Public Disclosure Synopsis
Protocol A9231001 –18 November 2014 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Unasyn®-S / Sulbactam
Sodium, Ampicillin Sodium
PROTOCOL NO.: A9231001
PROTOCOL TITLE: A Multicenter, Unblinded, Non-Comparative Study of Unasyn-S
12 g/Day Evaluating the Safety and Efficacy in Japanese Adult Subjects WithCommunity Acquired Pneumonia
Study Center(s): 22 centers in Japan
Study Initiation and Final Completion Dates: 15 October 2010 to 28 April 2011

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Phase of Development: Phase 3
Study Objective(s): The primary objective was to evaluate the clinical efficacy andsafety of high-dose sulbactam sodium/ampicillin sodium (SBT/ABPC) for intravenoususe (3 g, QID) in patients with moderate to severe community-acquired pneumonia(CAP) for whom injectable antibacterial drugs were indicated and who were judged torequire in-hospital treatment.
The secondary objectives were as follows:
To evaluate the bacteriological response of SBT/ABPC.
To measure the plasma concentrations of sulbactam (SBT) and ampicillin (ABPC)
following intravenous administration of SBT/ABPC to characterize the pharmacokineticsof SBT/ABPC.
METHODS
Study Design: This is a phase 3, multicenter, unblinded, non-comparative study
conducted in Japan. Clinical efficacy was measured at End of Treatment (EOT), at Testof Cure (TOC) which is 7 days after EOT visit, and at Long-Term Follow-Up (LTFU)
which is 7 days after TOC visit.
Study schedule is presented in Table 1.

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Table 1.

Study Schedule

Procedure

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Visit Window 2)
Informed Consent
Demographics, Medical History, Underlying Diseases andComplications
Medical Interview and Examination
Vital Signs
Body Temperature and Clinical Symptoms
SpO2
Hematology
Serum Chemistry
Urinalysis
Pregnancy Test 3)
Chest Radiography (Chest CT if necessary)5)

Sputum Culture and MIC Testing
Sputum Gram Staining 5)
Influenza Virus Antigen Test
Pneumococcal Urinary Antigen Test
PK Sampling 6)
Treatment Compliance
Efficacy Assessment
Safety Assessment (Adverse Events)

Day 1(before firstdose)

Day 1(after firstdose)

Day 41)

Day 0 to 1－Day 4 to 5EOT1)
Day of completion (ordiscontinuation) oftreatment
Day of completion (ordiscontinuation) oftreatment to thefollowing day

TOC
LTFU
7 days after completion
7 days after TOC
of treatment
5 to 10 days after
completion oftreatment

7 to 14 days
after TOC

X
X
X
X

X
X

X
X

X
X
X
X
XX 4)
(Day -1 to 1)
X
X
XX
X

X
X
X
X

7)

X
XX
XX
X
X
X
X
X
X

X
X
X
XX
X
X
X
X

X

X

X

X

X
X

X
X

X
X

X
X

X

X

X

X
8)

Concomitant Medications/Therapies
Sample Banking for Exploratory Research 9)XX
X: mandatory, XX: when necessary
EOT=end of treatment, TOC=test of cure, LTFU=long-term follow-up, SpO2= percutaneous oxygen saturation, CT=computed tomography, MIC=minimum inhibitory concentration,
PK=pharmacokinetics
1) Investigators were to determine whether or not to continue treatment on Day 4. When treatment is completed or discontinued before Day 4, EOT procedures on EOT were to be
performed instead of those specified on Day 4.
2) In principle, all procedures were to be performed on days designated above.
3) For women of childbearing potential. Pregnancy tests may be re-performed according to institutional review board/independent ethics committee’s requests or local regulations.

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4) Chest Radiography or CT performed within 48 hours after initiation of study may be used. Radiographies and CTs preformed prior to initiation of study may only be used for patients
without apparent improvement, and have no prior antimicrobial therapy, or their prior antimicrobial therapy (administered for more than 3 days) have been confirmed ineffective.
5) Only necessary if sputum is coughed up.
6) Blood samples to be collected at 2 to 3 time points between 0 to 2.5 hours, and at 2 time points between 2.5 to 6 hours after initiation of infusion, on any given treatment during the study.
7) Serious adverse events only.
8) Serious adverse events occurring after LTFU may be collected by telephone or postal mail.
9) To be performed according to protocol (addendum on molecular profiling). Subject consent needed separately from study participation.

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Number of Subjects (Planned and Analyzed): The number of subjects planned for thisstudy was 30. A total of 47 subjects were assigned to treatment and were analyzed forefficacy and safety.
Diagnosis and Main Criteria for Inclusion: The study enrolled moderate to severe CAP
patients 16 years or older (younger than 80 years as a general rule) for whom injectableantibacterial drugs were indicated and who were judged to require in-hospital treatment.
Study Treatment: The enrolled subjects received 3 g QID of SBT/ABPC intravenously for
3 to 14 days according to subjects’ conditions. SBT/ABPC was intravenously administeredover 30 minutes.
Efficacy Endpoints: The primary endpoint was clinical response assessed by the Data
Review Committee (DRC) at EOT, TOC, and LTFU.

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The secondary endpoints were as follows:

Clinical response assessed by the investigator (subinvestigator) at EOT, TOC, and LTFU

Tendency toward clinical improvement assessed by the investigator (subinvestigator) onDay 4

Bacteriological response assessed by the DRC on Day 4 and at EOT, TOC, and LTFU

Bacteriological response assessed by the investigator (subinvestigator) on Day 4 and atEOT, TOC, and LTFU

Pharmacokinetic Evaluations: For pharmacokinetic analysis, blood samples were collected
at the following time points (at least 4 time points for each subject): 2 to 3 time points
between 0 to 2.5 hours after the start of intravenous dosing, 2 time points between 2.5 to 6
hours after the start of intravenous dosing (prior to the start of the next dosing) in any dosing
during the period of treatment with SBT/ABPC for intravenous use (Target sampling timepoints were immediately after the completion of infusion and at 1, 2, 3, and 6 hours after thestart of intravenous dosing). Blood samples were assayed for plasma concentrations of SBTand ABPC using a validated liquid chromatography/tandem mass spectrometry.
Safety Evaluations: Adverse events were recorded in the case report form from the time thesubject received their first dose of the investigational product to LTFU. Serious adverse
events were reported from the time when the subject provided informed consent up to 28
days after the last administration of the investigational product. Clinical laboratory tests
were performed, and blood pressure, pulse rate and respiration rate were recorded on Day 1(prior to dosing) and Day 4; and at EOT, TOC, and LTFU.
Statistical Methods: The Per Protocol Set (PPS) was the primary analysis set for theefficacy analyses. In this study, 2 PPS populations were established: the Clinical Per
Protocol Set (CPPS) and the Bacteriologic Per Protocol Set (BPPS). The CPPS consisted ofall subjects who received at least 1 dose of the investigational product, had no significant
protocol violation, namely regarding inclusion and exclusion criteria, and who underwent
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Protocol A9231001 –18 November 2014 – Finalscheduled assessments in the appropriate visit window as specified in the protocol. TheBPPS consisted of all subjects in the CPPS, in whom a baseline bacterial pathogen wasidentified by culture and/or urine antigen test. The Full Analysis Set (FAS) consisted of all
subjects who received at least 1 dose of the investigational product.
Regarding the primary analysis of the primary endpoint, the efficacy rate and 95%
confidence interval (CI) in the CPPS at TOC were calculated, based on the DRC-assessedclinical response. Regarding the secondary analysis of the clinical response assessed by theDRC, the efficacy rate and 95% CI in the CPPS at EOT and LTFU and the efficacy rate and95% CI in the BPPS and the FAS on each assessment days (EOT, TOC, and LTFU) werecalculated. The frequency and proportion were calculated for the secondary endpoints, andthe 95% CIs were also calculated for clinical and bacteriological responses.

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In the pharmacokinetic analysis, population pharmacokinetic analysis of SBT/ABPC for
intravenous use 12 g/day after intravenous administration was to be performed using the dataobtained in the present study. Population pharmacokinetic parameters of SBT and ABPCand those for each subject were to be analyzed with nonlinear mixed-effects modeling.
Results of the population pharmacokinetic analysis will be described in the report preparedseparately.
Safety was analyzed with all subjects who received at least 1 dose of the investigational
product. The safety analysis was performed mainly according to the algorithm and theformat specified by Pfizer Data Standards (PDS).
RESULTS
Subject Disposition and Demography: A total of 47 subjects were assigned to treatment inthis study, and they all received the investigational product. Table 2 presents a summary ofsubject disposition and subjects analyzed.
Table 2.

Subject Dispositions and Analysis Sets

Number (%) of subjects
Assigned to treatment
47
Treated47
Completed
44 (93.6)
Discontinued
3 (6.4)Lack of efficacy
2 (4.3)Treatment-related adverse event
1 (2.1)Analyzed for efficacy
FAS
47 (100)
CPPS
40 (85.1)
BPPS
28 (59.6)
Analyzed for safety
Adverse events47 (100)
Laboratory data
47 (100)
FAS=full analysis set, CPPS=clinical per protocol set, BPPS=bacteriologic per protocol set.

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Protocol A9231001 –18 November 2014 – Final

Demographic characteristics for each analysis set are presented in Table 3. None of theparameters showed any major differences among the analysis sets.
Table 3.

Demographic Characteristics

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FAS(N=47)

CPPS(N=40)

BPPS(N=28)

Age (years) [n (%)]
16-44
9 (19.1)
9 (22.5)
6 (21.4)
45-64
11 (23.4)
8 (20.0)
7 (25.0)
65-74
15 (31.9)
12 (30.0)
8 (28.6)
75-79
7 (14.9)
6 (15.0)
4 (14.3)80<=
5 (10.6)
5 (12.5)
3 (10.7)
MeanSD
62.316.4
61.817.5
61.417.3
Range
28-85
28-85
28-85
Sex [n (%)]
Male
26 (55.3)
21 (52.5)
15 (53.6)
Female21 (44.7)
19 (47.5)
13 (46.4)
Race [n (%)]
Asian
47 (100)
40 (100)
28 (100)
Weight (kg)MeanSD
52.811.8
50.610.5
51.910.8
Range
31.3-78.7
31.3-78.7
31.3-78.7Body Mass Index a (kg/m2)
MeanSD
20.63.7
20.03.2
20.43.6
Range
13.7-29.0
13.7-29.0
13.7-29.0
Height (cm)MeanSD
159.58.6
158.78.7
159.37.8
Range
137.7-176.7
137.7-176.7
144.3-176.5
Smoking Classification [n (%)]
Never smoked
18 (38.3)
16 (40.0)
9 (32.1)
Ex-smoker
22 (46.8)
18 (45.0)
15 (53.6)
Smoker7 (14.9)
6 (15.0)
4 (14.3)
SD=standard deviation, FAS=full analysis set, CPPS=clinical per protocol set,
BPPS=bacteriologic per protocol set.
aBody Mass Index is calculated as Weight / (Height  0.01) 2.

Nine different species of causative pathogens were identified from 28 of 40 subjects in theCPPS. A single causative pathogen was identified in 21 subjects and multiple causative
pathogens were identified in 7 subjects. The major causative pathogens were Streptococcus
pneumoniae (14 strains), Haemophilus influenzae (9 strains), and Moraxella catarrhalis (8strains).
Efficacy Results: As for the clinical response assessed by the DRC (primary efficacy
endpoint), the efficacy rate in the CPPS was 94.6% at TOC (primary analysis), 97.4% at
EOT, and 94.4% at LTFU (Table 4).

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Table 4.

Clinical Response (DRC Assessment, CPPS)

Clinical response
Efficacy
95% CI
Effective Ineffective Indeterminate
ratea
(%)
(%)
(%)
TOC
40
35 (87.5)
2 (5.0)3 (7.5)
94.6(81.8, 99.3)
EOT
40
38 (95.0)
1 (2.5)
1 (2.5)
97.4(86.5, 99.9)
LTFU
40
34 (85.0)
2 (5.0)4 (10.0)
94.4(81.3, 99.3)
DRC=data review committee, CPPS=clinical per protocol set, CI=confidence interval, TOC=test of cure,
EOT=end of treatment, LTFU=long-term follow-up.
aEfficacy rate = effective / (total − indeterminate)  100.

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Total

Major causative pathogens identified at baseline were S. pneumoniae, H. influenzae, and M.
catarrhalis. The DRC-assessed clinical response (efficacy rate) against major causative
pathogen in the BPPS across all assessed time points was 91.7% to 100% in subjects with S.
pneumoniae at baseline, 83.3% to 100% in subjects with H. influenzae at baseline, and 87.5%
to 100% in subjects with M. catarrhalis at baseline. There was no subject whose clinicalresponse was judged to be “ineffective” to any of the causative pathogens at EOT. The
clinical response turned out to be “ineffective” to all causative pathogen at TOC or LTFU inthe following subjects: 1 subject with S. pneumoniae (benzylpenicillin-susceptible: PSSPa), 1subject with H. influenzae (β-lactamase-negative ampicillin-susceptible: BLNASb), 1 subject
with M. catarrhalis (β-lactamase hyperproducing), and 1 subject with Staphylococcus aureus(β-lactamase-negative oxacillin-susceptible: MSSAc).
The efficacy rate as assessed by the investigator (subinvestigator) was 100% at all of EOT,
TOC, and LTFU (Table 5).
Table 5.

Clinical Response (Investigator [Subinvestigator] Assessment, CPPS)

Clinical response
Efficacy
95% CI
Effective Ineffective Indeterminate
ratea
(%)
(%)
(%)
TOC
4038 (95.0)
02 (5.0)100(90.7, 100)
EOT
4040 (100)00100(91.2, 100)
LTFU4034 (85.0)
06 (15.0)
100(89.7, 100)
CPPS=clinical per protocol set, CI=confidence interval, TOC=test of cure, EOT=end of treatment,
LTFU=long-term follow-up.
aEfficacy rate = effective / (total − indeterminate)  100.
Total

As for the tendency toward clinical improvement on Day 4 in the CPPS as assessed by theinvestigator (subinvestigator), it was assessed as present in all 40 subjects (100%) and study
treatment was continued (Table 6).

aS.pneumoniae, Benzylpenicillin  0.06 g/mLbH.influenzae, Ampicillin 1 g/mL, -lactamase (−)

cS. aureus, Oxacillin 2 g/mL

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Table 6.

Tendency Toward Clinical Improvement at Day 4 (Investigator[Subinvestigator] Assessment)

Clinical response
Effective (%)
Ineffective (%)
Indeterminate (%)
CPPS
4040 (100)00BPPS
2828 (100)00FAS4747 (97.9)
1 (2.1)0CPPS=clinical per protocol set, BPPS=bacteriologic per protocol set, FAS=full analysis setTotal

The bacteriological response (eradication rate) by subject in the BPPS was 91.7% to 100% as
assessed by the DRC and 95.7% to 100% as assessed by the investigator (subinvestigator)
across all assessment time points (Table 7).
Table 7.

Bacteriological Response by Subject (DRC Assessment and Investigator[Subinvestigator] Assessment, BPPS)

Bacteriological response
Eradication Presumed Persistence Microbial Indeter(%)
eradication(%)
substitution minate
(%)
(%)
(%)
DRC Assessment27
19 (70.4)
5 (18.5)003 (11.1)
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N

Eradication
ratea
(%)

95% CI

100(85.8, 100)

EOT

28

12 (42.9)

11 (39.3)

1 (3.6)

1 (3.6)

3 (10.7)

96.0(79.6, 99.9)

TOC

28

6 (21.4)

16 (57.1)

2 (7.1)04 (14.3)

91.7(73.0, 99.0)

LTFU

28

3 (10.7)

17 (60.7)

1 (3.6)07 (25.0)

95.2(76.2, 99.9)

1 (3.7)04 (14.8)

95.7(78.1, 99.9)

Investigator (Subinvestigator) Assessment27
18 (66.7)
4 (14.8)
Day 4
EOT

28

13 (46.4)

11 (39.3)004 (14.3)

100(85.8, 100)TOC

285 (17.9)

17 (60.7)

1 (3.6)05 (17.9)

95.7(78.1, 99.9)

LTFU

283 (10.7)

16 (57.1)009 (32.1)

100(82.4, 100)

DRC=data review committee, BPPS=bacteriologic per protocol set, CI=confidence interval, EOT=end oftreatment, TOC=test of cure, LTFU=long-term follow-upaCalculated as (total number of subjects assessed as eradication, presumed eradication, and microbial substitution) /(number of assessable subjects excluding subjects in whom bacteriological response was indeterminate) × 100.

The eradication rate by major causative pathogen identified at baseline as assessed by theDRC was 88.9% to 100% for S. pneumoniae, 75.0% to 100% for H. influenzae, and 87.5% to100% for M. catarrhalis across all assessment time points. Only one strain of Klebsiella
oxytoca (β-lactamase unknown) was bacteriologically persistent at EOT and the following
strains were bacteriologically persistent at TOC or LTFU: 1 strain of S. pneumoniae (PSSP),
2 strains of H. influenzae (1 β-lactamase-negative ampicillin-resistant [BLNARd] strain and 1dH.influenzae, Ampicillin  4 g/mL, -lactamase (−)

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BLNAS strain), 1 strain of M. catarrhalis (β-lactamase hyperproducing), and 1 strain of S.
aureus (β-lactamase-negative MSSA).
Clinical signs and symptoms (cough, sputum volumes, nature of sputum, dyspnoea,
consciousness disturbed, chest pain, chest rales, and dehydration) in subjects in the CPPStended to improve from Day 4. Body temperature, white blood cell count, C-reactive protein(CRP), and percutaneous oxygen saturation (SpO2) also improved from Day 4. The chest xray score improved from Day 4, and further improved over the therapeutic course.
Pharmacokinetic Results: The results will be presented in a separate document.
Safety Results: Of the 47 subjects, all-causality adverse events were reported in 30 subjects(63.8%), and treatment-related adverse events were reported in 10 subjects (21.3%). An
overview of adverse events is presented in Table 8.

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Table 8.

Overall Summary of Adverse Events

Number of adverse events
Number (%) of subjects
Number (%) of subjects with serious adverse events a
Number of subjects with severe adverse events
Number (%) of subjects with dose or study discontinuation due toadverse events
Number of subjects with dose reduced or temporary discontinuation
due to adverse eventsaData of serious adverse events were based on the safety database.
bIncludes 1 death.

All causality
N=477130 (63.8)
3 (6.4) b02 (4.3)

Treatment related
N=472910 (21.3)
002 (4.3)

00

Treatment-emergent non-serious adverse events reported at an incidence of 3% or more arepresented in Table 9.

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Table 9.

Treatment-Emergent Non-Serous Adverse Events (Incidence ≥ 3%)

System Organ Class
Preferred Term (MedDRA v14.0)
Total adverse events (not including serious)
GASTROINTESTINAL DISORDERS
Constipation
DiarrhoeaGENERAL DISORDERS AND ADMINISTRATION
SITE CONDITIONS
Pyrexia
INFECTIONS AND INFESTATIONS
Nasopharyngitis
INVESTIGATIONS
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Gamma-glutamyltransferase increased
NERVOUS SYSTEM DISORDERS
Headache
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
EczemaPruritus

All Causality

Treatment Related

N=47

N=47

19(40.4)

7(14.9)53(10.6)(6.4)

02(4.3)2(4.3)

03(6.4)07643(14.9)(12.8)(8.5)(6.4)

5543(10.6)(10.6)(8.5)(6.4)

2(4.3)

1(2.1)

22(4.3)(4.3)

11(2.1)
(2.1)
n (%)

Serious adverse events reported in this study were presented in Table 10. One death wasreported 20 days after the end of treatment. An 81-year old woman was reported to have diedfrom drowning, but the investigator considered that it was unrelated to treatment. Two
subjects experienced pneumonia (one after the end of study and the other during treatment),
but both of these were considered to be unrelated to treatment by the investigator.
Table 10. Serious Adverse Events
Sex/Age
123

F/81
M/62
F/67

MedDRA 14.0
Preferred Term
Drowning b
Pneumonia
Pneumonia b

Causality aNoNoNoAction onstudy drug or procedures
Not applicable cNo
Not applicable cOutcome
Death
Resolved
Resolvinga Causality by investigator.
b Occurred after the end of study.
c Not applicable as the event occurred after the end of the study.

Two subjects (4.3%) discontinued treatment or the study because of adverse events(Table 11). These adverse events were all considered to be treatment-related. One subject
with interstitial lung disease (investigator term, interstitial pneumonia aggravated)discontinued both treatment and the study, and 1 subject with aspartate aminotransferase
increased discontinued treatment with the investigational product but remained in the study.
Resolution of both adverse events was confirmed.

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Table 11. Adverse Events Leading to Discontinuation of Treatment
MedDRA 14.0
Severity
Preferred Terma
1 Aspartate aminotransferase increasedModerate
2 Interstitial lung disease
ModerateaDiscontinued treatment, but did not discontinue the study.

OutcomeResolved
Resolved

Relation toStudy Drug
Suspected
Suspected

SAENoNo

The most common laboratory abnormalities according to the PDS criteria were albumin
decreased, blood glucose increased, and monocytes increased. There was no obvious change
in blood pressure from baseline. Most of the changes in pulse rate and respiratory rate frombaseline were those associated with the recovery from the target disease of the study.
CONCLUSION(S): The following conclusions were derived from the results of themulticenter, unblinded, non-comparative study of high-dose SBT/ABPC for intravenous use(3 g, QID) in moderate to severe CAP patients for whom injectable antibacterial drugs wereindicated.

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The efficacy rate based on the clinical response assessed by the DRC (primary endpoint) was94.6% at TOC (primary analysis), 97.4% at EOT, and 94.4% at LTFU.
The bacteriological response (eradication rate) by subject in the BPPS as assessed by theDRC was 91.7% to 100% across all assessment time points. The eradication rate by majorcausative pathogen as assessed by the DRC was 88.9% to 100% for S. pneumoniae, 75.0% to100% for H. influenzae, and 87.5% to 100% for M. catarrhalis across all assessment time
points.
All reported adverse events were mild to moderate in severity. The adverse events that led to
discontinuation of treatment or the study were treatment-related interstitial lung disease(investigator term, interstitial pneumonia aggravated) in 1 subject and treatment-related
aspartate aminotransferase increased in 1 subject. Resolution of both adverse events wasconfirmed. No treatment-related serious adverse events were reported.
The above results demonstrated that the investigational product was well tolerated and posedno safety problem.

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