations:
Safety evaluations included clinical monitoring, physical examination, vital signs (heart rate,
blood pressure), oxygen saturation, adverse events and safety laboratory tests. Safetyassessments were performed as shown in Table 2.
Statistical Methods:
Efficacy: The primary analysis population was the full analysis set defined as all subjects
who received at least 1 dose of study drug, and excluded subjects whose SE or repetitive
SE/cluster seizures was determined by the EEG. The 95% confidence intervals (CIs) were
calculated based on the exact CI by the Clopper-Pearson method. For the efficacy rate in theendpoint, the point estimate and 95% CI were presented. For the endpoints of the time
resolution of seizures or relapse, the time was descriptively summarized and Kaplan Meierestimates of the time to resolution of seizure or relapse was provided. The efficacy endpoints
were presented in subgroups of adult or pediatric subjects; however, 95% CIs were not to be
calculated in these subgroups. For the subjects with SE or repetitive SE/cluster seizures who
had seizures which were evaluated by EEG, the data were listed by subject.

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Safety: The safety data were summarized based on the safety analysis set (SAS) which
consisted of all subjects who received at least 1 dose of study drug. The subjects who wereenrolled as subjects with SE or repetitive SE/cluster seizures who had seizures which were
evaluated by EEG were included in SAS. The safety was analyzed according to thealgorithm and formats that were specified according to the sponsor data standards. The lastmeasurement before first dose was defined as baseline. The safety endpoints were presented
in subgroups of adult or pediatric subjects.
RESULTS
Subject Disposition and Demography:
Subject disposition is presented in Table 3. A total of 26 subjects were enrolled in the study
and treated. All subjects completed the study. One (1) subject was excluded from theefficacy analysis due to SE seizures that were evaluated by EEG. All subjects were analyzed
for safety.
Table 3.

Subject Disposition
Lorazepam
26
26
26
0

Number of subjects assigned to study treatment
TreatedCompleted
Discontinued
Analyzed for efficacy
Full analysis set
Analyzed for safety
Adverse events
Laboratory data
Safety analysis set

25
26
26
26

Overall demographic characteristics are summarized in Table 4. Of the 26 subjects,
10 (38.5%) subjects were adults with mean age 27.6 years while 16 (61.5%) subjects werefrom the pediatric population with a mean age of 5.4 years.

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Table 4.

Demographic Characteristics

Number (%) of
Total
AdultsPediatrics
Subjects
All
Nursing Infants InfantsChildren
Number of subjects
26
10
16
1
8
7
Sex
Male
16
6
10
1
4
5
Female
10
4
6
0
4
2
Age
Mean (SD)
14.0 (12.9) 27.6 (9.9)
5.4 (4.3)0
2.5 (1.6)
9.6 (2.7)
Median
9.5
27.0
4.5
0
2.0
8.0
Range (min-max)
0-49
17-49
0-13
0-0
1-5
7-13
Race
Asian
26 (100.0) 10 (100.0) 16 (100.0)
1 (100.0)
8 (100.0)
7 (100.0)
Ethnicity
Not Hispanic/Latino
26 (100.0) 10 (100.0) 16 (100.0)
1 (100.0)
8 (100.0)
7 (100.0)
Adult: 16 years, pediatric: <16 years, nursing infants: 3 months to <1 year, infants: 1 year to <7 years,
children: 7 years to <16 years.
Abbreviations: max=maximum; min=minimum; SD=standard deviation.

Efficacy Results:
Primary Endpoint:
Proportion of Subjects Whose Initial Seizure Stopped Within 10 Minutes and who Continued
Seizure-Free for At least 30 Minutes After the Completion of Initial Dose:A total of 12 subjects (48.0%) had initial seizure that stopped within 10 minutes andcontinued seizure-free for at least 30 minutes after the completion of initial dose (Table 5).
The lower bound of 95% CI of the primary efficacy endpoint was lower than
30% (pre-specified expected minimum responder rate).
Table 5.

Proportion of Subjects Whose Initial Seizure Stopped Within 10 Minutes
and who Continued Seizure-Free for At least 30 Minutes After theCompletion of Initial Dose
Total
(N=25)

Pediatric (N=16)
All
Nursing Infants
Infants
Children(N=16)
(N=1)
(N=8)
(N=7)
N (%)
95% CI
n (%)
n (%)
n (%)
n (%)
n (%)
12 (48.0)
27.8-68.7
6 (66.7)
6 (37.5)04 (50.0)
2 (28.6)
Adult: 16 years, pediatric: <16 years, nursing infants: 3 months to <1 year, infants: 1 year to <7 years,
children: 7 years to <16 years.
Abbreviations: CI=confidence interval; N/n=number of subjects with observations.

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Secondary Endpoints:
Proportion of Subjects Whose Initial Seizure Stopped Within 10 Minutes and who Continued
Seizure-Free for a Given Time Period:
A total of 16 subjects (64.0%) had initial seizure stopped within 10 minutes after theadministration of study drug (either initial or second dose [in 10 minutes to 30 minutes fromthe initial dose]) and continued seizure-free for at least 30 minutes (Table 6).
Table 6.

Proportion of Subjects Whose Initial Seizure Stopped Within 10 Minutes
and who Continued Seizure-Free for a Given Time Period
Total(N=25)

Adults(N=9)

Pediatric (N=16)
All
Nursing Infants
Infants
Children(N=16)
(N=1)
(N=8)
(N=7)
n (%)
95% CI
n (%)
n (%)
n (%)
n (%)
n (%)
Key secondary
16 (64.0)
42.5-82.0
7 (77.8)
9 (56.3)
05 (62.5)
4 (57.1)
Secondary 1-1
8 (32.0)
14.9-53.5
4 (44.4)
4 (25.0)03 (37.5)
1 (14.3)
Secondary 1-2
11 (44.0)
24.4-65.1
5 (55.6)
6 (37.5)03 (37.5)
3 (42.9)
Secondary 2-1
6 (24.0)
9.4-45.1
4 (44.4)
2 (12.5)0
1 (12.5)
1 (14.3)
Secondary 2-2
8 (32.0)
14.9-53.5
4 (44.4)
4 (25.0)0
1 (12.5)
3 (42.9)
Adult: 16 years, pediatric: <16 years, nursing infants: 3 months to <1 year, infants: 1 year to <7 years,
children: 7 years to <16 years.
Key secondary: Subjects whose seizures stopped within 10 minutes after the administration of study drug
(either initial or second dose [in 10 to 30 minutes from the initial dose]) and who continued seizure-free forat least 30 minutes.
Secondary 1-1: Subjects whose seizures stopped within 10 minutes after the administration of study drug (onlythe initial dose) and who continued seizure-free for at least 12 hours postdose.
Secondary 1-2: Subjects whose seizures stopped within 10 minutes after the administration of study drug (either
initial or second dose [in 10 to 30 minutes from the initial dose]) and who continued seizure-free for at least
12 hours postdose.
Secondary 2-1: Subjects whose seizures stopped within 10 minutes after the administration of study drug (onlythe initial dose) and who continued seizure-free for at least 24 hours postdose.
Secondary 2-2: Subjects whose seizures stopped within 10 minutes after the administration of study drug (either
initial or second dose [in 10 to 30 minutes from the initial dose]) and who continued seizure-free for at least
24 hours postdose.
Abbreviations: CI=confidence interval; N=number of subjects.

Time to Resolution of Seizures From the Administration of Study Drug:
Time to resolution of seizures from the administration of study drug is presented in Table 7.
Median time for the resolution of the seizures was 1 minute for the overall population in
subjects with initial dose as well as subjects with either dose (initial or second dose).

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Table 7.

Time to Resolution of Seizures From the Administration of Study Drug
Total
(N=25)

Adults(N=9)

All(N=16)

Pediatric (N=16)
Nursing
Infants
Infants
(N=8)
(N=1)

Children(N=7)

Secondary 3-1
n (%)*1
15 (60.0)
6 (66.7)
9 (56.3)
1 (100)4 (50.0)
4 (57.1)
*2
0
0
0
0
0
0
*3
10 (40.0)
3 (33.3)
7 (43.8)04 (50.0)
3 (42.9)
Time to resolution (minutes)
Summary statistics
n
15
6
9
1
4
4
Mean (SD) 2.7 (3.27) 3.2 (3.37) 2.3 (3.35)
2.0 (-)
0.3 (0.50) 4.5 (4.20)
Median121204Minimum
0002
00Maximum
10
9
10
2
1
10
Kaplan-Meier estimates (percentiles)
10%
0
0
0
2
0
0
25%
1
1
0.5
2
0
3
50%
5
5
7.5
2
10
75%
2
90%
2
Secondary 3-2
n (%)#1
17 (68.0)
7 (77.8)
10 (62.5)
05 (62.5)5 (71.4)#2
1 (4.0)1 (11.1)0000#37 (28.0)
1 (11.1)
6 (37.5)
1 (100)3 (37.5)
2 (28.6)
#4
0
0
0
0
0
0
Time to resolution (minutes)
Summary statistics
n
17
7
10
0
5
5
Mean (SD) 2.4 (3.18) 2.7 (3.30) 2.2 (3.26)
0.2 (0.45) 4.2 (3.70)
Median1
10.5
03Minimum
00000Maximum
10
9
10
1
10
Kaplan-Meier estimates (percentiles)
10%
0
0
0
0
0
25%
0
1
0
0
3
50%
3
3
4
0.5
5
75%
9
90%
Adult: 16 years, pediatric: <16 years, nursing infants: 3 months to <1 year, infants: 1 year to <7 years,
children: 7 years to <16 years.
Secondary 3-1: Only the initial dose.
*1 Subjects whose seizure stopped within 10 minutes after the initial dose without receiving the prohibited
medications.
*2 Subjects who received the prohibited medications within 10 minutes after the initial dose.
*3 Subjects whose seizure did not stop within 10 minutes after the initial dose.
Secondary 3-2: Either initial or second dose.
#1 Subjects whose seizure stopped within 10 minutes after either initial or second dose without receiving theprohibited medications and took second dose for seizures which were evaluated on EEG.
#2 Subjects who received the prohibited medications within 10 minutes after either initial or second dose.
#3 Subjects whose seizure did not stop within 10 minutes after either initial or second dose.
#4 Subjects who took second dose for seizures which were evaluated on EEG.
Abbreviations: EEG=electroencephalogram; N=number of subjects; n=number of subjects with observations;
SD=standard deviation.

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Protocol B3541002 – 03 April 2017 – FinalTime to Relapse From the Resolution of Seizures Following the Administration of Study
Drug:
Time to relapse from resolution of seizures from the administration of study drug is presented
in Table 8.
Median time for the relapse of the seizures was 62 minutes for the overall population in
subjects with initial dose while 103 minutes for subjects with either initial or second dose.

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Table 8.

Time to Relapse From the Resolution of Seizures Following theAdministration of Study Drug (Within 24 Hours)

Secondary 4-1
n (%)
*1
*2
Time to relapse (minutes)
Summary statisticsn
Mean (SD)MedianMinimum
Maximum
Kaplan-Meier estimates (percentile)
10%
25%
50%
75%
90%
Secondary 4-2
n (%)
#1
#2
Time to relapse (minutes)
Summary statisticsn
Mean (SD)

Total(N=25)

Adults(N=9)

Pediatric(N=16)

Pediatric (N=16)
Nursing
Infants
Infants
(N=8)
(N=1)

Children(N=7)

6 (24.0)
9 (36.0)

4 (44.4)
2 (22.2)

2 (12.5)
7 (43.8)

0
1 (100)1 (12.5)
3 (37.5)

1 (14.3)
3 (42.9)9216.3(340.07)
62
11
879

2
83.0
(28.28)
83
63
103

7
254.4
(382.68)
49
11
879

1
11 (-)
11
11
11

3
557.0
(445.17)
743
49
879

3
33.0
(25.51)
23
14
62

14
49
743
-

63
103
-

11
23
62
879
-

11
11
11
11
11

49
396
811
-

14
18.5
42.5
-

8 (32.0)
9 (36.0)

4 (44.4)
3 (33.3)

4 (25.0)
6 (37.5)

00

1 (12.5)
4 (50.0)

3 (42.9)
2 (28.6)9385.0(454.52)
103
23
1246

3
470.7
(671.76)
103
63
1246

6
342.2
(378.74)
179.5
23
879

0
-

4
492.0
(386.02)
520.0
49
879

2
42.5
(27.58)42.5
2362MedianMinimum
Maximum
Kaplan-Meier estimates (percentile)
10%
49
63
36
49
23
25%
103
103
62
297
62
50%
1246
811
743
75%
879
90%
Adult: 16 years, pediatric: <16 years, nursing infants: 3 months to <1 year, infants: 1 year to <7 years,
children: 7 years to <16 years.
Secondary 4-1: Only the initial dose.
*1 Subjects who continued seizure-free for at least 24 hours postdose after the initial dose.
*2 Subjects who did not continue seizure-free for at least 24 hours postdose after the initial dose.
Secondary 4-2: Either initial or second dose.
#1 Subjects who continued seizure-free for at least 24 hours postdose after either initial or second dose.
#2 Subjects who did not continue seizure-free for at least 24 hours postdose after either initial or second dose.
Abbreviations: N=number of subjects; n=number of subjects with observations; SD=standard deviation.

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Safety Results:
All-causalities and treatment-related treatment-emergent adverse events (TEAEs) arepresented in Table 9. A total of 12 subjects (46.2%) experienced 17 TEAEs of which
4 TEAEs were reported as treatment-related.
The majority of TEAEs were mild or moderate in severity. One (1) TEAE of pneumonia
aspiration was considered severe.
No treatment-emergent death was reported in this study. One (1) treatment-emergent serious
adverse event of pneumonia aspiration was reported, but it was considered not to be related
to treatment. No permanent or temporary discontinuations were reported in the study.
The incidence of all-causalities and treatment-related TEAEs (system organ class andpreferred terms) are summarized in Table 9. The most common TEAEs by preferred term
were somnolence (2 TEAEs) and insomnia (2 TEAEs).

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Table 9.

Treatment-Emergent Non-Serious Adverse Events Incidences:
All-Causalities and Treatment-Related

Number of Subjects, n (%)
Lorazepam
System Organ Class
n (%)
n1
n2
Preferred Term
Subjects evaluable for non-SAE
26
Subjects with non-SAE
12 (46.15)
Gastrointestinal disorders
1 (3.85)10Vomiting
1 (3.85)10General disorders and administration site
1 (3.85)
10conditions
Pyrexia
1 (3.85)
10Infections and infestations
2 (7.69)
2
0
Pneumonia
1 (3.85)
10Urinary tract infection
1 (3.85)10Injury, poisoning and procedural complications
1 (3.85)
20Fall
1 (3.85)10Laceration
1 (3.85)10Investigations
1 (3.85)
10
Blood creatine phosphokinase increased
1 (3.85)
10
Nervous system disorders
4 (15.38)
4
4
Ataxia1 (3.85)1
1
Balance disorder
1 (3.85)1
1
Somnolence
2 (7.69)
2
2
Psychiatric disorders
2 (7.69)20
Insomnia
2 (7.69)
20
Renal and urinary disorders
1 (3.85)10Pollakiuria
1 (3.85)10Respiratory, thoracic and mediastinal disorders
1 (3.85)10Epistaxis
1 (3.85)10Skin and subcutaneous tissue disorders
1 (3.85)10Erythema
1 (3.85)
10
Except for ’n1’ and ’n2’, subjects were only counted once per treatment for each row.
Included data up to 999 days after last dose of study drug.
Occurrences were calculated as the number of records having distinct value of subject ID, start of AE, severity,causality and treatment group for that preferred term.
MedDRA (V19.1) coding dictionary applied.
Abbreviations: AE=adverse event; ID=identification; MedDRA=Medical Dictionary for Regulatory Activities;
n=number of subjects in this reporting group affected by any occurrence of this adverse event, all-causalities;
n1=number of occurrences of treatment-emergent all-causalities adverse events; n2=number of occurrences oftreatment-emergent causally related to treatment adverse events; SAE=serious adverse event; V=version.

No clinically significant changes were observed in the laboratory parameters or vital signs
data during study.
CONCLUSIONS:

Proportion of subjects whose initial seizure stopped within 10 minutes and who continued
seizure-free for at least 30 minutes after the completion of initial dose was
48.0% (12/25, 95% CI: 27.8%-68.7%). The lower bound of 95% CI of the primary
efficacy endpoint was lower than 30% (pre-specified expected minimum efficacy rate).

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Protocol B3541002 – 03 April 2017 – Final

Proportion of subjects whose seizures stopped within 10 minutes after the administrationof study drug (either initial or second dose [in 10 to 30 minutes from the initial dose]) and
who continued seizure-free for at least 30 minutes was 64.0% (16/25,
95% CI: 42.5%-82.0%).

The most common TEAEs were somnolence (7.7%, 2/26) and insomnia (7.7%, 2/26),
and the most common treatment-related TEAE was somnolence (7.7%, 2/26). Almost all
TEAEs were mild or moderate in severity.

No subject experienced serious or severe treatment-related TEAEs nor discontinued thestudy due to TEAEs.



Lorazepam was safe and well tolerated in the adult and pediatric populations.

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