Tygacil Drug Use Investigation (Tigecycline Evaluation Study For Safety And Effectiveness In Patient Infected With Multi-Drug Resistance.)
Conditions: Intra-Abdominal Infections, Skin Disease, Infectious
Sponsor: Pfizer

Tygacil®Injection
Drug Use Investigation
Protocol
Pfizer Japan Inc.
Date prepared: December 17, 2012 (Ver. 2)
Date revised: May 25, 2016 (Ver. 3)
Protocol No.: B1811187

Date revised: May 25, 2016 
(Ver. 3)
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Protocol №B1811187
INTRODUCTION
Tygacil®Injection(hereinafter referred to as "Tygacil") is the first glycylcycline antibacterial drugmarketed 
in Japan; the drug was discoveredby U.S. Wyeth Inc. (present Pfizer). Tygacil, by binding to the 30S 
ribosomal subunit, inhibits ribosome, and generates antibacterial activity by inhibiting the protein synthesis of 
bacteria. 
In Japan, Tygacil obtained the marketing authorizationin September 2012for theindication of "Deep skin 
infections, chronic pyoderma, secondary infections associated with trauma, thermal burns, surgical wounds, 
etc., secondary infection of erosion or ulcer, peritonitis, intra-abdominal abscess, cholecystitis" with 
"Tigecycline-susceptible multiple resistant gram-negative bacteria (Escherichia coli, Citrobacter spp., 
Klebsiella spp., Enterobacter spp., Acinetobacter spp.)" as susceptible strains. 
The drug use investigationof Tygacil Injection(hereinafter referred to as "Study") isintended to investigate 
the incidence of diseases, etc. duetoadverse drug reactionsof Tygacilby disease types, and to detect or 
confirm data concerning quality, effectiveness, and safety of Tygacilunder actual use. The information 
obtained in this studywill be used to provide Proper-Use Information, and to prepare documents forthe
Re-examinationapplication. This study
, therefore, shallbe conducted in strict compliance with the "MHLW 
Ordinance on theStandard for Post-Marketing Studies and ClinicalTrials of Medical Products" (MHLW 
OrdinanceNo. 171,dated December 20, 2004). Data obtained from the patients registered in this studywill be 
reported to the MHLW pursuant to the Pharmaceutical Affairs Law. Also, data concerning adverse drug 
reactions may be publicly posted in MHLW
's "Pharmaceutical and Medical Device Safety Information" and 
"Pharmaceuticals and Medical Devices Information Website (http://www.info.pmda.go.jp)" as a listing of 
patients, which will present the names of drugs, adverse drug reactions, gender, age (increment of 10 years), 
and other relevant information. Furthermore, the data collected may also be disclosed if the MHLW is required 
to disclose such informationin accordance with the "Act on Access to Information Held by Administrative 
Organs" (Law No. 42 dated May 14, 1999); provided that in no event will the names of physicians, medical 
institutions,and other personal information be subject to such disclosure, nor will it be posted or disclosed in 
any form or shape.

Date revised: May 25, 2016 
(Ver. 3)
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Protocol №B1811187
1 OBJECTIVES
This study is intended to assessthe following information concerning Tygacilin daily medical 
practice. 
・Adverse drug reactions which cannot be predicted from the post-marketing precautions of this 
drug
・Incidenceof adverse drug reactions under the actual use, and
・Factorsconsidered to affect the safety and effectiveness, etc. 
Additionally
, as the major investigation items, the incidence of the following adverse events will be 
confirmed. 
・Thrombocytopenia
・Hepatobiliary disorder
・Pancreatitis
・Diarrhea and pseudomembranous colitis
2 PATIENTS
Patients who receiveTygacilwill be included in this study. 
Theindications,dosageand administration, andtarget patients for this studyare as follows. When 
using this drug, referto the latestpackage insert of this drug. 
INDICATIONS
(Susceptible strains)
Tigecycline-susceptible Escherichia coli, Citrobacter spp., Klebsiella spp., Enterobacter 
spp., Acinetobacter spp.
It should be limited to the strain being resistant to other antibacterial drug.
(Indications)
Deep skin infections, chronic pyoderma, secondary infections associated with trauma, 
thermal burns, surgical wounds, etc., secondary infection of erosion or ulcer, 
peritonitis, intra-abdominal abscess, cholecystitis
[Precautions related to INDICATIONS]
1. Tigecycline should be only use the strain showing resistant to two or more antimicrobial 
agentsin beta-lactams, fluoroquinolones and aminoglycosides, and when other antibacterial
drug showing antibacterial activity cannot be used.
DOSAGE AND ADMINISTRATION
For adults, 100 mg of tigecycline is initially administered via intravenous infusion over 30 to 60
minutes followed by 50 mg every 12 hours over 30 to 60 minutes.

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3 STUDY SIZE
Target sample size is to be 100 subjects for safety analysis.
[Rationale]
The data collected from 100 subjects to whom Tygacilis administered should enable to detect 
and verify,with a probability of 95%, at least 1 subject in whom each adverse event withan
incidence of 3% occurs, and thus enable to verify the post-marketing occurrences of major adverse 
drug reactions that occurred in domestic and overseas clinical studies (nausea, vomiting, diarrhea, 
abdominal pain, headache, hypoproteinaemia, ALT increased, and AST increased). 
Also, the target 
sample size of 100 subjects should enable to grasp the actual use status of Tygacil in clinical setting
including patient backgroound and responder rate,in addition to safety evaluation. 
Tygaciluse is restricted to strains showing resistant to two or moreantimicrobial agentsin 
beta –lactams, fluoroquinolones and aminoglycosides, and when other antibacterialdrug 
showing antibacterialactivity cannot be used. The number of patients in whom multi-drug
resistant Acinetobacter was reported in JANIS in 2011 was only 115,regardless of the presence 
of infection, and thus,it is estimated thatTygaciluse will be extremelylimitedin actual clinical 
settings. 
4 PLANNED INVESTIGATION PERIOD
The investigation period isfrom December 2012 to April 15, 2016. 
(Case report forms should be collected for patients who complete the observation period and 
follow-up period as of April 15, 2016.)
For patients who do not complete the observation period and follow-up period as of April 15, 
2016 or who are confirmed to use the targeted drug after this date, registration only should be 
continued until the condition for approval is lifted.
However, if collection of additional information is required for patients who continue registration 
only, case report forms should be collected for those who undergo observation and follow-up beyond 
the investigation period described above.
5 STUDY PROCEDURES
5.1 Studymethod
Thisstudywill be conducted with all patients surveillance system, and performed 
retrospectively. 
At contract sites (including sites in which the contract is being concluded) as of April 15, 2016, 

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Protocol №B1811187
case report forms should be collected for patients who complete the observation period and 
follow-up period by April 15, 2016. For patients who do not complete the observation period and 
follow-up period as of April 15, 2016 or who are confirmed to use the targeted drug after this date, 
registration only should be continued. If collection of additional information is required for 
patients who continue registration only, the investigator will complete case report forms as 
requested by Pfizer Japan Inc. (hereinafter referred to as "Sponsor").
5.2 Data collectionmethod
Registration and data for this studywill be collected and recorded in the registration form and 
case report forms to be supplied by the Sponsor.
5.3 Patient registration
If a patient receives Tygacil, theinvestigatorshallcomplete the patient registration form with 
site name, name of department, name of physician, the initialsof the patient(as necessary), 
identification number, gender, date of birth,and date of Tygaciltreatmentcommencement, and 
register such patient by sending it to the Registration Center by FAX. 
[Registration Center]
FAX: 
5.4 Observation period
The observationperiod for this studywill be from the commencement of Tygaciltreatment
(Day 1) to Day 14at maximum; provided that a period of 28 days from the completion of the 
observationperiod will be considered as follow-up period during which, adverse events occurred 
will be recorded in the case report form. 
5.5 Reminders concerningcompleting, revising, and reviewingof case report forms
(1) Completing
The investigator shall, upon confirming the studyitems, completethecase report form
based on medical charts and other medical recordsincluding relevant test results, using a pen, 
ballpoint pen, or other inerasable means. Refer to a sample form to be provided separately for 
the details of procedures. 
(2) Revising
Corrections in the case report formshould be struck out with a double line (=) witha 
PPD

Date revised: May 25, 2016 
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Protocol №B1811187
"correction seal"on the double line; the double line should be drawn so that the original 
contents prior to correction are legible.Upon receiving Sponsor
's inquiry on the contentsof 
the case report form, the investigator willagain confirm the contentsof the medical records, 
and as required, correct relevant sections in the case report form. In addition, a correction 
concerning effectivenessand safety must be, in principle, indicated with the reason for such 
correction, together with the date on which the correction is made. 
(3) Reviewing
Upon completion of all entries and corrections of the study items, the investigator shall 
once again review the information in the case report formand associated query forms, and 
sign or seal/name these forms. 

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Protocol №B1811187
6 INVESTIGATION ITEMS AND SCHEDULE
Background
Record of Tygaciltreatment
Concomitant therapy
Examination
Clinical 
laboratory
Bacteriological 
examination
Record concerning 
termination/discontinuation 
of investigation
Effectiveness
evaluation
Clinical response
Bacteriological 
response
Adverse event
6.1 Background
(1) The following information at the commencement of Tygaciltreatmentwill be recorded in the case 
report form:
[1] Gender
[2] Date of birth (age, if the date of birth cannot be disclosed)
[3] Inpatient/outpatient status
[4] Height
[5] Weight
[6] Disease subject to study (infection for which Tygacilis used)
・Name of disease
・Severity
[7] Medical history (past history and concurrent illness other than the underlying disease subject 
Observationperiod (14
days at maximum)
Tygacil treatmentperiod
Follow-up period
(28 days)

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Protocol №B1811187
to study*)
・Presence/absenceof liver functional impairment, renal functional impairment
・Names of diseases/syndromesother than the above, and whether such diseases are past or 
current
[8] Reason for deciding to use Tygacil(select from among below)
・Patient did not respond to other antibacterialdrugs(the name(s) of previous antibacterial
drugsto which the patient did not respond should also be recorded)
・The causative bacteria were resistant to the following drug(s) (Details should be described 
in the bacteriological examination section):
Beta-lactam antibacterialdrugs
Fluoroquinolone antibacterialdrugs
Aminoglycoside antibacterial drugs
・Other drug with antibacterial activity could not be used as determined by the physician
(reason for such decision should also be recorded)
・Others (specific reason(s)should be described)
*: Chronic diseases (including allergy), diseases requiring medical treatment, diseases/disorders 
accompanied by surgery, hospitalization, and/or subsequent complications, or any other 
diseases/syndromes determined problematic are applicable herein; of which, those occurred prior to the 
commencement of Tygaciltreatmentwill be considered as "Past history", and those concurrent at the 
time of treatment will be considered as "Concurrent illness." 
Pregnancy status at the completion of the observationperiod,and in case pregnancy is 
confirmed, the actual/expected date of deliveryshould also be recorded.
6.2 Targeted drug use record
The following Tygacil drug use information willbe recorded:
[1] Date of administration
[2] Dose
[3] Time the infusion is commenced
[4] Duration of infusion
6.3 Concomitant therapy
(1) Drug therapy
The following information concerning all concomitant drug therapyeach patient receives 

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during the observationperiod should be recorded. 
Also, any drug(s)used for the treatment of anadverse event should be recorded. 
[1] Drug name(product name)
[2] Route of administration
[3] Date of treatment commencement
[4] Presence/absence of treatment foradverse event
(2) Non-drug therapy
The following information concerning all non-drug concomitant therapyimplemented during 
the observationperiod should be recorded. 
Also, any non-drug concomitant therapy used as treatment for anadverse event should be 
recorded. 
[1] Name of therapy
[2] Date oftreatment commencement
[3] Presence/absence of treatment foradverse event
6.4 Tests/clinical laboratory tests
(1) Clinical laboratorytests
The following parameters of clinical laboratory tests performed at the commencement of 
Tygaciltreatment, during and at the end of the observationperiod should be recorded. 
[1] Laboratory parameters
White blood cell count
Plateletcount
Hemoglobin count
Total protein
Total bilirubin
AST
ALT
ALP
γ-GTP
CRP
Amylase
Lipase
Serum creatinine
BUN
Prothrombin time
Activated partial thromboplastin time (APTT)
Urine bilirubin
[2] Unit
[3] Test date
[4] Test results
(2) Bacteriological examinations
The following information concerning the causative bacteria, for which Tygacilwas used, 
should be recorded for its status at the commencement of Tygaciltreatment, at the end of

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observationperiod, and at the time the disease was determined to be "cure." 
[1] Specimen
[2] Name of the strain
[3] Date of specimen collection
[4] Bacteria count(-, +, ++, +++)
[5] Susceptibility to Tygaciland other antibacterialdrugs (for other antibacterialdrugs, 
only the data at the commencement of Tygaciltreatmentshallbe collected) 
Ifdiarrhea occurs in the patient after commencement of Tygaciltreatment, the results of the 
following tests should be recorded, if conducted. 
[6]Bacteriologic culture test for Clostridium difficile
[7]Antigen test for Clostridium difficile
6.5 Record of completion/discontinuation of observationperiod
If the observationperiod is 14 days or shorter, the reason should be selected from among the 
below. If "Adverse event" or "Death" is selected, the details should also be recorded in the adverse 
event section. 
[Completion]
・Cure
[Reason for discontinuation]
・Insufficient clinical responses
・Adverse event
・Death (date of death)
・Lost to follow-up
・Transfer to another hospital/department (name of medical institution/department)
・Others
6.6 Effectiveness evaluation
(1) Clinical response
[1] Clinical responseat the end of observationperiod
Clinical response tothe treatment by Tygacil should be evaluated on the day of 
completion of the observationperiod, and the laboratory and clinical findings that 
contributed to the effectivenessassessment should be recorded. 
・Effective
・Ineffective

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・Indeterminate(reason(s)should be recorded)
Clinical responseshould be evaluated based on laboratory and clinical findings; 
bacteriological responseshould be excluded. 
Any findings that are considered clinically problematic compared to the baseline should 
be recorded in detail in the adverseevent section. 
[2] Clinical responseat the time the disease is judged to be"cure." 
Whether the disease is recoveredor not should be judged within28 days from the 
completion of Tygacil treatment. 
・Cured
・Ineffective
・Indeterminate(reason(s)should be recorded)
(2) Bacteriological response
Bacteriological responseshould be evaluated on the day of completion of the observation
period, and the results thereof should be recorded. 
・Eradication
・Presumed eradication
・Colonization
・Persistence
・Presumed persistence
・Microbial substitution
・Superinfection
・Relapse
・Indeterminate
6.7 Adverse event
The status of adverse events from the commencement of Tygaciltreatmentto 28 days after 
completion of the observationperiod (or treatment discontinuation) should be confirmedandthe 
following information should be recorded. Upon occurrence of any adverse event, the investigator 
shall provide appropriate treatment, promptly report totheSponsor, and if a causal relationship 
withTygacilcannot be ruled out, follow up on the courseand outcome as appropriate. 
Also, occurrence of a serious adverse drug reaction,an unexpected adverse drug reaction, or 
other adverse drug reactionsshould be separately investigated indetail if determined necessary by 
the Sponsor. 
[2] Presence/absence of adverse event
[3] Name of adverse event

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[4] Date and time of occurrence(only the observationperiod)
[5] Intervention
[6] Seriousness
[7] Outcome
[8] Causal relationship
[If the adverse event is associated with abnormal laboratory values, i.e., clinical laboratorytests, 
the following information should also be recorded.]
[1] Laboratory parameter
[2] Site reference value
[3] Unit
[4] Date measured
[5] Results
Note: Adverse events areany and all unfavorable events (including clinically significant abnormal 
changes in laboratory tests) occurringin patientsafter starting the target drug treatment 
regardless of their causal relationship. Serious adverse events are any unfavorable medical 
occurrences that result in death, are life-threatening, require (or prolong) hospitalization, cause 
persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or 
are other conditions which represent significant health hazards. 
6.8 Major investigation items
(1) Thrombocytopenia
[Rationale for setting]
Thrombocytopenia hasbeen reported in patients with severe systemic infection for 
which Tygacilis indicated as well as in patients receiving various other drugs, thus adverse 
drug reaction status of thrombocytopenia was selected as a major investigation item. 
[Investigation method]
Presence/absence and the incidence of thrombocytopenia and adverse events related to 
thrombocytopenia will be confirmed. Furthermore, platelets and hemoglobin count before 
the commencement and at the completion (discontinuation) of Tygaciltreatmentwill be 
collected to investigate the changes in platelet count before and after Tygaciltreatment. 
(2) Hepatobiliary disorder
[Rationale for setting]
Tygacilis a drug excreted in the bile, and also patients with severe systemic infection 
for which Tygacilis indicated are usually vulnerable to hepatobiliary disorder, and 
therefore, adverse drug reaction status of hepatobiliary disorder was selected as a major 

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Protocol №B1811187
investigation item. 
[Investigation method]
Presence/absence and the incidence of hepatobiliary disorder and adverse events related 
to hepatobiliary disorder will be confirmed. Furthermore, ALT, AST, ALP
, total bilirubin, 
and urinary bilirubinbefore the commencement and at the completion (discontinuation) of 
Tygaciltreatmentwill be collected to investigate the changes in these values before and 
after Tygaciltreatment. 
(3) Pancreatitis
[Rationale for setting]
Effect of tetracycline antibacterialdrugs on the pancreas such as increased 
amylase/lipase and acute pancreatitis hasbeen reported, thus, adverse drug reaction status 
of pancreatitis was selected as a major investigation item. 
[Investigation method]
Presence/absence and the incidenceof pancreatitis and adverse events related to 
pancreatitis will be confirmed. Furthermore, amylase, lipase, and γ-GTP before the 
commencement and at the completion (discontinuation) of Tygaciltreatmentwill be 
collected to investigate the changes in these values before and after Tygaciltreatment. 
(4) Diarrhea and pseudomembranous colitis
[Rationale for setting]
Diarrhea related to Clostridium difficileand diarrhea accompanying pseudomembranous 
colitis have been reported with various antibacterialdrugs, thus, adverse drug reaction 
status for diarrhea and pseudomembranous colitis were selected as major investigation 
items. 
[Investigation method]
Presence/absence and the incidence of diarrhea and pseudomembranous colitis will be 
confirmed. Also, relevant information including the dosage of Tygacil, backgroundsuch as 
concurrentillness, and concomitant medications should be collected, and if diarrhea or 
pseudomembranous colitis occurs, bacteriologic culture or antigen test for Clostridium 
difficileshould be performed, and the results should be evaluated. 
7 STATISTICAL ANALYSIS PLAN
7.1 Analysis set
The safety analysis set includedpatients who received Tygacilas reportedby the physicians.
The effectivenessanalysis set shall, in accordance with a statistical analysis plan separately 

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prepared, include all evaluable patients (patients determined to have been appropriately 
evaluated). 
7.2 Method of analysis
(1) Analysis for safety evaluation
Inthe safety analysis set, occurrence/incidence of adverse drug reactions (percentage of 
patients with adverse events for which the causal relationship with this drug cannot be ruled 
out) will be set as primary analysis items.Also, factorsthat may have affected the occurrence 
of adverse drug reactions will be evaluated, as appropriate. 
Major investigation items (thrombocytopenia, hepatobiliary disorders, pancreatitis, 
diarrhea, and pseudomembranous colitis) will be tabulated/analyzed for occurrence/incidence 
of adverse drug reactions and changes in associated laboratory values for safety assessment. 
(2) Analysis for effectivenessevaluation
In effectivenessanalysis set,[the total number of patients who clinically responded 
divided by the total number of patients evaluable for effectiveness]will be set as a primary 
analysis item. In addition, bacteriological responsewill be evaluated. An exploratory analysis 
including that on factors that may have affected the effectivenesswill be performed, as 
appropriate. 
8 DISSEMINATION OF THE RESULTS
The results of this studyshall bedisseminatedwith one of the following that are applicable. In 
addition, as required, the results may be published during scientific meetings, in research paper, etc.
for the purpose of providingproper-use information, etc. 
・Studiesregistered to www.clinicaltrials.gov (ClinicalTrials.gov), regardless of the 
reason for such registration. 
・Studies other thantheabove with results that are of scientific and medical importance as 
determined by Sponsor. 
The timing of public release isdependent on the presence of any country with approval of the 
product at the time of completion of the study. 
Any studyinvolving an already-approved Pfizer product in any country will require Pfizer to 
publicly release the results within 1 year of the finalization of last-patient last-visit data. 
Literature references to be used will be limited to those widely recognized and accessible 
through searchable literature databases. 

Date revised: May 25, 2016 
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Protocol №B1811187
10 REFERENCES
Attachment 1: Adverse events report
PPD
PPD
PPD