PhRMA Web Synopsis
Protocol A0661191 –21 December 2010 –Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
For publications based on this study, see associated bibliography.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Zithromax® /Azithromycin
THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See United States
Package Insert (USPI)NATIONAL CLINICAL TRIAL NO.: NCT00809328
PROTOCOL NO.: A0661191

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PROTOCOL TITLE: A Multicenter, Non-Randomized, Open-Label Study ofAzithromycin Intravenous Followed by Oral Administration in Japanese Adult Subjects With
Community Acquired Pneumonia (CAP) Requiring Initial Intravenous Therapy
Study Center(s): Thirty-five (35) centers in Japan
Study Initiation and Completion Dates: 4 February 2009 to 25 March 2010
Phase of Development: Phase 3
Study Objectives:
The primary objective was to evaluate the clinical response and safety of azithromycin
switch therapy (switch from intravenous to oral) in patients with community acquired
pneumonia requiring intravenous therapy.
The secondary objectives were the following:
To evaluate the bacteriological response of azithromycin
To measure the serum concentration of azithromycin following intravenous and/or oral
administration and characterize the pharmacokinetics of azithromycin, and to explore thepharmacokinetics-pharmacodynamics (PK-PD) of intravenous azithromycin if minimum
inhibitory concentrations (MICs) against causative pathogens were obtained
METHODS
Study Design: This is a Phase 3, multicenter, non-controlled, open-label study. Efficacy
was measured on Day 3, at the end of treatment (EOT), on Day 15 and on Day 29.
Number of Subjects (Planned and Analyzed): A total of 100 subjects were targeted fortreatment. A total of 102 subjects received treatment in this study.
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Protocol A0661191 –21 December 2010 –Final

Diagnosis and Main Criteria for Inclusion: Patients, 16 years old or older (less than 80
years old as a general rule) who were diagnosed as having CAP requiring intravenous
therapy and the severity of which was moderate or severe according to the pneumonia patient
seriousness evaluation method in the “Clinical evaluation methods for new antimicrobial
agents to treat respiratory infections: Report (draft) of the Committee for the Respiratory
System, Japan Society of Chemotherapy (June 1997),” were included in the study (as forpatients evaluated as severe, only those diagnosed as none or mild in the severity ofunderlying diseases and complications and as severe in the severity of pneumonia infection
were included).
Study Treatment: The subjects received 500 mg intravenous azithromycin QD for 2 to 5
days. The 500 mg intravenous azithromycin was administrated at concentrations of 1 mg/mL
over 2 hours or more. Following intravenous administration, the subjects received 500 mg
oral azithromycin (tablet formulation) QD to complete a total of 7 to 10 days therapy. The
period of oral dosing was also judged by the investigator (subinvestigator) according to thepatients’ conditions.

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The switch from intravenous to oral azithromycin was done at the discretion of theinvestigator (subinvestigator).
Efficacy Evaluations: The primary endpoint was clinical response assessed by the Data
Review Committee at EOT, on Day 15 and Day 29.
The secondary endpoints were the following:
Clinical response at EOT, on Day 15 and on Day 29 and the tendency toward clinicalimprovement on Day 3 as assessed by the investigator (subinvestigator)
Bacteriological response on Day 3, at EOT, on Day 15 and Day 29 as assessed by both theData Review Committee and the investigator (subinvestigator)
Reasons for switching from intravenous to oral therapy
Pharmacokinetic Evaluation: For pharmacokinetic analysis, blood samples were collected
at the following time points: Just before the end of intravenous dosing, 0 to 2 hours after theend of intravenous dosing, between 4 hours after the end of intravenous dosing and the startof the next dosing, EOT, and Day 15. Serum samples were assayed using a validated highperformance liquid chromatography/tandem mass spectrometry.
Safety Evaluations: Adverse events were recorded in the case report form from the time thesubject received at least 1 dose of study treatment to the last subject visit. Serious adverse
events were reported beginning from the time when the subject provided informed consent
until 28 days after the last administration of the study treatment. Clinical laboratory tests
were performed, and blood pressure, pulse rate and respiration rate were recorded on Day 1(prior to dosing), Day 3, at the time of switching from intravenous to oral therapy, at EOT, at
the time of discharge, on Day 15, and Day 29.

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Protocol A0661191 –21 December 2010 –Final

Statistical Methods: The Per Protocol Set (PPS) was the primary analysis set for theefficacy analyses. In this study the Clinical Per Protocol Set (CPPS) and the Bacteriologic
Per Protocol Set (BPPS) were used as the PPS. The CPPS consisted of all subjects who
received at least 1 dose of the study drug, have no significant violation of protocol, andunderwent prescribed evaluations during the observation period as specified in the protocol.
The BPPS consisted of all subjects in the CPPS in whom bacterial pathogens were identified
at baseline. The Full Analysis Set (FAS) consisted of all subjects who received at least 1
dose of the study drug.

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Regarding the primary analysis of the primary endpoints, the efficacy rate and 95%
confidence interval (CI) in the clinical response in the CPPS on Day 15 as evaluated by the
Data Review Committee were calculated. Regarding the secondary analysis of the clinicalresponse evaluated by the Data Review Committee, the efficacy rate and 95% CI at EOT andon Day 29 in the CPPS and the efficacy rate and 95% CI on each evaluation day (EOT andDays 15 and 29) in the BPPS and the FAS were calculated. The frequency and proportion
were calculated for the secondary endpoints, and further, the 95% CIs regarding the clinicaland bacteriological efficacies were also calculated.
In the PK-PD analysis, population pharmacokinetic analysis in azithromycin intravenous
therapy was to be performed using the data obtained in the present study and those obtainedin Japanese and foreign Phase 1 studies as necessary, and PK-PD parameters such as
AUC/MIC were to be evaluated from the AUC calculated and MICs of causative pathogens.
Since the efficacy result in BPPS was limited, investigation of PK-PD parameters could not
be performed. Results of the population PK analysis were described in the report preparedseparately.
Safety was analyzed with all subjects who received at least 1 dose of the study drug. The
safety analysis was performed mainly by descriptive statistics. Except the onset of adverse
events, duration of adverse events, and vital signs, analyses were performed according to thealgorithm and the format specified by Pfizer Data Standards (PDS).
RESULTS
Subject Disposition and Demography: A total of 102 subjects were assigned to treatmentgroups in this clinical study, and all of them received the study drug. Of those receiving thestudy drug, 29 subjects (28.4%) discontinued the study. The most common reasons for the
discontinuation as judged by the investigator were insufficient efficacy in 18 subjects(17.6%) and adverse events in 6 subjects (5.9%). CPPS include 73 subjects. Most common
reason for exclusion from CPPS was subjects were not the CAP of which criteria was
specified in protocol. The subject disposition and the analysis sets are shown in Table 1.

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Protocol A0661191 –21 December 2010 –Final

Table 1. Subject Disposition and Subjects Analyzed
Azithromycin

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Number (%) of Subjects
Assigned to Treatment
TreatedCompleted
Discontinued
Lack of efficacy
Adverse event
Does not meet inclusion criteria
Subject no longer willing to participate in study
Analyzed for Efficacy
Full Analysis Set
Clinical Per Protocol Set
Bacteriologic Per Protocol Set
Analyzed for Safety
Adverse events
Laboratory data102
102
73 (71.6)
29 (28.4)
18 (17.6)
6 (5.9)3 (2.9)2 (2.0)102 (100.0)
73 (71.6)
33 (32.4)
102 (100.0)
101 (99.0)

The demographic characteristics are shown in Table 2. The FAS consisted of 63 malesubjects (61.8%) and 39 female subjects (38.2%), with male subjects accounting for thehigher percentage. The mean age of the subjects was 55.4 years, with 43 subjects (42.2%)
being 65 years or older, and 16 subjects (15.7%) being 75 years or older. None of theparameters showed any major differences among the analysis sets.

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Protocol A0661191 –21 December 2010 –Final

Table 2. Demographic Characteristics

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FAS(N=102)Azithromycin
CPPS(N=73)

BPPS(N=33)

Age (years) [n (%)]
16-44
29 (28.4)
23 (31.5)
15 (45.5)
45-64
30 (29.4)
21 (28.8)
6 (18.2)
65-74
27 (26.5)
20 (27.4)
10 (30.3)
75-79
13 (12.7)7 (9.6)2 (6.1)80<=
3 (2.9)2 (2.7)0
MeanSD
55.418.6
54.018.8
49.219.6
Range
16-84
16-80
16-78
Sex [n (%)]
Male
63 (61.8)
46 (63.0)
19 (57.6)
Female39 (38.2)
27 (37.0)
14 (42.4)
Height (cm)MeanSD
161.79.1
161.69.1
162.210.2
Range
140.0-184.0
140.0-184.0
140.0-184.0
Weight (kg)MeanSD
57.210.8
57.010.2
57.510.3
Range
35.0-91.5
35.0-91.5
40.3-78.3
Body Mass Indexa (kg/m2)
MeanSD
21.93.8
21.83.7
21.93.6
Range
15.5-35.8
15.8-35.8
15.8-35.8
Smoking Classification [n (%)]
Never smoke
45 (44.1)
35 (47.9)
18 (54.5)
Ex smoker
30 (29.4)
21 (28.8)
6 (18.2)
Smoker27 (26.5)
17 (23.3)
9 (27.3)
Alcohol Classification [n (%)]
Yes
43 (42.2)
28 (38.4)
14 (42.4)
No
59 (57.8)
45 (61.6)
19 (57.6)
SD = standard deviation, FAS = full analysis set, CPPS = clinical per protocol set, BPPS = bacteriologic per
protocol set.
a
Body Mass Index is calculated as Weight / (Height  0.01) 2.

Four different species of causative pathogens were identified from 33 of 73 subjects in the
CPPS. A single causative pathogen was identified in 26 subjects and multiple causative
pathogens were identified in 7 subjects. The major causative pathogens were H. influenzae(17 strains) and S. pneumoniae (14 strains).
Efficacy Results: As for the clinical response assessed by the Data Review Committee(primary efficacy endpoint), the efficacy rate in the CPPS was 84.5% on Day 15 (primary
analysis), 86.3% at EOT, and 82.9% on Day 29. The efficacy rate exceeded 80% at all
evaluation time points (Table 3).

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Protocol A0661191 –21 December 2010 –Final

Table 3. Clinical Response (Data Review Committee Assessment, CPPS)
Total

Effective(%)
63 (86.3)
60 (84.5)
58 (81.7)

Clinical Response
Ineffective Indeterminate(%)(%)
10 (13.7)
011 ( 15.5)
0
12 (16.9)
1 (1.4)End of Treatment73
Day 1571
Day 2971
CI = confidence interval.
aResponse rate = effective / (total − indeterminate)  100.

Efficacy
Ratea

95%CI

86.3
84.5
82.9

(76.2, 93.2)(74.0, 92.0)(72.0, 90.8)

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Major causative pathogens identified at baseline were S. pneumoniae and H. influenzae.
Clinical response (efficacy rate) by causative pathogen on Day 15 in the BPPS as judged by
the Data Review Committee was 85.7% (12/14) in subjects with S. pneumoniae at baseline
and 88.2% (15/17) in subjects with H. influenzae at baseline (Table 4). Total 10 out of 11
subjects with azithromycin resistant strains (MIC: ≥2 g/mL) of S. pneumoniae, were judged
as effective. Only 2 subjects in whom S. pneumoniae was identified (azithromycin-resistantstrain in 1 subject and a strain with unknown MIC in another subject) and 2 subjects in whom
H. influenzae was isolated and identified (azithromycin-sensitive strains in both subjects)
were judged ineffective at all evaluation time points.
Table 4. Clinical Response by Baseline Causative Pathogen (Data Review Committee
Assessment, BPPS)
Clinical Response
End of Treatment
Day 15
Day 29n/N
Efficacy Rate b
n/N
Efficacy Rateb
n/N
Efficacy Rateb
S. pneumoniae
12/14
85.7
12/14
85.7
12/14
85.7
H. influenzae
15/17
88.2
15/17
88.2
15/17
88.2
M. catarrhalis
5/5
100
5/5
100
5/5
100
M. pneumoniae
5/5
100
4/4
100
4/4
100
n = number of subjects with effective, N = total subjects − number of subjects with indeterminate.
aA subject may have more than 1 pathogen isolated.
b
Calculated as efficacy rate = n/N × 100.
Pathogena

Efficacy rate in the CPPS as judged by the investigator (subinvestigator) was 80.8% at EOT,
98.4% on Day 15, and 95.1% on Day 29.
As for the tendency toward clinical improvement on Day 3 in the CPPS as judged by theinvestigator (subinvestigator), 68 subjects (93.2%) continued the study.
Bacteriological response (eradication rate) by subject on Day 15 in the BPPS was 83.3% asjudged by the Data Review Committee (Table 5) and 100% as judged by the investigator(subinvestigator).

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Protocol A0661191 –21 December 2010 –Final

Table 5. Bacteriological Response by Subject (Data Review Committee Assessment,
BPPS)
Eradication
95%CI
Ratea
Day 3
30
28
20
71.4
(51.3, 86.8)
End of Treatment
33
31
25
80.6
(62.5, 92.5)
Day 15
32
30
25
83.3
(65.3, 94.4)
Day 29
32
30
25
83.3
(65.3, 94.4)
N = number of subjects with total − indeterminate, n = total number of subjects with eradication, presumed
eradication or microbial substitution, CI = confidence interval.
aCalculated as eradication rate = n/N × 100.
Total

N

n

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The eradication rate by causative pathogen identified at baseline on Day 15 as judged by the
Data Review Committee was 85.7% (12/14 strains) for S. pneumoniae and 82.4% (14/17
strains) for H. influenzae (Table 6). Ten of the 11 resistant strains of S. pneumoniae were
evaluated as eradication or presumed eradication. The total 2 strains of S. pneumoniae(azithromycin-resistant strain and a strain with unknown MIC) and 3 strains of H. influenzae(azithromycin-sensitive strains) were bacteriologically persistent on Day 15. The eradication
rates by causative pathogen on Day 15 as assessed by the investigator (subinvestigator) were100% (11/11 strains) for S. pneumoniae and 100% (14/14 strains) for H. influenzae as well.
Table 6. Bacteriological Response by Baseline Causative Pathogen (Data Review
Committee Assessment, BPPS)
Bacteriological Response
Day 3
End of Treatment
Day 15
Day 29Pathogen
Eradication
Eradication
Eradication
Eradication
n/N
n/N
n/N
n/N
Rateb
Rateb
Rateb
Rateb
S. pneumoniae
6/13
46.2
9/14
64.3
12/14
85.7
12/14
85.7
H. influenzae
14/15
93.3
16/17
94.1
14/17
82.4
14/17
82.4
M. catarrhalis
5/5
100
5/5
100
5/5
100
5/5
100
M. pneumoniae
3/3
100
3/3
100
2/2
100
2/2
100
M. pneumoniae
3/3 (100)
3/3 (100)
3/3 (100)
2/2 (100)n = the number of pathogen with eradication or presumed eradication, N = total pathogens − number ofpathogens with indeterminate.
aA subject may have more than 1 pathogen isolated.
b
Calculated as eradication rate = n/N × 100.
aClinical signs and symptoms (cough, sputum volumes, nature of sputum, dyspnoea,
consciousness disturbed, chest pain, chest rales, dehydration, pain pharyngeal) in subjects in
the CPPS tended to improve from Day 3. Body temperature, white blood cell count, CRP,
and SpO2 improved in most of the subjects after switching to the oral preparation comparedto the values observed on Day 1 (prior to dosing). The chest x-ray score improved from Day
3, and further improved over the therapeutic course. The reasons for switching fromintravenous to oral therapy for subjects in the CPPS for whom clinical response on Day 15
was evaluated as effective by the Data Review Committee were improvement in clinicalsigns and symptoms (body temperature, white blood cell count, CRP) in 93.3% of subjects

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Protocol A0661191 –21 December 2010 –Final(56/60) and improvement in clinical symptoms (other than body temperature, white blood
cell count, CRP) in 6.7% of subjects (4/60).
Safety Results: Adverse events are summarized in Table 7. The number of subjects
exhibiting all-causality adverse events among the 102 subjects was 55 (53.9%) during theentire period and in 42 (41.2%) during the intravenous therapy. Treatment-related adverse
events were observed in 34 subjects (33.3%) during the entire period and 26 subjects (25.5%)
during the intravenous therapy out of 102 subjects.
Table 7. Overall Summary of Adverse Events

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Azithromycin
All Causalities
Treatment Related
Entire Period During IV Therapy Entire Period During IV Therapy
N=102
N=102
N=102
N=102
116
63
44
32

Number of adverse events
Number (%) of subjects
Adverse events55 (53.9)42 (41.2)
34 (33.3)
Serious adverse events
9 (8.8)a2 (2.0)1 (1.0)
Severe adverse events
2 (2.0)0
0
Dose or study discontinuation due to7 (6.9)b3 (2.9)b2 (2.0)adverse events
Dose reduced or temporary000discontinuation due to adverse events
IV = intravenous.
aIncludes 1 subject who experienced serious adverse event after study discontinuation.
b
Includes 1 subject who discontinued the study drug, but continued the study.

26 (25.5)
1 (1.0)02 (2.0)0

The most common all-causality adverse events were diarrhoea (15 subjects, 14.7%),
constipation (8 subjects, 7.8%), headache (8 subjects, 7.8%), injection site pain (6 subjects,5.9%), and insomnia (6 subjects, 5.9%). Among these common adverse events, those that
occurred during intravenous therapy were diarrhoea (11 subjects, 10.8%), constipation (3subjects, 2.9%), headache (7 subjects, 6.9%), injection site pain (6 subjects, 5.9%), andinsomnia (3 subjects, 2.9%); the adverse events observed during the entire study period andthose observed during intravenous therapy were similar in type (Table 8).

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Protocol A0661191 –21 December 2010 –Final

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Table 8. All-Causality Adverse Events Occurred in 2 Subjects or More During theEntire Period
System Organ Class and
MedDRA (version 12.1) Preferred Term
Number (%) of subjects
Gastrointestinal disorders
Abdominal discomfort
Abdominal pain
Constipation
Diarrhoea
NauseaGeneral disorders and administration site
conditions
Injection site erythema
Injection site pain
Infections and infestations
Pneumonia
Investigations
Alanine aminotransferase increased
Musculoskeletal and connective tissue disorders
Back pain
Myalgia
Nervous system disorders
Headache
Psychiatric disorders
Insomnia
Respiratory, thoracic and mediastinal disorders
AsthmaHaemoptysis
Skin and subcutaneous tissue disorders
Dermatitis contact
EczemaIV = intravenous.

Azithromycin
Entire Period
During IV Therapy
N=102
N=102
2 (2.0)2 (2.0)8 (7.8)15 (14.7)
2 (2.0)1 (1.0)1 (1.0)3 (2.9)11 (10.8)
2 (2.0)3 (2.9)6 (5.9)3 (2.9)6 (5.9)3 (2.9)1 (1.0)2 (2.0)1 (1.0)3 (2.9)2 (2.0)1 (1.0)2 (2.0)8 (7.8)7 (6.9)6 (5.9)3 (2.9)2 (2.0)3 (2.9)0
1 (1.0)2 (2.0)2 (2.0)1 (1.0)1 (1.0)

Severity of adverse events as summarized by preferred term was mild in 101 subjects,
moderate in 13 subjects, and severe in 2 subjects. The 2 severe adverse events included
pneumonia in 1 subject (investigator term, underlying disease aggravated) and lung neoplasm
malignant in 1 subject. Causal relationship of these severe adverse events was ruled out.
Seven subjects (6.9%) discontinued the study or the administration of the study drug becauseof adverse events (Table 9). Of these adverse events, diarrhoea and abdominal pain in 1
subject each were judged to be treatment-related adverse events. The abdominal pain was
confirmed to have resolved. Diarrhoea was not recovered at the time of study
discontinuation, but was confirmed to have resolved at the follow-up monitoring.

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Protocol A0661191 –21 December 2010 –Final

Table 9. Adverse Events Leading to Dose or Study Discontinuation

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System Organ Class and
MedDRA (version 12.1) Preferred Term
Number (%) of subjects
Gastrointestinal disorders
Abdominal pain
Diarrhoea
Infections and infestations
Pneumonia
Neoplasms benign, malignant and unspecified(incl cysts and polyps)
Lung neoplasm malignant
Respiratory, thoracic and mediastinal disorders
Organising pneumonia

Azithromycin
N=102
2 (2.0)1 (1.0)1 (1.0)3 (2.9)3 (2.9)1 (1.0)1 (1.0)1 (1.0)1 (1.0)No subject died in this study. Ten serious adverse events were observed in 9 subjects(Table 10). Serious adverse events that resulted in discontinuation of the administration werepneumonia in 2 subjects (investigator term: pneumonia aggravated and underlying disease
aggravated) and organising pneumonia in 1 subject. Other serious adverse events that
resulted in study discontinuation were lung neoplasm malignant in 1 subject and pneumonia(investigator term: pneumonia aggravated) in 1 subject. The only serious adverse event
judged by the investigator to be treatment-related adverse event was prothrombin time
prolonged (mild) in 1 subject, which was confirmed to have resolved.
Table 10. Serious Adverse Events
System Organ Class andAzithromycin
MedDRA (version 12.1) Preferred Term
N=102
Number (%) of subjects with serious adverse events
9 (8.8)
Cardiac disorders
1 (1.0)
Cardiac failure congestive
1 (1.0)
Infections and infestations
5 (4.9)Bronchopulmonary aspergillosisa
1 (1.0)Peritonsillar abscess
1 (1.0)Pneumonia
3 (2.9)Investigations
1 (1.0)Prothrombin time prolonged
1 (1.0)
Neoplasms benign, malignant and unspecified (incl
1 (1.0)cysts and polyps)
Lung neoplasm malignant
1 (1.0)Respiratory, thoracic and mediastinal disorders
2 (2.0)Organising pneumonia
1 (1.0)Pneumothorax
1 (1.0)a
The subject experienced serious adverse event after study discontinuation.

The most common laboratory abnormalities according to the PDS criteria were positive
urinary occult blood, increased casual blood glucose level, and decreased lymphocyte count.

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Protocol A0661191 –21 December 2010 –Final

There were no cases of dose reduction, temporary discontinuation of administration,
discontinuation of administration, or study discontinuation due to adverse events related tolaboratory values. Most of the changes in systemic blood pressure, diastolic blood pressure,pulse rate, and respiratory rate from baseline were those associated with the recovery fromthe target disease of the study.
CONCLUSION(S):The following conclusions were derived from the results of the multicenter, open-label, noncontrolled study of azithromycin intravenous followed by oral administration in subjects with
community acquired pneumonia requiring initial intravenous therapy.
As for the clinical response assessed by the Data Review Committee (primary endpoint), theefficacy rate was 84.5% on Day 15 (primary analysis), 86.3% at EOT, and 82.9% on Day 29.
The efficacy rate exceeded 80% at all evaluation time points.

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The bacteriological response (eradication rate) by subject on Day 15 in the BPPS as judged
by the Data Review Committee was 83.3%. The eradication rate of the major causative
pathogens S. pneumoniae and H. influenzae on Day 15 was 85.7% and 82.4%, respectively.
Most adverse events observed were mild to moderate in severity. Among adverse events that
resulted in the discontinuation of the administration or study, diarrhoea and abdominal painthat occurred in 1 subject each and judged to be treatment-related were confirmed to haveresolved during the study or at the follow-up after study discontinuation. Severe adverse
events observed were pneumonia in 1 subject (investigator term, underlying disease
aggravated) and lung neoplasm malignant in 1 subject, but causal relationship was ruled out
for both of these adverse events. The treatment-related serious adverse event (prothrombin
time prolonged) was mild in severity and confirmed to have resolved. The above results
demonstrated that the study drug was well tolerated and posed no safety problem.

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