Clinical trial NCT02674386
Conditions: Osteoarthritis
Sponsor: Pfizer
Start date: 2016-08-23; Completion date: 2019-07-15
Enrollment: 154 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A4091064 is a multicenter, long-term observational study of subjects from tanezumab interventional studies (regardless of treatment group) who undergo a total knee, hip or shoulder replacement during participation in the study. The study is designed with a total duration of subject follow-up of 24 weeks after the total joint replacement surgery. There will be two methods of data collection utilized in this study: interview by site staff via the telephone and interactive web-response system (or paper if the subject has no access to the internet).

Detailed description:
A4091064 is a long-term observational follow up study of subjects from tanezumab interventional studies A4091056, A4091057 or A4091058.

Arms: arm 1: long-term observational study of subjects from tanezumab parent study
Interventions: intervention 1: Investigational Medical Product (IMP) administered in parent study
Intervention descriptions: intervention 1: IMP as administered in parent study. IMP would have been either placebo, tanezumab, celecoxib, naproxen or diclofenac administered in parent study.

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL
A PHASE 3, MULTICENTER, LONG-TERM OBSERVATIONAL STUDY OF 
SUBJECTS FROM TANEZUMAB STUDIES WHO UNDERGO A TOTAL KNEE, 
HIP OR SHOULDER REPLACEMENT
Compound:
PF-04383119
Compound Name:
Tanezumab
United States (US) Investigational New 
Drug (IND):
BB-IND 11,680
European Clinical Trial Database 
(EudraCT) Number:
2013-002549-12
Protocol Number:
A4091064
Phase:
Phase 3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes 
Sweden and United 
Kingdom Specific -
Amendment 1
06 January 2016

Section 1.2.6: Summary of Benefits and 
Risks to Subjects enrolled in Study 
A4091064 added. 

Section 4.2: Reference to Appendix 4 
added. 

Section 12.1: Institutional Review 
Board/Ethics Committee updated to add 
that investigator should also receive 
approval from the national competent 
authority before implementing a 
substantial amendment.

Appendix 4: Life Style Guidelines for 
subjects from sites in Sweden and the 
United Kingdom added.
Original Protocol
01 April 2015
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.  


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PROTOCOL SUMMARY
Background
Tanezumab is a monoclonal antibody that binds to and inhibits the actions of nerve growth 
factor (NGF).  The Nerve Growth Factor Inhibitor (NGFI) class may offer an important 
breakthrough in the treatment of chronic pain and is under clinical investigation for the 
treatment of pain associated with osteoarthritis or other chronic pain conditions. 
The completed Phase 2 and Phase 3 studies conducted to date have demonstrated that 
tanezumab is efficacious and generally safe and well tolerated for the treatment of pain due 
to osteoarthritis and chronic low back pain.  In addition, completed Phase 1/2 studies suggest 
tanezumab is also efficacious and generally safe for the treatment of neuropathic, visceral, 
and cancer pain. 
In 2010, the United States (US) Food and Drug Administration’s (FDA) Division of 
Analgesia, Anesthetic, and Addiction Products (DAAAP) placed tanezumab (June/July 2010) 
and subsequently the entire NGFI class (December 2010) on partial clinical hold due to 
adverse events initially described by investigators as osteonecrosis that in some cases 
resulted in total joint replacement.  Pfizer voluntarily imposed the partial clinical hold on 
study conduct in all countries.
Extensive analyses of the reports of osteonecrosis and other total joint replacements were 
conducted.1  On March 12, 2012, the FDA Arthritis Advisory Committee reviewed these
results as well as those prepared by the FDA.2,3  The committee endorsed continued clinical 
development of the NGFI class of compounds with additional measures to minimize the risk 
and further protect subject safety.  On August 28, 2012, the FDA lifted the partial clinical 
hold on tanezumab allowing the resumption of clinical studies for chronic low back pain, 
osteoarthritis and all other chronic pain conditions. 
Measures to better characterize the joint safety issue have been developed and agreed with 
FDA.  This study is one component of the agreed risk characterization measures and is an 
attempt to address the potential concern that subjects treated with tanezumab have a different 
post-surgical outcome than those not treated with tanezumab.  The total joint replacement 
data from completed tanezumab studies does not suggest a different post-surgical outcome in 
tanezumab treated subjects however those data were gathered retrospectively. The types of 
endpoints to be assessed in this prospective study and the duration of the study have been 
agreed to with the FDA.
The FDA placed another partial clinical hold on the tanezumab clinical development program 
as well as all anti-NGF antibody studies in December 2012 due to concerns about adverse 
changes in the sympathetic nervous system of mature animals.  Only studies in patients with 
cancer pain were allowed to continue. 
In animal studies in rats and non-human primates, tanezumab treatment for up to 6 months, 
with doses producing greater systemic exposure than observed with clinical doses, was 
associated with lower sympathetic ganglion volume and lower average size of 


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post-ganglionic sympathetic neurons when compared to control animals.  All effects were 
completely reversible following a dosing-free recovery period.  In a separate cardiovascular 
function study in non-human primates, functional changes in the cardiovascular system 
controlled by the sympathetic nervous system were not observed.  In March 2015, the FDA 
lifted the partial clinical hold on tanezumab allowing the resumption of clinical studies for 
osteoarthritis, chronic low back pain, and all other chronic pain conditions.
Although evidence of clinically important effects on the sympathetic nervous system have 
not been identified in previously completed tanezumab studies, per agreement with the FDA, 
this and other clinical studies of tanezumab will incorporate additional safety measures to 
monitor for and manage subjects who may develop evidence of clinically important 
sympathetic nervous system dysfunction.  
Study Objectives and Endpoints
Primary Objective:

To describe the post-operative outcome of subjects who underwent a total knee, hip, 
or shoulder replacement while participating in tanezumab Study A4091056, 
A4091057 or A4091058 (treatment period and safety follow-up period).
Secondary Objectives:

To compare the post-operative outcome for tanezumab 2.5 mg and 5 mg versus 
non-steroid anti-inflammatory drugs (NSAIDs) for subjects who underwent a total 
knee, hip, or shoulder replacement while participating in tanezumab Study 
A4091058.

To describe the post-operative outcome of subjects from tanezumab Study A4091059, 
A4091061 or A4091063 who underwent a total knee, hip, or shoulder replacement
Endpoints:
The following endpoints are considered co-equal:

Surgeon’s Assessment of Procedural Difficulty: number and percentage of surgeries 
assessed as uneventful, minor complications or major complications.

Subject’s overall satisfaction with surgery as assessed by the Self-Administered 
Patient Satisfaction (SAPS) Scale: number and percentage of subjects satisfied vs.
unsatisfied with their total joint replacement at Week 24.

Number and percentage of subjects with a post-surgical complication(s) up to 
Week 24 (derived from reported adverse events; see also Section 9).

Number and percentage of subjects with additional or corrective procedures related to
their total joint replacement up to Week 24.


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
Number and percentage of subjects participating in physical rehabilitation activities 
related to the replaced joint up to Week 24.

Change from Baseline to Week 24 in average pain in the replaced joint.

Change from Baseline to Week 24 in Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain, Stiffness and Physical Function subscales in 
the replaced joint (subjects undergoing total hip or knee replacement surgery only).

Change from Baseline to Week 24 in the Shoulder Pain and Disability Index (SPADI)
in the replaced shoulder (subjects undergoing total shoulder replacement surgery 
only).

Concomitant analgesic medication use.
Study Design
This is a Phase 3, multicenter, long-term observational study of subjects from tanezumab 
Study A4091056, A4091057 or A4091058 (regardless of treatment group) who undergo a 
total knee, hip or shoulder replacement during participation in the study (treatment period or 
safety follow-up period).  If while the subject is participating in this study (A4091064), the 
subject undergoes an additional total joint replacement surgery or the site becomes aware that 
an additional total joint replacement surgery has been scheduled for the subject, the subject 
will be requested to provide information on the additional total joint replacement surgery as 
well.  Finally, any subject with a qualifying total joint replacement after the last subject in the 
study completes the treatment period in tanezumab studies A4091059, A4091061 or 
A4091063 may be followed in this study (A4091064).
This study is designed with a total duration of subject follow-up of 24 weeks after the total 
joint replacement surgery.  There will be two methods of data collection utilized in this 
study: interview by site staff via the telephone and interactive web-response system (IWRS) 
accessed by desktop, laptop or tablet computer (or paper if the subject has no access to the 
internet via a desktop, laptop or tablet computer).  Following the surgery, the subject will be 
contacted monthly via telephone by study site personnel to ascertain whether the subject has 
experienced any adverse events and to record any concomitant analgesic medications the 
subject is taking as well as the reason for the medication use.  An assessment of the subject’s 
overall satisfaction with their total joint replacement (IWRS), average pain in the replaced 
joint (IWRS), the subject’s level of function and activity in the replaced joint (IWRS) and 
physical rehabilitation activities (telephone interview) will be made at Weeks 4, 12 and 24.  
At Weeks 12 and 24, subjects will be queried during the telephone interview as to whether 
any additional or corrective procedures related to the total joint replacement are planned. 
All events of total knee, hip or shoulder replacement will be reviewed by the Joint Safety 
Adjudication Committee (Adjudication Committee) established for the tanezumab clinical 
program. 


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Statistical Methods
This study is designed to collect information sufficient to describe the post-operative 
outcome of subjects who underwent a total knee, hip, or shoulder replacement while 
participating in tanezumab Study A4091056, A4091057 or A4091058.  In addition subjects 
with a qualifying total joint replacement after the last subject in the study completes the 
treatment period in studies A4091059, A4091061 or A4091063 may be included.  The 
number of subjects who will enroll in this study is unknown but is estimated to be less than 
250 subjects. Also unknown is the distribution of subjects across treatment groups (ie, the 
treatment given in Study A4091056, A4091057, A4091058, or other tanezumab study). 
Therefore, it is predicted that there will be insufficient statistical power to perform statistical 
inferential analyses.  All analyses will be descriptive in nature.
All subjects enrolled in the study who have a total joint replacement will be included in the 
summary tables. 
A summary of data will be shown using subjects from study A4091058.  The incidence of 
subjects with a total joint replacement will be summarized for all subjects, and split by Study 
A4091058 treatment group.  Comparisons of the total joint replacement rates will be made 
between tanezumab versus active comparator treatment groups, using risk differences and 
ratios with 95% confidence intervals. Summaries of the time to total joint replacement 
surgery and time to first symptom (leading to total joint replacement surgery) will be 
summarized using Kaplan-Meier survival estimates from the date of first subcutaneous dose 
in Study A4091058, and shown overall, and split by Study A4091058 treatment group where 
there are sufficient numbers of subjects.  A further summary of the incidence of subjects with 
total joint replacements will be shown separately for studies A4091056, A4091057,
A4091059, A4091061 and A4091063, as applicable.  Similar summaries by study will be 
shown for adjudication outcomes.  The summary of time to total joint replacement surgery 
and time to first symptom (leading to total joint replacement surgery) will also be performed 
using data for subjects from Studies A4091056 and A4091057.
Unless otherwise stated, data from this study will be presented at Baseline and Weeks 4, 12, 
and 24 using observed data (no imputation for missing data), and at Week 24 using Last 
Observation Carried Forward (LOCF) for missing data.  Data will be shown at the timepoints 
specified and also using change from (pre-surgery) Baseline when Baseline data are available 
and where relevant.  Data will be shown overall, and split by treatment group.  Data on 
surgical difficulty and outcomes, and subject safety data will be summarized by study, with 
an additional combined summary for the subjects from the osteoarthritis studies.
For the Surgeon’s Assessment of Procedural Difficulty, the number and percentage of 
subjects in each category (Uneventful, Minor complications, Major complications) will be 
presented.  Complications reported by the surgeon will be listed.
For the subject’s overall satisfaction with surgery assessments (using the Self-Administered 
Patient Satisfaction scale, SAPS), the responses [score] for each category will be stratified by 
surgery type (hip, knee or shoulder) and summarized for each of the four items. The total 


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score will be stratified by surgery type (hip, knee or shoulder) and summarized. Reponses to 
the question “How satisfied are you with the results of your surgery?” will also be stratified 
by surgery type (hip, knee or shoulder) and summarized as satisfied (very satisfied and 
somewhat satisfied categories combined) and dissatisfied (somewhat dissatisfied and very 
dissatisfied categories combined).
Similarly, the number and percentage of subjects who have required (i) additional or 
corrective procedures related to their total joint replacement and (ii) participating in physical 
rehabilitation activities related to their replaced joint will be presented. 
Average pain (Numeric Rating Scale, NRS) in the replaced joint for all subjects, WOMAC 
Pain, Stiffness and Physical Function sub-scale scores for subjects who had total knee or hip 
replacement and SPADI Pain, Function and Total Score for subjects who had total shoulder 
replacement will be summarized (including change from Baseline summaries).
Standard safety reporting tables will summarize and list adverse event and concomitant 
analgesic medications data.
The number and percent of subjects with specified post-surgical complications will be 
presented. The list of post-surgical complications will be derived from reported adverse 
events and will consist of complications that are clinically significant and attributable to the 
total arthroplasty procedure eg, periprosthetic joint infection/wound infection, periprosthetic 
fracture, pulmonary embolism or sepsis/septicemia/shock.  Literature reported analyses of 
post-surgical complications will be used for guidance in developing the list of post-surgical 
complications. The list of post-surgical complications will be developed during Study
A4091064 and finalized prior to Study A4091058 database lock. 
Separate adverse event summaries by parent study treatment group for adverse events of 
decreased sympathetic function will be presented. 
For subjects from study A4091058 and for subjects from any of the osteoarthritis studies, 
summaries of total joint replacement, adjudication event rates and post-surgical outcomes 
will be shown for subgroups including age, gender, body-mass index (BMI), baseline 
Kellgren-Lawrence grade of the replaced joint (knees and hips only) and number of joints 
with osteoarthritis (OA).
Data Monitoring Committee
An independent, external Data Monitoring Committee (E-DMC) has been re-instituted for 
the tanezumab clinical program.  This committee will be composed of at least one 
rheumatologist, neurologist, statistician, and epidemiologist.  The E-DMC will review 
unblinded safety data including (but not limited to) adverse events and serious adverse events 
on a regular basis throughout the trial.  The E-DMC will have written operating procedures 
and a Charter, including a specific description of the scope of their responsibilities.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table (Table 1) provides an overview of the protocol visits and 
procedures.  Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol 
for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the subject.


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Table 1.
SCHEDULE OF ACTIVITIES
Study Activities
Post-Surgery
Visit Identifier
Baselinea
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 
24/ET
Last visit in 
Study A4091056, 
A4091057 or 
A4091058b or 
when notified of 
TJR surgery
Day of 
Surgery 
Day 29
Day 57
Day 85
Day 113
Days 141
Day 169
Visit Window
+10 days
5 days
5 days
5 days
5 days
5 days
5 days
Pre-surgery Activities
Informed Consent
X
Inclusion Criteria Review 
X
Record ongoing adverse events and 
concomitant analgesic medication
X
Train subject in the use of the ePRO 
system (IWRS) if applicablec
X
Assessment of Pain in Joint to be 
Replaced (11-point NRS)d
X
Assessment of Functional Status
(WOMAC [total hip or knee replacement 
candidates] or SPADI [total shoulder 
replacement candidates ]) d
X
Provide surgery-related documents 
(Surgeon’s Assessment of Procedural 
Difficulty and Pathology Specimen 
Collection/Shipment Guidelines) to 
Surgeon
X
Surgery - related Activities
Obtain Surgeon’s Assessment of 
Procedural Difficulty
X
Confirm pathology specimens were 
shipped according to instructions 
X
Ensure required source documents are 
provided to Endpoint Management Team
X


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Study Activities
Post-Surgery
Visit Identifier
Baselinea
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 
24/ET
Last visit in 
Study A4091056, 
A4091057 or 
A4091058b or 
when notified of 
TJR surgery
Day of 
Surgery 
Day 29
Day 57
Day 85
Day 113
Days 141
Day 169
Post-Surgery Subject Follow-up Activities
Telephone-based Assessments
Adverse events
X
X
X
X
X
X
Concomitant analgesic medication use
X
X
X
X
X
X
Participation in physical rehabilitation 
activities related to the replaced joint
X
X
X
Additional or corrective procedures 
related to the replaced joint
X
X
Remind subjects not utilizing the IWRS to 
return paper-based assessments to the site 
within 5 days
X
X
X
Remind subjects of contraceptive 
requirements (if applicable) e
X
X
X
X
Web-based Assessmentsf
Subject’s overall satisfaction with joint 
replacement surgery (SAPS)
X
X
X
Pain in replaced joint (11-point NRS)
X
X
X
Functional status (WOMAC [total hip and 
knee replacement subjects] or SPADI 
[total shoulder replacement subjects] g
X
X
X
a.
Baseline activities must be conducted at the site.
b.
Last visit in Study A4091056, A4091057 or A4091058 can be either the end of study visit or early termination visit; if a TJR occurs or is scheduled to occur
after the last subject in the study completes the treatment period in studies A4091059, A4091061 or A4091063 baseline activities would be conducted at 
either the end of study visit or at the early termination visit in the A4091059, A4091061 or A4091063 study.
c.
Training in the use of the ePRO system (IWRS) is appropriate for subjects who will have access to the internet via a desktop, laptop or tablet computer for 
the duration of the study.


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d.
To be collected via the Interactive Web Response System (IWRS).  If the subject will not have access to the IWRS via a desktop, laptop or tablet computer 
for the duration of the study, paper versions of the assessment should be completed by the subject with subsequent entry into the IWRS by site staff.  
Note: the WOMAC and SPADI should be completed in their entirety.
e.
Female subjects of child-bearing potential should be reminded of contraception requirements if less than 112 days (16 weeks) have elapsed since the last 
dose of subcutaneous investigational product in Study A4091056, A4091057 or A4091058 (or other tanezumab study).
f.
If the subject does not have access to the IWRS via a desktop, laptop or tablet computer for the duration of the study, paper versions of the assessments 
should be completed by the subject.  Completed paper assessments should be returned to the clinical site as soon as possible, but no later than 5 days, after 
completion of the assessment. Site staff will enter the subject reported outcomes into the IWRS upon receipt of the completed assessment.
g.
The WOMAC and SPADI should be completed in their entirety.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
APPENDICES .........................................................................................................................15
1. INTRODUCTION ...............................................................................................................16
1.1. Mechanism of Action/Indication.............................................................................16
1.2. Background and Rationale ......................................................................................16
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain...........................16
1.2.2. Description of Investigational Product.......................................................16
1.2.3. Overview of Clinical Studies......................................................................16
1.2.3.1. Overview of Efficacy in Clinical Studies..................................18
1.2.3.2. Overview of Safety in Clinical Studies.....................................20
1.2.4. Rationale for Study.....................................................................................22
1.2.5. Rationale for Selected Subject Reported Outcome Measures ....................22
1.2.5.1. Interactive Web Response System ............................................23
1.2.6. Summary of Benefit and Risks to Subjects Enrolled in Study 
A4091064.........................................................................................................24
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................24
2.1. Primary Objective ...................................................................................................24
2.2. Secondary Objectives..............................................................................................24
2.3. Endpoints.................................................................................................................24
3. STUDY DESIGN.................................................................................................................25
4. SUBJECT SELECTION......................................................................................................26
4.1. Inclusion Criteria.....................................................................................................26
4.2. Life Style Guidelines...............................................................................................27
4.3. Sponsor Qualified Medical Personnel.....................................................................28
5. STUDY TREATMENTS.....................................................................................................28
5.1. Concomitant Medication(s).....................................................................................28
6. STUDY PROCEDURES .....................................................................................................29
6.1. Baseline Visit ..........................................................................................................29
6.2. Day of Surgery Day 1 (+10 days) ...........................................................................31
6.3. Week 4 Day 29 (5 days)........................................................................................31
6.4. Week 8 Day 57 (5 days)........................................................................................32


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6.5. Week 12 Day 85 (5 days)......................................................................................32
6.6. Week 16 Day 113 (5 days)....................................................................................33
6.7. Week 20 Day 141 (5 days)....................................................................................33
6.8. Week 24 Day 169 (5 days)....................................................................................33
6.9. Subject Withdrawal/Early Termination ..................................................................34
7. ASSESSMENTS..................................................................................................................35
7.1. Surgeon’s Assessment of Procedural Difficulty .....................................................35
7.2. Pathology Specimens ..............................................................................................35
7.3. Telephone-based Assessments ................................................................................36
7.3.1. Adverse Events ...........................................................................................36
7.3.2. Concomitant Analgesic Medication ...........................................................36
7.3.3. Physical Rehabilitation Activities...............................................................37
7.3.4. Additional or Corrective Procedures ..........................................................37
7.4. Web-based Assessments .........................................................................................37
7.4.1. Overall Satisfaction with Surgery...............................................................37
7.4.2. Pain in Replaced Joint ................................................................................38
7.4.3. Assessment of Functional Activity.............................................................38
7.4.3.1. WOMAC ...................................................................................39
7.4.3.2. The Shoulder Pain and Disability Index (SPADI) ....................40
8. ADVERSE EVENT REPORTING......................................................................................40
8.1. Adverse Events (AEs) .............................................................................................40
8.2. Reporting Period .....................................................................................................40
8.3. Definition of an Adverse Event...............................................................................41
8.4. Medication Errors....................................................................................................42
8.5. Abnormal Test Findings..........................................................................................42
8.6. Serious Adverse Events...........................................................................................43
8.6.1. Protocol-Specified Serious Adverse Events ...............................................43
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................43
8.7. Hospitalization ........................................................................................................45
8.8. Severity Assessment................................................................................................46
8.9. Causality Assessment..............................................................................................46
8.10. Exposure During Pregnancy (EDP) ......................................................................46


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8.10.1. Additional Post-Natal Follow-up..............................................................48
8.11. Occupational Exposure .........................................................................................48
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal/Early Termination) ................................................................................48
8.13. Eliciting Adverse Event Information ....................................................................48
8.14. Reporting Requirements........................................................................................48
8.14.1. Serious Adverse Event Reporting Requirements .....................................48
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................49
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................49
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................49
9.1. Sample Size Determination.....................................................................................49
9.2. Analysis of Endpoints .............................................................................................50
9.3. Data Monitoring Committee (DMC).......................................................................51
9.4. External Adjudication Committee...........................................................................52
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................53
11. DATA HANDLING AND RECORD KEEPING .............................................................53
11.1. Case Report Forms/Electronic Data Record .........................................................53
11.2. Record Retention...................................................................................................54
12. ETHICS..............................................................................................................................54
12.1. Institutional Review Board /Ethics Committee.....................................................54
12.2. Ethical Conduct of the Study ................................................................................55
12.3. Subject Information and Consent..........................................................................55
12.4. Subject Recruitment ..............................................................................................56
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................56
13. DEFINITION OF END OF TRIAL...................................................................................56
13.1. End of Trial in a Member State.............................................................................56
13.2. End of Trial in All Other Participating Countries.................................................56
14. SPONSOR DISCONTINUATION CRITERIA ................................................................56
15. PUBLICATION OF STUDY RESULTS..........................................................................57
15.1. Communication of Results by Pfizer ....................................................................57
15.2. Publications by Investigators ................................................................................57
16. REFERENCES ..................................................................................................................59


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LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES ..............................................................................9
Table 2.
Adverse Drug Reactions in All Subjects Receiving Tanezumab .........................20
APPENDICES
Appendix 1. Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC)............................................................................................................61
Appendix 2. The Shoulder Pain and Disability Index (SPADI)..............................................67
Appendix 3. Abbreviations......................................................................................................68
Appendix 4. Lifestyle Guidelines for Subjects from Sites in Sweden and the United 
Kingdom ...............................................................................................................70


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Tanezumab (PF-04383119, formerly RN624) is an anti-nerve growth factor monoclonal 
antibody under development for the relief of signs and symptoms of osteoarthritis (OA) and 
management of chronic pain including chronic low back pain (CLBP).
1.2. Background and Rationale
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain
During mammalian development, nerve growth factor (NGF) is required for the survival and 
growth of several populations of neurons.  In adults, the effect of NGF signaling shifts from 
the regulation of neuronal survival to the regulation of neuronal phenotype and function.  The 
role of NGF in the adult mammal appears to principally be as a modulator of nociceptive 
neuronal activity.  Thus, NGF plays an important role in modulation of the pain response.4,5  
Many studies employing a variety of antibodies to NGF or tropomyosin receptor kinase 
A (trkA)-IgG fusion protein have demonstrated that blocking NGF bioactivity normalizes 
pain sensitivity, particularly in states of allodynia and hypersensitivity, following a variety of 
insults such as Freund’s adjuvant, carrageenan, or surgical incision.5,6
Both interleukin (IL)-1and tumor necrosis factor alpha (TNF-) have been shown to induce 
synthesis of NGF.  Inhibition of NGF in turn blocks the hyperalgesia experienced after 
administration of these cytokines.7,8  Together these observations suggest that NGF may play 
a role in pain secondary to inflammation or injury.
1.2.2. Description of Investigational Product
Tanezumab is a humanized immunoglobulin G Type 2 (IgG2) monoclonal antibody, derived 
from a murine precursor by grafting the murine complementarity determining regions onto a 
human antibody framework, followed by extensive site-directed mutagenesis using 
proprietary technology to improve binding affinity and specificity.  A mutation was 
performed in the Fc portion of the antibody to decrease its ability to activate complement or 
to support antibody dependent cell-mediated cytotoxicity.9,10
Tanezumab is highly potent in sequestering NGF and preventing interaction with the trkA or 
p75 receptors.  Tanezumab and/or the murine precursor have been shown to be an effective 
analgesic in nonclinical animal models of pathological pain including arthritis, cancer pain, 
and post-surgical pain models.11
1.2.3. Overview of Clinical Studies
A total of 32 clinical studies involving over 11,000 subjects have been conducted with 
tanezumab as of September 2014.  No additional clinical studies have been conducted since 
that time. Approximately 9810 healthy volunteers or patients have been treated with 
tanezumab in non cancer pain clinical studies.  In patients treated with tanezumab 
monotherapy or tanezumab + NSAID in completed non cancer pain studies, treatment 
experience with tanezumab approximates 5900 patient-years of treatment exposure.


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A total of 17 clinical studies overall (4 Phase 2 studies and 13 Phase 3 studies) were initiated 
to provide evidence of efficacy and safety of tanezumab with intravenous (IV) or 
subcutaneous (SC) administration for the relief of the signs and symptoms of osteoarthritis 
alone or in combination with NSAIDs.  Both IV and SC routes of administration with 
tanezumab at fixed dose levels of 2.5 mg, 5 mg, and 10 mg every 8 weeks were evaluated in 
Phase 3 clinical studies of osteoarthritis subjects. 
The efficacy and safety of tanezumab IV in chronic low back pain has been evaluated in 
3 Phase 2 studies (N=1564).  The first was a small Phase 2 proof-of-concept study 
(A4091004; N=217) which evaluated the efficacy and safety of tanezumab 200 g/kg IV 
relative to placebo or naproxen 500 mg twice a day (BID).  This study was followed by a 
Phase 2 dose-ranging study (A4091012; N=1347) that evaluated the efficacy and safety of 
fixed doses of tanezumab of 5 mg, 10 mg, and 20 mg IV relative to placebo or naproxen 
500 mg BID and a long term safety extension study (A4091039; N=848) which evaluated the 
safety and efficacy of tanezumab 10 mg and 20 mg IV and SC administered every 8 weeks 
for 56 weeks.11
In addition to the osteoarthritis studies, 11 Phase 1/2 studies were conducted to examine the 
efficacy and safety of tanezumab in neuropathic, and visceral pain conditions and 2 Phase 2 
studies in metastatic bone pain have been conducted. In these studies, tanezumab was 
administered by IV or SC administration every 8 weeks at fixed doses ranging 1 mg to 20 mg 
or equivalent body-weight adjusted doses up to 100 mg. 
In 2010, the US Food and Drug Administration’s (FDA) Division of Analgesia, Anesthetic, 
and Addiction Products (DAAAP) placed tanezumab (June/July 2010) and subsequently the 
entire NGFI class (December 2010) on partial clinical hold due to adverse events initially 
described by investigators as osteonecrosis that in some cases resulted in total joint 
replacement.  Pfizer voluntarily imposed the partial clinical hold on study conduct in all 
countries.  The conduct of Phase 2/3 studies in osteoarthritis or other chronic pain conditions 
was impacted to varying extents by the partial clinical hold placed on the tanezumab clinical 
development program in June/July 2010.
Extensive analyses of the reports of osteonecrosis and other total joint replacements were 
conducted.1  On March 12, 2012, the FDA Arthritis Advisory Committee reviewed these 
results as well as those prepared by the FDA.2,3 The committee endorsed continued clinical 
development of the NGFI class of compounds with additional measures to minimize the risk 
and further protect subject safety. On August 28, 2012, the FDA lifted the partial clinical
hold on tanezumab allowing the resumption of clinical studies for osteoarthritis and all other 
chronic pain conditions. 
The FDA placed another partial clinical hold on the tanezumab clinical development program 
as well as all NGFI antibody studies in December 2012 due to concerns about adverse 
changes in the sympathetic nervous system of mature animals.  Only studies in patients with 
cancer pain were allowed to continue.  During 2013-2014, Pfizer conducted a comprehensive 
series of nonclinical studies to investigate the nonclinical effects on the sympathetic nervous 
system which led to the partial clinical hold (described in Sections 5.3 of the tanezumab 
Investigator’s Brochure). 


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In animal studies in rats and non-human primates (described in Section 5.3 of the tanezumab 
Investigator’s Brochure), tanezumab treatment for up to 6 months, with doses producing 
greater systemic exposure than observed with clinical doses, was associated with lower 
sympathetic ganglion volume and lower average size of post-ganglionic sympathetic neurons 
when compared to control animals.  All effects were completely reversible following a 
dosing-free recovery period.  In a separate cardiovascular function study in non-human 
primates (described in Section 5.1 of the tanezumab Investigator’s Brochure), functional 
changes in the cardiovascular system controlled by the sympathetic nervous system were not 
observed. In March 2015, the FDA lifted the partial clinical hold on tanezumab allowing the 
resumption of clinical studies for chronic low back pain, osteoarthritis and all other chronic 
pain conditions.
Although evidence of clinically important effects on the sympathetic nervous system have 
not been identified in previously completed tanezumab studies, per agreement with the FDA, 
this and other clinical studies of tanezumab will incorporate additional safety measures to 
monitor for and manage subjects who may develop evidence of clinically important 
sympathetic nervous system dysfunction.
1.2.3.1. Overview of Efficacy in Clinical Studies
In the treatment of pain associated with OA, tanezumab monotherapy doses of 2.5 mg to 
10 mg have been shown to provide efficacy that is superior to placebo.  In addition, 
tanezumab monotherapy doses of 5 and 10 mg have demonstrated efficacy above that of 
NSAIDs.  Relative to oxycodone, tanezumab monotherapy doses of 5 mg or 10 mg were 
shown to have a favorable efficacy profile.  Tanezumab 10 mg provided minimal additional 
benefit over tanezumab 5 mg in the treatment of OA.11
In the treatment of CLBP, tanezumab monotherapy doses of 10 mg and 20 mg demonstrated 
efficacy that was superior to that of placebo and naproxen.  Tanezumab 20 mg provided 
minimal additional benefit over tanezumab 10 mg in the treatment of CLBP.11
The available efficacy data in other chronic pain conditions suggests that tanezumab may 
provide meaningful analgesia in subjects with neuropathic pain, visceral pain and subjects 
with pain associated with cancer who have metastatic bone pain.11
Study A4091056 is a randomized, double-blind, placebo-controlled, multicenter, 
parallel-group, Phase 3 study of the efficacy and safety of tanezumab when administered by 
SC injection for 16 weeks compared to placebo in subjects with osteoarthritis of the knee or 
hip.  Approximately 690 subjects will be randomized to one of 3 treatment groups in a 
1:1:1 ratio.  Subjects will receive a total of two SC injections, separated by 8 weeks:

tanezumab 2.5 mg (Day 1) and tanezumab 2.5 mg (Week 8);

tanezumab 2.5 mg (Day 1), and tanezumab 5 mg (Week 8);

placebo to match tanezumab (Day 1) and placebo to match tanezumab (Week 8).


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Study A4091056 is designed with a total duration of 40 weeks and will consist of three 
periods: Screening (37 days), Double-blind Treatment (16 weeks) and Safety Follow-up 
(24 weeks).
Study A4091057 is a randomized, double-blind, placebo-controlled, multicenter, 
parallel-group, Phase 3 study of the efficacy and safety of tanezumab when administered by 
SC injection for 24 weeks compared to placebo in subjects with osteoarthritis of the knee or 
hip.  Approximately 810 subjects will be randomized to one of 3 treatment groups in a 
1:1:1 ratio.  Subjects will receive a total of three SC injections, separated by 8 weeks:

tanezumab 2.5 mg;

tanezumab 5 mg;

placebo to match tanezumab.
Study A4091057 is designed with a total duration of 48 weeks and will consist of three 
periods: Screening (37 days), Double-blind Treatment (24 weeks) and Safety Follow-up 
(24 weeks).
Study A4091058 is a randomized, double blind, active-controlled, multicenter, parallel-group 
Phase 3 study of the safety, efficacy, and tolerability of tanezumab when administered by SC 
injection for 56 weeks compared to NSAIDs in subjects with osteoarthritis of the knee or hip.  
Approximately 3000 subjects will be randomized to one of 3 treatment groups in a 1:1:1 ratio 
(N=1000/treatment group).  Treatment groups will include:  
1. SC placebo (to match tanezumab) once every 8 weeks (a total of 7 administrations) 
plus naproxen 500 mg BID per os (PO), celecoxib 100 mg BID PO, or diclofenac ER
75 mg BID PO through Week 56.
2. Tanezumab 2.5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
matching naproxen, celecoxib or diclofenac ER to maintain blinded BID oral study 
treatment administration through Week 56.
3. Tanezumab 5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
matching naproxen, celecoxib or diclofenac ER to maintain blinded BID oral study 
treatment administration through Week 56. 
Study A4091058 is designed with a total duration of 80 weeks and will consist of three 
periods: Screening (37 days), Double-blind Treatment (56 weeks) and Safety Follow-up 
(24 weeks).
Study A4091059 is a Phase 3 study of the efficacy and safety of tanezumab in subjects with 
chronic low back pain, Study A4091061 is a Phase 3 study of the efficacy and safety of 
tanezumab in cancer patients with pain due to bone metastases.  Study A4091063 is a 
Phase 3 study of the safety and efficacy of tanezumab in Japanese adult subjects with chronic 
low back pain.


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1.2.3.2. Overview of Safety in Clinical Studies
Based on data from all patient populations who have received tanezumab in completed 
clinical studies to date, the adverse drug reactions listed in Table 2 are considered to be 
expected in subjects who are treated with tanezumab. 
Table 2.
Adverse Drug Reactions in All Subjects Receiving Tanezumab
System Organ Class
Adverse Drug Reaction
Frequency2
Nervous system disorders
Burning sensation
Carpal tunnel syndrome
Hyperesthesia 
Hypoesthesia
Paraesthesia
Common
Allodynia
Neuropathy peripheral
Uncommon
Musculoskeletal and connective 
tissue disorders
Rapidly Progressive Osteoarthritis
(in patients with underlying osteoarthritis1)
Uncommon
Arthralgia
Joint swelling
Myalgia
Pain in extremity
Common
General disorders and 
administration site conditions
Oedema peripheral
Common
1. Rapidly Progressive Osteoarthritis may occur in subjects with underlying osteoarthritis.  The frequency is 
estimated from adjudicated events of rapidly progressive osteoarthritis in historic clinical studies of 
tanezumab, which did not include specific risk minimization measures for this adverse reaction.
2. Common (1% and <10%); Uncommon (0.1% and <1%).
The majority of information regarding the safety profile of tanezumab comes from studies 
conducted in subjects with osteoarthritis.  The safety profile observed to date in chronic low 
back pain and other chronic pain subject populations does not differ markedly from the 
results observed in the osteoarthritis studies.
A total of 7491 subjects were treated in 9 controlled Phase 3 osteoarthritis studies.  The 
majority of these subjects were treated in studies using IV administration of tanezumab; 
however, 985 subjects with osteoarthritis were treated in 2 studies using SC administration.  
The adverse event profile of SC administration of tanezumab is comparable to the IV route. 
The incidence of adverse events, withdrawals due to adverse events, and serious adverse 
events in subjects treated with tanezumab monotherapy (5-10 mg) was similar to subjects 
receiving active comparator treatment and increased over placebo-treated subjects.  In the 
tanezumab 2.5 mg monotherapy treatment group, the incidence of adverse events was similar 
to active comparator while the incidence of withdrawals due to adverse events, and serious 
adverse events was similar to that of the placebo treatment group. Across the tanezumab 
monotherapy doses, the rates of adverse events, withdrawals due to adverse events, and 
serious adverse events were similar with tanezumab 5 mg and 10 mg, and elevated in 
comparison to tanezumab 2.5 mg.  Tanezumab/NSAID combination therapy was associated 
with higher overall adverse event rates.  The relationship of incidence to the dose of 
tanezumab administered was similar to that observed with tanezumab monotherapy.


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Among the most frequently reported adverse events in the controlled Phase 3 osteoarthritis 
studies, the incidence of peripheral edema, upper respiratory tract infection, fall, arthralgia, 
back pain, joint swelling, pain in extremity, hypoesthesia, and paresthesia tended to be higher 
in patients receiving tanezumab monotherapy than patients receiving either placebo or active 
comparator treatment.  The incidence of peripheral edema, arthralgia, joint swelling, pain in 
extremity, and paresthesia increased with increasing doses of tanezumab monotherapy.  The 
adverse events with increased incidence observed with active comparator over tanezumab 
monotherapy included the following: constipation, nausea, urinary tract infection, 
nasopharyngitis, osteoarthritis, and hypertension.
The most common adverse events reported in the non-controlled, long-term Phase 3 
osteoarthritis studies were similar to those seen in the controlled Phase 3 osteoarthritis 
studies with the exception of the inclusion of musculoskeletal pain and exclusion of 
hypertension and nasopharyngititis and all gastrointestinal-related adverse events.  
Dose-related increases in the incidence of peripheral edema, joint swelling, osteoarthritis and 
paresthesia were observed.
Based on data from the Phase 3 osteoarthritis studies and results of an independent 
adjudication of investigator-reported adverse events of osteonecrosis and total joint 
replacements, the risk of rapidly progressive osteoarthritis with tanezumab treatment is 
greater than with placebo or active comparator treatment.  
1.2.3.2.1. Sympathetic Nervous System
In completed Phase 3 osteoarthritis studies, the incidence and discontinuation rates due to 
adverse events consistent with decreased sympathetic function associated with tanezumab 
monotherapy (combined doses of 2.5 to 10 mg) were less than or equal to rates with placebo 
or active comparator.  No evidence of dose related elevations in the frequency of adverse 
events suggestive of decreased sympathetic nervous system function were observed at 
tanezumab doses of 2.5 to 10 mg in subjects with osteoarthritis or chronic low back pain. 
Tanezumab 20 mg in chronic low back pain had marginally higher event rates compared to 
placebo and active comparator treatment groups. 
Based on completed osteoarthritis studies where orthostatic blood pressure, heart rate deep 
breathing, or autonomic symptoms captured with the Neuropathy Symptom Change (NSC) 
questionnaire were specifically assessed, the data are not suggestive of an adverse effect of 
tanezumab on autonomic function. 
1.2.3.2.2. Joint Safety 
Following the imposition of the clinical hold, a comprehensive investigation and analyses 
related to joint-safety were conducted, based on tanezumab monotherapy exposure in over 
6400 subjects and tanezumab/NSAID combination therapy in 3400 subjects.  There were 
over 5000 subjects who received tanezumab treatment alone or in combination with NSAIDs 
for 6 months or longer.  These data were sufficient to define and characterize the adverse 
event of concern – rapidly progressive osteoarthritis – and evaluate the risk of rapidly 
progressive osteoarthritis in the context of the overall benefit-risk profile of tanezumab 
compared to standard of care.  The results and conclusions regarding tanezumab and the 
other anti-NGF therapies are provided in detail elsewhere.1,2,3


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After careful investigation no evidence was found to indicate that tanezumab is associated 
with an increased risk of osteonecrosis, a disease process quite distinct from osteoarthritis. A 
risk of rapidly progressive osteoarthritis was identified.  The risk of rapidly progressive 
osteoarthritis with tanezumab monotherapy was well below that observed with 
tanezumab/NSAID combination therapy but greater than with placebo or active comparator 
treatment.  A majority of subjects identified with rapidly progressive osteoarthritis had 
advanced osteoarthritis of the affected joint prior to treatment.  The event rate of all-cause 
joint replacements in subjects with osteoarthritis was comparable among placebo, active 
comparator, and tanezumab monotherapy treatment groups.
Risk mitigation measures have been developed as an outgrowth of the joint-related safety 
analyses to reduce the risk of rapidly progressive osteoarthritis. Risk mitigation measures 
were developed using recommendations from discussions with European agencies [United 
Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA), Germany’s 
Paul Ehrlich Institute (PEI) and Spain’s Agency on Medicinal Products and Medical Devices 
(AEMPS)] as well as the FDA Arthritis Advisory Committee and interactions with FDA. 
These risk mitigation measures have been included in the tanezumab clinical development 
program.
1.2.4. Rationale for Study
Measures to better characterize the joint safety issue have been developed and agreed with 
FDA.  This study is one component of the agreed risk characterization measures and is an 
attempt to address the potential concern that subjects treated with tanezumab have a different 
post-surgical outcome than those not treated with tanezumab.  The total joint replacement 
data from completed tanezumab studies does not suggest a different post-surgical outcome in 
tanezumab treated subjects however those data were gathered retrospectively. The types of 
endpoints to be assessed in this prospective study and the duration of the study have been 
agreed to with the FDA.  Every effort will be made to enroll all A4091056, A4091057 and 
A4091058 subjects who undergo a qualifying total joint replacement into this study however 
it is acknowledged that to a certain extent the population enrolled in this study will be 
'self-selected' and thus there may be subjects with a qualifying total joint replacement who 
choose not to enter the study.
1.2.5. Rationale for Selected Subject Reported Outcome Measures
Subject-based measures of health-related quality of life have increasingly been used by the 
orthopedic research community as a means to define a successful intervention.12 Subject
reported outcomes typically assessed post-arthroplasty include overall satisfaction with the 
joint replacement, pain and function. 
The Self-Administered Patient Satisfaction Scale (SAPS) will be utilized to assess subject
satisfaction in this study.  The SAPS is a multidimensional, disease specific measure that 
evaluates subject satisfaction with the outcome of hip or knee arthroplasty and was designed 
to be used in conjunction with other clinical measures and functional health status 
instruments to evaluate the results of hip and knee arthroplasty.  The validity and reliability 
of the scale has been demonstrated.13 The scale consists of four items focusing on 
satisfaction with the extent of pain relief, improvement in ability to perform home or yard 
work, ability to perform recreational activities and overall satisfaction with joint replacement.


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Average pain in the joint to be replaced (pre-surgery) and the replaced joint (post-surgery) 
will be assessed with an 11-point Numeric Rating Scale (NRS) ranging from zero (no pain) 
to 10 (worst possible pain). The validity and reliability of the scale has been demonstrated.14
The functional measures chosen for this study were those which have been shown to be valid, 
reliable and sensitive and in addition were region-specific and easy to administer.  Subjects 
undergoing total knee or hip replacement will be asked to complete the Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) with the knee or hip that will be or 
was replaced serving as the “index joint”.  Subjects undergoing total shoulder replacement 
will be asked to complete the Shoulder Pain and Disability Index (SPADI).
The WOMAC is a self-administered condition-specific instrument which assesses pain, 
disability and joint stiffness in knee and hip osteoarthritis.  It is a valid, reliable and 
responsive measure of outcome in subjects with arthritis and has been used extensively.12,15,16
The SPADI is a self-administered questionnaire that was developed to measure the pain and 
disability associated with shoulder pathology in people with shoulder pain of 
musculoskeletal, neurogenic or undetermined origin.  The psychometric properties of the 
SPADI have been shown to be acceptable for research use and the SPADI has been 
recommended to assess outcomes in subjects undergoing shoulder arthroplasty.17,18 The 
instrument consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use.
For each of the selected subject reported outcome measures there are data available in the 
literature. These data will be utilized to contextualize the results of this study.
1.2.5.1. Interactive Web Response System
To avoid a social desirability bias in the subject reported outcomes, an Interactive Web 
Response System (IWRS) will be utilized in this study.  Contingency plans will be in place to 
address system and/or connectivity issues with the IWRS. 
However, eligibility for this study does not require access to the internet via a desktop, laptop 
or tablet computer so, for those subjects without access to the internet via a desktop, laptop or 
tablet computer, paper versions of the assessments will be utilized. Though not optimal, the 
use of two methods to collect subject reported outcomes will maximize the ability to capture
information from all subjects who undergo a total knee, hip, or shoulder replacement surgery 
while participating in tanezumab Study A4091056, A4091057 or A4091058. Additional 
considerations which mitigate the concerns about using two methods to collect subject
reported outcomes in the same study include that this study has not been formally powered 
and all analyses will be descriptive rather than inferential.


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1.2.6. Summary of Benefit and Risks to Subjects Enrolled in Study A4091064
There is no treatment benefit to subjects participating in Study A4091064 however subjects 
may derive benefit from the increased post-surgery medical oversight dictated by this study.
In addition, information from this study may benefit future patients who receive tanezumab.  
A detailed discussion of the risks of tanezumab is provided in Section 7 of the Investigator’s 
Brochure.  Because no investigational product is administered in Study A4091064, the 
anticipated investigational product-related risk to subjects participating in Study A4091064 is 
considered low.  However, female subjects who are of childbearing potential and are sexually 
active and who withdraw from any of the tanezumab studies less than 16 weeks after the last 
dose of subcutaneous investigational product need to use acceptable methods of 
contraception due to the potential risk of adverse effects on the fetus if they become 
pregnant.  Finally, although it is considered unlikely given the number of subjects who have 
been treated with tanezumab to date, it cannot be excluded that some adverse effects of the 
treatment may become evident after the last administration of the investigational product.
The increased post-surgery medical oversight dictated by this study should facilitate 
recognition of such events if they occur.
Complete information for tanezumab may be found in the Single Reference Safety Document 
(SRSD), which for this study is the Investigator’s Brochure.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Primary Objective

To describe the post-operative outcome of subjects who underwent a total knee, hip, 
or shoulder replacement while participating in tanezumab Study A4091056, 
A4091057 or A4091058 (treatment period and safety follow-up period).
2.2. Secondary Objectives

To compare the post-operative outcome for tanezumab 2.5 mg and 5 mg versus 
NSAID for subjects who underwent a total knee, hip, or shoulder replacement while 
participating in tanezumab Study A4091058.

To describe the post-operative outcome of subjects from the A4091059, A4091061 or 
A4091063 studies who underwent a total knee, hip, or shoulder replacement.
2.3. Endpoints
Given the design of this study, the following endpoints are considered co-equal:

Surgeon’s Assessment of Procedural Difficulty: number and percentage of surgeries 
assessed as uneventful, minor complications or major complications.

Subject’s overall satisfaction with surgery as assessed by the Self-Administered 
Patient Satisfaction (SAPS) Scale: number and percentage of subjects satisfied vs.
unsatisfied with their total joint replacement at Week 24.


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
Number and percentage of subjects with a post-surgical complication(s) up to 
Week 24 (derived from reported adverse events; see also Section 9).

Number and percentage of subjects with additional or corrective procedures related to 
their total joint replacement up to Week 24.

Number and percentage of subjects participating in physical rehabilitation activities 
related to the replaced joint up to Week 24.

Change from Baseline to Week 24 in average pain in the replaced joint.

Change from Baseline to Week 24 in WOMAC Pain, Stiffness and Physical Function 
subscales in the replaced joint (subjects undergoing total hip or knee replacement 
surgery only).

Change from Baseline to Week 24 in the SPADI in the replaced shoulder (subjects 
undergoing total shoulder replacement surgery only).

Concomitant analgesic medication use.
3. STUDY DESIGN
This is a Phase 3, multicenter, long-term observational study of subjects from tanezumab 
Study A4091056, A4091057 or A4091058 (regardless of treatment group) who undergo a 
total knee, hip or shoulder replacement during participation in the study (treatment period or 
safety follow-up period).  If while the subject is participating in this study (A4091064), the 
subject undergoes an additional total joint replacement surgery or the site becomes aware that 
an additional total joint replacement surgery has been scheduled for the subject, the subject 
will be requested to provide information on the additional total joint replacement surgery as 
well. Finally, any subject with a qualifying total joint replacement after the last subject in the 
study completes the treatment period in studies A4091059, A4091061 or A4091063 may be 
followed in this study (A4091064). 
This study is designed with a total duration of subject follow-up of 24 weeks after the total 
joint replacement surgery.  There will be two methods of data collection utilized in this 
study: interview by site staff via the telephone and IWRS accessed by desktop, laptop or 
tablet computer (or paper if the subject has no access to the internet via a desktop, laptop or 
tablet computer).  Following the surgery, the subject will be contacted monthly via telephone 
by study site personnel to ascertain whether the subject has experienced any adverse events 
and to record any concomitant analgesic medications the subject is taking as well as the 
reason for the medication use.  An assessment of the subject’s overall satisfaction with their 
total joint replacement (IWRS), average pain in the replaced joint (IWRS), the subject’s level 
of function and activity in the replaced joint (IWRS) and physical rehabilitation activities 
(telephone interview) will be made at Weeks 4, 12 and 24.  At Weeks 12 and 24, subjects 
will be queried during the telephone interview as to whether any additional or corrective 
procedures related to the total joint replacement are planned. 


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Any subject who expresses a desire to leave this study before 24 weeks of follow-up have 
been completed should be asked to complete all assessments scheduled for Week 24.
All events of total knee, hip or shoulder replacement will be reviewed by the Joint Safety 
Adjudication Committee (Adjudication Committee) established for the tanezumab clinical 
program.  This Committee will adjudicate in an independent and blinded fashion if the event 
is primary osteonecrosis, worsening OA (further sub-divided into rapidly progressive OA 
[RPOA] type 1 or type 2, normal progression of OA or not enough information to distinguish 
between RPOA and normal progression of OA), subchondral insufficiency fracture, 
pathologic fracture, other (with diagnosis specified) or not enough information to specify a 
diagnosis.  Prior to the Adjudication Committee’s review of a given event, Committee
members will be provided with blinded, available source documentation of progress reports 
from the investigator, orthopedic consult reports, operative reports, the pathology report from 
the central laboratory, radiology reports, Dual Energy X-ray Absorptiometry (DXA ) reports, 
x-ray images and magnetic resonance images (MRI) for review.  Sites will be requested to 
submit required source documentation to the Endpoint Management Team as soon as 
possible and ideally within 29 5 days after the total joint replacement surgery (ie, by the 
time the Week 4 visit occurs). In addition, blinded summaries of the following data from the 
parent study (A4091056, A4091057, A4091058 or other studies) will be provided to the 
Committee members for review for each event undergoing adjudication: demographic and 
baseline characteristics, medical history and concomitant medications, investigational 
product administration, non-drug treatments, subject disposition, efficacy data, adverse event 
information, neurological safety data and a serious adverse event narrative (if applicable).  
The Adjudication Committee, in coordination with the Data Monitoring Committee
(E-DMC), is responsible for ongoing analysis of these outcomes and for informing the 
sponsor of recommendations made.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Appropriate members of the investigator's study team are the investigator or sub-investigator.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.


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2. Subject has been randomized and treated with SC investigational product in 
tanezumab Study A4091056, A4091057, A4091058, A4091059, A4091061 or 
A4091063 and has completed the study or has been withdrawn from the study. 
3. Actual or planned total knee, hip or shoulder replacement surgery during tanezumab 
Study A4091056, A4091057 or A4091058 or after the last subject in the study 
completes the treatment period in tanezumab Study A4091059, A4091061 or 
A4091063.  Note: additional procedures in a subject undergoing total joint 
replacement surgery (eg, revision of a previously replaced joint in addition to a new 
total joint replacement) will be allowed, but subjects undergoing solely sub-total 
arthroplastic procedures (eg, hemi-arthroplasty) will not be eligible.
4. Subject is willing and able to comply with scheduled visits and other study 
procedures. 
4.2. Life Style Guidelines 
All female subjects who are of childbearing potential and are sexually active and at risk for 
pregnancy, and who withdraw from Study A4091056, A4091057 A4091058, or other 
tanezumab study less than 16 weeks after the last dose of subcutaneous investigational 
product must agree to use two (2) methods of highly effective contraception consistently and 
correctly until 112 days (16 weeks) after the last dose of subcutaneous investigational 
product.  The investigator or his/ or her designee, in consultation with the subject, will 
confirm the subject has selected the most appropriate forms of contraception for the 
individual subject from the permitted list of contraception methods (see below), and instruct
the subject in their consistent and correct use.  Subjects need to affirm that they meet the 
criteria for correct use of at least two of the selected methods of contraception.  The 
investigator or his/her designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly according to the schedule of activities and document 
such conversation in the subject’s chart.  In addition, the Investigator or his/ or her designee
will instruct the subject to call immediately if the selected birth control methods are
discontinued or if pregnancy is known or suspected in the subject.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject remains on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.


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4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
NOTE: For Sweden and the United Kingdom, please refer to Appendix 4 for Life Style 
Guidelines for subjects from clinical sites in these countries.
There are no contraception requirements for sexually active female subjects of childbearing 
potential who withdraw from Study A4091056, A4091057, A4091058 or other tanezumab 
study more than 16 weeks after the last dose of subcutaneous investigational product.
4.3. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
5. STUDY TREATMENTS
This is an observational study of subjects who were randomized and treated in tanezumab 
Study A4091056, A4091057 or A4091058 and who subsequently underwent a total knee, hip 
or shoulder replacement during the treatment or safety follow-up period. Any subject with a 
qualifying total joint replacement after the last subject in the study completes the treatment 
period in studies A4091059, A4091061 or A4091063 may also be followed in this study 
(A4091064). 
There are no protocol defined study medications in this observational study.
Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons, clinical 
research associates (CRAs) and staff directly involved with this study at Pfizer and its 
designees will be blinded to treatment assignment in the parent study (ie, Study A4091056, 
A4091057, A4091058 or other tanezumab study).
5.1. Concomitant Medication(s)
No medications are specifically prohibited in this observational study. 
Subjects who enter into this study <16 weeks after their last dose of subcutaneous 
investigational product in the parent study (ie, Study A4091056, A4091057, A4091058 or 
other tanezumab study) will be advised to avoid chronic non-steroidal anti-inflammatory 
drug (NSAID) use, until at least 16 weeks has elapsed, if possible.
Subjects will be instructed to keep a record of concomitant analgesic medication usage 
(including dose, dosing regimen and reason for use).  This information will be recorded on 
the appropriate concomitant medication case report form (CRF) during the monthly 
telephone interviews.


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6. STUDY PROCEDURES
Study visit windows are +10 days for activities related to the total joint replacement surgery 
and 5 days for activities performed on Weeks 4, 8, 12, 16, 20 and 24.  Site staff should 
make every effort to contact the subject within the protocol defined visit window for 
Weeks 4, 8, 12, 16, 20 and 24 however, data obtained outside of the visit window while a 
protocol deviation, should still be recorded. In the event that the activities related to a visit 
are performed within the extremes of the visit windows, following study visits and associated 
activities should be scheduled with reference to the total joint replacement surgery date.  
Subject scheduling issues should be brought to the attention of the assigned study monitor or 
study clinician for resolution.
The investigator must make sure that delegations of responsibility to site staff for 
administering the IWRS or entering data into the IWRS are specifically documented using 
the appropriate forms and are based on documented evidence of adequate training in 
administration and use of the IWRS.  The investigator (or other site staff specifically 
delegated by the investigator) is responsible for regular monitoring of the compliance of the 
subjects with the required data entry by means of reports in the IWRS.  The IWRS will also 
be programmed to notify designated site staff when data has not been recorded within the 
requested timeframe.  Regardless of how the investigator delegates responsibility for 
administering the IWRS or entering data into the IWRS, the investigator remains responsible 
for providing adequate supervision and oversight of the investigator’s colleagues, employees 
and any third parties as per FDA regulations and guidelines and Good Clinical Practice.
6.1. Baseline Visit
Baseline information for this study should be obtained as close as possible to, and prior to, 
the total joint replacement surgery.  The Baseline Visit may coincide with the last visit in 
Study A4091056, A4091057 or A4091058 (End of Study or Early Termination Visit) or 
occur when the site is notified of a planned total joint replacement surgery. If a total joint 
replacement occurs or is scheduled to occur after the last subject in the study completes the 
treatment period in Study A4091059, A4091061 or A4091063 baseline activities could be 
conducted at either the end of study visit or at the early termination visit in Study A4091059, 
A4091061 or A4091063.  Baseline Visit activities must be conducted at the clinical site. 
Subjects should be queried about their access to the internet via a desktop, laptop or tablet 
computer so as to determine the appropriate format for the subject reported outcomes of pain 
in the joint to be (or post-surgery, that has been) replaced, functional status and, post-surgery, 
satisfaction with surgery. 
Subjects with access to the internet via a desktop, laptop or tablet computer should be trained 
in the use of the ePRO system (IWRS) and in their responsibilities for data entry in 
compliance with the protocol. IWRS technical support (Help Desk) will be available to the 
subject for the duration of the study. Beginning with the Baseline Visit, subjects with access 
to the internet via a desktop, laptop or tablet computer should complete the aforementioned 
assessments via the IWRS.  In the event of internet connectivity issues at the Baseline Visit, 
paper versions of the assessments should be completed.


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Only subjects without access to the internet via a desktop, laptop or tablet computer during 
Study A4091064 should complete the aforementioned assessments on paper for the duration 
of Study A4091064.  Simple preference for the use of paper is not sufficient to allow its use 
by the subject who has access to the internet via a desktop, laptop or tablet computer during 
Study A4091064.
Except in unusual circumstances, subjects should not switch between paper-based and 
web-based completion of the subject reported outcome measures. 
Thorough instruction should be provided for completion of self-administered scales (subject
reported outcomes) however, no coaching or other interpretative assistance should be given 
to the subject during the completion of the questionnaires. 
Telephone contact information should also be confirmed at the Baseline Visit.
Activities at the Baseline Visit:

Informed consent.

Review of inclusion criteria.

Record ongoing adverse events and concomitant analgesic medications.

Assessment of pain in the joint to be replaced (11-point NRS).

Assessment of functional status in the joint to be replaced (WOMAC for subjects 
undergoing total knee or hip replacement or SPADI for subjects undergoing total 
shoulder replacement).  NOTE: the WOMAC and SPADI should be completed in 
their entirety.

Subjects without access to the internet via a desktop, laptop or tablet computer for the 
duration of the study should be provided with paper copies of the subject reported 
outcomes assessments for subsequent entry into the IWRS by site staff. 

Subjects should be instructed on the timing of assessments and the need to return the 
assessments to the site as soon as possible, but no later than 5 days, after completion 
of the assessment.

Study site staff must contact the subject’s orthopedic surgeon to discuss the 
completion of the required forms and specimen collection and handling. The surgeon
will be provided with the surgery related documents (Surgeon’s Assessment of 
Procedural Difficulty and instructions for the shipment of pathology specimens).

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
investigational product in Study A4091056, A4091057 ,A4091058 or other 
tanezumab study, female subjects of child-bearing potential should be reminded of 
contraceptive requirements.


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6.2. Day of Surgery Day 1 (+10 days)
During this interval, sites should ensure receipt of a completed Surgeon’s Assessment of 
Procedural Difficulty and confirm that pathology specimens were shipped according to 
instructions.  Required source document collection (eg, operative report and discharge 
summary) should begin in this interval.
Sites will be requested to submit required source documentation to the Endpoint 
Management Team as soon as possible, and ideally within 29 5 days, after the total joint 
replacement surgery (ie, by the time the Week 4 visit occurs provided the source 
documentation has been completed).
6.3. Week 4 Day 29 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).

Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement); NOTE: the WOMAC and 
SPADI should be completed in their entirety.

Overall satisfaction with joint replacement surgery (SAPS).
At the conclusion of the telephone call, site staff should:

Remind subjects not utilizing the IWRS to return paper-based assessments to the site 
as soon as possible, but no later than 5 days, after completion of the assessment. Site 
staff will enter the subject reported outcomes into the IWRS upon receipt of the 
completed assessment.

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
investigational product in Study A4091056, A4091057, A4091058 or other 
tanezumab study, remind female subjects of child-bearing potential of contraceptive 
requirements.

Confirm the approximate timing of the next telephone call.


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6.4. Week 8 Day 57 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
investigational product in Study A4091056, A4091057,A4091058 or other tanezumab 
study, remind female subjects of child-bearing potential of contraceptive 
requirements.

Confirm the approximate timing of the next telephone call.
6.5. Week 12 Day 85 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).

Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.

Query for additional or corrective procedures related to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement); NOTE: the WOMAC and 
SPADI should be completed in their entirety.

Overall satisfaction with joint replacement surgery (SAPS).
At the conclusion of the telephone call, site staff should:

Remind subjects not utilizing the IWRS to return paper-based assessments to the site 
as soon as possible, but no later than 5 days, after completion of the assessment. Site 
staff will enter the subject reported outcomes into the IWRS upon receipt of the 
completed assessment.


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
If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
investigational product in Study A4091056, A4091057, A4091058 or other 
tanezumab study, remind female subjects of child-bearing potential of contraceptive 
requirements.

Confirm the approximate timing of the next telephone call.
6.6. Week 16 Day 113 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
investigational product in Study A4091056, A4091057, A4091058 or other 
tanezumab study, remind female subjects of child-bearing potential of contraceptive 
requirements.

Confirm the approximate timing of the next telephone call.
6.7. Week 20 Day 141 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

Confirm the approximate timing of the next telephone call.
6.8. Week 24 Day 169 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).


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
Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.

Query for additional or corrective procedures related to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement); NOTE: the WOMAC and 
SPADI should be completed in their entirety.

Overall satisfaction with joint replacement surgery (SAPS).
At the conclusion of the telephone call, site staff should remind subjects not utilizing the 
IWRS to return paper-based assessments to the site as soon as possible, but no later than 
5 days, after completion of the assessment. Site staff will enter the subject reported 
outcomes into the IWRS upon receipt of the completed assessment.
6.9. Subject Withdrawal/Early Termination 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site. 
If a subject cannot be contacted within the window for a scheduled visit, every effort should 
be made to contact the subject outside of the visit window.  A subject thought lost to 
follow-up, must be contacted through a minimum of 3 documented phone call attempts and, 
if phone calls are unsuccessful, a certified letter sent to the subject. All attempts to contact 
the subject and information received during the contact attempts must be documented in the 
subject’s medical records. In any circumstance, every effort should be made to document the 
subject’s outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request that the subject return for a final visit, if applicable, and follow-up with 
the subject regarding any unresolved adverse events (AEs).
If the subject is willing, the investigator should query for any new adverse events, query 
about concomitant analgesic medication use, physical rehabilitation activities or corrective 
procedures related to the joint replacement surgery and request that the subject complete the 
following assessments via the IWRS or via paper, as established at the Baseline Visit: 

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement) (WOMAC or SPADI).


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
Overall satisfaction with joint replacement surgery (SAPS).
Subjects not utilizing the IWRS should be reminded to return paper based assessments to the 
site as soon as possible, but no later than 5 days, after completion of the assessment.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required procedures are completed as 
described. However it is anticipated that from time to time there may be circumstances,
outside of the control of the investigator, that may make it unfeasible to perform a procedure. 
In these cases the investigator will take all steps necessary to ensure the safety and well-
being of the subject. When a protocol required procedure cannot be performed the
investigator will document the reason for this and any corrective and preventive actions that
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Surgeon’s Assessment of Procedural Difficulty
Following the total joint replacement surgery, the orthopedic surgeon performing the surgery 
will be asked to answer the following question:
“Taking into consideration the subject’s medical history and physical condition prior to 
surgery would you classify the operative procedure as:
1. Uneventful; or 
2. Minor complications; or
3. Major complications.
If the category of minor or major complications is chosen, the surgeon will be requested to 
specify the complication(s).
7.2. Pathology Specimens
Surgeons will be requested to ship pathology specimens from the total joint replacement 
surgery to a central laboratory for processing and/or analysis.  Detailed instructions for the 
shipping of pathology specimens will be provided. Identification of specimens of adequate 
quality, preparation and histopathologic examination of the specimens will be performed in a 
standardized manner by the central laboratory under the direction of an expert orthopedic 
pathologist.  


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7.3. Telephone-based Assessments
Post-surgery, subjects will be contacted monthly via telephone by study site personnel.
7.3.1. Adverse Events
At each post-surgery telephone contact, subjects will be queried for the occurrence of adverse 
events.  All adverse events reported by the subject must be recorded on the appropriate case 
report form (CRF).
A neurologic evaluation should be performed by a consulting neurologist if any of the 
following occurs: 

If an adverse event suggestive of new or worsening peripheral neuropathy or an 
adverse event of abnormal peripheral sensation (eg, allodynia, burning sensation, 
carpal tunnel syndrome, dysesthesia, hyperesthesia, hyperpathia, hypoesthesia, 
neuralgia, neuritis, neuropathy peripheral, pallanesthesia, paresthesia, peripheral 
sensory neuropathy, sciatica, sensory disturbance, sensory loss, tarsal tunnel 
syndroma) is reported as: 1) a serious adverse event or 2) an adverse event which has 
resulted in the subject being withdrawn from the study, or 3) an adverse event 
ongoing at the end of the subject’s participation in the study, or 4) an adverse event of 
severe intensity. 

A neurological adverse event which is non-neuropathic (eg, stroke, seizure) but which 
the investigator considers medically important should also result in a neurological 
consultation.
In these cases, a neurologic evaluation should be obtained as soon as possible after these 
signs and symptoms are known.  The results of the neurological consultation will be recorded 
on the appropriate CRF and adverse event (if applicable) forms. Adverse events will be 
reported where applicable as described in Section 8.
Subjects reporting adverse events (any seriousness or severity) with preferred terms of 
bradycardia, syncope, orthostatic hypotension, anhidrosis or hypohidrosis should be further 
evaluated for the presence of sympathetic autonomic neuropathy by a cardiologist or 
neurologist as soon as possible. 
The investigator should determine the appropriate type of consultation (neurology or 
cardiology) depending on the subject’s symptom presentation and the investigator’s 
assessment as to the specialist best able to evaluate the subject.  Pfizer will provide a 
guidance document which outlines appropriate recommendations regarding tests to consider 
for subject work-up.
7.3.2. Concomitant Analgesic Medication
At each post-surgery telephone contact, subjects will be queried about concomitant analgesic 
medication usage including dose, dosing regimen and reason for use. This information 
should be recorded on the appropriate case report form (CRF).


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7.3.3. Physical Rehabilitation Activities
At the Week 4, 12 and 24 post-surgery telephone contacts, subjects will be queried for 
rehabilitation activities related to the replaced joint.  Specifically, subjects will be asked to 
respond yes or no to the following question:

Are you participating in physical rehabilitation activities related to your replaced 
joint?
Subjects will be queried for details if the answer to the question is yes. This information 
should be recorded on the appropriate case report form (CRF).
7.3.4. Additional or Corrective Procedures
At the Week 12 and 24 post-surgery telephone contacts, subjects will be queried for 
additional or corrective procedures related to the total joint replacement surgery.  
Specifically, subjects will be asked to respond yes or no to the following question:

Have you been told by your orthopedic surgeon that additional or corrective 
procedures (for example a revision or implant replacement) are necessary for your 
total joint replacement?
Subjects will be queried for details if the answer to the question is yes. If necessary, the 
orthopedic surgeon may be contacted to confirm/expand upon the information regarding 
additional or corrective procedures. This information should be recorded on the appropriate 
case report form (CRF).
7.4. Web-based Assessments
7.4.1. Overall Satisfaction with Surgery
The Self-Administered Patient Satisfaction Scale (SAPS) evaluates subject satisfaction with 
the outcome of hip and knee arthroplasty and was designed to be used in conjunction with 
other clinical measures and functional health status instruments to evaluate the results of hip 
and knee arthroplasty. 
The scale consists of four items focusing on satisfaction with the extent of pain relief, 
improvement in ability to perform home or yard work, ability to perform recreational 
activities and overall satisfaction with joint replacement. 
Specifically, subjects will be asked to respond to the following questions:

How satisfied are you with the results of your surgery?

How satisfied are you with the results of your surgery for improving your pain?

How satisfied are you with the results of surgery for improving your ability to do 
home or yard work?


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
How satisfied are you with the results of surgery for improving your ability to do 
recreational activities?
Items are scored on a 4-point Likert scale with response categories consisting of ‘very 
satisfied’ (100 points), ‘somewhat satisfied’ (75 points), ‘somewhat dissatisfied’ (50 points), 
and ‘very dissatisfied’ (25 points). The scale score is the unweighted mean of the scores 
from the individual items, ranging from 25 to 100 per item with higher scores indicating 
greater satisfaction.
Subjects will be requested to complete the SAPS at Weeks 4, 12, and 24 either via the IWRS
or by paper if the subject does not have access to the internet via a desktop, laptop or tablet 
computer.  When completed on paper, the subject will be requested to return the assessment 
to the site as soon as possible, but no later than 5 days, after completion of the assessment.
7.4.2. Pain in Replaced Joint
Average pain in the joint to be replaced (pre-surgery) and average pain in the replaced joint 
(post-surgery) will be assessed with an 11-point Numeric Rating Scale (NRS) ranging from 
zero (no pain) to 10 (worst possible pain).
Question:
Select the number that best describes your average pain in the (joint to be replaced or 
replaced joint) the past 24 hours. 
0
1
2
3
4
5
6
7
8
9
10
No Pain
Worst 
Possible 
Pain
At Baseline and at Weeks 4, 12 and 24 following total joint replacement surgery, subjects 
will be asked to indicate their average pain in the joint to be replaced (pre-surgery) or the 
replaced joint (post-surgery) via the IWRS or by paper if the subject does not have access to 
the internet via a desktop, laptop or tablet computer.  When completed on paper, the subject
will be requested to return the assessment to the site as soon as possible, but no later than 
5 days, after completion of the assessment.
7.4.3. Assessment of Functional Activity 
Subjects undergoing total knee or hip replacement will be asked to complete the Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with the knee or hip that 
will be or was replaced serving as the “index joint”.  Subjects undergoing total shoulder 
replacement will be asked to complete the Shoulder Pain and Disability Index (SPADI). 
Descriptions of these assessments are provided below.


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7.4.3.1. WOMAC
Subjects who will be proceeding to total knee or hip arthroplasty will be requested to 
complete all subscales of the WOMAC (ie, pain, physical function and stiffness) at Baseline 
and Weeks 4, 12, and 24 following total joint replacement surgery either via the IWRS or by 
paper if the subject does not have access to the internet via a desktop, laptop or tablet 
computer.  When completed on paper, the subject will be requested to return the assessment 
to the site as soon as possible, but no later than 5 days, after completion of the assessment.
7.4.3.1.1. WOMAC Pain Subscale
The WOMAC Pain subscale is comprised of 5 questions regarding the amount of pain 
experienced due to OA in the index joint (selected study knee or hip) in the past 48 hours. 
For this study, the index joint (selected study knee or hip) is defined as the joint to be or 
that has been replaced.  This may or may not have been the index joint in Study 
A4091056, A4091057 or A4091058.  The WOMAC Pain subscale is calculated as the mean 
of the scores from the five individual questions, which may not be a whole (integer) number.  
The WOMAC Pain subscale NRS scores for each question, and the WOMAC Pain subscale 
score, range from 0 to 10, with higher scores indicating higher pain.
7.4.3.1.2. WOMAC Physical Function Subscale
The WOMAC Physical Function subscale is comprised of 17 questions regarding the degree 
of difficulty experienced due to arthritis in the index joint (selected study knee or hip) in the 
past 48 hours.  For this study, the index joint (selected study knee or hip) is defined as 
the joint to be or that has been replaced.  This may or may not have been the index joint 
in Study A4091056, A4091057 or A4091058.  The WOMAC Physical Function subscale is 
calculated as the mean of the scores from the seventeen individual questions, which may not 
be a whole (integer) number.  The WOMAC Physical Function subscale NRS scores for each 
question, and the WOMAC Physical Function subscale score, range from 0 to 10 with higher 
scores indicating worse function.  This refers to the subject's ability to move around and 
perform usual activities of daily living.
7.4.3.1.3. WOMAC Stiffness Subscale
The WOMAC Stiffness subscale is comprised of 2 questions regarding the amount of 
stiffness experienced in the index joint (selected study knee or hip) in the past 48 hours.  For 
this study, the index joint (selected study knee or hip) is defined as the joint to be or 
that has been replaced.  This may or may not have been the index joint in Study 
A4091056, A4091057 or A4091058.  The WOMAC Stiffness subscale is calculated as the 
mean of the scores from the two individual questions, which may not be a whole (integer) 
number.  The WOMAC Stiffness subscale NRS scores for each question, and the WOMAC 
Stiffness subscale score, range from 0 to 10 with higher scores indicating more stiffness.  
Stiffness is defined as a sensation of decreased ease with which the subject moves the index 
knee or hip.
A copy of the WOMAC can be found in Appendix 1.


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7.4.3.2. The Shoulder Pain and Disability Index (SPADI)
Subjects who will be proceeding to shoulder arthroplasty will be requested to complete both 
dimensions of the SPADI (ie, pain and function) at Baseline and at Weeks 4, 12, and 24 
following total joint replacement surgery either via the IWRS or by paper if the subject does 
not have access to the internet via a desktop, laptop or tablet computer.  When completed on 
paper, the subject will be requested to return the assessment to the site as soon as possible, 
but no later than 5 days, after completion of the assessment.
The SPADI consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use. The scores from both 
dimensions are averaged to derive a total score from 0 (best) to 100 (worst).
A copy of the SPADI can be found in Appendix 2.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events (AEs)
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
Subjects entering study A4091064 may have left Study A4091056, A4091057 or A4091058 
at variable intervals relative to the last dose of subcutaneous investigational product in Study 
A4091056, A4091057 or A4091058. 
There is no investigational product administered in study A4091064.  


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The reporting requirements for Study A4091056, A4091057 and A4091058 are as follows:

For SAEs, the active reporting period to Pfizer or its designated representative begins 
from the time that the subject provides informed consent, which is obtained prior to 
the subject’s participation in the study, ie, prior to undergoing any study-related 
procedure and/or receiving investigational product, through the end of the safety 
Follow up period or through and including 112 calendar days after the subject’s last 
administration of the subcutaneous investigational medication if the subject refuses 
the protocol defined Follow up period.

Serious adverse events occurring to a subject after the active reporting period has 
ended should be reported to the Sponsor if the investigator becomes aware of them; at 
a minimum, all serious adverse events that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.

AEs (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of study treatment through last subject visit. 
SAEs should be reported to the respective parent study A4091056 / A4091057 / A4091058 
using the Clinical Trial SAE Report Form (see Section 8.12.1 of the parent study protocol).
An AE/SAE should be recorded on the A4091064 CRF from the time the subject has signed 
the informed consent document through last subject visit in study A4091064.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;


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
Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or


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
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires in subject hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the Section on Serious Adverse Event Reporting Requirements) 
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a subject, such LFT results should be handled and followed up 
as described below. 


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Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal 
(x ULN) concurrent with a total bilirubin 2 x ULN with no evidence of hemolysis 
and an alkaline phosphatase 2 x ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 x ULN, or 8 x ULN 
(whichever is smaller).

Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1x ULN
or 3 normal ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/ international 
normalized ratio (INR), and alkaline phosphatase.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of 
contact with a jaundiced person, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or 
C infection and liver imaging (eg, biliary tract) may be warranted. All cases confirmed on 
repeat testing as meeting the laboratory criteria defined above, with no other cause for LFT 
abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be reported as SAEs.


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8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.


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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy (EDP)
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having 
been exposed (eg, because of treatment or environmental exposure) to the 
investigational product; or the female becomes or is found to be pregnant after 
discontinuing and/or being exposed to the investigational product; 


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An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to 
the investigational product prior to or around the time of conception and/or is 
exposed during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The Investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.10.1. Additional Post-Natal Follow-up
The Investigator will be asked to assist with collection of assessments of postnatal 
development as part of a separate protocol.  Participation in that protocol is optional and will 
require that the subject review, agree and sign a separate informed consent document specific 
to that study, explaining the details of the post-partum follow-up for the subject and the 
newborn to participate in these assessments of postnatal development.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject
Withdrawal/Early Termination)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding cases and 
occuptational exposure cases.


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In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for the summary and descriptive analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan, which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the planned analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
This study is designed to collect information sufficient to describe the post-operative 
outcome of subjects who underwent a total knee, hip, or shoulder replacement while 
participating in tanezumab Study A4091056, A4091057 or A4091058 (treatment or safety 
follow-up period).  In addition subjects with a qualifying total joint replacement after the last 
subject in the study completes the treatment period in Study A4091059, A4091061 or 
A4091063 may be included.  The number of subjects who will enroll in this study is 
unknown but is estimated to be less than 250 subjects. Also unknown is the distribution of 
subjects across treatment groups (ie, the treatment given in Study A4091056, A4090157, 
A4091058, or other tanezumab study). Therefore, it is predicted that there will be 
insufficient statistical power to perform statistical inferential analyses.  All analyses will be 
descriptive in nature.


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9.2. Analysis of Endpoints
All subjects enrolled in the study who have a total joint replacement will be included in the 
summary tables. 
A summary of data will be shown using subjects from study A4091058.  The incidence of 
subjects with a total joint replacement will be summarized for all subjects, and split by Study 
A4091058 treatment group.  These summaries will be shown as percentages, and for 
exposure-adjusted rates (using Study A4091058 treatment and follow-up period up to the 
time of surgery).  Comparisons of the total joint replacement rates will be made between 
tanezumab versus active comparator treatment groups, using risk differences and ratios with 
95% confidence intervals.  Summaries of the time to total joint replacement surgery and time 
to first symptom (leading to total joint replacement surgery) will be summarized using 
Kaplan-Meier survival estimates from the date of first subcutaneous dose in Study 
A4091058, and shown overall, and split by Study A4091058 treatment group where there are 
sufficient numbers of subjects.  A further summary of the incidence of subjects with total
joint replacements will be shown separately for studies A4091056, A4091057, A4091059, 
A4091061 and A4091063, if applicable.  Similar summaries by study will be shown for 
adjudication outcomes.  The summary of time to total joint replacement surgery and time to 
first symptom (leading to total joint replacement surgery) will also be performed using data 
for subjects from Studies A4091056 and A4091057.
Unless otherwise stated, data from this study will be presented at Baseline and Weeks 4, 12, 
and 24 using observed data (no imputation for missing data), and at Week 24 using Last 
Observation Carried Forward (LOCF) for missing data.  Data will be shown at the timepoints 
specified and also using change from (pre-surgery) Baseline when Baseline data are available 
and where relevant.  Data will be shown overall, and split by treatment group.  Data on 
surgical difficulty and outcomes, and subject safety data will be summarized by study, with 
an additional combined summary for the subjects from the osteoarthritis studies.
For the Surgeon’s Assessment of Procedural Difficulty, the number and percentage of 
subjects in each category (Uneventful, Minor complications, Major complications) will be 
presented.  Complications reported by the surgeon will be listed. 
For the subject’s overall satisfaction with surgery assessments (using the Self-Administered 
Patient Satisfaction scale, SAPS), the responses [score] for each category (Very Satisfied 
[100], Somewhat Satisfied [75], Somewhat Dissatisfied [50], Very Dissatisfied [25]) will be 
stratified by surgery type (hip, knee or shoulder) and summarized for each of the four items. 
The scale score is the unweighted mean of the scores from the individual items, ranging from 
25 to 100 per item with higher scores indicating greater satisfaction. This total score will be 
stratified by surgery type (hip, knee or shoulder) and summarized. Reponses to the question 
“How satisfied are you with the results of your surgery?” will also be stratified by surgery 
type (hip, knee or shoulder) and summarized as satisfied (very satisfied and somewhat 
satisfied categories combined) and dissatisfied (somewhat dissatisfied and very dissatisfied 
categories combined).


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Similarly, the number and percentage of subjects who have required (i) additional or 
corrective procedures related to their total joint replacement and (ii) participating in physical 
rehabilitation activities related to their replaced joint will be presented.  For these 
assessments, change from Baseline summary data are not relevant and will not be presented.
Average pain (NRS) in the replaced joint for all subjects, WOMAC Pain, Stiffness and 
Physical Function sub-scale scores for subjects who had total knee or hip replacement and 
SPADI Pain, Function and Total Score for subjects who had total shoulder replacement will 
be summarized (including change from Baseline summaries).
Adverse events and concomitant analgesic medications will be collected for each subject
during the study according to the Schedule of Assessments. Standard safety reporting tables 
will summarize and list these safety data.
In addition, the number and percent of subjects with specified post-surgical complications 
will be presented. The list of post-surgical complications will be derived from reported 
adverse events and will consist of complications that are clinically significant and attributable 
to the total arthroplasty procedure eg, periprosthetic joint infection/wound infection, 
periprosthetic fracture, pulmonary embolism or sepsis/septicemia/shock.  Literature reported 
analyses of post-surgical complications19,20 will be used for guidance in developing the list of 
post-surgical complications. The list of post-surgical complications will be developed during 
Study A4091064 and finalized prior to Study A4091058 database lock. 
Separate adverse event summaries by parent study treatment group for adverse events of 
decreased sympathetic function will be presented. 
For subjects from study A4091058 and for subjects from any of the osteoarthtitis studies, 
summaries of total joint replacement, adjudication event rates and post-surgical outcomes 
will be shown for subgroups including age, gender, body-mass index (BMI), baseline 
Kellgren-Lawrence grade of the replaced joint (knees and hips only) and number of joints 
with OA.
9.3. Data Monitoring Committee (DMC)
This study will use an external data monitoring committee (EDMC). 
An independent, E-DMC has been re-instituted for the tanezumab clinical program.  This 
committee will be composed of at least one rheumatologist, neurologist, statistician, and 
epidemiologist.  The E-DMC will review unblinded safety data including (but not limited to) 
general adverse events and serious adverse events on a regular basis throughout the 
tanezumab clinical program.  The E-DMC will have written operating procedures and a 
Charter, including a specific description of the scope of their responsibilities.
Adverse events of syncope, bradycardia, orthostatic hypotension, anhidrosis or hypohidrosis 
will be designated as adverse events of interest.  These adverse events along with other 
adverse events that are possibly related to the sympathetic nervous system will be monitored 
by the E-DMC during review of unblinded safety data.


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The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the 
program according to the charter.  If the blinded Adjudication Committee (see Section 9.4)
identifies adjudicated events of rapidly progressive osteoarthritis type 2, subchondral 
insufficiency fracture (spontaneous osteonecrosis of the knee [SPONK]), primary 
osteonecrosis or pathological fracture, occurring at a rate that could trigger protocol-based 
stopping criteria, an urgent, ad hoc assessment of the events will be made by the E-DMC. 
Any recommendations made by the E-DMC to alter the conduct of one or more of the studies
will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data which are not 
endpoints, to regulatory authorities, as appropriate.
Pfizer Standard Operating Procedures regarding periodic safety reviews by the study team 
and the Tanezumab Risk Management Committee will be followed.  This committee will be 
composed of members inside and outside the immediate study team who will review blinded 
safety data from individual studies as well as data pooled across the studies on an ongoing 
basis.  A safety review plan will be in place governing the frequency and extent of safety 
review. 
9.4. External Adjudication Committee
A blinded Adjudication Committee consisting of external experts in orthopedic surgery, 
rheumatology, orthopedic pathology, or radiology with expertise in subjects with end stage 
osteoarthritis and osteonecrosis will be convened.  The Adjudication Committee will have 
written operating procedures and a Charter, including a specific description of the scope of 
their responsibilities.  In general, the Adjudication Committee will be asked to review all 
possible or probable joint-related safety events identified by the Central Reader, total joint 
replacements as well as investigator-reported adverse events of osteonecrosis, rapidly 
progressive osteoarthritis, or subchondral insufficiency fracture (spontaneous osteonecrosis 
of the knee [SPONK]) or pathologic fracture.  Adverse events related to joint safety that the 
investigator or sponsor considers medically important may also be reviewed by the 
Adjudication Committee.  These will include, but will not be limited to events identified for 
adjudication by the Central Reader.
Prior to the Adjudication Committee’s review of a given event, the Committee will be 
provided with blinded, available source documentation of progress reports from the 
Investigator, orthopedic consult reports, operative reports, radiology reports, pathology 
reports, X-ray images, MRI images, and pathology specimens for review.  Copies of all 
relevant clinical information including the items listed above should be provided to Pfizer or 
its designee for review by the external Adjudication Committee.  Copies of the information 
should include the study number, site number and subject number, but it should not include 
the subject’s name or initials.
The E-DMC will be provided with a blinded summary of the Adjudication Committee’s 
review of events after each review meeting.


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 


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In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to the ICH guidelines, local regulations, or as specified 
in the Clinical Study Agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board /Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer. The investigator should also receive the approval from the national 
competent authority before implementing a substantial amendment.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by laws.
When study data are compiled for transfer to Pfizer and other authorized parties, subject
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject, or his/her legally acceptable
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then, 
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his or her own consent, the source documents 
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative before any 
study-specific activity is performed. The investigator will retain the original of each subject's 
signed consent document.
12.4. Subject Recruitment
Subject recruitment efforts are not required for this study because this is an observational 
extension study. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of Trial in all other participating countries is defined as database lock.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of
tanezumab at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 1 week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively “Publication”) 
before it is submitted or otherwise disclosed.


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The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenteer study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this Section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the Clinical Study Agreement.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Pfizer. TANEZUMAB ARTHRITIS ADVISORY COMMITTEE BRIEFING 
DOCUMENT. February 8, 2012; In; 2012. 
URL:http://www.fda.gov/AdvisoryCommittees/Calendar/ucm286556.htm?utm_source=
fdaSearch&utm_medium=website&utm_term=March 12, 2012&utm_content=1.Access 
Date: April 4, 2012.
2.
Hertz S, Fields E. Addendum to the Background Package for the March 12, 2012, AAC 
Meeting, Regarding the Agency Adjudication of Cases of Joint Replacements Occurring 
in Clinical Trials of Anti-NGF Agents. In; March 2, 2012. 
URL:http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Art
hritisDrugsAdvisoryCommittee/ucm295201.htm. Access date: April 4, 2012. 
3.
Rappaport BA. FOOD AND DRUG ADMINISTRATION Center for DrugEvaluation 
andResearch:BackgroundMaterials.February13,2012.URL:http://www.fda.gov/Advisory
Committees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/uc
m295201.htm. Access date: April 4, 2012.
4.
Bennett DLH, McMahon SB, Rattray M, Shelton D.  Nerve growth factor and sensory 
nerve function.  In “Pain and Neurogenic Inflammation”, eds. SD Brain and PK Moore.  
Birkhauser, Basel. 1999.
5.
Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J.  Nerve growth factor
contributes to the generation of inflammatory sensory hypersensitivity.  Neuroscience 
1994; 62:327-31.
6.
McMahon SB, Bennett DLH, Priestley JV, Shelton DL.  The biological effects of 
endogenous nerve growth factor on adult sensory neurons revealed by a trkA IgG fusion 
molecule.  Nature Med 1995; 1:774-780.
7.
Safieh-Garabedian B, Poole S, Allchome A, Winter J, Woolf CJ.  Contribution of 
interleukin 1 beta to the inflammation induced increase in nerve growth factor levels and 
inflammatory hyperalgesia.  Br J Pharmacol 1995; 115:1265-1275.
8.
Woolf CJ, Allchorne B, Safieh-Garabedian B, Poole S.  Cytokines, nerve growth factor 
and inflammatory hyperalgesia: the contribution of tumor necrosis factor α.  Br J 
Pharmacol 1997; 121:417-424.
9.
Armour KL, Clark MR, Hadley AG, Williamson LM.  Recombinant human IgG 
molecules lacking Fcgamma receptor I binding and monocyte triggering activities.  Eur 
J Immunol 1999; 29(8):2613-2624.
10. Armour KL, van de Winkel JG, Williamson LM, Clark MR.  Differential binding to 
human FcgammaRIIa and FcgammaRIIb receptors by human IgG wild type and mutant 
antibodies.  Mol Immunol 2003; 40(9):585-593.


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11. February 2015 Tanezumab (PF-04383119) Investigator Brochure.
12. Beaton DE, and Schemitsch E. Measures of Health-Related Quality of Life and Physical 
Function. Clin Orth and Rel Research 413:2003; 90-105.
13. Mahomed N, et al. The self-administered patient satisfaction scale for primary hip and 
knee arthroplasty. Arthritis 2011; doi:10.1155/2011/591253.
14. Hawker GA, et al. Measures of adult pain. Arthritis Care Res 2011;63:S240-S252.
15. Rolfson O, et al. Use of patient-reported outcomes in the context of different levels of 
data. J Bone Joint Surg Am 2011; 93 Suppl3(E):66-71.
16. Rogers JC and Irrgang JJ.  Measures of adult lower extremity function. Arthritis Care 
Res 2003;49:S67-S84.
17. Angst F, et al. Measures of adult shoulder function.  Arthritis Care Res
2011;63:S174-S188.
18. Roy J-S, MacDermid JC and Woodhouse LJ. Measuring shoulder function: a systemic 
review of four questionnaires. Arthritis Care Res 2009; 61:623-632.
19. Grosso, LM et al., Hospital-Level Risk-Standardized Complication Rate Following 
Elective Primary Total  Hip Arthroplasty and/or Total Knee Arthroplasty Measure 
Methodology Report 25 June 2012.
20. Bohsali KI, Wirth MA and Rockwood CA. Complications of total shoulder arthroplasty. 
J Bone Joint Surgery 88:2006; 2279 – 2292.


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Appendix 1. Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) 
CCI


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CCI


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CCI


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CCI


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CCI


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CCI


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Appendix 2. The Shoulder Pain and Disability Index (SPADI)


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Appendix 3. Abbreviations
This is a list of abbreviations used in the protocol.  
Abbreviation
Term
AE
adverse event
AEMPS
Agency on Medicinal Products and Medical Devices (Spain)
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BID
twice a day
CLBP
chronic low back pain
CRF
case report form
CRA
Clinical Research Associate
CSA
clinical study agreement
CTA
clinical trial application
DAAAP
Division of Analgesia, Anesthetic, and Addiction Products
DEXA
dual energy x-ray absorptiometry
EC
ethics committee
EDP
exposure during pregnancy
E-DMC
External Dafety Monitoring Committee
ePRO
electronic patient reported outcome
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IND
investigational new drug application
Ig
immunoglobulin
IgG2
immunoglobulin G Type 2
IRB
institutional review board
IL
interleukin
INR
International Normalize Ratio
IUD
intrauterine device
IV
intravenous 
IWRS
interactive web response system
LFT
liver function test
LOCF
Last Observation Carried Forward
MHRA
Medicines and Healthcare products Regulatory Agency
(United Kingdom)
MRI
magnetic resonance imaging
NGF
nerve growth factor
NGFI
nerve growth factor inhibitor
NRS
numeric rating scale
NSAID
non-steroidal anti-inflammatory drug
NSC
Neuropathy Symptom and Change
OA
osteoarthritis


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PEI
Paul Ehrlich Institute (Germany)
PCD
primary completion date
PT
prothrombin time
RPOA
rapidly-progressive osteoarthritis
SAE
serious adverse event
SAPS
Self-Administered Patient Satisfaction Scale
SC
subcutaneous
SPADI
Shoulder Pain and Disability Index
SPONK
spontaneous osteonecrosis of the knee
SRSD
single reference safety document
TNFα
tumor necrosis factor alpha
trkA
tropomyosin receptor kinase A
ULN
upper limit of normal
US
United States
WOMAC
Western Ontario and McMaster University Osteoarthritis 
Index


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Appendix 4. Lifestyle Guidelines for Subjects from Sites in Sweden and the United 
Kingdom
All female subjects who are of childbearing potential and are sexually active and at risk for 
pregnancy, and who withdraw from Study A4091056, A4091057 A4091058, or other 
tanezumab study less than 16 weeks after the last dose of subcutaneous investigational 
product must agree to use one (1) method of highly effective contraception consistently and 
correctly until 112 days (16 weeks) after the last dose of subcutaneous investigational 
product.  The investigator or his/ or her designee, in consultation with the subject, will 
confirm the subject has selected the most appropriate form of contraception for the individual 
subject from the permitted list of contraception methods (see below), and instruct the subject
in its consistent and correct use.  Subjects need to affirm that they meet the criteria for correct 
use of the selected method of contraception.  The investigator or his/her designee will discuss 
with the subject the need to use highly effective contraception consistently and correctly 
according to the schedule of activities and document such conversation in the subject’s chart.  
In addition, the Investigator or his/ or her designee will instruct the subject to call 
immediately if the selected birth control methods are discontinued or if pregnancy is known 
or suspected in the subject.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception is allowed provided the subject 
remains on the same treatment throughout the entire study and has been using that 
hormonal contraceptive for an adequate period of time to ensure effectiveness.  
Acceptable methods include:

Combined (estrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation:

Oral

Intravaginal

Transdermal

Progestogen-only hormonal contraception associated with inhibition of 
ovulation1:

Oral

Injectable

Implantable


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2. Correctly placed intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS). 
3. Bilateral tubal occlusion.
4. Vasectomized partner provided that the partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.
5. Sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.
There are no contraception requirements for sexually active female subjects of childbearing 
potential who withdraw from Study A4091056, A4091057, A4091058 or other tanezumab 
study more than 16 weeks after the last dose of subcutaneous investigational product.
1.
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action is not acceptable as a highly effective method.
Source: Clinical Trial Facilitation Group. Recommendations related to contraception and 
pregnancy testing in clinical trials [Internet]. Germany: Heads of Medicines Agencies 
(HMA); 2014 [2014 Sep 15; cited 2015 Aug 12]. Available from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.

SAP_001.pdf: 
Protocol A4091064 (PF-04383119) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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PROTOCOL A4091064
A PHASE 3, MULTICENTER, LONG-TERM OBSERVATIONAL STUDY OF 
SUBJECTS FROM TANEZUMAB STUDIES WHO UNDERGO A TOTAL KNEE, 
HIP OR SHOULDER REPLACEMENT
STATISTICAL ANALYSIS PLAN 
(SAP)
Version:
4.0 (Final)
Author:
(GPD Statistics)
Date:
2nd July 2019
PPD


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TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Full Analysis Set .......................................................................................................7
5.2. ‘Per Protocol’ Analysis Set .......................................................................................7
5.3. Safety Analysis Set....................................................................................................7
5.4. Other Analysis Sets ...................................................................................................7
5.5. Treatment Misallocations..........................................................................................7
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Endpoints...................................................................................................................8
6.2. Other Endpoints.......................................................................................................12
6.2.1. PK Endpoints..............................................................................................12
6.2.2. PD Endpoints..............................................................................................12
6.2.3. Outcomes Research Endpoints ...................................................................12
6.3. Covariates................................................................................................................12
7. HANDLING OF MISSING VALUES ................................................................................12
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................12
8.1. Statistical Methods ..................................................................................................12
8.1.1. Analyses for Continuous Data....................................................................12
8.1.2. Analyses for Categorical Data....................................................................12
8.1.3. Analyses for Binary Endpoints...................................................................13
8.2. Statistical Analyses .................................................................................................13
8.2.1. Analysis of Endpoints.................................................................................13


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8.2.2. Summary of Analyses.................................................................................16
9. REFERENCES ....................................................................................................................19
10. APPENDICES ...................................................................................................................20
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................20
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................20
Appendix 2. UNBLINDING PLAN ........................................................................................21


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
This is the third amendment to the previously approved SAP (version 3.0 on 29Mar2019).    
Summary of changes of this amendment versus the previously amended SAP (version 2.0)
include:

Updated the analysis of additional or corrective procedure, post-surgical 
complications, AE special interest, adjudicated outcome, under Section 6 and 8.2.1,

Updated subgroup analysis (removed by age, gender, BMI, KL grade, number of joint 
of OA and added sub-population for subjects who had RPOA, Primary ON, SIF or 
NPOA for three endpoints) under Section 6.3, and Section 8.2.1.  The first group of 
subgroup analyses are recognized as less informative due to small N based on the 
discussion with clinical.  Subgroups were added for considering joint safety outcomes
of parent studies regardless of the number of subjects.

Updated summary of analysis based on the discussion with team under Section 8.2.2.
This is the second amendment to the previously approved SAP (version 2.0 on 19June2018).    
Summary of changes of this amendment versus the previously amended SAP (version 2.0)
include:

Clarified the status of patients from A4091059, A4091061 and A4091063 under 
Section 2.2,

Changed the name of clinical research organization name from “inVentiv" to
“Syneos” due to integration of the companies under Section 3,  

Changed the definition of analysis set from Full Analysis Set to Safety Analysis Set 
with considering endpoint characteristics under Section 5, and Section 8,

Updated preferred term of adverse events about the abnormal peripheral sensation,
and the sympathetic nervous system under Section 6.1,

Updated analysis methodology under Section 8,

Updated total joint replacement and adjudicated outcome under Section 8.1.3,

Added subpopulation summary table about RPOA (type 1 and type 2), RPOA (type 
1), RPOA (type 2), Primary ON, SIF and NPOA under Section 8.2.1, and removed all 
other subgroup analysis under Section 8.2.1 and 8.2.2,

Updated summary of analysis (Section 8.2.2) based on above section


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This is the first amendment to the previously approved SAP (version 1.0 on 01October2015). 
Summary of changes of this amendment versus the previously amended SAP (version 1.0)
include:

Amended the possibility of adverse events summarize of decreased sympathetic 
function under Section 8.2.1.  

Added to summarize for combined all osteoarthritis studies for our clarity under 
Section 8.  

Added the unblinding plan related to section 5 of A4091064 protocol under 
Appendix 2 of this document.  
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicised. 
2.1. Study Design
This is a Phase 3, multicenter, long-term observational study of subjects from tanezumab 
Study A4091056, A4091057 or A4091058 (regardless of treatment group) who undergo a 
total knee, hip or shoulder replacement during participation in the study (treatment period or 
safety follow-up period).  If while the subject is participating in this study (A4091064), the 
subject undergoes an additional total joint replacement surgery or the site becomes aware 
that an additional total joint replacement surgery has been scheduled for the subject, the 
subject will be requested to provide information on the additional total joint replacement 
surgery as well.  Finally, any subject with a qualifying total joint replacement after the last 
subject in the study completes the treatment period in studies A4091059, A4091061 or 
A4091063 may be followed in this study (A4091064).  However, due to change of the 
enrolment strategy, patients will not be enrolled from A4091061 and A4091063.  In addition, 
patients were not enrolled from A4091059.  The patients with TJR in these three studies will 
be summarized within each individual study or be listed if there are too few to summarize.
This study is designed with a total duration of subject follow-up of 24 weeks after the total 
joint replacement surgery. 
Following the surgery, the subject will be contacted monthly via telephone by study site 
personnel to ascertain whether the subject has experienced any adverse events and to record 
any concomitant analgesic medications the subject is taking as well as the reason for the 
medication use.  An assessment of the subject’s overall satisfaction with their total joint 
replacement (Interactive Web-Response System, IWRS), average pain in the replaced joint 
(IWRS), the subject’s level of function and activity in the replaced joint (IWRS) and physical 
rehabilitation activities (telephone interview) will be made at Weeks 4, 12 and 24.  At 
Weeks 12 and 24, subjects will be queried during the telephone interview as to whether any 
additional or corrective procedures related to the total joint replacement are planned. 


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All events of total knee, hip or shoulder replacement will be reviewed by the Joint Safety 
Adjudication Committee (Adjudication Committee) established for the tanezumab clinical 
program.  This Committee will adjudicate in an independent and blinded fashion if the event
is primary osteonecrosis, worsening OA (further sub-divided into rapidly progressive OA
[RPOA] type 1 or type 2, normal progression of OA or not enough information to distinguish
between RPOA and normal progression of OA), subchondral insufficiency fracture,
pathologic fracture, other (with diagnosis specified) or not enough information to specify a
diagnosis.
2.2. Study Objectives
Primary Objective:

To describe the post-operative outcome of subjects who underwent a total knee, hip, 
or shoulder replacement while participating in tanezumab Study A4091056, 
A4091057 or A4091058 (treatment period and safety follow-up period).
Secondary Objectives:

To compare the post-operative outcome for tanezumab 2.5 mg and 5 mg versus 
non-steroid anti-inflammatory drugs (NSAIDs) for subjects who underwent a total 
knee, hip, or shoulder replacement while participating in tanezumab Study 
A4091058.

To describe the post-operative outcome of subjects from the A4091059, A4091061 or 
A4091063 studies who underwent a total knee, hip, or shoulder replacement
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
The final analysis for this study will be performed after the database has been released.
The incidence of subjects with total joint replacements, and resulting adjudicated outcomes 
will be summarized throughout the tanezumab program.  This includes the parent studies of 
this protocol (A4091056, A4091057, and A4091058), this study itself, and other tanezumab 
studies (A4091059, A4091061, and A4091063).  These analyses will be produced for the 
Data Monitoring Committee (DMC) and will be unblinded to the DMC members.  These 
analyses will be produced by a separate unblinded group at Syneos who are separate from the 
corresponding study team at both Syneos and Pfizer. 
Information from this study will be blinded for the parent study treatment group until the 
parent study itself has been unblinded.
In all cases the adjudication of joint safety events is made in a blinded fashion by the 
adjudication committee.
Interim analyses of these data may be produced for inclusion in a regulatory submission.  In 
this case, a snap-shot of the database will be taken and stored.  If this interim analysis occurs, 
then all parent study databases would have been finalized and those studies unblinded, 
therefore it is not envisioned that subjects would be unblinded due to this interim analysis.


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4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There is no given sample size for this study, both for the overall number of subjects and for 
the number of subjects in any single (parent study) treatment group.  Data will be 
summarized overall and then by parent study and parent study treatment group.  Given the 
likely lack of statistical power for treatment comparisons, no inferential testing will be 
performed, and all summaries and analyses will be descriptive in nature.
4.2. Statistical Decision Rules
There will be no statistical inferential testing in this study.
5. ANALYSIS SETS
5.1. Full Analysis Set
Not Applicable.  
5.2. ‘Per Protocol’ Analysis Set 
There will be no per-protocol analysis set defined for this study.
5.3. Safety Analysis Set
The ‘Safety Analysis Set’ (SAS) is the analysis set for all analyses.  It consists of all treated 
subjects who enrolled in Study A4091064, and who have a qualifying total joint replacement
for Study A4091064.  This analysis set is used in the presentations of all data summaries and 
listings and is labeled as the ‘Safety Analysis Set’ or ‘SAS’.
5.4. Other Analysis Sets
No other analysis sets are defined.
5.5. Treatment Misallocations 
Parent study treatment allocation will be based on the actual treatment group received.  
Where a subject received an incorrect treatment (versus the planned treatment group as 
required by the randomisation procedure) then the subject will be allocated to a treatment 
group received where this matches a treatment group from that study or other studies, ie,
from the following list:

Placebo SC;

Tanezumab 2.5mg;

Tanezumab 2.5/5mg (tanezumab 2.5mg at Baseline and tanezumab 5mg at Week 8);

Tanezumab 5mg;

Tanezumab 10mg;

NSAID (with placebo SC);

Tramadol (with placebo SC).


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Where the subject’s actual treatment does not match one of the groups listed above, then the 
subject will be allocated to a treatment group based on the highest dose of tanezumab 
received (eg, if a subject received placebo SC at Baseline and tanezumab 5mg at Week 8 the 
subject would be allocated to the tanezumab 5mg group).
5.6. Protocol Deviations
Given this is an observational safety study and there is no per-protocol analysis set being 
used, then no deviations for the purpose of analyses will be defined.
5.6.1. Deviations Assessed Prior to Randomization
Not applicable.
5.6.2. Deviations Assessed Post-Randomization
Not applicable.
6. ENDPOINTS AND COVARIATES
6.1. Endpoints
Given the design of this study, the following endpoints are considered co-equal:

Surgeon’s Assessment of Procedural Difficulty: number and percentage of surgeries 
assessed as uneventful, minor complications or major complications.

Subject’s overall satisfaction with surgery as assessed by the Self-Administered 
Patient Satisfaction (SAPS) Scale: number and percentage of subjects satisfied vs. 
unsatisfied with their total joint replacement at Week 24.

Number and percentage of subjects with a post-surgical complication(s) up to 
Week 24 (derived from reported adverse events).

Number and percentage of subjects with additional or corrective procedures related 
to their total joint replacement up to Week 24.

Number and percentage of subjects participating in physical rehabilitation activities 
related to the replaced joint up to Week 24.

Change from Baseline to Week 24 in average pain in the replaced joint.

Change from Baseline to Week 24 in WOMAC Pain, Stiffness and Physical Function 
subscales in the replaced joint (subjects undergoing total hip or knee replacement 
surgery only).

Change from Baseline to Week 24 in the Shoulder Pain and Disability Index (SPADI)
in the replaced shoulder (subjects undergoing total shoulder replacement surgery 
only).


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
Concomitant analgesic medication use.
The WOMAC subscale scores of Pain, Stiffness and Physical Function are calculated as the 
mean of the 5, 2 and 17 items, respectively, from the WOMAC questionnaire.  Each item is 
scored on a 0-10 numerical rating scale (NRS), and so the WOMAC subscale scores 
themselves have a range of 0-10, with 0 being the best response.
The Average Pain in the replaced joint will be scored on a 0-10 NRS scale, where 0 is ‘no 
pain’ and 10 is the ‘worst possible pain’.
The Self-Administered Patient Satisfaction (SAPS) contains the following four questions:

How satisfied are you with the results of your surgery?

How satisfied are you with the results of your surgery for improving your pain?

How satisfied are you with the results of surgery for improving your ability to do 
home or yard work?

How satisfied are you with the results of surgery for improving your ability to do 
recreational activities?
Items are scored on a 4-point Likert scale with response categories consisting of ‘very 
satisfied’ (100 points), ‘somewhat satisfied’ (75 points), ‘somewhat dissatisfied’ (50 points), 
and ‘very dissatisfied’ (25 points).  The scale score is the unweighted mean of the scores 
from the individual items, ranging from 25 to 100 per item with higher scores indicating 
greater satisfaction.
The SPADI consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use.  The scores from both 
dimensions are averaged to derive a total score from 0 (best) to 100 (worst).  The pain 
dimension is calculated as the sum of non-missing scores divided by the maximum possible 
score (50 with no missing items) multiplied by 100.  The disability (function) dimension 
score is calculated as the sum of non-missing scores divided by the maximum possible score 
(80 with no missing items) multiplied by 100.  The dimension scores can be calculated with 
up to 2 missing items, however if there are >2 missing items from a dimension then that 
dimension cannot be scored, and is set to missing.  A SPADI total score will be calculated as 
the mean of the pain and disability (function) dimensions.
The Surgeon’s Assessment of Procedural Difficulty asks the question “Taking into 
consideration the subject’s medical history and physical condition prior to surgery would 
you classify the operative procedure as” with the following three possible outcome 
categories:

Uneventful;

Minor complications;

Major complications.


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In the case of any complications the surgeon is then asked to specify the complication.
At the Week 12 and 24 post-surgery telephone contacts, subjects will be queried for 
additional or corrective procedures related to the total joint replacement surgery.  
Specifically, subjects will be asked to respond yes or no to the following question:

Have you been told by your orthopedic surgeon that additional or corrective 
procedures (for example a revision or implant replacement) are necessary for your 
total joint replacement?
Subjects will be queried for details if the answer to the question is yes.
At the Week 4, 12 and 24 post-surgery telephone contacts, subjects will be queried for 
rehabilitation activities related to the replaced joint.  Specifically, subjects will be asked to 
respond yes or no to the following question:

Are you participating in physical rehabilitation activities related to your replaced 
joint?
Subjects will be queried for details if the answer to the question is yes.
The data relating to the endpoints of physical rehabilitation, or additional or corrective 
procedure, related to the replaced joint up to Week 24 will be derived from an ongoing 
clinical review of the concomitant non-drug treatment/procedure case report form (CRF) 
page.  This review will identify treatments that are relevant for these endpoints, and a log of 
such data will be maintained.  The data relating to the endpoint of concomitant analgesic 
medication use will be derived from an ongoing review of the concomitant analgesic drug 
CRF page.  These reviews will be made during the study and data will be finalized prior to 
the database release for this study. 
Events identified as the first symptom leading to total joint replacement will be reviewed and 
determined prior to the unblinding for the respective parent study.
The list of post-surgical complications will be derived from reported adverse events and will 
consist of complications that are clinically significant and attributable to the total 
arthroplasty procedure eg, periprosthetic joint infection/wound infection, periprosthetic 
fracture, pulmonary embolism or sepsis/septicemia/shock.  The list of post-surgical 
complications will be developed during Study A4091064 and finalized prior to Study 
A4091058 unblinding. Other adverse events may be identified as post-surgical complications 
after the unblinding of the Study A4091058 database.  These events will also be summarized 
as complications, and will be noted as having been included in the list after the unblinding of 
the Study A4091058 database.
Adverse Events which are “treatment emergent” in relation to the Baseline study day will be 
reported overall and by prior study treatment group.  Adverse events ongoing from the parent 
study will continue to be followed in this study.  They will not be included in incidence 
tables from this study unless the severity worsens.


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Groups of the adverse events of abnormal peripheral sensation, sympathetic nervous system 
and decreased sympathetic function are shown below.  These events will be evaluated from 
overall adverse events summaries if needed.
The preferred terms for adverse events of abnormal peripheral sensation are defined below. 
Allodynia
Neuralgia
Axonal neuropathy
Neuritis
Burning sensation
Neuropathy, peripheral
Decreased Vibratory Sense
Paraesthesia
Demyelinating polyneuropathy
Paraesthesia oral
Dysaesthesia
Peripheral sensorimotor neuropathy
Formication
Peripheral sensory neuropathy
Hyperaesthesia
Polyneuropathy
Hyperpathia
Polyneuropathy chronic
Hypoaesthesia
Sensory disturbance
Sensory loss
Hypoaesthesia oral
Thermohypoaesthesia
Intercostal neuralgia
Carpal tunnel syndrome
Sciatica
Tarsal tunnel syndrome
The preferred terms for adverse events of the sympathetic nervous system are defined below.
Abdominal discomfort
Micturition urgency
Anhidrosis
Nausea
Blood pressure orthostatic decreased
Nocturia
Bradycardia
Orthostatic hypotension
Diarrhea
Presyncope
Dizziness postural
Respiratory distress
Early satiety
Respiratory failure
Ejaculation delay
Sinus bradycardia
Ejaculation disorder
Syncope
Ejaculation failure
Urinary hesitation
Heart rate decreased
Urinary incontinence
Hypertonic bladder
Vomiting
Hypohidrosis
Anal incontinence
Pollakiuria
The preferred terms for adverse events of decreased sympathetic function are defined below.
Anhidrosis
Orthostatic hypotension
Bradycardia
Syncope
Hypohidrosis


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Case Report Forms are available in Study A4091064 to capture results from neurological 
consultations or sympathetic nervous system consultations.  If any such consultations occur, 
they will be reported overall and by prior study treatment group, as possible.
6.2. Other Endpoints
6.2.1. PK Endpoints 
There are no PK endpoints in this study.
6.2.2. PD Endpoints 
There are no PD endpoints in this study.
6.2.3. Outcomes Research Endpoints 
There are no Outcomes Research endpoints in this study.
6.3. Covariates 
There are no statistical models that will be fitted for the data in this study, and so there are no 
definitions of covariates.
Data will be summarized by parent study.  
7. HANDLING OF MISSING VALUES
Data will be reported based on observed findings.  No data will be imputed except as 
described next.  Where a Week 24 summary is shown, it will relate to observed data collected 
at the Week 24/Early Termination visit and within the Week 24 window defined in 
Appendix 1.1.  Additionally, data for the last observation carried forward (LOCF) will be 
presented for Week 24. This data can be thought of as a type of LOCF assessment, where the 
investigator has brought forward subject assessment from the point of early termination to 
the Week 24/Early Termination visit. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
8.1.1. Analyses for Continuous Data
Continuous endpoints will be summarized using the following statistics: number of subjects, 
arithmetic mean, standard deviation, median, minimum, and maximum values. These 
statistics will be shown by treatment group and overall.  
8.1.2. Analyses for Categorical Data 
Categorical data will be summarized by parent study and treatment group.


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8.1.3. Analyses for Binary Endpoints
The incidence of subjects with total joint replacement and specific adjudication outcomes 
(listed below) will be summarized for all combined osteoarthritis studies.  This incidence are
shown by treatment group (with a tanezumab combined group, and a total for that parent 
study).  The events to be analyzed are:

Total Joint Replacement.

Total Joint Replacement, with outcome adjudicated as:

Any of Rapidly Progressive Osteoarthritis (RPOA) type 1 or 2, Subchondral 
insufficiency fracture (SIF), Primary Osteonecrosis (ON), Pathological Fracture;

Any of RPOA type 2, SIF, Primary Osteonecrosis, Pathological Fracture;

RPOA type 1 or 2;

RPOA type 1;

RPOA type 2;

ON;

Pathological Fracture;

SIF;

Not enough information to determine rapid or Normal Progression of OA;

Normal Progression of OA;

Other Joint Outcome.
The analysis will show the number of subjects with the event, the number of subjects in the 
parent study treatment group (using the ‘Safety Analysis Set’), 
An overall summary of subjects with events (total joint replacement and then by adjudication 
outcome) for all combined osteoarthritis studies and by study will be shown, overall and by 
treatment group.  In addition, two types of summarization, subject level with primary
outcome and joint level, will be prepared for adjudicated outcome.  
8.2. Statistical Analyses 
8.2.1. Analysis of Endpoints
All subjects enrolled in the study who have a qualified total joint replacement will be 
included in the summary tables. In addition, three types of endpoints, the surgeon’s 
assessment of procedural difficulty, the subject’s overall satisfaction, and concomitant 


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nondrug treatment, will be summarized for subjects who were adjudicated with RPOA (type 
1 and 2), RPOA (type 1), RPOA (type 2), Primary ON, SIF, or NPOA. 
The events considered in the incidence of event summary are total joint replacement and total 
joint replacement with specific individual or grouped adjudication outcomes, as defined in 
Section 8.1.3.  
Unless otherwise stated, data from this study will be presented at Baseline and Weeks 4, 12, 
and 24 using observed data (no imputation for missing data), and at Week 24 using Last 
Observation Carried Forward (LOCF) for missing data.  Data will be shown at the 
timepoints specified and also using change from (pre-surgery) Baseline when Baseline data 
are available and where relevant.  Data will be shown overall, and split by treatment group.  
Data on surgical difficulty and outcomes, and subject safety data will be summarized by 
study (if needed), with an additional combined summary for the subjects from the 
osteoarthritis studies.
For the Surgeon’s Assessment of Procedural Difficulty, the number and percentage of 
subjects in each category (Uneventful, Minor complications, Major complications) will be 
presented.  Complications reported by the surgeon will be listed. 
For the subject’s overall satisfaction with surgery assessments (using the Self-Administered 
Patient Satisfaction scale, SAPS), the responses [score] for each category (Very Satisfied 
[100], Somewhat Satisfied [75], Somewhat Dissatisfied [50], Very Dissatisfied [25]) will be 
stratified by surgery type (hip, knee or shoulder) and summarized for each of the four items.  
The scale score is the unweighted mean of the scores from the individual items, ranging from 
25 to 100 per item with higher scores indicating greater satisfaction.  This total score (mean 
of the 4 items) will be summarized by surgery type (hip, knee or shoulder) and overall.  
Reponses to the question “How satisfied are you with the results of your surgery?” will also 
be stratified by surgery type (hip, knee or shoulder) and summarized as satisfied (very
satisfied and somewhat satisfied categories combined) and dissatisfied (somewhat 
dissatisfied and very dissatisfied categories combined).
The total satisfaction score will be summarized using the mean (with standard deviation), 
median, and minimum and maximum values.  These results will be shown by visit, with 
Week 24 (LOCF).
Similarly, the number and percentage of subjects who have required (i) additional or 
corrective procedures related to their total joint replacement and (ii) participating in 
physical rehabilitation activities related to their replaced joint will be presented.  For this
assessment, change from Baseline summary data are not relevant and will not be presented.  
This summary will be shown separately for total joint replacements of the hip, knee and 
shoulder, as well as shown overall.  These summaries will be shown for any post-surgery 
timepoint.  Average pain (NRS) in the replaced joint for all subjects, WOMAC Pain, Stiffness 
and Physical Function sub-scale scores for subjects who had total knee or hip replacement 
and SPADI Pain, Function and Total Score for subjects who had total shoulder replacement 
will be summarized (including change from Baseline summaries).


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In addition, the number and percent of subjects with specified post-surgical complications 
will be presented.  The list of post-surgical complications will be derived from reported 
adverse events and non-drug treatment/procedure.  It will consist of complications that are 
clinically significant and attributable to the total arthroplasty procedure eg, periprosthetic 
joint infection/wound infection, periprosthetic fracture, pulmonary embolism or 
sepsis/septicemia/shock.  The list of post-surgical complications will be developed during 
Study A4091064 and finalized prior to Study A4091058 unblinding. Other adverse events 
may be identified as post-surgical complications after the unblinding of the Study 
A4091058 database.  These events will also be summarized as complications, and will be 
noted as having been included in the list after the unblinding of the Study 
A4091058 database.
Adverse events and concomitant analgesic medications will be collected for each subject 
during the study according to the Schedule of Assessments.  Standard safety reporting tables 
will summarize and list these safety data.
Separate adverse event summaries by parent study treatment group for adverse events of 
abnormal peripheral sensation, and sympathetic nervous system will be presented. Adverse 
event summaries of decreased sympathetic function may be presented. 


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8.2.2. Summary of Analyses
Endpoint
Time points
Analysis 
Set
Statistical 
Method
Model/ 
Covariates/ 
Strata
Missing Data
Objective
Summary of total joint 
replacement (TJR) and 
adjudication outcomes (Joint 
Level)
Any time 
during parent 
study or 1064
SAS
None
N/A
Observed
Summary of frequency and the 
proportion
Summary of detail of 
adjudication outcomes (Joint 
Level)
Any time 
during parent 
study or 1064
SAS
None
N/A
Observed
Summary of frequency and the 
proportion
Summary of total joint 
replacement (TJR) and 
adjudication outcomes
(Subject Level)
Any time 
during parent 
study or 1064
SAS
None
N/A
Observed
Summary of frequency and the 
proportion
Summary of detail of 
adjudication outcomes
(Subject Level)
Any time 
during parent 
study or 1064
SAS
None
N/A
Observed
Summary of frequency and the 
proportion
Surgeon’s assessment of 
procedural difficulty by TJR 
joint and total (All OA parent 
studies)
Assessed after 
surgery
SAS
None
N/A
Observed
Summary of surgical outcome
Subject’s overall satisfaction 
with surgery by TJR joint and 
Total (All OA parent studies)
Week 4, 12, 
24
SAS
None
N/A
Observed
% and frequency of each category
Subject’s overall satisfaction 
with surgery by TJR joint and 
Total (All OA parent studies)
Week 4, 12, 
24 and 
24 (LOCF)
SAS
None
N/A
Observed (LOCF 
for Week 
24 (LOCF))
Summary of surgical outcome
Physical rehabilitation in 
relation to replaced joint by 
TJR joint and Total (All OA 
parent studies)
Any time 
post-surgery 
SAS
None
N/A
Observed
Summary of surgical outcome
Additional or corrective 
procedures relating to TJR by 
TJR joint and Total (All OA 
parent studies)
Any time 
post-surgery
SAS
None
N/A
Observed


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Endpoint
Time points
Analysis 
Set
Statistical 
Method
Model/ 
Covariates/ 
Strata
Missing Data
Objective
Average Pain in the joint to be 
replaced/replaced joint by 
visit and change from BL by 
TJR joint and Total (All OA 
parent studies) 
BL, Week 4, 
12, 24, 
24 (LOCF)
SAS
None
N/A
Observed (LOCF 
for Week 
24 (LOCF))
Summary of surgical outcome
WOMAC Pain, Physical 
Function and Stiffness 
subscales by visit and change 
from BL by TJR joint 
[Hip/Knee] and Total (All OA 
parent studies) 
BL, Week 4, 
12, 24, 
24 (LOCF)
SAS
None
N/A
Observed (LOCF 
for Week 
24 (LOCF))
Summary of surgical outcome
SPADI dimensions and total 
by visit and change from BL 
(All OA parent studies) 
BL, Week 4, 
12, 24, 
24 (LOCF)
SAS
None
N/A
Observed (LOCF 
for Week 
24 (LOCF))
Summary of surgical outcome
Post-surgical complications 
(All OA parent studies)
Any time 
post-surgery
SAS
None
N/A
Observed 
Concomitant analgesic 
medication use (All OA parent 
studies)
Any time 
post-surgery
SAS
None
N/A
Observed 
Summary of surgical outcome
Subpopulation summary of 
Surgeon's Assessment of 
Procedural Difficulty for 
subjects who had RPOA (type 
1 and type2), RPOA (type 1), 
RPOA (type 2), primary ON, 
SIF, or NPOA
BL, Week 4, 
12, 24, 
24 (LOCF)
SAS
None
N/A
Observed 
Subgroup presentation
Subpopulation summary of 
Subject’s Overall Satisfaction
for subjects who had RPOA 
(type 1 and type2), RPOA 
(type 1), RPOA (type 2), 
primary ON, SIF, or NPOA
BL, Week 4, 
12, 24, 
24 (LOCF)
SAS
None
N/A
Observed 
Subgroup presentation


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Endpoint
Time points
Analysis 
Set
Statistical 
Method
Model/ 
Covariates/ 
Strata
Missing Data
Objective
Subpopulation summary of 
concomitant nondrug 
treatment for subjects who had 
RPOA (type 1 and type2), 
RPOA (type 1), RPOA (type 
2), primary ON, SIF, or 
NPOA
Any time 
post-surgery
SAS
None
N/A
Observed 
Subgroup presentation
SAS: Safety analysis set for subjects with TJR and entered into 1064


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9. REFERENCES 
N/A.


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10. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. Definition and Use of Visit Windows in Reporting
Study visits/telephone contacts are planned at Baseline, Day of Surgery (Day 1, with 
assessments made by the surgeon within 10 days after the date of surgery), and Weeks 4, 8, 
12, 16, 20 and 24.  Information relating to the post-operative outcome measures is collected 
at Weeks 4, 12 and 24, and it is for these visits that windows will be defined.  If a subject 
discontinues from the trial then the Week 24/Early termination visit assessments will be 
completed.
When multiple observations occur in a visit window, the observation closest to the protocol 
specified target day will be used, noting that the latter will be used in the case of a tie.
Visit
Target Study Day
Window
Baseline
Variable
[No lower limit, Day -1]
Day of Surgery
1
N/A
Week 4
29
[2,57]
Week 12
85
[58,127]
Week 24
169
[128, No upper limit]


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Appendix 2. UNBLINDING PLAN
1. Introduction
The A4091064 is the long-term observational study without dosing to follow up subjects who 
undergo total joint replacement (TJR) of knee, hip or shoulder from one of parent studies 
(A4091056, A4091057, or A4091058) or sub-studies (A4091059, A4091061, or A4091063), 
and one of the secondary objectives is to compare the post-operative outcomes for tanezumab 
2.5mg and 5 mg versus NSAIDs for subjects who underwent a TJR in A4091058.
The purpose of this unblinding plan is to describe who can access to the unblinding 
information of parent phase 3 studies (and sub-studies) while A4091064 is ongoing and the 
rationale.  The goal is to maintain the double blind (subjects and investigator) at any study 
sites and among operational colleagues interacting with site directly about patient data in 
order to minimize the potential to introduce bias for comparison of the post-operative
outcomes.  
2. Rationale for Unblinding of Parent Phase 3 Studies to A4091064 Study Team Members
The rationale for the appropriateness of this approach for unblinding includes the following:

Major endpoints to evaluate TJR follow-up of A4091064 are based on patient and/or 
surgeon reported outcomes, and an investigator or Pfizer study team will not evaluate 
them.   

All endpoints of A4091064 will be summarized descriptively and there is no formal 
hypothesis testing.

A4091064 is a study being incorporated into the data package for regulatory 
submission.  Pfizer team needs to evaluate TJR based on the data of both A4091064 
and these parent studies (and sub-studies) simultaneously with considering these
relationships by representatives who are familiar with these studies.     

No changes will be made to A4091064 study designs, conduct, or analysis based on 
the parent phase 3 studies unless the program is terminated or otherwise modified for 
safety findings, in which case, the changes would be reflected in a protocol 
amendment.
3. Unblinding Prior to Database Release of any Parent Phase 3 Studies
The phase 3 program is using a safety monitoring committee (SMC), which will have access 
to unblinded data throughout the parent phase 3 studies for the monitoring of subject safety.  
A separate SMC charter specifies the role and responsibilities of the SMC and the contact 
individuals within the Pfizer’s organization and the SMC responsible for communication 
between these organizations.  


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4. At or after Database Release of any Parent Phase 3 Studies
This section describes who remains blind and who will become unblinded at or after database 
release of any parent phase 3 studies for A4091064 evaluation.  The process of unblinding 
follows the following standard of procedure: 

Pfizer: DMB08 (Study Data Set Review, Release, and Archive)
4.1 Unblinded at or after Database Release
Following database release for phase 3 parent studies, unblinding of each parent study (and 
sub-studies) will occur at the individual subject level as well as at the summary (ie, treatment 
group) level to the A4091064 team members who are NOT defined as colleagues who remain 
blind in the section 4.2.  
4.2 Blinded until Database Release of final phase 3 study
At the time of database release/unblinding for reporting of each parent study, 
Pfizer/Syneos/EPS roles of A4091064 study in below lists are to remain blinded of individual
subject level in order to maintain the integrity of the blinding to subjects and investigators;

Pfizer: Clinician interacting with site directly for TJR evaluation, and regional clinical 
site lead (RCSL);

Syneos/EPS(Japan Local CRO): Clinical research associate, monitoring lead, CTA, 
and CMPL.
An investigator site (investigators, and all other site staff) participating in A4091064 is to 
remain blinded to individual subject treatment assignment until all subjects in the site will be 
finished A4091064 and until all data for these subjects will be cleaned. 
Pfizer SOPs CT20 (Public Disclosure of Pfizer Clinical Study Data and Authorship) and 
DMB10 (Clinical Study Report) require unblinded results to be provided to study sites after 
the trial has completed.  Some amendment/deviation may be applied to delay sending results 
from the parent studies or sub-studies until a site has completed participation of all subjects 
in the site of A4091064.
Selected investigators may be required to review an interim CSR for A4091064 in order to 
sign the Investigator’s Declaration.  In order to minimize any potential bias after unblinding 
of any parent study, an investigator will be selected who would not have any on-going 
A4091064 subjects at the time of the investigator’s review of an interim A4091064 CSR.  
It is also recognized that unblinded summary results may become publicly known through 
press release, presentations at scientific conference, publication and so on.