A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF THE SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN SUBJECTS WITH OSTEOARTHRITIS OF THE HIP OR KNEE
Phase: PHASE3
Conditions: Osteoarthritis, Hip, Osteoarthritis, Knee
Sponsor: Pfizer

Tanezumab (PF-04383119)
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CLINICAL PROTOCOL
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF THE
SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN SUBJECTS WITH 
OSTEOARTHRITIS OF THE HIP OR KNEE
Compound:
PF-04383119
Compound Name:
Tanezumab
United States (US) Investigational New 
Drug (IND) Number:
BB-IND 11,680
European Clinical Trial Database 
(EudraCT) Number:
2013-004508-21
Protocol Number:
A4091057
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
Original protocol
25 August 2015
Not Applicable (N/A)
Amendment 1
13 November 2015
Section 1.2.7. This section on 
Benefit-Risk Assessment was 
added.
Sections 4.1, 4.2, 4.4 and 
6.1.1. The text was revised 
concerning contraception.
Section 5.2. Details for 
unblinding with an electronic 
system and a back-up 
procedure added.
Section 5.7.1 and Appendix 
3. The routes of NSAID 
administration were clarified. 
Details on the use of 
glucosamine sulfate and 
chondroitin sulfate, and 
duloxetine were add.
Sections 5.8 and 6.1.2. 
Rescue medication was 
modified.
Section 12.1. Wording for 
approval needed from the 
national competent authority 
before implementing a 
substantial amendment is 
added.
Section 13.1. The section 
amended to specify that the
end of the trial will be last 
patient last visit.
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Amendment 2 Sweden and 
France country-specific 
10 February 2016
For Sweden: 
Sections 4.1, 4.2, 4.4, 6.1.1
and Appendix 14. Additional 
text was added for Sweden
concerning contraception.
Section 12.2. Additional text 
was added for Sweden 
concerning the Declaration 
of Helsinki.
For France: 
Appendix 15 for contrat 
unique for study sites located 
in France.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
LIST OF FIGURES .................................................................................................................10
APPENDICES .........................................................................................................................10
1. INTRODUCTION ...............................................................................................................26
1.1. Mechanism of Action/Indication.............................................................................26
1.2. Background and Rationale ......................................................................................26
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain...........................26
1.2.2. Description of Investigational Product .......................................................26
1.2.3. Overview of Clinical Studies......................................................................26
1.2.3.1. Overview of Efficacy in Osteoarthritis Clinical Studies...........27
1.2.3.2. Overview of Safety in Clinical Studies.....................................27
1.2.3.3. Subcutaneous Administration of Tanezumab in Clinical 
Studies ...............................................................................................30
1.2.4. Dose Selection Rationale............................................................................30
1.2.5. Rationale for Placebo Treatment ................................................................30
1.2.6. Subject Population Selection Rationale......................................................31
1.2.7. Benefit-Risk Assessment............................................................................31
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................32
2.1. Objectives................................................................................................................32
PRIMARY OBJECTIVE.........................................................................................................32
SECONDARY OBJECTIVE...................................................................................................32
2.2. Endpoints.................................................................................................................32
2.2.1. Co-primary Efficacy Endpoints:.................................................................32
2.2.2. Secondary Endpoints ..................................................................................33
2.2.2.1. Efficacy Measures.....................................................................33
2.2.2.2. Safety Measures ........................................................................34
2.2.3. Tertiary Endpoints ......................................................................................34
2.2.3.1. Pharmacokinetic and Pharmacodynamic ..................................34
3. STUDY DESIGN.................................................................................................................35
4. SUBJECT SELECTION......................................................................................................36
4.1. Inclusion Criteria.....................................................................................................36
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4.2. Exclusion Criteria....................................................................................................38
4.3. Randomization Criteria ...........................................................................................42
4.4. Life Style Guidelines...............................................................................................42
4.5. Sponsor Qualified Medical Personnel.....................................................................43
5. STUDY TREATMENTS.....................................................................................................44
5.1. Allocation to Treatment ..........................................................................................44
5.2. Breaking the Blind ..................................................................................................45
5.3. Compliance..............................................................................................................45
5.4. Investigational Product Supplies.............................................................................46
5.4.1. Dosage Form(s) and Packaging..................................................................46
5.4.1.1. Tanezumab ................................................................................46
5.4.1.2. Placebo for Tanezumab.............................................................46
5.4.1.3. Acetaminophen/Paracetamol (Rescue Medication) ..................46
5.4.2. Preparation and Dispensing........................................................................46
5.4.3. Administration............................................................................................46
5.5. Investigational Product Storage ..............................................................................47
5.6. Investigational Product Accountability...................................................................47
5.6.1. Destruction of Investigational Product Supplies ........................................47
5.7. Concomitant Treatment(s).......................................................................................48
5.7.1. Prohibited Treatment(s)..............................................................................48
5.7.2. Permitted Treatments..................................................................................49
5.8. Rescue Therapy.......................................................................................................50
6. STUDY PROCEDURES .....................................................................................................51
6.1. Screening.................................................................................................................52
6.1.1. Screening Period:........................................................................................53
6.1.2. Washout Period...........................................................................................55
6.1.3. Initial Pain Assessment Period (IPAP).......................................................56
6.2. Double-Blind Treatment Period..............................................................................56
6.2.1. Baseline (Day 1) Clinic Visit......................................................................56
6.2.1.1. Assessment of Randomization Criteria and 
Randomization...................................................................................56
6.2.1.2. Randomization ..........................................................................57
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6.2.1.3. Pre-dosing (Day 1) ....................................................................57
6.2.1.4. Dosing (Day 1)..........................................................................58
6.2.1.5. Post-dosing (Day 1)...................................................................58
6.2.2. Routine Clinic Visits (Week 2, Week 4 and Week 12)..............................58
6.2.3. Dosing Visits (Week 8 and Week 16) ........................................................59
6.2.4. Phone Contact Visit (Week 20)..................................................................59
6.2.5. Week 24 Clinic Visit (End of Double-Blind Treatment)............................59
6.3. Safety Follow-up Period..........................................................................................59
6.3.1. Phone Contact Visits (Weeks 28, 36, 40 and 44) .......................................59
6.3.2. Routine Clinic Visit (Week 32)..................................................................60
6.3.3. Week 48 Clinic Visit (End of Study)..........................................................60
6.4. Subject Withdrawal / Early Termination ................................................................60
6.4.1. Early Termination Follow-Up Procedures..................................................62
6.4.1.1. Early Termination Visit 1 (~8 weeks after last dose of SC 
investigational product).....................................................................62
6.4.1.2. Early Termination Telephone Contacts 1 and 2 (~12 
weeks and ~20 weeks after last dose of SC investigational 
product)..............................................................................................62
6.4.1.3. Early Termination Visit 2 (~16 weeks after last dose of 
SC investigational product) ...............................................................63
6.4.1.4. Early Termination Follow-up Visit 3 (~24 weeks after last 
dose of SC investigational product) ..................................................63
6.4.2. Procedures for Subjects Undergoing Joint Replacement............................63
7. ASSESSMENTS..................................................................................................................64
7.1. Subject Diary Assessments .....................................................................................64
7.1.1. Daily / Weekly Pain Assessments ..............................................................64
7.1.2. Rescue Medication and Amount.................................................................65
7.1.3. Concomitant NSAID Use ...........................................................................65
7.2. Study Visit Efficacy Assessments...........................................................................66
7.2.1. Western Ontario and McMaster Universities Osteoarthritis Index ............66
7.2.1.1. WOMAC Pain Subscale............................................................66
7.2.1.2. WOMAC Physical Function Subscale ......................................66
7.2.1.3. WOMAC Stiffness Subscale.....................................................66
7.2.2. Patient’s Global Assessment of Osteoarthritis ...........................................67
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7.2.3. Work Productivity and Activity Impairment Questionnaire -
Osteoarthritis – Knee or Hip v2.0 (WPAI:OA)................................................67
7.2.4. EuroQol 5 Dimension (EQ-5D-5L)............................................................67
7.2.5. Patient Reported Treatment Impact Assessment-modified (mPRTI).........67
7.2.6. Assessment of Health Care Resource Utilization of Healthcare 
Resources Assessment .....................................................................................68
7.3. Safety Assessments .................................................................................................68
7.3.1. Physical Examination .................................................................................68
7.3.1.1. General Physical Examination ..................................................68
7.3.1.2. Musculoskeletal History and Physical Examination.................68
7.3.2. Laboratory Safety Assessments..................................................................69
7.3.2.1. Blood Tests................................................................................69
7.3.2.2. Urinalysis and Urine Toxicology Screen ..................................69
7.3.2.3. Pregnancy Tests.........................................................................70
7.3.2.4. Serum FSH Testing ...................................................................70
7.3.3. Assessment of Pain in Major Joints at Screening with Numeric Pain 
Scale Rating (NRS)..........................................................................................71
7.3.4. Vital Signs ..................................................................................................71
7.3.4.1. Orthostatic Blood Pressure Measurement.................................71
7.3.5. 12-Lead Electrocardiogram ........................................................................72
7.3.6. Survey of Autonomic Symptoms (SAS).....................................................73
7.3.7. Radiographic Assessments .........................................................................73
7.3.7.1. Radiation Exposure ...................................................................74
7.3.8. Neurologic Examination.............................................................................75
7.3.9. Anti-Drug Antibody Testing.......................................................................76
7.4. Triggered Requirements and Subject-Level Stopping Rules ..................................76
7.4.1. Dysesthesia/Allodynia ................................................................................76
7.4.2. Hypersensitivity or Injection Site Reactions ..............................................76
7.4.3. Orthostatic Hypotension and Sympathetic Function Adverse Events........76
7.4.4. Evaluation and Follow-up for Increased, Severe Persistent Joint Pain ......79
7.4.5. Central Reader and Subject-Level Stopping Criteria for Joint Safety 
Events...............................................................................................................80
7.4.6. Procedures for Subjects Undergoing Joint Replacement............................80
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7.5. Pharmacokinetic (PK) and Pharmacodynamic (PD)...............................................80
7.5.1. Plasma for Analysis of Tanezumab ............................................................80
7.5.2. Nerve Growth Factor (NGF) for Pharmacodynamic Analyses ..................81
7.6. Biomarkers ..............................................................................................................81
7.6.1. Serum Biomarkers ......................................................................................81
7.6.2. Urine Biomarkers........................................................................................82
7.7. Banked Biospecimens .............................................................................................82
7.7.1. Markers of Drug Response.........................................................................82
7.7.2. Additional Research....................................................................................83
8. ADVERSE EVENT REPORTING......................................................................................84
8.1. Adverse Events........................................................................................................84
8.2. Reporting Period .....................................................................................................84
8.3. Definition of an Adverse Event...............................................................................85
8.4. Medication Errors....................................................................................................85
8.5. Abnormal Test Findings..........................................................................................86
8.6. Serious Adverse Events...........................................................................................86
8.6.1. Protocol-Specified Serious Adverse Events...............................................87
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................87
8.7. Hospitalization ........................................................................................................88
8.8. Severity Assessment................................................................................................90
8.9. Causality Assessment..............................................................................................90
8.10. Exposure During Pregnancy..................................................................................90
8.10.1. Additional Postnatal Development Follow-up .........................................92
8.11. Occupational Exposure .........................................................................................92
8.12. Withdrawal Due to Adverse Events (See Also Section 6.4. Subject 
Withdrawal)...............................................................................................................92
8.13. Eliciting Adverse Event Information ....................................................................92
8.14. Reporting Requirements........................................................................................92
8.14.1. Serious Adverse Event Reporting Requirements .....................................92
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................93
8.14.3. Medical Device Reporting Requirements.................................................93
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ................93
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9. DATA ANALYSIS/STATISTICAL METHODS...............................................................94
9.1. Sample Size Determination.....................................................................................94
9.2. Efficacy Analysis ....................................................................................................94
9.2.1. Analysis of Primary Endpoint ....................................................................94
9.2.2. Analysis of Secondary Endpoints...............................................................95
9.3. Safety Analysis........................................................................................................97
9.3.1. Anti-Tanezumab Antibodies (ADA) ..........................................................99
9.4. Analysis of Other Endpoints ...................................................................................99
9.5. External Adjudication Committee...........................................................................99
9.6. Data Monitoring Committee .................................................................................100
9.6.1. Protocol-Level Rules for Dosing Suspension/Safety Assessment............100
9.6.1.1. Serious Adverse Events...........................................................100
9.6.1.2. Events consistent with Hy’s Law............................................102
9.6.2. Joint Safety Events ...................................................................................102
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................103
11. DATA HANDLING AND RECORD KEEPING ...........................................................103
11.1. Case Report Forms/Electronic Data Record .......................................................103
11.2. Record Retention.................................................................................................104
12. ETHICS............................................................................................................................104
12.1. Institutional Review Board / Ethics Committee..................................................104
12.2. Ethical Conduct of the Study ..............................................................................105
12.3. Subject Information and Consent........................................................................105
12.4. Subject Recruitment ............................................................................................106
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................106
13. DEFINITION OF END OF TRIAL.................................................................................106
13.1. End of Trial in a Member State...........................................................................106
13.2. End of Trial in all other Participating Countries.................................................107
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................107
15. PUBLICATION OF STUDY RESULTS........................................................................107
15.1. Communication of Results by Pfizer ..................................................................107
15.2. Publications by Investigators ..............................................................................108
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16. REFERENCES ................................................................................................................109
LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES ............................................................................16
Table 2.
EARLY TERMINATION SCHEDULE OF EVENTS........................................23
Table 3.      ADVERSE DRUG REACTIONS IN ALL SUBJECTS RECEIVING 
TANEZUMAB .....................................................................................................27
Table 4.      ORTHOSTATIC BLOOD PRESSURE CHANGES AND SUSJECT 
MANAGEMENT .................................................................................................72
LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................35
Figure 2.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events...............78
APPENDICES
Appendix 1. American College of Rheumatology (ACR) Classification Criteria for 
Osteoarthritis.......................................................................................................112
Appendix 2. American Society of Anesthesiologists (ASA) Physical Status 
Classification ......................................................................................................113
Appendix 3. Half-Lives of Prohibited Prior and Concomitant Medications .........................114
Appendix 4. Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) NRS3.1 V5 US................................................................................118
Appendix 5. Patient’s Global Assessment of Osteoarthritis..................................................124
Appendix 6. Work Productivity and Activity Impairment Questionnaire: Osteoarthritis 
of the Knee or Hip V2.0 (WPAI:OA).................................................................125
Appendix 7. EuroQol 5 Dimension (EQ-5D-5L) ..................................................................127
Appendix 8. Neuropathy Impairment Score (NIS) Sample...................................................129
Appendix 9. Patient Health Questionnaire (PHQ-9)..............................................................130
Appendix 10. Adjudication Categories..................................................................................131
Appendix 11. Survey of Autonomic Symptoms (SAS)22 ......................................................132
Appendix 12. Patient Reported Treatment Impact Assessment-Modified (mPRTI).............133
Appendix 13. Abbreviations..................................................................................................134
Appendix 14. Lifestyle Guidelines for Subjects from Sites in Sweden.................................138
Appendix 15. France Appendix.............................................................................................140
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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.1
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.
The primary objective of this study is to demonstrate superior efficacy of tanezumab 5 mg 
and 2.5 mg administered subcutaneously (SC) every 8 weeks versus placebo at Week 24 in 
subjects with osteoarthritis of the knee or hip. The 2.5 mg dose was shown to provide 
efficacy benefits with a favorable safety profile when administered intravenously in previous 
Phase 3 clinical trials. The 5 mg dose is expected to provide added efficacy benefit over the 
2.5 mg dose based on data from previous studies.  
OBJECTIVES AND ENDPOINTS
Primary Objective
•
Demonstrate superior efficacy of tanezumab 5 mg and 2.5 mg administered 
subcutaneously (SC) every 8 weeks versus placebo at Week 24.
SECONDARY OBJECTIVE
•
Evaluate the safety of tanezumab 2.5 mg SC and 5 mg SC.
PRIMARY ENDPOINTS
The co-primary efficacy endpoints are:
•
Change from Baseline to Week 24 in the Western Ontario and McMaster University 
Osteoarthritis Index (WOMAC) Pain subscale;
•
Change from Baseline to Week 24 in the WOMAC Physical Function subscale;
•
Change from Baseline to Week 24 in the Patient’s Global Assessment of Osteoarthritis.
SECONDARY ENDPOINTS
Efficacy Measures
•
WOMAC Pain subscale change from Baseline to Weeks 2, 4, 8, 12, 16, and 32.
•
WOMAC Physical Function subscale change from Baseline to Weeks 2, 4, 8, 12, 16, and 
32.
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•
Patient’s Global Assessment of Osteoarthritis (5 point Likert scale) change from Baseline 
to Weeks 2, 4, 8, 12, 16, and 32.
•
Outcome Measures in Rheumatology – Osteoarthritis Research Society Initiative
(OMERACT-OARSI) responder index at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Cumulative distribution of percent change from Baseline in the WOMAC Pain subscale 
score to Week 16 and 24 (endpoint for summary only).
•
Treatment Response:  Reduction in the WOMAC Pain subscale of ≥30%, ≥50%,  ≥70% 
and ≥90%, at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Treatment Response: Reduction in the WOMAC Physical Function subscale of ≥30%, 
≥50%, ≥70% and ≥90% at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Cumulative distribution of percent change from Baseline in the WOMAC Physical 
Function subscale score to Week 16 and 24 (endpoint for summary only).
•
Treatment Response:  Improvement of ≥2 points in Patient’s Global Assessment of 
Osteoarthritis at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Average pain score in the index knee or hip change from Baseline to Weeks 1, 2, 3, 4, 6, 
8, 10, 12, 16, 20, 24, 28 and 32.
•
WOMAC Stiffness subscale change from Baseline to Weeks 2, 4, 8, 12, 16, 24 and 32.
•
WOMAC Average score change from Baseline to Weeks 2, 4, 8, 12, 16, 24, and 32.
•
WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface, change from 
Baseline to Weeks 2, 4, 8, 12, 16, 24, and 32.
•
WOMAC Pain Subscale Item: Pain When Going Up or Downstairs, change from 
Baseline to Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) 
impairment scores change from Baseline to Weeks 8, 16 and 24.
•
EQ-5D-5L Health State Utility and Five Items (Mobility; Self-Care; Usual Activities; 
Pain/Discomfort; Anxiety/Depression) change from Baseline to Weeks 8, 16 and 24.
•
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 24.
•
Health Care Resource Utilization at Baseline, and Weeks 32 and 48.
•
Incidence and time to discontinuation due to Lack of Efficacy.
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•
Usage of rescue medication (incidence and number of days of use) during Weeks 2, 4, 8, 
12, 16, 24, and 32.
•
Usage of rescue medication (amount taken) during Weeks 2, 4, 8, 12, 16 and 24.
Safety Measures
•
Adverse Events.
•
Standard safety assessments (safety laboratory testing [chemistry, hematology], sitting 
vital signs, electrocardiogram (ECG; 12-lead).
•
Joint Safety Adjudication outcomes.
•
Total joint replacements.
•
Orthostatic (supine / standing) blood pressure assessments.
•
Survey of Autonomic Symptom scores.
•
Neurologic exam (Neuropathy Impairment Score [NIS]).
•
Anti-tanezumab antibody assessments.
•
Physical examinations.  
Tertiary Endpoints
Pharmacokinetic and Pharmacodynamic
•
Plasma tanezumab concentrations. 
•
Serum NGF concentrations.
•
Serum and urine osteoarthritis biomarker concentrations.
STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-group multicenter 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 1 of 3 treatment groups in a 1:1:1 ratio (ie, 270/group).  
Subjects will receive three SC injections of one of the following treatments at an 8-week 
interval:
1. tanezumab 2.5 mg;
2. tanezumab 5 mg;
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3. Placebo to match tanezumab.  
The study is designed with a total post-randomization duration of 48 weeks and will consist 
of three periods: Screening (up to 37 days), Double-blind Treatment (24 weeks) and Safety
Follow-up (24 weeks).  The Screening period (beginning up to 37 days prior to 
Randomization) includes a Washout Period (lasting a minimum of 2 days), if required, and
an Initial Pain Assessment Period (the 7 days prior to Baseline [Day 1]).  
STATISTICAL METHODS
Sample Size Determination
A sample size of 270 subjects per treatment group is needed to provide approximately 80% 
power to achieve statistical significance (at the 5% two-sided level) for the two comparisons 
of tanezumab 2.5 and 5 mg SC versus placebo, over all three co-primary endpoints.  The total 
sample size will be approximately 810 subjects.
PRIMARY ANALYSIS
The co-primary efficacy endpoints will be analyzed using an analysis of covariance
(ANCOVA) model, with model terms for Baseline score, Baseline Diary Average Pain,
index joint (knee or hip), highest Kellgren-Lawrence grade, and treatment group, and study 
site as a random effect.  The assessment of significance for the tanezumab SC versus placebo 
treatment contrasts will use a step-down testing strategy within each of the co-primary 
efficacy endpoints defined as first testing tanezumab 5 mg versus placebo, and if statistically 
significant (p≤0.05) to then test tanezumab 2.5 mg versus placebo.  Finally, a tanezumab 
treatment group is declared as superior to placebo if the corresponding treatment contrast is 
significant over all three co-primary endpoints.  This testing procedure will maintain the 
Type I error to 5% or less within each of the co-primary efficacy endpoints, and to less than 
5% for all three co-primary efficacy endpoints.  An additional (main effects ANCOVA) 
analysis for each of the co-primary efficacy endpoints will use a per-protocol analysis set,
which will exclude subjects who are major protocol deviators.
The primary analysis of the co-primary endpoints will use multiple imputations for missing 
data, to account for uncertainty around the subject response.  The basis for imputing missing 
values will be dependent on the reasons for missing data.  For subjects with missing data due 
to discontinuation prior to Week 24 for lack of efficacy or for an adverse event or death, 
imputation will be based on sampling from a normal distribution using a mean value equal to
the subject’s Baseline efficacy value and the standard deviation (over all treatment groups) of 
the observed efficacy data at Week 24.  For subjects with missing data for any other reason, 
imputation will be based on sampling from a normal distribution using a mean value equal to
the subject’s last observed efficacy value and standard deviation (over all treatment groups) 
of the observed efficacy data at Week 24.  One hundred imputation samples will be used, and 
the ANCOVA model described above will be used for each imputation dataset.  The final 
results will be calculated using the combined sets of results from each imputation dataset 
analysis.2
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DATA MONITORING COMMITTEE
An independent, external Data Monitoring Committee (E-DMC) has been 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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Table 1.
SCHEDULE OF ACTIVITIES
The Schedule of Activities table 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.
Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
Informed Consent
X
Inclusion/Exclusion Criteria 
X
X
General and Musculoskeletal 
Specific Medical History and 
Prior/Current Medication 
Used
X
Primary Diagnosis/ 
Demographics
X
Weight/Height/BMI/Smoking 
Status/Female Hormonal 
Status/Alcohol Use
X
Xe
General Physical Examination
X
X
Musculoskeletal Assessmentf
X
X
X
X
X
X
X
X
X
X
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Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
Radiograph Assessment of 
Hips, Knees and Shoulders  
X
X
X
Neurologic Exam Neuropathy 
Impairment Score (NIS)g
X
X
X
X
X
X
X
X
X
X
Sitting Vital Signs ( BP, HR), 
and orthostatic BP testing
X
X
X
X
X
X
X
X
X
X
Survey of Autonomic Symptoms 
(SAS) questionnairel
X
X
Electrocardiogram (ECG 
12-lead)
X
X
X
Laboratory
Hepatitis Screen (Hepatitis B 
& Hepatitis C); HIV test, 
Urine Toxicology screen
X
Hemoglobin A1c
X
Serum FSH Testh
X
Serum/Urine Pregnancy 
Testp
X
X
X
X
X
X
Hematology
X
X
X
X
Blood Chemistry
X
X
X
X
Urinalysis
X
Serum and Plasma 
Retention Samples
X
X
X
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Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
Plasma Pharmacokinetic 
samplei
X
X
X
X
X
X
Serum NGFi
X
X
X
X
X
Serum Anti-Drug Antibodyi
X
X
X
X
X
X
Serum and Urine Biomarkersj
X
X
Banked biospecimen 
(whole blood)
X
Washout
Discontinue Current Pain 
Medication
X
Subject Daily/Weekly Assessments (IRT)k
Numeric Pain Scale Rating
(X)
(X)
…....Daily Entries for Index Joint and Weekly For Non-index Joints……
Weekly Entries for Index and Non-index 
Joints
Rescue Medication Use
(X)
(X)
……….……..…….Daily entries….………………………
Weekly entries
Concomitant NSAID Use
Weekly Entries
Randomization
X
Study Treatment
SC Investigational Product
X
X
X
Subject Reported Assessments Completed at Study Visitsl
WOMAC Pain Subscale
X
X
X
X
X
X
X
X
X
WOMAC Physical 
Function and Stiffness 
Subscales
X
X
X
X
X
X
X
X
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Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
Patient Global Assessment 
of Osteoarthritis
X
X
X
X
X
X
X
X
WPAI:OA
X
X
X
X
EQ-5D-5L
X
X
X
X
mPRTI
X
X
Health Care Resource 
Utilization Assessment
(HCRU)
X
X
X
Other Assessments/Procedures Conducted at Study Visits
Adverse event assessment
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
review
X
X
X
X
X
X
X
X
X
X
X
Review compliance with 
subject IRT entryq
X
X
X
X
X
X
X
X
X
X
X
Rescue medication 
return/compliancem
X
X
X
X
X
X
X
X
Dispense rescue
medication
X
X
X
X
X
X
X
X
Assign standard of care 
treatment as neededn
X
Female Subjects of 
Childbearing Potential 
Reminded of Contraceptive 
Requirementss
X
X
X
X
X
X
X
X
X
X
X
X
X
(Week 28 
only)
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Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
Abbreviations: BP = Blood Pressure; ECG = electrocardiogram; HR = Heart Rate; HCRU = Health Care Resource Utilization; EC = ethics committee; EQ-5D-5L = EuroQol 5 Dimension; 
IRT = Interactive Response Technology;  mPRTI = Patient Reported Treatment Impact assessment-modified; NGF = Nerve Growth Factor; NIS = Neuropathy Impairment Score; 
NSAID = Non-Steroidal Anti-Inflammatory Drug; PD = Pharmacodynamics; SAS = Survey of Autonomic Symptoms; WPAI: OA = Work Productivity and Activity Impairment 
Questionnaire: Osteoarthritis; BMI = Body Mass Index; HIV = Human Immunodeficiency Virus; FSH = Follicle-Stimulating Hormone; SC = Sub-Cutaneous; WOMAC = Western Ontario 
and McMaster University Osteoarthritis Index.
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Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
a.      Day relative to start of study treatment (Day 1).
b.    The Screening period begins up to a maximum of 37 days prior to randomization. Prior to entering the IPAP, subjects must washout from prohibited pain medications for at least 
5 half-lives or 48 hrs (whichever is greater).  During the IPAP, diary entries (joint pain and rescue medication use) must be provided for a minimum of 3 days in the 7 days immediately 
preceding randomization.
c.   All study activities at dosing visits (Baseline [Day 1] and Weeks 8 and 16), including sample collection, are performed prior to dosing, unless otherwise noted.
d.    At Screening, a comprehensive musculoskeletal medical history is obtained; see Section 7.3.1.2 for details. History of insufficient pain relief from, inability to tolerate or 
contraindication to take acetaminophen, NSAIDs and tramadol or opioids should be collected. All treatments used to treat osteoarthritis and osteoarthritis pain and reasons for 
discontinuing should also be collected.
e.    Only body weight is collected at Week 24 (End of Treatment).
f.     A musculoskeletal directed physical examination will be performed at each clinic visit; findings will be recorded on a case report form and findings of worsening clinical status 
considered clinically significant will be reported as adverse events.  This physical examination is described in Section 7.3.1.2. 
g.    A neurological examination (NIS) will be performed by the Investigator (or designated physician) at each clinic visit and assessed for clinically significant changes from Baseline.  
Requirements for neurological consultation at which a full neurological examination is to be performed by a neurologist are detailed in Section 7.3.8.
h.    FSH testing in female subjects as described in Section 7.3.2.4.
i.     On dosing visits, samples for ADA, PK and NGF should be obtained pre-dose.
j.     Biomarker samples should be collected pre-dose at approximately the same time of the day at all scheduled time points and as much as possible following a fasting period of at least 8 
hours. Fasting status should be recorded on the eCRF. Urine collected for biomarkers should be the second or later void of the day.  
k.    IRT: interactive response technology. For the index joint, pain scores are collected daily from the beginning of the IPAP to Week 24 (End of Treatment visit) though collection may 
start as early as at the Screening Visit, and then weekly from Week 24 to Week 48. For non-index joints, pain assessments are collected weekly from the IPAP to Week 48 (End of 
Study visit) with a 24-hour recall. Rescue medication use is collected daily from the beginning of the IPAP to Week 24 (End of Treatment visit) though collection may start as early as 
at the Screening Visit; then weekly from Week 24 to Week 48. Concomitant NSAID use is collected weekly from Baseline to Week 48 via IRT.  Compliance with IRT assessments is 
to be reviewed at each study visit, including at telephone visits.
l.    The WOMAC subscales, PGA of Osteoarthritis, WPAI:OA and EQ-5D-5L, HCRU and SAS will be administered at sites using IRT.
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Study Activities Visit Identifier
Screeningb
Day -37 to Day -1
Double-Blind Treatment
End of 
Treat-
ment
Safety Follow-Upo
16 weeks 
post last 
dose
Visit
Phone 
Callsr
End of 
Study/
Final visit
Clinic visits
Phone
callr
Initial 
screen 
Was
hout 
and 
X-
rays
Initial 
Pain 
Assess
ment 
Period
Base
linec
Week 
2
Week 
4
Week 
8c
Week 
12
Week 
16c
Week 
20r
Week 24
Week 32
Weeks 28, 
36, 40, 44
Week 48
Visit Windowa
Day -7 
to 
Day -1
Day 
1
Day 
15
(±3 
days)
Day 
29
(±3 
days)
Day 
57
(±7
days)
Day 85
(±7 
days)
Day 
113
(±7 
days)
Day 
141
(±7 
days)
Day 169
(±7 days)
Day 225
(±7 days)
Days 197, 
253, 281, 
309  
(±7 days)
Day 337
(±7 days)
m.    Rescue medication use must be discontinued 24 hours prior to any on site study visit up to and including Week 32 (including during the Early Termination Follow-Up period).  
Subjects should bring back rescue medication bottles at each study visit for assessment of compliance. 
n.     If needed, following completion of the visit at which final efficacy assessments are collected (Week 32, 16 weeks after the last dose of investigational product administered), standard 
of care treatment (as described in Section 6.3.2.) may be initiated, and usage recorded on the concomitant medication CRF. 
o.    Subjects discontinuing the study at their request or at the decision of the investigator prior to Week 24 should be withdrawn from treatment and begin the 24-week Early Termination 
Follow-Up period described in Section 6.4 and Table 2.  The follow-up period for subjects who terminate early includes 3 clinic visits and 2 telephone visits as described in Section 
6.4.1.  Subjects who undergo joint replacement will be followed for 24 weeks after the procedure as described in Section 6.4.2.
p.    Serum pregnancy tests are obtained at Screening, Weeks 24 and 32 or Early Termination Visits 1 and 2 for subjects who discontinue (Refer to Section 6.4).  A urine pregnancy test will 
be obtained and confirmed as negative prior to dosing at Baseline before initial dosing, and at Weeks 8 and 16. Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
q.    Subject Daily / Weekly Assessments (IRT) - Compliance with IRT assessments is to be reviewed at each study visit, including telephone visits.
r.   Week 20, 28, 36, 40 and 44 Visits are made by telephone call.  
s.    During Washout and Initial Pain Assessment Periods, contraceptive requirement reminders may be done by telephone contact.
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Table 2.
EARLY TERMINATION SCHEDULE OF EVENTS
Visit Identifier
As soon as 
possible after 
determining 
subject will 
be 
discontinued 
from study
Early 
Termination 
Visit 1
Early 
Termination 
Telephone 
Contact 1
Early 
Termination 
Visit 2
Early 
Termination 
Telephone 
Contact 2
Early 
Termination 
Visit 3
~8 Weeks after 
last SC dose
~12 Weeks after 
last SC dose
~16 Weeks after 
last SC dose
~20 Weeks after 
last SC dose
~24 Weeks after 
last SC dose
Radiographs of each Hip, Knee and 
Shoulder
X
X
General Physical Examination
X
Musculoskeletal Physical 
Examinationa
X
X
X
Vital Signs (BP, HR)
X
X
X
Orthostatic Blood Pressure 
(supine/standing)
X
X
X
Body Weight 
X
Electrocardiogram (ECG 12-lead)
X
X
Survey of Autonomic Symptoms 
(SAS) questionnaireb
X
X
Neurologic Exam Neuropathy 
Impairment Score (NIS)c
X
X
X
Subject Weekly Assessments 
(IRT)d
Review Compliance With Subject 
IRT Entry and Data Reviewd
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
Female Subjects of Childbearing 
Potential Reminded of 
Contraceptive Requirements
X
X
X
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Visit Identifier
As soon as 
possible after 
determining 
subject will 
be 
discontinued 
from study
Early 
Termination 
Visit 1
Early 
Termination 
Telephone 
Contact 1
Early 
Termination 
Visit 2
Early 
Termination 
Telephone 
Contact 2
Early 
Termination 
Visit 3
~8 Weeks after 
last SC dose
~12 Weeks after 
last SC dose
~16 Weeks after 
last SC dose
~20 Weeks after 
last SC dose
~24 Weeks after 
last SC dose
SUBJECT REPORTED ASSESSMENTS (Completed at Study Visits)b
WOMAC Pain, Physical Function 
and Stiffness Subscales
X
X
Patient’s Global Assessment of 
Osteoarthritis
X
X
WPAI:OA
X
X
EQ-5D-5L
X
X
mPRTI
X
Health Care Resource Utilization
(HCRU)
X
X
RESCUE MEDICATION / STANDARD OF CARE
Concomitant Medication Review
X
X
X
X
X
Rescue medication 
return/compliancee
X
X
Assign Standard of Care Treatment 
as Neededf
X
LABORATORY
Serum Pregnancy Testg
X
X
Hematology
X
Blood Chemistry
X
Serum and Plasma Retention 
Samples
X
X
Serum Anti-tanezumab Antibody
X
X
X
Plasma Pharmacokinetic sample
X
X
Serum NGF (PD) sample
X
X
Serum and Urine Biomarkersh
X
Abbreviations: →= ongoing/continuous event; BP = Blood Pressure; ECG = electrocardiogram; HR = Heart Rate; HCRU = Health Care Resource Utilization; EC = ethics 
committee; EQ-5D-5L = EuroQol 5 Dimension; IRT = Interactive Response Technology; mPRTI = Patient Reported Treatment Impact assessment-modified; NGF = Nerve 
Growth Factor; NIS = Neuropathy Impairment Score; PD = Pharmacodynamics; SAS = Survey of Autonomic Symptoms; SC = Sub-Cutaneous; WPAI: OA = Work 
Productivity and Activity Impairment Questionnaire: WOMAC = Western Ontario and McMaster University Osteoarthritis Index.
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Visit Identifier
As soon as 
possible after 
determining 
subject will 
be 
discontinued 
from study
Early 
Termination 
Visit 1
Early 
Termination 
Telephone 
Contact 1
Early 
Termination 
Visit 2
Early 
Termination 
Telephone 
Contact 2
Early 
Termination 
Visit 3
~8 Weeks after 
last SC dose
~12 Weeks after 
last SC dose
~16 Weeks after 
last SC dose
~20 Weeks after 
last SC dose
~24 Weeks after 
last SC dose
a.   A musculoskeletal directed physical examination will be performed at each clinic visit; findings will be recorded on a case report form and findings of worsening clinical 
status considered clinically significant will be reported as adverse events.  This physical examination is described in Section 7.3.1.2.
b.   The WOMAC subscales, PGA of Osteoarthritis, WPAI:OA and EQ-5D-5L, HCRU and SAS will be administered at sites using IRT.
c.   A neurological examination (NIS) will be performed by the Investigator (or designated physician) at each clinic visit and assessed for clinically significant changes from 
Baseline.  Requirements for neurological consultation at which a full neurological examination is to be performed by a neurologist are detailed in Section 7.3.8.
d.   Subject Daily / Weekly Assessments (IRT) - Compliance with IRT assessments is to be reviewed at each study visit, including telephone visits.
e.   Rescue medication use must be discontinued 24 hours prior to any on site study visit up to and including Week 32 (including during the Early Termination Follow-Up 
period).  Subjects should bring back rescue medication bottles at each study visit for assessment of compliance. 
f.   If needed, following completion of the visit at which final efficacy assessments are collected (Week 32, 16 weeks after the last dose of investigational product 
administered), standard of care treatment (as described in Section 6.3.2.) may be initiated, and usage recorded on the concomitant medication CRF. 
g.  Serum pregnancy tests are obtained at Screening, Weeks 24 and 32 or Early Termination Visits 1 and 2 for subjects who discontinue (Refer to Section 6.4.).  A urine 
pregnancy test will be obtained and confirmed as negative prior to dosing at Baseline before initial dosing, and at Weeks 8 and 16. Pregnancy tests may also be repeated as 
per request of IRB/IECs or if required by local regulations.
h.  Biomarker samples should be collected at approximately the same time of the day at all scheduled time points and as much as possible following a fasting period of at least 
8 hours. Fasting status should be recorded on the eCRF. Urine collected for biomarkers should be the second or later void of the day.  
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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). Full 
details can be found in the Investigator’s Brochure.1
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 and modulation of the pain response.3,4  Many non-clinical studies 
employing a variety of antibodies to NGF or IgG fusion proteins coupled to tropomyosin 
receptor kinase A (trkA; one of the primary receptors for NGF) have demonstrated that 
blocking NGF bioactivity normalizes pain sensitivity.4,5 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 with a mutation in the Fc portion of the antibody to decrease its 
ability to activate complement or to support antibody dependent cell-mediated cytotoxicity.6,7
Tanezumab is highly potent in sequestering NGF and preventing interaction with the trkA or 
p75 receptors.
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. Most of these studies were conducted in subjects with 
osteoarthritis of the knee or hip. A total of 17 clinical studies (4 Phase 2 studies and 13 Phase 
3 studies [10 controlled]) 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 non-steroidal anti-
inflammatory drugs (NSAIDs).  In addition to the osteoarthritis studies, 11 Phase 1/2 studies 
were conducted to examine the efficacy and safety of tanezumab in other musculoskeletal, 
neuropathic, and visceral chronic pain conditions, and 2 Phase 2 studies were conducted in 
cancer subjects with metastatic bone pain. In these studies, tanezumab was administered by 
IV or SC administration every 8 weeks at fixed doses ranging from 1 mg to 20 mg or 
equivalent body-weight adjusted doses up to 100 mg.  
Robust efficacy was demonstrated in osteoarthritis and chronic low back pain studies. 
Efficacy and safety results observed in non-cancer pain populations are described in the 
tanezumab Investigator’s Brochure1 and in external publications of individual 
studies.8,9,10,11,12,15
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1.2.3.1. Overview of Efficacy in Osteoarthritis Clinical Studies
Across the 3 co-primary measures of efficacy in four completed Phase 3 studies of 
tanezumab monotherapy (IV administration), doses of 2.5 mg, 5 mg, and 10 mg provided 
significant improvement over placebo treatment. All of the tanezumab doses tested were 
consistently efficacious. In Studies A40910118 and A40910149, the degree of mean 
improvement across the three efficacy domains was similar and generally dose ordered with 
tanezumab 10 mg providing the greatest mean response in each of the 6 comparisons to 
placebo treatment although only small differences in the magnitude of response were evident 
among the three doses of tanezumab. In Studies A409101510 and A409101810, tanezumab 
5 mg provided modestly greater mean improvement over tanezumab 10 mg across most of 
the co-primary endpoints. 
Further details on the efficacy of tanezumab on osteoarthritis can be found in the
Investigator’s Brochure (IB).1
1.2.3.2. Overview of Safety in Clinical Studies
Based on data from all subject populations who have received tanezumab in completed 
clinical studies to date, the adverse drug reactions listed Table 3 are considered to be 
expected in subjects who are treated with tanezumab.
Table 3.      ADVERSE DRUG REACTIONS IN ALL SUBJECTS RECEIVING 
TANEZUMAB
System Organ Class
Adverse Drug Reactions
Frequency2
Nervous system disorders
Burning sensation
Carpal tunnel syndrome
Hyperesthesia
Hypoesthesia
Paresthesia
Common
Allodynia
Neuropathy peripheral
Uncommon
Musculoskeletal and connective tissue disorders
Rapidly Progressive 
Osteoarthritis
(in patients with 
underlying osteoarthritis)1
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%).
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, approximately 900 subjects were treated in 2 studies in subjects with osteoarthritis 
using SC administration.  The adverse event profile of SC administration of tanezumab is 
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comparable to the IV route based on the results of study A409102713 which compared SC 
versus IV administration in subjects with osteoarthritis.  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 seen with tanezumab monotherapy.
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 was 
greater than with placebo or active comparator treatment. 
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 subjects receiving tanezumab monotherapy than subjects 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 nasopharyngitis and all gastrointestinal-related adverse events.  
Dose-related increases in the incidence of peripheral edema, joint swelling, osteoarthritis and 
paresthesia were observed.
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 doses 
of 2.5 to 10 mg in subjects with osteoarthritis.  Tanezumab 20 mg in chronic low back pain 
had marginally higher event rates compared to placebo and active comparator treatment 
groups. 
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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. 
Although evidence of clinically important effects on the sympathetic nervous system have 
not been identified in previously completed tanezumab studies, per agreement with the Food 
and Drug Administration (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.
1.2.3.2.2. Joint Safety
A comprehensive investigation and analyses related to joint-safety has been 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.  The 
program was 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
After careful investigation, no evidence was found to substantiate 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. Further details can be found in 
the IB.1
Risk mitigation measures have been developed as an outgrowth of the joint-related safety 
analyses to reduce the risk of rapidly progressive osteoarthritis.  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 2012 FDA 
Arthritis Advisory Committee and interactions with FDA, risk mitigation measures were 
developed.  These risk mitigation measures have been included in this study and are outlined 
as follows:
Risk Minimization: (1) exclude chronic concomitant NSAID use, (2) exclude tanezumab 
doses that have been explored and do not demonstrate benefit over lower doses in the 
condition under study, (3) exclude subjects with evidence of rapidly progressive 
osteoarthritis or risk factors for such from participating in clinical studies, (4) discontinue 
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treatment with investigational product in subjects who fail to achieve adequate pain relief and 
(5) exclude subjects who are not suitable candidates for total joint replacement from study 
participation.
Risk Identification and Management: (1) evaluation and follow-up for severe persistent 
joint pain, (2) extended post-treatment follow-up, (3) a program-level Central Radiograph 
Reader and subject-level stopping criteria, (4) an Adjudication Committee, and (5) a Data 
Monitoring Committee and protocol-level stopping rules.
Risk Characterization: (1) Comprehensive evaluation of osteoarthritis medical history prior 
to study entry, (2) scheduled radiographic assessments during the studies, (3) surgical and 
post-operative total joint replacement outcomes, and (4) biomarker determinations.
1.2.3.3. Subcutaneous Administration of Tanezumab in Clinical Studies
The formulation of tanezumab that has been administered by SC injection is identical to what 
has been administered by IV infusion and is administered as a 1 mL SC injection in the thigh 
or abdomen.  The safety and efficacy of tanezumab when administered by SC injection has 
been evaluated in OA subjects primarily in two studies, A409102713 and A4091043,14 and in 
subjects with chronic low back pain in one study (A409103915).  A total of 1905 subjects 
were treated in these studies.  The observed efficacy and safety profile of tanezumab 
administered SC was similar to IV administration.
1.2.4. Dose Selection Rationale
Intravenous and SC administration of tanezumab at doses of 2.5 mg, 5 mg and 10 mg was 
shown to reduce pain and improve function in a dose-related manner in Phase 3 studies of 
osteoarthritis.  As one of the risk mitigation features identified through analysis of orthopedic 
safety and efficacy data, no further study of the tanezumab 10 mg dose will be conducted in 
subjects with osteoarthritis as this dose did not provide sufficient additional efficacy benefit 
over the 5 mg dose.  The 5 mg dose is expected to provide added efficacy benefit over the 
2.5 mg dose.  Based upon prior studies, this additional efficacy benefit is likely to be most 
evident in subjects considered to have severe symptomatic osteoarthritis as defined above in 
Section 1.2.3.1.  The current study will therefore investigate the safety and efficacy of fixed-
dose levels of tanezumab 2.5 mg and 5 mg administered up to 3 times at 8-week intervals 
relative to placebo.  
1.2.5. Rationale for Placebo Treatment
The use of a placebo comparator is the gold-standard for assessing efficacy in short-term pain 
studies.  Utilization of placebo as a comparator allows a smaller sample size and thus 
demonstrates the study objectives of efficacy more efficiently than a study using an active 
comparator.  In addition, the use of a placebo arm is most important when the trial endpoints 
are subjective measures such as those used in this study, because of the often great variation 
in the way individuals perceive subject-reported outcomes.  This was reported to be 
particularly relevant for studies involving pain relief, depression, and asthma.16 In this study 
SC placebo is used to blind investigators and subjects as to whether or not SC tanezumab has 
been administered.  Although no analgesic efficacy is expected from placebo treatment, some 
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placebo-treated subjects may experience a beneficial effect on well-being.  Rescue 
medication (acetaminophen/paracetamol) will be allowed to all subjects throughout the study
(refer to Section 5.8).
1.2.6. Subject Population Selection Rationale
The population selected for this study is subjects with moderate to severe osteoarthritis pain 
of the hip or knee based on American College of Rheumatology criteria with X-ray 
confirmation (a Kellgren-Lawrence x-ray grade of ≥2) who have had inadequate pain relief 
with previous conventional pharmacological treatment options for osteoarthritis, or who are 
unable to take these medications due to a contraindication or the inability to tolerate them 
and who are seeking effective treatment options other than or prior to joint replacement.  The 
rationale for the choice of this population is to optimize the potential benefit:risk relationship 
for subjects entering the study by selecting subjects who have pain that is more severe or 
treatment resistant and who have limited treatment options remaining.
Complete information for this compound may be found in the Single Reference Safety 
Document, which for this study is the Investigator’s Brochure.1
1.2.7. Benefit-Risk Assessment.
The determination of the benefit-risk assessment must take into account the efficacy and 
safety of tanezumab, and the population to be studied in this protocol.
Tanezumab has been studied for use in moderate to severe chronic pain conditions including 
osteoarthritis. Data from the available Phase 2 and 3 studies has shown that tanezumab 
treatment provides significant improvements in pain, physical function and global assessment 
in osteoarthritis compared with placebo, NSAID and opiate treatment.  
Concerning safety, relative to placebo, tanezumab monotherapy and active comparator 
treatment groups, tanezumab/NSAID treatment groups were associated with the highest 
overall adverse event rate and rate of discontinuations due to adverse events in Phase 3 
osteoarthritis studies.  The incidence of adverse events and discontinuations due to adverse 
events in Phase 3 studies in patients with osteoarthritis increased with increasing tanezumab 
dose and with the combination of tanezumab and NSAID.  (See Investigator’s Brochure 
Section 6.2.1.)
The rate of all-cause total joint replacements (patients who underwent total joint replacement 
+ patients with reported osteonecrosis regardless of whether they underwent total joint 
replacement or not) in patients with osteoarthritis was comparable between placebo, active 
comparator and tanezumab monotherapy treatment groups.  The rate of all-cause total joint 
replacements did not increase with increasing tanezumab monotherapy dose.  (See 
Investigator’s Brochure Section 6.2.10 and Section 1.2.3.2.2 of Protocol A4091057). The rate 
of rapidly progressive osteoarthritis increased with increasing tanezumab dose and was 
elevated above the rate observed in placebo and active comparator treatment groups.  The 
combination of tanezumab + NSAID treatment increased the rate of rapidly progressive 
osteoarthritis and all-cause total joint replacement by >2 to 3-fold above other treatment 
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groups. Because of those findings, risk mitigation measures have been incorporated into the 
protocol (see Section 1.2.3.2.2).
Adverse events of abnormal peripheral sensation with tanezumab treatment have been 
observed in all patient populations studied to date.  The adverse events are dose-related, 
generally resolve and are of mild-to-moderate intensity at the doses planned for future 
studies.  (See Investigator’s Brochure Section 6.2.11).
Based upon quantitative sensory testing, intraepidermal nerve fiber density, nerve conduction 
velocity testing and heart rate deep breathing assessments conducted to-date, administration 
of tanezumab does not have a clinically meaningful effect on sensory or autonomic nerve 
function based on data in heathy volunteers or patients with osteoarthritis or painful diabetic 
peripheral neuropathy (See Investigator’s Brochure Section 6.2.11.4).
Clinically meaningful changes in vital signs, laboratory values, or electrocardiograms (ECG)
(including QTc) have not been observed to-date (See Investigator’s Brochure Section 6.2).
In summary, tanezumab treatment has been shown to provide significant improvements in 
pain, physical function and global assessment in osteoarthritis compared to placebo, NSAID 
and opiate treatment.  The benefit to subjects participating in the study will be the potential 
for improvement in osteoarthritis pain that has not been adequately relieved by previous 
treatment regimens. 
Based on the overall assessment of risk and benefit, the data support further clinical 
investigation of tanezumab with the additional benefit-risk optimization and surveillance 
measures employed as outlined in the protocol.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
PRIMARY OBJECTIVE
•
Demonstrate superior efficacy of tanezumab 5 mg and 2.5 mg administered 
subcutaneously (SC) every 8 weeks versus placebo at Week 24.
SECONDARY OBJECTIVE
•
Evaluate the safety of tanezumab 2.5 mg SC and 5 mg SC.
2.2. Endpoints
2.2.1. Co-primary Efficacy Endpoints:
•
Change from Baseline to Week 24 in the WOMAC Pain subscale.
•
Change from Baseline to Week 24 in the WOMAC Physical Function subscale.
•
Change from Baseline to Week 24 in the Patient’s Global Assessment of Osteoarthritis.
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2.2.2. Secondary Endpoints
2.2.2.1. Efficacy Measures
•
WOMAC Pain subscale change from Baseline to Weeks 2, 4, 8, 12, 16, and 32.
•
WOMAC Physical Function subscale change from Baseline to Weeks 2, 4, 8, 12, 16, and 
32.
•
Patient’s Global Assessment of Osteoarthritis (5 point Likert scale) change from Baseline 
to Weeks 2, 4, 8, 12, 16, and 32.
•
OMERACT-OARSI responder index at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Cumulative distribution of percent change from Baseline in the WOMAC Pain subscale 
score to Week 16 and 24 (endpoint for summary only).
•
Treatment Response:  Reduction in the WOMAC Pain subscale of ≥30%, ≥50%,  ≥70% 
and ≥90%, at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Treatment Response: Reduction in the WOMAC Physical Function subscale of ≥30%, 
≥50%, ≥70% and ≥90% at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Cumulative distribution of percent change from Baseline in the WOMAC Physical 
Function subscale score to Week 16 and 24 (endpoint for summary only).
•
Treatment Response:  Improvement of ≥2 points in Patient’s Global Assessment of 
Osteoarthritis at Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Average pain score in the index knee or hip change from Baseline to Weeks 1, 2, 3, 4, 6, 
8, 10, 12, 16, 20, 24, 28 and 32.
•
WOMAC Stiffness subscale change from Baseline to Weeks 2, 4, 8, 12, 16, 24 and 32.
•
WOMAC Average score change from Baseline to Weeks 2, 4, 8, 12, 16, 24, and 32.
•
WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface, change from 
Baseline to Weeks 2, 4, 8, 12, 16, 24, and 32.
•
WOMAC Pain Subscale Item: Pain When Going Up or Downstairs, change from 
Baseline to Weeks 2, 4, 8, 12, 16, 24, and 32.
•
Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) 
impairment scores change from Baseline to Weeks 8, 16 and 24.
•
EQ-5D-5L Health State Utility and Five Items (Mobility; Self-Care; Usual Activities; 
Pain/Discomfort; Anxiety/Depression) change from Baseline to Weeks 8, 16 and 24.
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•
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 24.
•
Health Care Resource Utilization at Baseline, and Weeks 32 and 48.
•
Incidence and time to discontinuation due to Lack of Efficacy.
•
Usage of rescue medication (incidence and number of days of use) during Weeks 2, 4, 8, 
12, 16, 24, and 32.
•
Usage of rescue medication (amount taken) during Weeks 2, 4, 8, 12, 16 and 24.
2.2.2.2. Safety Measures
•
Adverse Events.
•
Standard safety assessments (safety laboratory testing [chemistry, hematology], sitting 
vital signs, electrocardiogram (ECG; 12-lead).
•
Joint Safety Adjudication outcomes.
•
Total joint replacements.
•
Orthostatic (supine / standing) blood pressure assessments.
•
Survey of Autonomic Symptom scores.
•
Neurologic exam (Neuropathy Impairment Score [NIS]).
•
Anti-tanezumab antibody assessments.
•
Physical examinations.
2.2.3. Tertiary Endpoints
2.2.3.1. Pharmacokinetic and Pharmacodynamic
•
Plasma tanezumab concentrations.
•
Serum NGF assessment.
•
Serum and urine osteoarthritis biomarker concentrations.
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3. STUDY DESIGN
Figure 1.
Study Schematic
This is a randomized, double-blind, placebo-controlled, parallel-group multicenter 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.  A total of 
approximately 810 subjects will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio (ie, 
270/group). The randomization will be stratified by index joint (hip or knee), and most severe 
Kellgren-Lawrence grade (of any knee or hip joint) at study entry (grade 2, 3 or 4). Subjects
will receive up to three SC doses of one of the following treatments at an 8-week interval
between each injection:
1. tanezumab 2.5 mg;
2. tanezumab 5 mg;
3. Placebo to match tanezumab.  
The study is designed with a total (post-randomization) duration of 48 weeks and will consist 
of three periods: Screening (up to 37 days), Double-blind Treatment (24 weeks) and Safety
Follow-up (24 weeks).  The Screening Period (beginning up to 37 days prior to 
Randomization) includes a Washout Period (lasting a minimum of 2 days for all prohibited 
pain medications), if required, and an Initial Pain Assessment Period (the 7 days prior to 
Randomization/Baseline).
Randomization 
1
st Dose of Study 
Medication
*Phone Contact with 
Patient
Double-Blind Treatment
Safety Follow -up
85
12
20
141
28
36
40
44
*
*
253
281
309
197
24 in WOMAC 
– Change from 
Primary Endpoint 
Baseline to Week
Pain, WOMAC Physical Function,
and Patient’s Global Assessment of 
Placebo 
(N =270 )
Tanezumab 
5 mg SC 
(N =270 )
Tanezumab 
2 .5 mg SC 
(N =270 )
Days
Weeks
1
57
113
169
225
337
15
29
BL
8
16
24
32
48
2
4
*
*
*
Screening
-37
-7
Baseline Pain 
Days -7 to -1
2nd Dose of 
Study 
Medication
3 rd and Final 
Dose of Study 
Medication
OA
End of Study
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Week 24 is the landmark analysis in this study.
Subjects who complete the Week 24 visit will be considered to have completed the 
Double-blind Treatment period and will enter the 24-week Safety Follow-up period.  
Subjects who have completed the Double-blind Treatment period and have entered the 24-
week Safety Follow-up period and complete the Week 48 visit will be considered to have 
completed the study.  Subjects who discontinue study treatment prior to completing the 
Week 24 visit will not be considered to have completed the Double-blind Treatment period.  
Subjects who do not complete the Double-blind Treatment period but who enter and 
complete the 24-week Early-termination follow-up period will be considered to have 
completed the study while those subjects who do not complete the 24-week Early-
termination follow-up period will not be considered to have completed the study.
For subjects who withdraw from the study, see Section 6.4. Every effort should be made to 
have the subject agree to complete the entire 24-week Early Termination Safety Follow-up.
The procedure for subjects in Japan who have not had a trial of acetaminophen is 
described in Section 6.1.1.
Details relevant to the study design can be found in Sections 6 and 7 and the Schedule of 
Activities (Tables 1 and 2).
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.
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.
2. Male or female ≥18 years of age.
3. A diagnosis of osteoarthritis of the hip or knee in the index joint based on American
College of Rheumatology criteria with x-ray confirmation (a Kellgren-Lawrence17 x-ray 
grade of ≥2 as diagnosed by the Central Reader; Appendix 1).
4. Documented history indicating that:
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•
acetaminophen therapy has not provided sufficient pain relief;
•
oral NSAID therapy has not provided adequate pain relief or subject is unable to take 
NSAIDs due to contraindication or inability to tolerate.
AND at least 1 of the following criteria: 
•
Documented history indicating that tramadol treatment has not provided adequate 
pain relief or subject is unable to take tramadol due to contraindication or inability to 
tolerate,
•
Documented history indicating that opioid treatment has not provided adequate pain 
relief or subject is unwilling to take opioids, or unable to take opioids due to 
contraindication or inability to tolerate.
5. WOMAC Pain subscale Numerical Rating Scale (NRS) ≥5 in the index joint at 
Screening.
6. Subjects must be willing to discontinue all pain medications for osteoarthritis except 
rescue medication (acetaminophen) and not use prohibited pain medications throughout
the duration of the study except as permitted per protocol.
7. Female subjects of childbearing potential and at risk for pregnancy must agree to use 
2 highly effective or acceptable methods of contraception throughout the study and for 
112 days (16 weeks) after the last dose of assigned subcutaneous investigational product. 
NOTE:  In Japan, only female subjects who are not of childbearing potential will be 
eligible for this study.
NOTE: In Sweden, female subjects of childbearing potential and at risk for pregnancy 
must agree to use at least one highly effective method of contraception throughout the 
study and for 112 days (16 weeks) after the last dose of assigned subcutaneous study 
medication. 
8. Female subjects who are not of childbearing potential meet at least one of the following 
criteria:
•
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
•
Have medically confirmed ovarian failure; or 
•
Achieved post-menopausal status defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological cause 
and have a serum follicle stimulating hormone (FSH) level confirming the post-
menopausal state.
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9. Subjects who are willing and able to comply with lifestyle guidelines, scheduled visits, 
treatment plan, laboratory tests, and other study procedures through the End of Study 
visit.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the 
trial.
2. Body Mass Index (BMI) of >39 kg/m2.
3. History of other disease that may involve the index joint including inflammatory joint 
disease such as rheumatoid arthritis, seronegative spondyloarthropathy (eg, ankylosing 
spondylitis, psoriatic arthritis, inflammatory bowel disease related arthropathy), 
crystalline disease (eg, gout or pseudogout), endocrinopathies, metabolic joint diseases, 
lupus erythematosus, joint infections, Paget’s disease, or tumors. 
4. Radiographic evidence of any of the following conditions in any screening radiograph as 
determined by the central radiology reviewer and as defined in the tanezumab program 
imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; other 
arthropathies (eg, rheumatoid arthritis), systemic metabolic bone disease (eg, pseudogout, 
Paget’s disease, metastatic calcifications), large cystic lesions, primary or metastatic 
tumor lesions, stress or traumatic fracture. 
5. Radiographic evidence of any of the following conditions as determined by the central 
radiology reviewer and as defined in the tanezumab program imaging atlas at Screening: 
1) rapidly progressive osteoarthritis, 2) atrophic or hypotrophic osteoarthritis, 
3) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of the knee 
(SPONK), 5) osteonecrosis, or 6) pathologic fracture.
6. A history of osteonecrosis or osteoporotic fracture (ie, a subject with a history of 
osteoporosis and a minimally traumatic or atraumatic fracture).
7. History of significant trauma or surgery to a knee, hip or shoulder within the previous 
year.
8. Planned surgical procedure during the duration of the study.
9. Largely or wholly incapacitated, (eg, subject bedridden or confined to a wheelchair, 
permitting little or no self-care).
10. Fibromyalgia, regional pain caused by lumbar or cervical compression with 
radiculopathy or other moderate to severe pain that may confound assessments or self-
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evaluation of the pain associated with osteoarthritis.  Subjects with a present (current) 
history of sciatica are not eligible for participation.  Subjects with a past history of 
sciatica who have been asymptomatic for at least one year and who have no evidence of 
radiculopathy or sciatic neuropathy on thorough neurologic examination are eligible for 
participation.
11. Subjects with a past history of carpal tunnel syndrome (CTS) with signs or symptoms of 
CTS in the one year prior to Screening.
12. Subjects considered unfit for surgery, defined as Grade >3 on the American Society of 
Anesthesiologists (ASA) physical classification system for surgery (see Appendix 2), or 
subjects who would not be willing to undergo joint replacement surgery if required.
13. History of intolerance or hypersensitivity to acetaminophen (paracetamol) or any of its 
excipients or existence of a medical condition or use of concomitant medication for 
which the use of acetaminophen is contraindicated (refer to product labeling).
14. Use of prohibited medications without the appropriate washout period (if applicable) 
prior to Screening or Initial Pain Assessment Period (refer to Section 5.7.1). 
15. Oral or intramuscular corticosteroids within 30 days prior to the Initial Pain Assessment 
Period.
16. Intra-articular corticosteroid injection in the index joint within 12 weeks, or to any other 
joint within 30 days prior to the Initial Pain Assessment Period.
17. Intra-articular hyaluronic acid injection in the index joint within 30 days (or within 
18 weeks for long-acting formulations such as Synvisc) prior to the Initial Pain 
Assessment Period.
18. History of cancer within 5 years prior to Screening, except for cutaneous basal cell or 
squamous cell cancer resolved by excision.
19. Signs and symptoms of clinically significant cardiac disease including but not limited to:
•
Ischemic cardiac disease (eg, unstable angina, myocardial infarction) in the 6 months 
prior to Screening;
•
Surgery or stent placement for coronary artery disease in the 6 months prior to 
Screening;
•
New York Heart Association (NYHA) Class III or IV congestive heart failure or 
known left ventricular dysfunction with ejection fraction ≤35%, cardiomyopathy, 
myocarditis in the 6 months prior to Screening;
•
Resting tachycardia (heart rate ≥120) or resting bradycardia (heart rate ≤45) on ECG 
at Screening;
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•
QTcF interval >500 msec in the absence of confounding factors like bundle branch 
block or paced rhythm at Screening;
•
Any other cardiovascular illness that in the opinion of the investigator would render a 
subject unsuitable to participate in the study.
•
Subjects with a history of heart block.
Patients with a history of heart block now controlled by a functioning cardiac
pacemaker and/or transient episodes of asymptomatic tachy- or bradyarrhythmia are 
eligible.
20. Diagnosis of a transient ischemic attack in the 6 months prior to Screening, diagnosis of 
stroke with residual deficits (eg, aphasia, substantial motor or sensory deficits), that 
would preclude completion of required study activities.
21. History, diagnosis, or signs and symptoms of clinically significant neurological disease, 
including but not limited to:
•
Alzheimer’s disease or other types of dementia;
•
Clinically significant head trauma within the past year;
•
Peripheral or autonomic neuropathy;
•
Multiple sclerosis
•
Epilepsy or seizure disorder with history of seizure within the last 2 years;
•
Myopathy.
22. History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder, 
including but not limited to:
•
Psychotic disorders;
•
Somatoform disorders;
•
Bipolar disorders;
•
Hospital admission for depression or suicide attempt within 5 years of Screening, or
active severe major depression at Screening (determined from medical history: if 
needed, severity of depression may be assessed using the Patient Health 
Questionnaire [PHQ-9].18  A score of ≥15 on questions 1-9 of the PHQ-9 corresponds 
to severe depression.  See Appendix 9);
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•
Any other psychiatric illness that in the opinion of the investigator would render a 
subject unsuitable to participate in the study.
23. History of known alcohol, analgesic or drug abuse within 2 years of Screening.
24. Previous exposure to exogenous NGF or to an anti-NGF antibody.
25. History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal 
antibody or IgG-fusion protein.
26. Resting, sitting blood pressure (BP) ≥160 mm Hg in systolic pressure or ≥100 mm Hg in 
diastolic pressure at Screening. If a subject is found to have untreated significant 
hypertension at Screening and antihypertensive treatment is initiated, assessment for 
study eligibility should be deferred until BP and antihypertensive medication have been 
stable for at least one month. For subjects with previously diagnosed hypertension, 
antihypertensive medications must be stable for at least 1 month prior to Screening.
27. Subjects who have evidence of orthostatic hypotension based upon replicate orthostatic 
blood pressure measurements (refer to Section 7.3.4.1).  If orthostatic blood pressure 
change is not able to be determined (eg, unable to establish a stable supine systolic and 
diastolic blood pressure) then subject is not eligible for the study. 
28. Subjects with a total impact score of >7 on the Survey of Autonomic Symptoms (SAS, 
see Appendix 11).
29. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3.0 times the 
upper limit of normal, or creatinine exceeding 1.7 mg/dL (150 μmol/L) in men or 
1.5 mg/dL (133 μmol/L) in women, or hemoglobin A1c ≥10% at Screening.  Repeat 
confirmatory tests may be performed.
30. Presence of drugs of abuse (including prescription medications without a valid 
prescription), or illegal drugs in the urine toxicology screen obtained at Screening.
31. Positive Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) tests at 
Screening indicative of current infection.
32. Participation in other studies involving investigational drug(s) within 30 days (or 90 days 
for biologics) prior to study entry and/or during study participation.
33. Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing 
potential who are unwilling or unable to use two (2) highly effective or acceptable
methods of contraception as outlined in this protocol for the duration of the study and for 
112 days (16 weeks) after last dose of investigational product.
NOTE: In Sweden, pregnant female subjects; breastfeeding female subjects; female 
subjects of childbearing potential who are unwilling or unable to use one (1) highly 
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effective method of contraception as outlined in this protocol for the duration of the 
study and for 112 days (16 weeks) after last dose of investigational product.
34. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4.3. Randomization Criteria
In addition to meeting all inclusion and exclusion criteria requirements listed above, there are
requirements for the following to be met before randomization can be called into the 
interactive response technology (IRT) system at the Baseline visit:
1. Subject must have completed appropriate washout of analgesics.
2. Subject must have made at least 3 pain diary entries in the 7 days prior to the Baseline 
(Day 1) visit.
3. Subject must have abstained from taking rescue medication (acetaminophen/paracetamol) 
within the 24 hours that precede dosing. 
4. WOMAC Pain subscale NRS ≥5 in the index knee or index hip at Baseline.
5. WOMAC Physical Function subscale NRS ≥5 in the index knee or index hip at Baseline
6. Patient’s Global Assessment of Osteoarthritis must be “fair”, “poor,” or “very poor” at 
Baseline.
7. Review of the ECG and laboratory results and confirmation that there are no clinically 
significant or exclusionary findings.
8. Subject must have had required Baseline x-rays.
9. Radiographic eligibility must have been confirmed by the Central Reader.
4.4. Life Style Guidelines
Subjects should maintain their normal daily routine, including stable doses of permitted 
medications and exercise program.  Subjects may continue with non-pharmacologic activities 
(eg, massage, physical therapy) during the trial.  Subjects should be cautioned against 
initiating or altering strenuous exercise regimens during the study as this may influence 
efficacy and laboratory results.  Subjects will be advised to avoid elective surgery (eg, oral 
surgery) during the course of the study if possible; the study clinician should be contacted for 
discussion prior to any surgery whenever possible.  Subjects who undergo joint replacement 
or arthroplasty will be discontinued from investigational product and followed as described 
in Section 6.4.2.
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Refer to Section 5.7.2 and Section 5.7.1, and Appendix 3 for guidance on permitted and 
prohibited medications.
All female subjects who, are of child-bearing potential and are sexually active and at risk for 
pregnancy, must agree to use two (2) methods of contraception (from the options listed 
below) consistently and correctly for the duration of the active treatment period and for 
112 days (16 weeks) after the last dose of SC investigational product.  The investigator or his
or her designee, in consultation with the subject, will confirm that the subject has selected the 
appropriate methods 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 at least two of the 
selected methods of contraception.  The investigator or his or 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 contraception methods are discontinued or if pregnancy is known or suspected in 
the subject or the subject’s partner.
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, with the exception of number 3 which is an acceptable birth control method:
1. Established use of oral, inserted, injected, implanted, or transdermal hormonal methods 
of contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness, with the exception of oral low-dose 
progestogens for which inhibition of ovulation is not the primary mode of action, and 
therefore such a method is not considered a highly effective contraceptive method.
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.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: For Sweden, please refer to Appendix 14 for Life Style Guidelines concerning 
contraception for subjects from clinical sites in this country. 
4.5. 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 study manual.
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To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact center number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigational site and the study team are not available.  It is therefore intended to augment, 
but not replace the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study.  
The contact number is not intended for use by the subject directly, and if a subject calls that 
number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Subjects will be randomized at Baseline to one of the following treatment groups, all subjects 
will receive SC treatment during the Double-blind Treatment period of the study: 
Treatment Group
Subcutaneous Treatment (SC)
1
Placebo for tanezumab once every 8 weeks x 3 doses
2
Tanezumab 2.5 mg once every 8 weeks x 3 doses
3
Tanezumab 5 mg once every 8 weeks x 3 doses
Subjects will be randomly assigned in a 1:1:1 ratio to the above treatment regimens 
according to a computer generated randomization schedule.  The randomization will be 
stratified by index joint (hip or knee), and most severe Kellgren-Lawrence grade (of any knee 
or hip joint) at study entry (grade 2, 3 or 4).  This will result in a 6-group stratified 
randomization scheme as follows:
1. Subjects with osteoarthritis of the hip and highest Kellgren-Lawrence grade of 2;
2. Subjects with osteoarthritis of the hip and highest Kellgren-Lawrence grade of 3;
3. Subjects with osteoarthritis of the hip and highest Kellgren-Lawrence grade of 4;
4. Subjects with osteoarthritis of the knee and highest Kellgren-Lawrence grade of 2;
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5. Subjects with osteoarthritis of the knee and highest Kellgren-Lawrence grade of 3;
6. Subjects with osteoarthritis of the knee and highest Kellgren-Lawrence grade of 4;
Randomization will be coordinated centrally through Interactive Response Technology 
(IRT).  The system will provide subject identification numbers at Screening, which will 
subsequently be linked to the treatment assignments at Randomization.  The randomization 
code will be securely maintained by a person(s) who is independent of the trial conduct and 
produces the randomization code.  It is the responsibility of the Principal Investigator to 
ensure that the subject is eligible for participation in the study before requesting 
Randomization.  The study site will obtain the subject’s randomization number and 
dispensable unit identification numbers (ie, the drug supply to be administered) from the 
IRT. Further details will be provided in the Pharmacist Manual.
5.2. Breaking the Blind
This is a randomized, double-blind, placebo-controlled, parallel group study.  The subjects, 
Investigators, Study Coordinators, clinical site staff, Clinical Research Associate (CRA), and 
staff directly involved with the study at Pfizer and its designees will be blinded to subject
assignment.
Blinding should be broken only in emergency situations for reasons of subject safety.  
Whenever possible, the investigator or sub-investigator consults with a member of the study
team prior to breaking the blind. When the blinding code is broken, the reason must be fully 
documented and entered on the Case Record Form (CRF).
•
The investigator or medical designee is responsible for contacting the Pfizer Clinical 
Support Help Desk to obtain the Principal Investigator’s user account information.  The 
account information will only be given to the investigator or medical designee.
•
The investigator at each site will have the ability to break the blind on a subject in the 
electronic system.
•
In the event the investigator is not available to perform the break blind, the Pfizer 
Clinician, and the Pfizer Clinical Support Help Desk, also have the ability to break the 
blind and can inform the Principal Investigator subsequently.
5.3. Compliance
Tanezumab and corresponding placebo dosing will be recorded on the appropriate CRF.  
Because tanezumab or corresponding placebo will be administered by site staff, subject 
compliance with SC treatment is not anticipated to be an issue.  
For rescue medication (acetaminophen / paracetamol), compliance will be reviewed and 
reconciled at each study visit.
Protocol rules governing the use of rescue medication are described in Section 5.8.  
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5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Tanezumab and placebo for tanezumab will be supplied by the Sponsor or designee.
5.4.1.1. Tanezumab
Tanezumab 2.5 mg is presented as a sterile solution for subcutaneous administration, in a 
glass pre-filled syringe (PFS).  Each PFS contains a sufficient amount of tanezumab to 
provide the intended dose of drug at a concentration of 2.5 mg/mL. 
Tanezumab 5 mg is presented as a sterile solution for subcutaneous administration, in a glass 
pre-filled syringe (PFS).  Each PFS contains a sufficient amount of tanezumab to provide the 
intended dose of drug at a concentration of 5 mg/mL.
Each prefilled syringe is packed in an individual carton.  Each prefilled syringe has a unique 
container number.
5.4.1.2. Placebo for Tanezumab
Placebo for tanezumab is presented as a sterile solution for subcutaneous administration, in a 
matching glass pre-filled syringe (PFS).  Each pre-filled syringe is packaged in an individual 
carton.  Each prefilled syringe has a unique container number.
5.4.1.3. Acetaminophen/Paracetamol (Rescue Medication)
Acetaminophen/paracetamol will be issued by the study sites in its approved marketed 
product dress (carton, bottle, documents).  Any approved commercial product of 
acetaminophen/paracetamol tablet/caplet/capsule is permitted. Subjects should bring back 
rescue medication bottles at each study visit for assessment of compliance.
5.4.2. Preparation and Dispensing
See Dosage and Administration Instructions (DAI) for instructions on how to prepare 
tanezumab 2.5 mg SC, 5 mg SC and placebo SC for administration.  Investigational product 
should be prepared and dispensed by an appropriately qualified and experienced member of 
the study staff (eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as 
allowed by local, state, and institutional guidance.
5.4.3. Administration
Tanezumab or matching placebo will be administered via SC injection by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, practitioner, or pharmacist) as allowed by local, state, and institutional guidance 
and at facilities which can handle allergic reactions.  All subjects will receive 1 mL of 
investigational product administered as a SC injection.  Subcutaneous injections are to be 
administered in the abdomen or anterior aspect of the thigh.  Selection of the SC injection 
site for each injection will be at the discretion of the investigator taking into account subject 
preferences when possible.  The SC injection should not be administered in areas where the 
skin is burned, reddened, inflamed, swollen, or scarred. 
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5.5. Investigational Product Storage
The Investigator or an approved representative (eg, Pharmacist) will ensure that all 
investigational products, including any marketed products, are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  See the Pharmacy Manual for storage conditions of the product. 
Storage conditions stated in the single reference safety document (SRSD) (ie, Investigator’s 
Brochure), will be superseded by the storage conditions stated in the investigational product
labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the sponsor approves the use of the investigational 
product after the temperature excursion.  Use of the investigational product prior to sponsor 
approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be
provided to the site.
5.6. Investigational Product Accountability
The Investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.   
5.6.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If Pfizer authorizes destruction to take place at the trial site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer.  Destruction must be adequately documented.
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5.7. Concomitant Treatment(s)
5.7.1. Prohibited Treatment(s)
Use of analgesics (including marijuana and duloxetine) other than acetaminophen/
paracetamol is prohibited throughout Week 32 of the study beginning 48 hours prior to the 
start of the Initial Pain Assessment Period (the seven days prior to Randomization/Baseline) 
or at the period of time prior to the start of the Initial Pain Assessment Period that is ≤5 times 
the half-life of the particular analgesic used, whichever is greater. Refer to Appendix 3: 
Half-Lives of Prohibited Prior and Concomitant Medications, for a detailed washout schedule 
for prohibited medications. This is not an exhaustive list and Pfizer study management 
should be consulted for assistance if needed, in determining whether or not specific 
medications are permitted. Sites must consult product labeling and conduct a taper according 
to the product instructions if a taper is required. 
Use of prescription or over-the-counter (OTC) NSAIDs irrespective of route, eg oral, topical 
or rectal, (including COX-2 selective inhibitors) is also prohibited except in the following 
circumstances. Limited concomitant use of prescription or OTC NSAID may be allowed on 
an occasional basis for self-limiting conditions not related to osteoarthritis however, they 
may not be taken within 48 hours (or 5 half-lives, whichever is greater) of a study visit where 
efficacy assessments are being collected. The study monitor or Pfizer clinician should be 
contacted for approval prior to use whenever possible, and all doses and days of use will be 
recorded on the concomitant analgesic CRF. NSAID use should not exceed a total of 
40 days between Day 1 (Baseline) and Week 32. Beginning at Week 32 (16-weeks after the 
last dose of study medication), subjects may use NSAIDs at their discretion. 
Subjects will be instructed that many over-the-counter medications contain NSAIDs and to 
guard against overuse. Subjects will be instructed to keep a recording of NSAID usage and 
amount. The number of days of NSAID use will be collected weekly via IRT from Baseline 
(Day 1) through the Week 48 visit. Additional information regarding NSAID use such as 
medication names, dosage and reason for use will be collected by the site on a CRF.
NSAID usage will be monitored at 2 levels: the cumulative use from Baseline to Week 32 (a 
maximum of 40 days of use) and the aggregate days of use during each 8 week dosing 
interval (a maximum of 10 days of use).
Subjects who exceed the allowable concomitant NSAID use limit of 40 days of use during 
the treatment phase of the study will be discontinued from the study and entered in the Early 
Termination Follow-up Period. Subjects taking greater than 10 days of aggregate use of 
NSAIDs per 8-week dosing interval (any dosage level of NSAIDs) should be interviewed by 
study site personnel to determine reason for use and if the subject anticipates being able to 
take NSAIDs according to protocol requirements in the future. The discussion should be 
noted in the patient’s source documents. Subjects who indicate that they anticipate being 
able to take NSAIDs no more than 10 days per 8-week period going forward will be allowed 
to continue in the treatment period. However, if these subjects continue to take NSAIDs 
more than 10 days per 8-week period, they should be withdrawn from study treatment and 
entered into the Early Termination Follow-Up period (See Section 6.4). Subjects who 
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indicate they are taking NSAIDs because of insufficient osteoarthritis pain relief or those 
who indicate they cannot or will not follow the protocol specified restrictions for NSAID use 
due to any other condition, should be withdrawn from study treatment and entered in the 
Early Termination Follow-Up period (See Section 6.4). 
Products containing glucosamine sulfate and chondroitin sulfate should not be initiated 
during the study; however, subjects who have taken a stable dose of these products for at 
least 6 months prior to the Initial Pain Assessment Period will be allowed to continue their 
regimen. Herbal, homeopathic, and naturopathic remedies should not be initiated during the 
study; however, subjects who have taken a stable dose of these products for at least 30 days 
prior to the Initial Pain Assessment Period will be allowed to continue their 
regimen. Subjects should be advised that St. John’s Wort and other inducers of CYP3A4/5 
such as carbamazepine and rifampin may interfere with the efficacy of hormonal 
contraceptive products. Biologics (for example: TNF-α inhibitors such as adalimumab, 
etanercept, infliximab) other than study medication, and live attenuated vaccines must not 
have been taken within 3 months prior to the Initial Pain Assessment Period and are 
prohibited during the study. Flumist® Influenza Virus Vaccine Live, Intranasal or other 
inhaled influenza vaccines are the only exception of a live attenuated vaccine that will be 
permitted during the study. 
5.7.2. Permitted Treatments 
Daily low dose aspirin (≤325 mg or per local prescribing practice) therapy for cardiovascular 
prophylaxis is permitted without restriction.
Medications for other (non-osteoarthritis, non-pain) conditions are permitted provided the 
subject has received a stable dose for at least 30 days before the IPAP (30 days prior to 
Screening for antihypertensive medications) and the dose is not expected to change during 
the study.  Note however that dose adjustments (includes starting a new therapy) during the 
study can be made if required, and recorded on the concomitant medication CRF.
Occasional use of pain medications for pain is permitted in situations such as outpatient 
diagnostic procedures (eg, colonoscopy, dental procedures) or limited accidental injury 
(eg, ankle sprains, minor fractures, minor burns/sunburns).  Subjects should be counseled to 
avoid scheduling prospective procedures such that pain medications would be needed within 
48 hours of a study visit (24 hours for acetaminophen/paracetamol).
Subjects should be counseled to contact the assigned study monitor or study clinician for 
guidance/approval regarding the use of prohibited medications for other self-limiting 
conditions, accidental injury or other surgical procedures as the extent of the condition, 
injury or procedure and the resulting pain medication usage may require termination from the 
study. Any use of NSAID must be consistent with the allowed limit described in the 
Prohibited Medications Section 5.7.1.
For subjects who have discontinued investigational product, the investigator may prescribe 
standard of care treatment for subjects to take while completing the 24-week Safety Follow-
up period once the last efficacy assessments have been obtained at the visit occurring 
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16 weeks after the last dose of SC investigational product.  In this study, standard of care 
treatment refers to analgesics approved by the relevant Health Authority to relieve the pain of 
osteoarthritis.  These medications include opioids, topical analgesics, NSAIDs, capsaicin 
products, injectable corticosteroids and viscosupplementation (eg, hyaluronan) and are 
prescribed at the discretion of the Investigator.  Pre-specified analgesics are not considered 
investigational product but will be reimbursed by Pfizer while the subject is participating in 
the 24-week Safety Follow-up period after at least 16 weeks have elapsed since their last 
dose of SC treatment was administered.  Their use will be recorded on the concomitant 
medication CRF. 
5.8. Rescue Therapy
Acetaminophen/paracetamol will be issued to the subject by the study sites in its approved 
marketed product dress (carton, bottle, documents) for use as rescue medication. 
During the Washout period and the Initial Pain Assessment Period, subjects may take rescue
medication (acetaminophen/paracetamol) as needed for osteoarthritis or other types of pain 
or illness up to a maximum daily dose of 4000 mg/day, or as permitted by local or national 
labeling.  Rescue medication must be discontinued at least 24 hours prior to the Baseline 
(Day 1) visit. 
In the event of inadequate pain relief for osteoarthritis during the Double-blind Treatment 
period (between the Baseline [Day 1] visit and Week 24), subjects may take up to a 
maximum permitted daily dose of 4000 mg but only up to 5 days per week, or as permitted 
by local or national labeling. 
From the Baseline (Day 1) visit through Week 24, subjects taking rescue medication greater 
than 5 days per week (any level of acetaminophen/paracetamol used specifically for 
osteoarthritis pain) must be interviewed by study site personnel to determine if this is due to 
lack of efficacy or other reasons, and the discussion should be noted in the subject’s source 
documents. Subjects who have taken rescue medication more frequently than specified in the 
protocol during the treatment period due to lack of efficacy and indicate that they cannot or 
will not follow the rescue medication protocol requirements because of insufficient 
osteoarthritis pain relief should be withdrawn from investigational product due to lack of 
efficacy and entered in the Early Termination Follow-up period (refer to Section 6.4). 
Subjects who indicate that they anticipate being able to take rescue medication no more than 
5 days per week going forward will be allowed to continue in the treatment period. However, 
if these subjects continue to take rescue medication more than 5 days per week, they should 
be withdrawn from investigational product and entered into the Early Termination Follow-up
period (refer to Section 6.4). 
Between the Week 24 and Week 32 visits, subjects may take acetaminophen/paracetamol
rescue medication daily, up to the maximum permitted dose of 4000 mg per day, or as 
permitted by local or national labeling. After the Week 32, subjects may be started on 
standard of care treatments for osteoarthritis pain.  Subjects may continue to use 
acetaminophen/paracetamol as needed up to the maximal permitted dose of acetaminophen 
per day as permitted by local or national labeling.
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During the Early Termination Follow-up period (described in Section 6.4), up to 16 weeks 
after the last dose of SC investigational product, subjects may take 
acetaminophen/paracetamol rescue medication up to the maximum permitted dose of 
4000 mg/day, or as permitted by local or national labeling.  After Early Termination Visit 2 
(approximately 16 weeks after the last dose of SC investigational product) subjects may be 
started on standard of care treatments for osteoarthritis pain. Subjects may continue to use 
acetaminophen/paracetamol as needed up to the maximal permitted dose of 
acetaminophen/paracetamol per day per local or national labeling.
All rescue medication must be discontinued at least 24 hours prior to any scheduled study 
visit at which efficacy data is collected (ie, up to the Week 32 visit that occurs 16 weeks after 
the last dose of SC investigational product).
Subjects should bring back rescue medication bottles at each study visit for assessment of 
compliance.
Subjects will be instructed that many over-the-counter medications contain 
acetaminophen/paracetamol, and to guard against overuse. Subjects will be instructed to 
record their acetaminophen/paracetamol rescue medication usage daily via IRT through 
Week 24.  After Week 24 and through the Week 48 visit, usage of
acetaminophen/paracetamol rescue medication will be recorded once weekly via the IRT.  
The dose and reason for acetaminophen/paracetamol use in instances other than as rescue 
medication (eg, toothache, headache, fever) must be recorded on the appropriate concomitant 
medication CRF.
6. STUDY PROCEDURES 
Refer to Schedule of Activities (Tables 1 and 2) for the lists of procedures to be performed 
throughout the study.
If possible, each subject’s clinic visit should be conducted at approximately the same time of 
day throughout their participation in the study. As a general rule, scales/instruments should 
be completed first by the subject upon arrival at the clinic and vital signs should be assessed 
prior to blood draws at clinic visits.  
Subjects should be thoroughly instructed on completion of the scales/instruments via IRT 
prior to completing them the first time (eg at Screening for WOMAC Pain subscale and 
Numeric Pain Scale Rating; at Baseline for Patient Global Assessment (PGA) of 
Osteoarthritis, EQ-5D-5L, WPAI:OA, mPRTI questionnaires).  No coaching or other 
interpretative assistance should be given to subjects during completion of these 
questionnaires. 
Continuing on from the Initial Pain Assessment Period, subjects will provide a daily 
assessment of their index joint pain through Week 24 via IRT (though these assessments 
could begin as early as at the Screening Visit).  Between Weeks 24 and 48 (End of Study / 
Early Termination), subjects will provide pain scores in the index joint weekly via IRT using 
a 24-hour recall period.  Subjects will also provide a weekly assessment of their non-index 
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joint (major joints, refer to Section 7.1.1) pain via IRT using a 24-hour recall period from the 
Initial Pain Assessment Period to Week 48.  The use of rescue medication will be collected 
daily via IRT beginning in the IPAP (though collection of rescue medication use could begin 
as early as at the Screening Visit) to the Week 24 visit and then weekly until Week 48.  On a 
weekly basis between Baseline and Week 48, subjects will record the number of days of 
concomitant NSAID use via IRT.  
Study visit windows are ±3 days for Weeks 2 and 4, and ±7 days for Weeks 8, 12, 16, 20, 24,
28, 32, 36, 40, 44 and 48.  Study visits should be scheduled with reference to the original 
baseline visit date as much as possible.  Subject scheduling issues should be brought to the 
attention of the assigned study monitor or study clinician for resolution.  Dosing visits should 
occur no earlier than 7 weeks from the previous injection.   Visit window for the Week 48 
(End of study) X-rays is +/-30 days from the nominal time point of the visit; however they 
should preferably be obtained prior to the Week 40 visit and, if possible, less than 14 days 
after the visit.
Subjects will be reminded to abstain from taking rescue medication 24 hours prior to any 
study visit at which efficacy data is collected.
6.1. Screening
The Screening period will consist of a maximum of 37 days prior to Randomization.  Prior to 
entering the Initial Pain Assessment Period (IPAP; see Section 6.1.3), subjects taking 
prohibited medications must complete the required washout from these medications for at 
least 5 half-lives or 48 hours (whichever is greater).  Screening procedures should be staged 
to minimize burden to the subject and to minimize conduct of procedures that may not be 
required if a subject is found to be ineligible.   
Written informed consent will be obtained from each subject prior to any trial assessments.  
Each subject will be assessed as to his/her suitability per inclusion/exclusion criteria review. 
Subject demographics and the date of OA diagnosis for every affected joint will be obtained. 
A comprehensive medical history and concomitant medication review will be performed for 
each subject.
History of insufficient pain relief from, inability to tolerate or contraindication to taking, 
acetaminophen/paracetamol, NSAID, and tramadol or opioid treatments will be clearly 
documented on the appropriate CRF page.  The required level of evidence to establish that 
subjects meet this inclusion criterion will be based upon the investigator’s judgment.  
Investigators should rely upon available medical records that he or she may already have 
access to, prescription medication records (eg, retail pharmacy records), records or 
information provided by referring physicians and/or subject historical recall if the 
investigator is satisfied with the level of detail subjects are able to provide on past medication 
use.  Investigators should clearly document in source records the information used to 
establish whether a subject does or does not meet this inclusion criterion.  As a guide, 
investigators should document medication names, medication doses, reasons for use, dates of 
use and reason for discontinuation.  If one or more of the above medications could not be 
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used due to contraindication or if the subject refuses to take the medication due to fear of 
known side effects, this should also be clearly documented with supporting detail.
NOTE: In Japan, Investigators will also need to document the outcome of a trial of 
acetaminophen.
In addition, a comprehensive evaluation of musculoskeletal history and musculoskeletal 
physical exam will be performed (refer to Section 7.3.1.2). The index joint (hip or knee) will 
be selected at Screening. If bilateral knee and/or hip pain is present, the investigator will 
select the more painful joint as the study (index) joint.  X-ray confirmation of eligibility 
(Kellgren-Lawrence grade ≥2 for selected index joint and absence of exclusionary 
conditions) will be obtained from the imaging Central Reader based on the radiographs of 
each knee, hip and shoulder (and any other major joints imaged at) at Screening.  Screening 
X-rays should be obtained as early as possible in the Screening period to facilitate 
completion of all required procedures within the 37-day Screening period and anticipate that 
it may take up to 2 weeks to obtain X-ray confirmation from the Central Reader.
Other major joints exhibiting signs or symptoms suggestive of osteoarthritis should also be 
imaged and will also be reviewed by the imaging Central Reader.  A major joint is defined as 
a mobile synovial joint in the limbs such as shoulders, elbows, wrists, hips, knees, ankles and 
excluding the joints of the toes and hands. During Screening, subjects will also provide a 
pain score (scored with an 11-point numerical rating scale [NRS]) via Interactive Response 
Technology (IRT) for any other major joint for which a radiograph is obtained (refer to 
Section 7.3.3).
6.1.1. Screening Period:
•
Informed consent.
•
Demographics and general medical history.
•
Assessment of depression by medical history (Use of PHQ-9 is optional and suggested 
as a tool to assess seriousness of depression if needed. If the PHQ-9 is utilized, the 
completed questionnaire should be archived in the subject’s source documents.).
•
Numeric Pain Scale rating (IRT) for major joints (bilateral shoulders, hips and knees) 
and any painful joint imaged at Screening.
•
Primary diagnosis and selection of index hip or knee.
NOTE: If the subject experiences pain in more than one joint, then the most painful joint 
should be selected as the index joint.  Radiographic eligibility of the selected index joint 
will need to be confirmed by the Central Reader. 
•
WOMAC (all subscales via IRT) for index hip or knee.
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NOTE: Subjects should be thoroughly instructed on completion of WOMAC scales, and 
no coaching or other interpretative assistance should be given to subjects during 
completion of these questionnaires.
•
Comprehensive musculoskeletal/joint related medical history (includes past history of 
osteoarthritis, osteoporosis, osteopenia, joint pain, injury, trauma, joint surgeries 
(including arthroscopic procedures), ligament tear or rupture, fractures, gout, joint 
injuries or other conditions.
•
Medication history (record any use of medications for osteoarthritis, prior 30 day use for 
all other medications).
•
Weight and Height with BMI calculation, Smoking Status, Alcohol Use/Dependency, 
Female Hormonal Status (if known or pending laboratory results).
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine / standing) measurement.
•
General physical examination.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score.
•
Survey of Autonomic Symptoms (SAS) questionnaire.
•
ECG (12-lead).
•
X-rays of each knee, hip and shoulder (and any other painful, major joint if appropriate).
•
Clinical laboratory tests (blood chemistry, hematology, and urinalysis, serum 
Hepatitis B, C, and HIV screen, urine toxicology screen, HbA1c), serum pregnancy 
testing/FSH testing if needed.
NOTE: Clinically significant abnormal laboratory tests (except urine toxicology screen) 
or tests not meeting inclusion/exclusion criteria may be repeated for verification prior to 
Baseline.  Refer to Section 7.3.2 for specific instructions related to laboratory screening 
tests.
•
Inclusion/exclusion review (pending results of laboratory tests, ECG and X-rays).  If a 
subject qualifies other than pending results they may begin the washout of prohibited 
pain medications (refer to Section 5.7.1 and Appendix 3).  Subjects who are found to be 
ineligible subsequent to the receipt of disqualifying laboratory, ECG or X-ray results 
may be asked to return requested study related materials and will exit the Screening 
period (Screen Failure).
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•
Female subjects of child-bearing potential will be instructed on the contraception
requirements for this study; the investigator or designee will confirm that female subjects 
of child-bearing potential have selected 2 highly effective or acceptable forms of 
contraception from the list of acceptable methods and instruct the subject in their 
consistent and correct use.  The conversation will be documented in the subject chart. 
NOTE: In Japan, only female subjects who are not of childbearing potential will be 
eligible for this study.
NOTE: In Sweden, the investigator or designee will confirm that female subjects of 
child-bearing potential have selected 1 highly effective form of contraception from the 
list of acceptable methods and instruct the subject in their consistent and correct use.  
The conversation will be documented in the subject chart.
•
Dispense Screening period rescue medication; subjects will be instructed on the 
permissible amounts of rescue medication during the washout period, during the IPAP 
and during the treatment period, as well as the need to refrain from rescue medication 
use at least 24 hours prior to a study visit (refer to Section 5.8).
•
Subjects will be instructed in the use of the IRT system to record daily/weekly pain 
ratings, rescue medication use and any NSAID use, with specific instructions as when to 
test the system and when to begin entering data;
•
Subjects in Japan who have not had a trial of acetaminophen (as monotherapy or in 
combination with tramadol) for their osteoarthritis, will undergo at least a 1-week trial of 
an approved daily dose of acetaminophen after obtaining informed consent because 
subjects are required to have documentation that acetaminophen has not provided 
sufficient pain relief. If they obtain sufficient response to acetaminophen, as judged by 
the subject and Investigator, they will then be withdrawn from the study. Those who do 
not have a sufficient response to acetaminophen will continue with the screening 
process.  Subjects who have not achieved an adequate response to an approved dose of 
Tramacet® (1 - 2 tablets four times a day (QID): total daily tramadol 150 mg - 300 mg 
and acetaminophen 1300 mg - 2600 mg) can be considered to meet the acetaminophen 
and tramadol inclusion criterion. 
•
Subjects who are found to be ineligible may be asked to return requested study related 
materials and will exit the Screening period (Screen Failure);
•
Subjects who do not require a washout of prohibited pain medications may begin the 
Initial Pain Assessment Period, preferably once X-ray confirmation of radiographic 
eligibility of the subject has been received from the Central Reader.
6.1.2. Washout Period
The beginning of the Washout Period will preferably be scheduled based on the planned start 
of the Initial Pain Assessment Period so as to minimize the time spent without analgesic 
medications prior to Randomization.  The Washout Period will include the discontinuation 
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and washout of all prohibited medications for at least 5 half-lives or 48 hours (whichever is 
greater) prior to the Initial Pain Assessment Period (the 7 days prior to randomization) and 
will be a minimum of 2 days for all prohibited pain medications (Refer to Appendix 3).  
Subjects experiencing pain during the Washout Period may take acetaminophen as needed up 
to 4000 mg per day, but must discontinue rescue medication for at least 24 hours prior to the 
Baseline (Randomization) Visit.  However, the total duration of the Screening period is not to 
exceed 37 days.
6.1.3. Initial Pain Assessment Period (IPAP)
The IPAP will begin 7 days prior to the Baseline (Day 1) randomization visit, and subjects 
must complete at least 3 diary entries during the IPAP period, but all diary entries will be 
used to determine the baseline value for the average pain score in the index joint. 
•   During this time, subjects will record daily pain scores for their index joint (knee or hip) 
and rescue medication use via the IRT (refer to Sections 7.1.1 and Section 7.1.2).  
Assessment of the non-index joints will be performed once during the IPAP.
NOTE: Study sites will monitor the IRT reports for compliance with diary recordings 
and rescue medication use and reschedule those subjects who fail to provide 3 diary days 
or fail to refrain from rescue medication use 24 hours prior to Baseline.
6.2. Double-Blind Treatment Period
The Double-blind Treatment period begins with the Baseline (Day 1) visit and concludes 
with completion of the Week 24 visit procedures.  The Double-blind Treatment period is 
24 weeks in duration and consists of 7 clinic visits (Day 1 and Weeks 2, 4, 8, 12, 16 and 24) 
and 1 telephone contact (Week 20) between site staff and study subjects.  
6.2.1. Baseline (Day 1) Clinic Visit
6.2.1.1. Assessment of Randomization Criteria and Randomization
Subjects must continue to satisfy Inclusion/Exclusion Criteria [general criteria and those 
specific to the Baseline (Day 1) visit – refer to Section 4.3] to be eligible for Randomization. 
Full eligibility, including (but not limited to) confirmation of appropriate washout of 
concomitant medication, abstinence from acetaminophen/paracetamol in the previous 
24 hours, completion of at least 3 diary entries in the past 7 days, required WOMAC Pain 
and Physical Function subscale and Patient’s Global Assessment of Osteoarthritis scores, and 
that no adverse events occurred since signing informed consent that would render the subject
ineligible for randomization, should be assessed before carrying out randomization in the 
IRT system.
Subjects will undergo the following assessments prior to randomization:
•
Inclusion/exclusion review (including results of ECG, laboratory and X-rays obtained at 
the Screening visits).
•
WOMAC (all subscales).
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•
Patient’s Global Assessment of Osteoarthritis.
NOTE: Subjects should be thoroughly instructed on completion of Patient’s Global 
Assessment of Osteoarthritis questionnaires, no coaching or other interpretative 
assistance should be given to subjects during completion of these questionnaires.
•
Musculoskeletal physical examination.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Review of concomitant medication.
•
Rescue medication (acetaminophen/paracetamol) review.
•
Instruction/review of subject compliance with daily/weekly assessments and operation of 
the IRT.
•
Confirm with females of child bearing potential that they understand and are willing to 
follow the contraceptive requirements.
•
Adverse events that occurred after signing the Informed Consent Document 
(pretreatment adverse events).
•
Urine pregnancy test for females of childbearing potential (must be negative).
6.2.1.2. Randomization 
Subjects satisfying eligibility requirements will be randomized via an IRT system.  The 
randomization number assigned to the subject will be provided by the system.  Subjects 
satisfying eligibility requirements will undergo the following assessments prior to the first 
dose of investigational product.  
6.2.1.3. Pre-dosing (Day 1)
Randomized subjects will undergo the following assessments prior to the first dose of 
investigational product.  Some of these may be performed prior to randomization for 
convenience:
•
WPAI:OA.
•
EQ-5D-5L.
•
Assessment of Health Care Resource Utilization.
•
Neurologic exam/Neuropathy Impairment Score.
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•
Clinical laboratory tests (blood chemistry and hematology).
•
Serum and plasma retention samples.
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.9).
•
Blood samples for pharmacokinetics (PK) and pharmacodynamics (PD) (NGF) analyses 
(refer to Section 7.5).
•
Blood and urine samples for biomarkers (fasting if possible, urine sample should be from 
2nd void of the day or after; refer to Section 7.6).
•
Blood sample for banked biospecimens (see Section 7.7.1 Markers of Drug Response and
Other Additional Research, Section 7.7.2).
•
Dispense rescue medication.
•
Female subjects of child-bearing potential to be reminded of contraceptive requirements.
6.2.1.4. Dosing (Day 1)
Subjects will receive a single SC injection of blinded investigational product according to the 
treatment assigned by the IRT system (refer to Section 5).
The administration of investigational product must be performed by trained medical staff and 
where facilities to handle allergic reactions are available.  Should a subject experience 
symptoms typical of an allergic reaction, then investigational product administration should 
be discontinued permanently.  Subjects will receive appropriate treatment such as 
corticosteroids or antihistamine at the discretion of the Investigator.  No other dosage 
modifications are allowed.
6.2.1.5. Post-dosing (Day 1)
Subjects will be observed in the clinic for at least 1 hour after dosing.  The following 
procedures will be completed at approximately 1-hour post-dose:
•
Review and record adverse events.
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.2. Routine Clinic Visits (Week 2, Week 4 and Week 12)
The subject will return for clinic visits at Week 2, Week 4 and Week 12 to be assessed for 
efficacy and safety. Refer to Schedule of Activities (Table 1) for the procedures to be 
performed at the Week 2, Week 4 and Week 12 Visits.
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6.2.3. Dosing Visits (Week 8 and Week 16)
The subject will return for clinic visits at Week 8 and at Week 16 to be assessed for efficacy 
and safety.  At Week 8 and Week 16 the subject will receive the second and third 
administrations of SC investigational product, respectively. Refer to Schedule of Activities 
(Table 1) for the procedures to be performed at the Week 8 and Week 16 Clinic Visits.  The 
dosing and post-dosing procedures are the same as those as described in Sections 6.2.1.4 and 
Section 6.2.1.5.
6.2.4. Phone Contact Visit (Week 20)
The subject will be contacted by telephone at Week 20 to review adverse events, concomitant 
medications, compliance with daily/weekly IRT entries and to remind female subjects of 
contraceptive requirements.
Refer to Schedule of Activities (Table 1) for the procedures to be performed at the Week 20 
Phone Contact. At the time of this phone contact visit, reminder to schedule Week 24 X-rays 
to occur within the window for Week 24 X-rays.
6.2.5. Week 24 Clinic Visit (End of Double-Blind Treatment)
The subject will return for a clinic visit at Week 24 to be assessed for efficacy and safety.  
Refer to Schedule of Activities (Table 1) for the procedures to be performed at Week 24 
Clinic Visit and Section 7 for more details on these procedures.
With the completion of the Week 24 visit, the subject will begin the 24-week Safety Follow-
up Period.  
6.3. Safety Follow-up Period
The Safety Follow-up period begins once the Week 24 procedures have been completed and 
concludes with completion of the Week 48 visit procedures.  The Safety Follow-up period is 
24 weeks in duration and consists of 2 clinic visits (Weeks 32 and 48) and 4 telephone 
contacts (Weeks 28, 36, 40 and 44) between site staff and enrolled subjects.
6.3.1. Phone Contact Visits (Weeks 28, 36, 40 and 44)
The subject will be contacted by telephone at Weeks 28, 36, 40 and 44 to review adverse 
events, concomitant medications, compliance with weekly IRT entries and to remind female 
subjects of contraceptive requirements (Week 28 only).
At the Week 44 phone contact visit, schedule Week 48 X-rays, to occur preferably prior to 
the nominal time point of the Week 48 visit and if possible, no more than 14 days after the 
Week 48 visit.
Refer to Schedule of Activities (Table 1) for the procedures to be performed at the Weeks 28, 
36, 40 and 44 Phone Contact.
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6.3.2. Routine Clinic Visit (Week 32)
The subject will return for a clinic visit at Week 32 to be assessed for efficacy and safety. 
Refer to Schedule of Activities (Table 1) for the procedures to be performed at the Week 32 
Visit.
Once the clinic visit has been completed and final efficacy assessments have been collected, 
standard of care treatment can be offered to subjects who intend to complete the remaining 
16 weeks of the required Safety Follow-up period. In this study, standard of care treatment 
refers to analgesics approved by the relevant Health Authority to relieve the pain of 
osteoarthritis.  Standard of care treatment may be initiated as needed and should be recorded 
on the concomitant medication CRF.
6.3.3. Week 48 Clinic Visit (End of Study)
The subject will return for a clinic visit at Week 48 to be assessed for safety. Week 48 is the 
End of Study Visit.  Refer to Schedule of Activities (Table 1) for the procedures to be 
performed at the Week 48 (End of Study) Clinic Visit.
If not already completed, schedule subject for follow-up radiographic assessments (X-rays) 
of bilateral shoulders, hips and knees and any other joint for which a radiograph was obtained 
at the Screening visit or any at risk joint identified during the study period (refer to Section 
7.3.7).
6.4. 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 does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, follow-up with the subject regarding any unresolved adverse 
events and request that the subject return for follow-up visits as indicated in the schedule 
below.  Subjects of child-bearing potential should be reminded to continue contraceptive 
measures at least 112 days (16 weeks) after the last dose of investigational product.  
Subjects discontinuing from treatment (prior to Week 24), either at their request or at the 
decision of the investigator, will be required to undergo 24 weeks of post-treatment follow-
up (as described in Section 6.4.1).  The 24 weeks of follow-up will be obtained through 3 
clinic visits and 2 phone calls to yield 24 weeks of follow-up, as described in Section 6.4.1.   
In addition, subjects will be asked to continue to enter pain scores for index and non-index 
joint pain scores and for major joints via IRT, weekly, until 24 weeks after the subject’s last 
dose of SC study treatment to the end of the 24-Week Safety Follow-up period.
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In the event a subject refuses the Early Termination safety follow-up, or chooses to 
discontinue during the safety follow-up (after Week 24 and through Week 48), a complete 
early termination visit should be performed that should include all procedures described in 
Section 6.4.1.1. Early Termination 1 (also described in Table 2 column 3), including the X-
rays of major joints provided at least 30 days have elapsed since the last X-rays were 
collected (see Section 6.4.1. and Table 2 column 2). In addition, female subjects will be 
advised to continue their contraception regimen during a period of 112 days (16 weeks) after 
the last dose of SC investigational product.
Withdrawal of Consent: Subjects who request to discontinue study treatment will remain in 
the study and will continue to be followed for protocol specified follow-up procedures unless 
they specifically withdraw consent for any further contact with him or her or persons 
previously authorized by the subject to provide this information. Subjects should notify the 
investigator in writing of the decision to withdraw consent from future follow-up in writing, 
whenever possible.  The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is only from further receipt of 
investigational product or also from study procedures and/or post treatment study follow-up, 
and entered on the appropriate CRF page.  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.  Pfizer may retain and continue to use 
any data collected before such withdrawal of consent.
Lost to Follow-Up: All reasonable efforts must be made to locate subjects as to determine 
and report their ongoing status.  This includes follow-up with persons authorized by the 
subject as noted above.  Lost to follow-up is defined by the inability to reach the subject after 
a minimum of 2 documented contacts (via phone calls, faxes, and/or emails) as well as lack 
of response by subject to 1 registered mail letter.  All attempts should be documented in the 
subject’s medical records.  If it is determined that the subject has died, the site will use 
permissible local methods to obtain the date and cause of death.  If the investigator’s use of a 
third-party representative to assist in the follow-up portion of the study has been included in 
the subject’s informed consent, then the investigator may use a Sponsor retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If after all attempts, 
the subject remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.
Brief summary of procedures for subjects discontinuing from study treatment 
X-rays of the knee, shoulder and hip (and any other joint imaged at Screening or identified as 
at risk during the study) should be performed as soon as possible after the decision to 
withdraw from the study has been made, provided at least 30 days have passed since the last 
set of X-rays were collected (refer to Section 6.4.1.).  
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The remainder of efficacy and safety assessments should be done at the scheduled first visit 
which is to occur approximately 8 weeks after the last dose of SC study treatment (refer to
Section 6.4.1.1., Early termination Visit 1).  The site should also schedule the subject for two 
additional clinic visits.  The second visit should be scheduled to occur approximately 
16 weeks after the subject’s last dose of SC study treatment (which corresponds to more than 
5 times the elimination half-life of tanezumab) to collect safety and efficacy data (refer to 
Section 6.4.1.3., Early Termination Visit 2).  Once the clinic visit 16 weeks after the last 
administration of SC study treatment has been completed and final efficacy assessments have 
been collected, standard of care treatment may be offered to subjects who are completing the 
remaining 8 weeks of the required follow-up period.  The third and final clinic visit should be 
scheduled to take place approximately 24 weeks after the subject received the last dose of SC 
study treatment (refer to Section 6.4.1.4., Early Termination Visit 3).  Telephone contact will 
be made with subjects at approximately 12 and 20 weeks following the last SC dose of study 
treatment.  Every effort should be made to have the subject agree to complete the entire 24-
week Early Termination Safety Follow-up described in Section 6.4.1.
6.4.1. Early Termination Follow-Up Procedures
As soon as possible following a decision to withdraw a subject from the study is made, 
provided at least 30 days have passed since the last set of X-rays were collected, X-rays of all 
joints for which X-rays were obtained at Screening and other at risk joint identified during 
the study period should be obtained (refer to Section 7.3.7.). X-rays should be submitted to 
imaging central reader.  
Refer to the Early Termination Schedule of Activities (Table 2).
6.4.1.1. Early Termination Visit 1 (~8 weeks after last dose of SC investigational 
product)
Refer to the Early Termination Schedule of Activities (Table 2) and Section 7 for information 
on the procedures to be performed at Early Termination Visit 2.
6.4.1.2. Early Termination Telephone Contacts 1 and 2 (~12 weeks and ~20 weeks after 
last dose of SC investigational product)
The subject will be contacted by telephone twice (~12 weeks and ~20 weeks after the last 
dose of SC investigational product) to review adverse events, concomitant medications, 
compliance with daily/weekly IRT entries and to remind female subjects of contraceptive 
requirements.
Refer to the Early Termination Schedule of Activities (Table 2) for the procedures to be 
performed at the Early Termination Telephone Contacts.
At Telephone Contact 2, schedule Week 24 X-rays, to occur preferably prior to the nominal 
time point of the visit but if possible, no more than 14 days after the Early Termination Visit
3.
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6.4.1.3. Early Termination Visit 2 (~16 weeks after last dose of SC investigational 
product)
Refer to the Early Termination Schedule of Activities (Table 2) and Section 7 for information 
on the procedures to be performed at Early Termination Visit 2.
6.4.1.4. Early Termination Follow-up Visit 3 (~24 weeks after last dose of SC 
investigational product)
Refer to the Early Termination Schedule of Activities (Table 2) and Section 7 for information 
on the procedures to be performed at Early Termination Visit 3.
6.4.2. Procedures for Subjects Undergoing Joint Replacement
Subjects who have undergone or plan to undergo total joint replacement or other arthroplasty 
procedure during the study will be discontinued from investigational product. 
Subjects who undergo total knee, hip or shoulder joint replacement surgery during the study 
(Double-blind Treatment Period or Follow-up Period) will be followed for 24 weeks after the 
procedure as part of a separate protocol (Study A4091064), provided the subject consents.
Transition procedures into Study A4091064 are determined by the timing of total joint 
replacement surgery:  
•
Subjects who have undergone or plan an immediate total knee, hip or shoulder joint 
replacement will be discontinued from the Double-Blind Treatment period and enter into 
the total joint replacement follow-up protocol (Study A4091064).  At the discontinuation 
visit, all procedures scheduled for the Week 24 and Week 32 visits should be completed 
unless the Subject has already completed the Week 24 and Week 32 visits, in which case 
only Week 48 procedures will be required.  In addition, if the Week 24 visit was not 
completed prior to termination, a general physical examination, body weight, WPAI:OA, 
EQ-5D-5L and mPRTI will also be obtained.  Applicable Study A4091064 Baseline Visit 
activities should be completed on the same day as the Study A4091057 End of Treatment 
Visit. 
•
Subjects who plan to undergo total knee, hip or shoulder joint replacement during the 
study will be discontinued from the Double-blind Treatment Period and entered into 
Early Termination Follow-up (See Section 6.4) until their joint replacement procedure.  
For these subjects, a complete early termination visit should be conducted prior to the 
total joint replacement (See Section 6.4) and entrance into Study A4091064.  Study 
A4091064 Baseline Visit activities should be completed on the same day as the Study 
A4091057 early termination visit.  Subjects who have not undergone or scheduled total 
joint replacement surgery within the study treatment period or safety follow-up period of 
this study will not be eligible for Study A4091064. 
Subjects who undergo other types of joint replacement surgery or arthroplasty during the 
study should be discontinued from investigational product and complete the protocol 
specified Safety Follow-up Period, but are not eligible for entry into Study A4091064.
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7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and 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 the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/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. Subject Diary Assessments
7.1.1. Daily / Weekly Pain Assessments
If possible diary assessments of pain in the index joint and assessment of the major non-
index joints will be completed by the subject at approximately the same time each day (or 
each week).  Average pain will be assessed with an 11-point Numeric Rating Scale (NRS) 
ranging from zero (no pain) to 10 (worst possible pain) captured through IRT. The subjects 
should describe their pain in the index joint (and non-index joint when applicable) during the 
past 24 hours by choosing the appropriate number from 0 to 10.  If possible, subjects should 
conduct the self-assessment in the evening.
Index Joint Pain Assessment
Average pain in the index joint will be assessed by the subject daily from the beginning of 
the IPAP to the Week 24 Visit, followed by weekly beginning after the Week 24 visit 
through Week 48 (and weekly during the Early Termination Follow-Up Period, if 
applicable).  
•
Example question when the identified index joint is the right knee:
“Select the number that best describes your average pain in your index joint, the right knee in 
the past 24 hours”:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
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•
Example question when the index joint is the right hip:
“Select the number that best describes your average pain in your index joint, the right hip in 
the past 24 hours”:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
Non-index Joint Pain Assessment
On a weekly basis beginning at the Initial Pain Assessment Period and through Week 48 of 
the study (and weekly during the Early Termination Follow-Up Period), subjects will also be 
asked if he/she experienced new onset or increased pain in any major non-index joint.  A 
major joint is defined as a mobile synovial joint in the limbs such as shoulders, elbows, 
wrists, hips, knees, ankles and excluding the joints of the toes and hands.  If a subject
responds that he/she has experienced new onset or increased pain in a non-index joint or 
other major joint (post-baseline), the subject will be asked to rate his/her pain in that joint on 
the same 11-point numeric rating scale shown above and will be asked to rate his/her pain in 
that joint for the remainder of the study.
7.1.2. Rescue Medication and Amount
Rescue medication use will be collected daily via IRT from the beginning of the IPAP to the 
Week 24 Visit.  The dosage strength of the acetaminophen/paracetamol
tablets/caplets/capsules will be captured.  The subject should note the number of 
tablets/caplets/capsules of rescue medication taken during the last 24 hours. 
Following the Week 24 visit up to the Week 48 visit and during the Early Termination 
Follow-Up Period for subjects who enter this phase of the study, the use of acetaminophen / 
paracetamol as rescue medication will be collected once weekly using IRT.  The subject will 
record the number of days when rescue medication was used and maximum number of 
tablets, capsules or caplets of rescue medication taken on any day in the past week.
7.1.3. Concomitant NSAID Use
Use of over-the-counter or prescription NSAID will be collected weekly via IRT from the 
Baseline (Day 1) visit until the Week 48 visit.  During the Early Termination Follow-Up 
Period for subjects who enter this phase of the study, the use of over-the-counter or 
prescription NSAID will be collected once weekly using IRT.  Subjects will record the 
number of days of NSAID use in the past week using IRT.  At telephone or clinic visits, sites 
will interview the subject regarding their NSAID use and record additional information on a 
CRF, such as the medication name, dosage and reason for use.  The investigator or designee 
should closely monitor for concomitant NSAID use.  Subjects reporting concomitant NSAID 
use will be managed per guidance provided in Section 5.7.1. 
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7.2. Study Visit Efficacy Assessments
For the timings of procedures, refer to Schedule of Activities (Tables 1 and 2). 
7.2.1. Western Ontario and McMaster Universities Osteoarthritis Index
A copy of the WOMAC19 Osteoarthritis NRS Index is provided in Appendix 4. The 
WOMAC subscales will be recorded via IRT at relevant study visits.
7.2.1.1. WOMAC Pain Subscale
At Screening and for the remainder of a subject’s participation in the study, a WOMAC pain 
subscale questionnaire will only be completed for the index knee or hip.
The WOMAC Pain subscale is comprised of 5 questions regarding the amount of pain 
experienced due to osteoarthritis in the index joint (selected study knee or hip) in the past 48 
hours.  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.
7.2.1.2. WOMAC Physical Function Subscale
At the Baseline (Day 1) visit and for the remainder of a subject’s participation in the study, a 
WOMAC Physical Function subscale questionnaire will only be completed for the index 
knee or hip.
The WOMAC Physical Function subscale is comprised of 17 questions regarding the degree 
of difficulty experienced due to arthritis in the index joint (selected knee or hip) in the past 
48 hours.  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.
7.2.1.3. WOMAC Stiffness Subscale
At the Baseline (Day 1) visit and for the remainder of a subject’s participation in the study, a 
WOMAC Stiffness subscale questionnaire will only be completed for the index knee or hip.
The WOMAC Stiffness subscale is comprised of 2 questions regarding the amount of 
stiffness experienced in the index joint in the past 48 hours.  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.
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7.2.2. Patient’s Global Assessment of Osteoarthritis
At the Baseline (Day 1) visit and for the remainder of a subject’s participation in the study, a 
Patient’s Global Assessment of Osteoarthritis questionnaire will only be completed for the 
index knee or hip (Appendix 5).
Subjects who have a knee as index joint will answer the following question: “Considering all 
the ways your osteoarthritis in your knee affects you, how are you doing today?”
Subjects who have a hip as index joint will answer the following question: “Considering all 
the ways your osteoarthritis in your hip affects you, how are you doing today?”
Subjects will rate their condition using the following scale:
Grade
Description
1 – Very Good
Asymptomatic and no limitation of normal activities
2 – Good 
Mild symptoms and no limitation of normal activities
3 – Fair 
Moderate symptoms and limitation of some normal activities
4 – Poor 
Severe symptoms and inability to carry out most normal activities
5 – Very Poor
Very severe symptoms which are intolerable and inability to carry 
out all normal activities
7.2.3. Work Productivity and Activity Impairment Questionnaire - Osteoarthritis –
Knee or Hip v2.0 (WPAI:OA)
The WPAI-OA Knee or Hip is a 6-item validated questionnaire that assesses the impact of 
osteoarthritis on absenteeism, presenteeism, work productivity, and activity impairment.20
Each subscale score is expressed as an impairment percentage (0-100) where higher numbers 
indicate greater impairment and less productivity.  The WPAI-OA is self-administered by the 
subject and takes less than 5 minutes to complete (Appendix 6).
7.2.4. EuroQol 5 Dimension (EQ-5D-5L)
The EQ-5D-5L™is a subject completed questionnaire designed to assess the subject’s 
current health and translate that score into an index value or utility score. Health status is 
described in terms of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression.  There are two components to the EQ-5D-5L™: a Health State Profile 
and a visual analog scale (VAS) item. The 5 item health state profile will be assessed to 
calculate a single index value (see Appendix 7). This instrument provides a mechanism for 
conducting cost-effectiveness and cost-utility analyses.21
7.2.5. Patient Reported Treatment Impact Assessment-modified (mPRTI)
The mPRTI is a self-administered questionnaire containing four items to assess subject
satisfaction, previous treatment, preference and willingness to continue using the 
investigational product. Higher scores indicate greater satisfaction, preference or willingness 
to use the investigational product; see Appendix 12. Subjects will record their responses 
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using IRT.
7.2.6. Assessment of Health Care Resource Utilization of Healthcare Resources 
Assessment
The utilization of health care resources (eg doctor office visits, hospitalizations, surgeries, or 
procedures, etc.) during the 3 months prior to Baseline will be assessed by questionnaire at 
Baseline (Day 1), Week 32 and Week 48, and also at Early Termination Visits 2 and 3 
(Tables 1 and 2). Subjects will record their responses using IRT.
7.3. Safety Assessments
For the timings of procedures, refer to Schedule of Activities (Tables 1 and 2). 
Each subject will provide a general medical history as well as a detailed 
musculoskeletal/joint specific medical history.  The information will be recorded on the 
appropriate CRF(s) at Screening.  Information on prior medications (within 30 days of the 
Screening Visit for non-analgesic medications, any used for pain and other medications for 
the treatment and relief of symptoms of osteoarthritis), non-pharmacologic therapies, 
supplements and concomitant medication use will be collected at Screening and concomitant 
medication at each scheduled study visit.  Information regarding tobacco and alcohol use and 
dependency will also be collected at Screening.
7.3.1. Physical Examination
7.3.1.1. General Physical Examination
Each subject will undergo a general physical examination.  
7.3.1.2. Musculoskeletal History and Physical Examination
At Screening, the investigator should collect a thorough musculoskeletal history. The 
investigator should inquire about current and past history of osteoarthritis, ligament tear or 
rupture, joint surgeries (including arthroscopic procedures), fractures, gout, osteoporosis,
osteopenia, joint injuries or other conditions.
At each visit, the investigator will conduct a thorough musculoskeletal physical examination
of all major joints.  The musculoskeletal physical examination should evaluate the joints for 
swelling, redness, tenderness, deformity, osteophytes or nodes, crepitus and pain on motion 
and will be documented on the CRF.  The investigator should also collect subject-reported 
information on any current joint symptoms including pain, stiffness, and swelling. Any 
clinically significant change in symptoms or the examination should be reported as an 
adverse event.  
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7.3.2. Laboratory Safety Assessments
Blood and urine tests for safety assessments and/or determination of eligibility will be 
performed as indicated in this table and described in the subsections below:
Chemistry
Hematology
Other
Urinalysis
Screening, Baseline (Day 1), 
Weeks 16 and 32 (or Early 
Termination Visit 2):
Sodium, 
potassium, 
chloride, 
bicarbonate, 
glucose (non fasting), 
Blood Urea Nitrogen (BUN),
creatinine, 
calcium, 
phosphorus, 
magnesium, 
total and direct bilirubin, 
total protein, 
albumin, 
cholesterol, 
triglycerides, 
gamma glutamyltransferase 
(GGT), 
alanine aminotransferase (ALT), 
aspartate aminotransferase (AST),
lactic dehydrogenase (LDH), 
alkaline phosphatase, 
creatine phosphokinase (CPK), 
and uric acid
Screening, Baseline 
(Day 1), Weeks 16 and 
32 (or Early 
Termination Visit 2):
Complete blood count 
with differential
Screening only:
HbA1c
Hepatitis screen (eg, HBsAg, 
Anti-HCV), 
HIV test (HIV Ab screen)
Urine toxicology screen (eg, for 
opiates, barbiturates, 
amphetamines, cocaine, 
propoxyphene, methadone,  
phencyclidine, and 
methaqualone).
Serum FSH if applicable
Screening, Weeks 24 and 32 (or 
Early Termination Visits 1 and 2):
Serum Pregnancy Test
Baseline, Weeks 8 and 16 (Prior 
to dosing at Dosing Visits):
Urine Pregnancy Test
Baseline, Weeks 24 and 32 (or 
Early Termination Visits 1 and 2):
Serum and plasma retention 
samples
Screening only:
pH, 
protein, 
glucose, 
ketones, 
blood, 
bilirubin, 
nitrite, 
specific gravity and 
leukocytes.  
Microscopic 
analysis performed 
if abnormalities are 
present on the above 
components.
Does not include PK, PD (NGF), anti-tanezumab antibodies, or biomarkers (refer to sections below for collection details)
7.3.2.1. Blood Tests
Blood tests for clinical laboratory testing (chemistry, hematology) will be performed.  An 
unscheduled visit(s) may be necessary for follow-up of abnormal test results.
Serum and plasma retention samples will be collected.
See Section 7.3.2.3. for sample collected for serum pregnancy test and Section 7.3.2.4. for 
sample collected for FSH testing.
Blood samples collected for PK, PD (NGF), biomarkers and anti-drug antibody 
measurements are described in Sections 7.5.1, 7.5.2, 7.6. and 7.3.9.
7.3.2.2. Urinalysis and Urine Toxicology Screen
Urinalysis and urine toxicology screen will be performed at Screening only.
See Section 7.3.2.3. for urine pregnancy test.
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Urine samples collected for biomarker analyses are described in Section 7.6.2.
7.3.2.3. Pregnancy Tests
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed at screening, before investigational 
product administration at the baseline visit, and at the end of treatment visit.  A negative 
pregnancy result is required before the subject may receive the investigational product.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected), and repeated at 
Visits 8, 16, at the end of the study to confirm the subject has not become pregnant during the 
study, and at Week 32 (16 weeks after the last dose of investigational product was 
administered).  Pregnancy tests may also be repeated as per request of institutional review 
boards (IRBs)/ethics committees (ECs) or if required by local regulations. 
Qualitative urine pregnancy tests must be sensitive to at least 25 mIU/mL.  Qualitative 
point-of-service urine pregnancy tests will be conducted with the test kit provided by the 
central laboratory in accordance with instructions provided in its package insert.  Subjects 
who have missed a menstrual period or who show an indeterminant or positive result on the 
qualitative point-of-service urine test may not further progress in the study until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test 
conducted at a certified laboratory).
In the case of a positive human Chorionic Gonadotropin (hCG) test, the subject will be 
withdrawn from investigational product but may remain in the study.  
Refer to Sections 8.10 and 8.10.1 for guidance pertaining to exposure during pregnancy and 
post-natal follow-up.
7.3.2.4. Serum FSH Testing
Female subjects of non-childbearing potential who have not had a hysterectomy or bilateral 
oophorectomy and who have been amenorrheic at least 1 year with no alternative 
pathological or physiological cause must undergo serum FSH testing to determine post-
menopausal status.  A serum FSH level within the laboratory’s reference range for post-
menopausal females is required.  Female subjects who have undergone documented total 
hysterectomy or bilateral oophorectomy or who have medically confirmed ovarian failure are 
not of childbearing potential and do not require serum FSH testing.
Female subjects who have been amenorrheic less than 1 year will be considered of child-
bearing potential.
Female subjects of childbearing potential do not require FSH testing.
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7.3.3. Assessment of Pain in Major Joints at Screening with Numeric Pain Scale Rating 
(NRS)
Average pain in the major joints (shoulders, hips and knees) or any other painful, major joint 
that will be imaged at Screening, will be assessed by the subject at the Screening Visit with 
an 11-point Numeric Rating Scale (NRS) ranging from zero (no pain) to 10 (worst possible 
pain) and captured using IRT.
7.3.4. Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) will be collected and 
recorded throughout the study.  Vital signs will be collected after the subject has been in a 
sitting position for at least five minutes at each noted visit.  
7.3.4.1. Orthostatic Blood Pressure Measurement
In addition to sitting vital sign measurements, orthostatic blood pressure measurements will 
be obtained using a standard manual sphygmomanometer.  At each of these clinic visits, 
blood pressure will be assessed in supine and standing positions.  Orthostatic blood pressure 
measurements will be obtained after collection of the sitting vital signs and before any 
required phlebotomy (and prior to dosing at dosing visits).  To minimize chances of 
orthostatic hypotension related to volume depletion, subjects should be reminded to report 
for clinic visits well hydrated.  In this regard, investigators could consider recommending to 
subjects that they consume 8 – 16 ounces (240 – 480 mL) of water prior to reporting to the 
clinic for study visits. All orthostatic blood pressure measurements will be recorded in the 
IRT system.
Supine blood pressure measurement will be obtained after subjects have been in the supine 
position for a minimum of 10 minutes.  To ensure that a stable supine blood pressure 
measurement is obtained, at least two systolic and diastolic measurements will be performed.  
If the replicate systolic and diastolic measurements differ by no more than 10 mmHg and 5 
mmHg, respectively, the supine blood pressure will be considered to be stable.  The mean of 
the two stable replicate measures will be considered to represent the baseline supine blood 
pressure (mean systolic and mean diastolic blood pressure) for that visit.  Once the supine 
blood pressure is considered to be stable, subjects will be asked to assume the standing 
position.  After subjects have been in the standing position for 1 minute and 3 minutes, 
systolic and diastolic blood pressure will be measured and recorded for both time points.  If 
the measurements do not meet the criteria for orthostatic (postural) hypotension, no further 
measurements are needed.  If either the 1 minute or 3 minute standing BP measurements 
show decreases meeting the criteria shown in Table 4, the sequence of supine and standing 
measurements should be repeated up to 2 more times.  Refer to Table 4 for the criteria 
defining orthostatic hypotension and actions that should be taken when orthostatic 
hypotension criteria are met.  
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Table 4.      ORTHOSTATIC BLOOD PRESSURE CHANGES AND SUBJECT 
MANAGEMENT
Mean Supine 
Systolic Blood 
Pressure
Decrease in Blood 
Pressure Defining 
Orthostatic (postural) 
Hypotension
Actions
≤150 mmHg
≥20 mmHg systolic or
≥10 mmHg diastolic
- Repeat the sequence of measurements (supine, and standing) 
up to 2 times.  If either the 1 minute or 3 minute standing BP 
meets the orthostatic (postural) hypotension criteria, then that 
sequence is considered positive.  If 2 of 2 or 2 of 3 sequences 
are positive, then orthostatic hypotension is considered 
confirmed and an adverse event of orthostatic hypotension will 
be reported.  
- Refer to Section 7.4.3. for subject management and dosing 
guidance.
OR
>150 mmHg
≥30 mmHg systolic or
≥15 mmHg diastolic
Refer to Section 7.4.3. for guidance on determining which subjects with confirmed 
orthostatic hypotension will require consultation with a neurologist or cardiologist. Subjects 
who meet criteria defining orthostatic hypotension at any post-Baseline clinic visit should 
follow the procedures described in Section 7.4.3.
7.3.5. 12-Lead Electrocardiogram
A 12-lead ECG will be performed at Screening for determination of ECG-related eligibility. 
Additional 12-Lead ECGs will be performed at Weeks 24 and 48 (or at Early Termination
Visits 1 and 3, as described in Section 6.4. and Table 2).  Post-Screening ECGs may be 
collected if needed (for cause), at the discretion of the investigator.  
A 12–lead ECG should be recorded after subjects have been resting at least 5 minutes in the 
supine position in a quiet environment.  Digital ECG tracings will be performed using 
equipment from and analyzed by a central ECG laboratory.  All standard intervals (PR, QRS, 
QT, QTcF, QTcB, RR intervals and heart rate (HR)) will be collected.  The QTc interval 
reading produced by machine will be listed in the data listings.  The QT interval will be 
manually measured by the central laboratory.  The cardiologist at the central ECG laboratory 
reading the ECGs will be blinded regarding investigational product assignment.  In the event 
a clinically significant ECG abnormality is seen at a visit on an ECG obtained for cause 
(post-treatment), the investigator should consider evaluation of the subject by a cardiologist.
Investigators will also be alerted of subjects with evidence of the following as a potential 
indicator of sympathetic nervous system dysfunction:
•
Significant bradycardia (heart rate of ≤45 beats per minute (BPM) on an ECG, 
exclusionary at Screening).
•
Heart rate decrease from Screening of ≥25% with resulting heart rate <60 BPM.
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Investigators should report adverse events of bradycardia for subjects who meet the ECG 
criteria listed above.  Refer to Section 7.4.3. for additional details pertaining to subject 
evaluation and further dosing with investigational product in subjects with sympathetic 
function adverse events.  
7.3.6. Survey of Autonomic Symptoms (SAS)
The Survey of Autonomic Symptoms (SAS)22 is a validated, easily administered instrument 
to measure autonomic symptoms that has been proposed to be valuable in assessing 
neuropathic autonomic symptoms in clinical trials (refer to Appendix 11).  
Subjects will complete the SAS at Screening and Week 24 (or at Early Termination Visits 1 
and 3, as described in Section 6.4.).  Subjects will enter responses in IRT.
7.3.7. Radiographic Assessments
Scheduled X-rays of each shoulder, hip and knee will be obtained at Screening and at Weeks
24 and 48 (or at Early Termination, as described in Section 6.4.) visits.  
Radiographic assessments of other major joints exhibiting signs or symptoms suggestive of 
osteoarthritis should also be imaged.  A major joint is defined as a mobile synovial joint in 
the limbs such as shoulders, elbows, wrists, hips, knees, ankles and excluding the joints of 
the toes and hands.  Any joint imaged at Screening or other at-risk joints identified during the 
study period should also be imaged at Week 24 and 48 (or at Early Termination Visit 3, as 
described in Section 6.4.) visits.  
NOTE: It is recommended that the radiographs required at Screening be obtained as soon as 
possible after the Screening visit to permit central radiology review of the images for 
determination of subject radiographic eligibility for initial dosing in the study.  Subjects will 
not be permitted to start dosing in the study until the Screening radiographs are reviewed by 
the Central Reader and eligibility is established. X-rays required for the Week 24 visit may 
be conducted within 30 days of the visit (ie, before or after the visit).  X-rays for the Week 48
visit may be conducted up to 30 days before and, preferably, no more than 14 days after the 
visit.
For subjects who are discontinued prior to the Week 48 visit, follow-up radiographs of each 
shoulder, hip and knee (and any other major joint imaged at Screening or other at risk joints 
identified during the study period) should be performed as soon as possible (refer to 
Section 6.4) after the decision to withdraw from the study has been made, provided at least 
30 days have passed since the last set of X-rays were collected.  A final set of follow-up 
radiographs of each knee, hip and shoulder (and any other major joint imaged at Screening or 
other at risk joints identified during the study period) should be obtained 24 weeks (Early 
Termination Visit 3, Section 6.4.1.4) after the last dose of SC investigational product was 
administered. 
The X-ray technologists, in addition to their professional training and certifications, will be 
trained in performing the radiographic protocols for the knees, hips, and shoulders for this 
study and given approval by Pfizer or its representative to perform study X-rays.  To 
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facilitate reproducibility and accuracy of joint space width measurement in the knees and 
hips, a standardized subject and joint positioning protocol will be utilized.  The Core Imaging 
Laboratory will be responsible for working with the sites to ensure quality, standardization 
and reproducibility of the radiographic images/assessments made at the Screening and 
follow-up time-points.  Additional details regarding the required X-rays will be provided in a 
site imaging manual.
Central radiology readers (Central Readers) will be board certified radiologists or have the 
international equivalent as musculoskeletal radiologists. The Central Readers will be 
governed by an imaging atlas and an imaging Charter which includes a specific description 
of the scope of their responsibilities.  Central Readers will review radiology images at 
Screening for assessment of eligibility (including determination of Kellgren-Lawrence 
Grade) and identification of exclusionary joint conditions such as rapidly progressive 
osteoarthritis, atrophic or hypotrophic osteoarthritis, subchondral insufficiency fractures 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis and pathological 
fractures. After randomization, Central Readers will review radiology images for diagnosis 
of joint conditions that would warrant further evaluation by the Adjudication Committee such 
as possible or probable rapidly progressive osteoarthritis, subchondral insufficiency fractures 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis or pathological 
fracture and subjects undergoing total joint replacement for any reason, all images and other 
source documentation will be provided to the blinded tanezumab Adjudication Committee 
for review and adjudication of the event.  The Adjudication Committee’s assessment of the 
event will represent the final classification of the event.
7.3.7.1. Radiation Exposure
The International Commission on Radiation Protection (ICRP) has developed and applied the 
As Low As Reasonably Achievable (ALARA) principle in developing guidelines that 
balance the benefits of radiation exposures against possible risks.  This principle states that 
human exposures to radiation should be “As Low As Reasonably Achievable, with economic 
and social considerations taken into account.” 
Within the context of medical and research exposures, this is usually taken to mean that each 
individual should receive no more radiation than is necessary to obtain reliable information 
and that no more research participants should be irradiated than is necessary to answer a 
particular scientific question.  
Radiograph
Annual Effective dose (mSv)
Knee23
0.036 mSv
Hip24,25
2.6 mSv
Shoulder24
0.06 mSv
TOTAL
2.696 mSv
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Subject exposure per body part imaged is shown in the table above.  The total effective dose 
per subject in this study is expected to be approximately 2.7 millisievert (mSv).26 This can be 
compared to the annual effective dose from natural background radiation of approximately 
3.0 mSv.  In some cases, it is expected that a repeat image of a joint may be necessary due to 
the quality of the X-ray images.
7.3.8. Neurologic Examination
Neurologic examinations will be performed by a designated physician and assessed for 
clinically significant changes from Baseline.    The examinations will be performed at
Screening, Baseline (Day 1), and Weeks 2, 4, 8, 12, 16, 24, 32 and 48 (or at each Early 
Termination Visit, as described in Section 6.4. and Table 2) and the Neuropathy Impairment 
Score (NIS) will be completed at these time points based on this neurological exam (refer to
Appendix 8).  Neurologic examination will assess strength of groups of muscles of the head 
and neck, upper limbs and lower limbs, deep tendon reflexes and sensation (tactile, vibration, 
joint position sense and pin prick) of index fingers and great toes in order to complete the 
NIS.  The NIS is a standardized instrument which has been tested in both healthy subjects 
and subjects with neuropathy and which has been used to evaluate subjects for signs of 
peripheral neuropathy in clinical trials.27  Investigators and other designated physicians 
performing the neurologic evaluations are required to attend a training session for 
neurological exam in order to apply consistency across sites.  The neurological exams must 
be performed in a controlled and consistent manner and by the same examiner when possible.
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 syndrome) 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 new or worsened clinically significant abnormality on the neurologic exam should be 
reported as an adverse event and may result in a neurologic evaluation/consult further to 
the guidance above. 
•
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.
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7.3.9. Anti-Drug Antibody Testing
Blood samples for the assessment of anti-tanezumab antibody (ADA) against tanezumab 
(anti-tanezumab antibodies) will be collected and will be analyzed using a validated 
analytical method in compliance with Pfizer Standard Operating Procedures.
Samples may be used for further evaluation of the bioanalytical method. These data will be
used for internal exploratory purposes and will not be included in the clinical report.
The shipment address and assay lab contact information will be provided to the investigator.
7.4. Triggered Requirements and Subject-Level Stopping Rules
The following rules will apply to individual subjects at the time of the second and subsequent 
injections of SC investigational product.
7.4.1. Dysesthesia/Allodynia
Transient, resolved dysesthesia/allodynia: Administer SC investigational product as planned 
as long as the condition has resolved before the next scheduled dose of SC investigational 
product. 
Unresolved dysesthesia/allodynia: Withhold the SC investigational product for a maximum 
of 14 days beyond the planned dosing day to allow for resolution of the adverse event.  If the 
dysesthesia/allodynia has not resolved within the 14-day period after the scheduled dosing 
date, the subject will not receive any additional doses of investigational product and will 
enter the Early Termination Follow-up period (refer to Section 6.4). 
7.4.2. Hypersensitivity or Injection Site Reactions
If a severe hypersensitivity reaction or severe injection reaction occurs following any 
administration of SC investigational product, the investigational product should be 
discontinued immediately and no further administrations of SC investigational product will 
be allowed.  Subjects experiencing these types of reactions will enter the Early Termination 
Follow-up period (refer to Section 6.4).
Severe hypersensitivity reactions are defined as those causing anaphylaxis.  Severe injection 
site reactions are defined as those in which ulceration or severe necrosis occurs. 
7.4.3. Orthostatic Hypotension and Sympathetic Function Adverse Events
Blood pressure changes meeting the pre-specified criteria for orthostatic hypotension and 
confirmed as described in Section 7.3.4.1 will be designated as confirmed orthostatic 
hypotension episode and should be reported as an adverse event whether or not the subject 
had accompanying symptoms.
Confirmed episodes of orthostatic hypotension: If a confirmed episode of orthostatic 
hypotension occurs (as defined in Section 7.3.4.1) it should be reported as an adverse event 
and the subject should be further evaluated as described below to determine if a neurology or 
cardiology consultation should be obtained and/or whether further treatment with 
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investigational product should occur. Figure 2 provides a flow diagram for the process 
described below.
1. If no apparent medical cause (eg, dehydration, illness, medications) is identified at the 
time the orthostatic hypotension criterion is met and the subject is symptomatic, the 
subject should be further evaluated for the presence of sympathetic autonomic 
neuropathy by a cardiologist or neurologist as soon as possible.  See “Sympathetic 
function adverse events” below for decisions regarding subject management and 
continued dosing with investigational product.
2. If an apparent medical cause is identified at the time the orthostatic hypotension criterion 
is met or if the subject is asymptomatic, the subject should have a repeat assessment of 
orthostatic hypotension performed at least 1 week later but not more than 4 weeks later.  
During this time the investigator should attempt to address the underlying medical cause 
of the orthostatic hypotension.  If confirmed orthostatic hypotension (as defined in 
Section 7.3.4.1) is present at the follow-up visit, the subject should be further evaluated 
for the presence of sympathetic autonomic neuropathy by a cardiologist or neurologist as 
soon as possible.  See “Sympathetic function adverse events” below for decisions 
regarding subject management and repeat dosing. 
Sympathetic function adverse events:  Subjects reporting adverse events (any seriousness or 
severity) with preferred terms of bradycardia (see Section 7.3.5 for ECG criteria for 
bradycardia), syncope, orthostatic hypotension (as described above and in boxes C and E of 
flow diagram, Figure 2, 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.
These subjects should not be dosed with SC investigational product until the absence of 
sympathetic autonomic neuropathy has been confirmed.  Subjects who are not deemed to 
have a sympathetic autonomic neuropathy based on this evaluation can continue the study 
provided no more than 12 weeks have elapsed since the last dose of SC treatment (Boxes H 
and K of flow diagram, Figure 2).  However, if the subject is still symptomatic with 
bradycardia, syncope, orthostatic hypotension, anhidrosis or hypohidrosis up to 12 weeks 
after the last dose of SC treatment, s/he should not receive additional investigational product, 
even if a sympathetic autonomic neuropathy has not been confirmed (Boxes J and L of flow 
diagram, Figure 2), and will enter the Early Termination Follow up period (refer to 
Section 6.4).  Subjects found to have a sympathetic autonomic neuropathy (Boxes I and L of 
flow diagram, Figure 2) should not receive additional investigational product and will enter 
the Early Termination Follow up period (refer to Section 6.4).
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Figure 2.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events
No apparent medical cause for OH and 
subject is symptomatic 
Obtain neurology or cardiology consultation 
as soon as possible
No further dosing until absence of sympathetic 
neuropathy confirmed 
Apparent medical cause identified at time of 
OH occurrence or subject asymptomatic, 
Address medical cause as appropriate, repeat 
assessment of OH ≥1 week later but ≤4 weeks later
Confirmed OH episode 
Adverse event of OH must be reported whether or not 
subject has accompanying symptoms
Investigator should determine:
1) if a neurology or cardiology consultation should be obtained 
and/or 
2) whether further treatment with study medication should occur
Confirmed OH 
(see Section 7.3.4.1) 
at follow-up visit 
(1 to 4 weeks later),
Obtain neurology or cardiology
consultation as soon as possible
No further dosing until absence of 
sympathetic neuropathy 
confirmed
No confirmed OH 
at follow-up visit 
(1 to 4 weeks later)
Consultation not required, 
Subject continue in study as 
planned
Sympathetic autonomic 
neuropathy not confirmed 
and 
No symptoms of bradycardia, 
syncope, OH, anhidrosis, or 
hypohidrosis
Investigator to determine  
appropriate type of consultation 
(neurology or cardiology) based on 
subject’s symptom presentation
Refer to Pfizer guidance document 
outlining  recommended tests for 
subject work-up  
Diagnosis of 
sympathetic autonomic 
neuropathy 
Symptoms of bradycardia, 
syncope, OH, anhidrosis, or 
hypohidrosis  present up to 12 
weeks after last dose of SC study 
medication even though 
sympathetic autonomic 
neuropathy not confirmed
Dosing with study medication may 
continue provided no more than 
12 weeks have elapsed since the last 
dose of SC treatment
Subject to continue in study as planned
No further dosing with study medication
Subjects should enter Early Termination 
Follow-up Period (see Section 6.4)
B
C
D
E
F
G
H
I
J
K
L
A
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7.4.4. Evaluation and Follow-up for Increased, Severe Persistent Joint Pain
Average daily pain in the index joint (hip or knee) will be assessed with an 11-point numeric 
rating scale (0 to 10) and collected via IRT beginning in the IPAP through Week 24 of the 
study followed by weekly assessments between Weeks 24 and 48.  In addition, on a weekly 
basis beginning at the Initial Pain Assessment Period and through Week 48 of the study, the 
subject will also be asked if he/she experienced new onset or increased pain in a major 
non-index joint (refer to Section 7.1.1).  If a subject responds that he/she has experienced 
new onset or increased pain in a non-index joint or other major joint (post-baseline), the 
subject will be asked to rate his/her pain in that joint on the same 11-point numeric rating 
scale, using a 24-hour recall (refer to Section 7.1.1) and will be asked to rate his/her pain in 
that joint for the remainder of the study. 
Joint pain scores recorded electronically will be monitored by site staff to identify subjects 
who have a pattern of severe pain over several days or a rapid increase in pain.  Subjects who 
record increased pain scores of severe intensity (eg, a score of 7-10 out of 10 on a numerical 
rating scale) in a knee, hip, shoulder or other major joint which is persistent for at least 
2 weeks despite treatment with analgesic medication should be evaluated radiographically.  
An earlier evaluation of the subject can be made at the discretion of the investigator. 
At each study visit, systematic site review of the WOMAC Pain Scores, electronically 
recorded pain scores, and relevant spontaneously reported adverse events will be 
implemented.  In addition, adverse events of joint pain, joint swelling, joint injury/accidents, 
fractures or worsening of osteoarthritis symptoms in index or non-index joints will be 
evaluated by the site personnel.  An assessment of the subjects’ general health and major 
joints for any changes in their osteoarthritis status will be carried out. 
Musculoskeletal physical exam findings, review of reported musculoskeletal adverse events, 
and in-clinic efficacy assessments will be recorded on specific case report forms for each 
study visit. 
Subjects meeting the criteria for increased severe or persistent pain or with other clinically 
significant findings based on the assessment of the Investigator are considered to have a 
joint(s) at risk and must have radiographs (X-rays) of the joint(s) obtained and sent to the 
Central Reader for assessment.  MRI scans will not be required but may be obtained if 
warranted for diagnostic purposes.  If warranted, the subject will be referred to an orthopedic 
surgeon for evaluation.
Radiographic (and any MRI) images collected as part of follow-up procedures for reports of 
increased severe or persistent pain or clinically significant findings of the investigator will be 
assessed by the Central Reader for possible or probable events of rapidly progressive 
osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee 
[SPONK]), primary osteonecrosis, or pathological fracture (refer to Section 7.4.5 and 
Section 9.5). 
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7.4.5. Central Reader and Subject-Level Stopping Criteria for Joint Safety Events
Subjects identified through the measures described above (in Section 7.4.4) who are 
determined by the Central Reader to have a possible or probable joint safety event (rapidly 
progressive osteoarthritis (type-1 or type-2), subchondral insufficiency fractures 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis, or pathological 
fracture), will be withdrawn from treatment and enter the Early Termination Follow-up 
period (refer to Section 6.4).
The Central Reader will review the radiology images on an ongoing basis and provide 
assessments to the investigator and Pfizer.  For subjects who are identified with a possible or 
probable joint safety event described above and for subjects undergoing total joint 
replacement for any reason, all images and other source documentation will be provided to 
the blinded tanezumab Adjudication Committee for review and adjudication of the event.  
The Adjudication Committee’s assessment of the event will represent the final classification 
of the event (refer to Appendix 10). 
Subjects with adverse event reports of rapidly progressive osteoarthritis (type-1 or type-2), 
subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), 
primary osteonecrosis, or pathological fracture, will be withdrawn from treatment and enter 
the Early Termination Follow-up period (refer to Section 6.4).
In addition to Subject-Level Stopping Criteria for Joint Safety Events, this study will also 
employ Protocol-Level Stopping Criteria.  Protocol-Level Stopping Criteria for Joint Safety 
Events are described in Section 9.6.2.
7.4.6. Procedures for Subjects Undergoing Joint Replacement
Subjects who have undergone or plan to undergo total joint replacement or other arthroplasty 
procedure during the study will be discontinued from investigational product.  Follow-up 
procedures for these subjects are described in Section 6.4.2  In addition, subjects who 
undergo total knee, hip or shoulder joint replacement surgery during the study (Treatment 
Period or Follow-up Period) will be followed for 24 weeks after the procedure as part of a 
separate protocol, provided the subject consents.
7.5. Pharmacokinetic (PK) and Pharmacodynamic (PD)
7.5.1. Plasma for Analysis of Tanezumab
Blood samples for the assessment of the pharmacokinetics of tanezumab will collected and
will be analyzed using a validated analytical method in compliance with Pfizer standard 
operating procedures.
Samples may be used for further evaluation of the bioanalytical method. These data will be
used for internal exploratory purposes and will not be included in the clinical report.
The shipment address and assay lab contact information will be provided to the investigator
site prior to initiation of the trial.
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7.5.2. Nerve Growth Factor (NGF) for Pharmacodynamic Analyses
Blood samples will be collected for the assessment of NGF. NGF can exist in different forms 
including but not limited to NGF bound to drug or not bound to drug, NGF bound to soluble 
p75, and proNGF. Blood volume collected will limit the number of NGF assessment to 3 to 4 
NGF endpoints including a measure of total NGF (sum of all NGF forms). The final set of 
NGF forms that will be measured will depend on the availability of the analytical assay that 
can reliably measure the NGF concentration.
NGF samples will be collected at Baseline (Day 1; predose) and Week 8 (predose), Week 24 
(predose), Week 32 and Week 48 (or at Early Termination Visits 1 & 2, as described in 
Section 6.4).
Instructions regarding sample processing (eg, sample volumes, tube types, storage 
temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
NGF samples may be used for further evaluation of the bioanalytical methods used for 
measuring NGF. These data will be used for internal exploratory purposes and will not be 
included in the clinical report.
The shipment address and assay lab contact information will be provided to the investigator
site prior to initiation of the study.
7.6. Biomarkers
7.6.1. Serum Biomarkers
Blood samples for the assessment of biomarkers that can be modulated by the osteoarthritis 
condition will be collected.
If possible, the samples should be obtained at approximately the same time at each study visit 
to control for diurnal variations in the biomarkers and following a fasting period of at least 8 
hours. Fasting status should be recorded on the eCRF.
Currently measurement of 12 biomarkers are planned: 
 This selection of biomarkers could change due to blood 
volume limitations and/or assay performance issues. Possibly OA biomarkers different from 
the ones listed could be added or substituted if considered informative to further understand 
the osteoarthritis condition.
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Instructions regarding sample processing (eg, sample volumes, tube types, storage
temperature) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer
standard operating procedures.
Biomarker samples may be used for further evaluation of the bioanalytical methods. These 
data will be used for internal exploratory purposes and will not be included in the clinical 
report.
7.6.2. Urine Biomarkers
For the assessment of the cartilage biomarker 
 
urine samples will be collected. In the Early Termination follow-up, only a sample after 8 
weeks should be taken if termination was before Week 8.
The urine sample should be collected from the second void of the day or later. If possible, 
the samples should be obtained at approximately the same time at each study visit to control 
for diurnal variations in the biomarkers and following a fasting period of at least 8 
hours. Fasting status should be recorded on the eCRF. Sites will provide collection 
containers and storage instructions for subjects doing home collection.
Instructions regarding sample processing (eg, sample volumes, tube types, storage
temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer
standard operating procedures.
Biomarker samples may be used for further evaluation of biomarkers other than the ones
listed that could improve the understanding of the safety and efficacy profile of tanezumab.
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study. 
7.7. Banked Biospecimens
7.7.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the DNA (deoxyribonucleic acid), 
RNA (ribonucleic acid), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. 
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Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited as such by local regulations or ethics committee decision. 
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by swiping a badge.  Data will be stored on password-protected 
computer systems.  The key between the code and the subject’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information.  Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/subject information sheet; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
post-marketing research.  Subjects can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses.  It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants.  Subjects are notified in the informed 
consent document/subject information sheet that their results will not be given to them, 
unless required by local laws or regulations, in which case results will be returned via the 
investigator.  Results will not be provided to family members or other physicians; nor will 
they be recorded in the subject’s medical record.  There is no intention to contact subjects 
after completion of the clinical study.
A 4 mL blood biospecimen Prep D1 (K2 EDTA whole blood collection optimized for 
DNA analysis) will be collected at the Baseline (Day 1) visit to be retained for potential 
pharmacogenomic/biomarker analyses related to drug response, unless prohibited by local 
regulations or ethics committee decision.  For example, putative safety biomarkers, drug 
metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to 
the mechanism of drug action may be examined.
The Banked Biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual. 
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/subject information sheet that 
they will not be compensated in this event.
7.7.2. Additional Research
Unless prohibited by local regulations, or ethics committee decision, subjects will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:
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•
Investigations of the disease under study in the clinical trial, and related conditions.
•
Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the natural 
variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Markers of Drug Response (see Section 7.7.1.) will be used.  
Subjects may still participate in the clinical trial if they elect not to allow their banked 
biospecimens to be used for the additional purposes described in this section.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events (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 non-serious adverse event 
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
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 SAEs that the investigator believes have at least a reasonable possibility of being related
to investigational product are to be reported to the Sponsor.
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Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least 1 dose of investigational product through the subject’s last visit.  
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;
•
Drug withdrawal;
•
Drug misuse; 
•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy (EPD);
•
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
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error CRF, which is a specific version of the adverse event (AE) page and on the serious 
adverse event (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 adverse event, as determined by 
the investigator, the medication error is to be captured on the medication error version of the 
adverse event (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
•
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
A Serious Adverse Event is any untoward medical occurrence at any dose that:
•
Results in death;
•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
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•
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.
Medical device complaints may meet the SAE reporting requirement criteria (see Section 
8.14.3 on Medical Device Complaint Reporting Requirements).  An incident is any 
malfunction (ie, the failure of a device to meet its performance specifications or to perform as 
intended; performance specifications include all claims made in the labeling for the device) 
that, directly or indirectly, might lead to or might have led to the death of a subject, or user, 
or of other persons, or to a serious deterioration in their state of health. 
A serious injury that can cause a serious deterioration in state of health can include:
•
a life-threatening illness, even if temporary in nature;
•
a permanent impairment of a body function or permanent damage to a body structure; 
•
a condition necessitating medical or surgical intervention to prevent the above 2 bulleted 
items;
•
Examples: clinically relevant increase in the duration of a surgical procedure, a condition 
that requires hospitalization or significant prolongation of existing hospitalization;
•
any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;
•
fetal distress, fetal death, or any congenital abnormality or birth defects.
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 Section 8.14.1).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
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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 value ≥3 times the upper limit of normal (X 
ULN) concurrent with a total bilirubin value ≥2 X ULN with no evidence of hemolysis 
and an alkaline phosphatase value ≤2 X ULN or not available.
•
For subjects with preexisting ALT OR AST OR total bilirubin values above the ULN, 
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 values ≥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 1 X ULN or if the 
value reaches ≥3 X 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 
measurements of 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/paracetamol, 
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 liver function test (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.
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 
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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 laboratory 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;
•
Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
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.
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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 non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse 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 (refer to Section 8.14. 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 that 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
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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2. 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).
3. 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 Exposure During 
Pregnancy (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 pre-procedure 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 serious 
adverse events 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 document that 
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the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.10.1. Additional Postnatal Development 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 Section 6.4. Subject Withdrawal)
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 because of 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 or legally acceptable representative.  In addition, each study subject or 
legally acceptable representative 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 timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
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well as to the initial and follow-up reporting of EDP, exposure via breastfeeding cases and 
occupational exposure.  
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 or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes 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. Medical Device Reporting Requirements
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be collected on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might have led to death or serious deterioration 
in health. 
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.
Refer to the Pharmacy Manual for procedures for forwarding medical device complaints not 
associated with an SAE to Pfizer.
8.14.4. 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.
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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical 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 primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
A sample size of 270 subjects per treatment group is needed to provide approximately 80% 
power to achieve statistical significance (at the 5% two-sided level) for the two comparisons 
of tanezumab 2.5 and 5 mg SC versus placebo, over all three co-primary endpoints.  The total
sample size will be approximately 810 subjects.
The assumed treatment differences for this calculation come from a combined analysis of 
Studies A4091011 and A4091014, using an ANCOVA model for the change from Baseline 
to Week 24 for each of the 3 co-primary endpoints.  Imputation for missing data used mixed 
Last Observation Carried Forward (LOCF) and Baseline Observation Carried Forward 
(BOCF) matching the reasons for the primary analysis described below in Section 9.2.1.
Under this model the difference between tanezumab 2.5 & 5 mg versus placebo were 
approximately -0.75/-0.77 & -1.01/-1.05 for WOMAC Pain/Physical Function subscales, and 
-0.25 & -0.34 for the Patient’s Global Assessment of Osteoarthritis.  The within-group 
standard deviations were 2.76, 2.63 and 0.94 for WOMAC Pain, WOMAC Physical Function 
and Patient’s Global Assessment of Osteoarthritis, respectively.  The correlation of the
change from Baseline to Week 24 value for WOMAC Pain versus Physical Function was 
0.92.  The correlations between Patient’s Global Assessment of Osteoarthritis and WOMAC 
Pain and Physical Function were approximately 0.67. 
Using the treatment differences, variability and correlations given above, the sample size of 
270 subjects per group would give 80% power to show significant treatment differences 
using the two-sided 5% significance, for the two tanezumab versus placebo comparisons over 
all three co-primary efficacy endpoints.
9.2. Efficacy Analysis
9.2.1. Analysis of Primary Endpoint
The primary efficacy population will be the intent to treat (ITT) population, defined as all 
randomized subjects who received SC investigational product (either tanezumab or matching 
placebo). The primary analysis will use multiple imputation methods for missing data at 
Week 24.  Details of the multiple imputation procedure are given below. All treatment 
comparisons will use the two-sided 5% significance level.
The co-primary efficacy endpoints will be analyzed using an ANCOVA model, with model 
terms for Baseline score, Baseline diary average pain, index joint (knee or hip), highest 
Kellgren-Lawrence grade, and treatment group, and study site as a random effect.  The 
assessment of significance for the tanezumab SC versus placebo treatment contrasts will use 
a step-down testing strategy within each of the co-primary efficacy endpoints defined as first 
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testing tanezumab 5 mg versus placebo, and if statistically significant (p≤0.05) to then test 
tanezumab 2.5 mg versus placebo.  Finally, a tanezumab treatment group is declared as 
superior to placebo if the corresponding treatment contrast is significant over all three co-
primary endpoints.  This testing procedure will maintain the Type I error to 5% or less within 
each of the co-primary efficacy endpoints, and to less than 5% for all three co-primary 
efficacy endpoints.  An additional (main effects ANCOVA) analysis for each of the co-
primary efficacy endpoints will use a per-protocol analysis set, which will exclude subjects
who are major protocol deviators.
The primary analysis of the co-primary endpoints will use multiple imputation for missing 
data, to account for uncertainty around the subject response.  The basis for imputing missing 
values will be dependent on the reasons for missing data.  For subjects with missing data due 
to discontinuation prior to Week 24 for lack of efficacy or for an adverse event or death, 
imputation will be based on sampling from a normal distribution using a mean value equal to
the subject’s Baseline efficacy value and the standard deviation (over all treatment groups) of 
the observed efficacy data at Week 24.  For subjects with missing data for any other reason, 
imputation will be based on sampling from a normal distribution using a mean value equal to
the subject’s last observed efficacy value and standard deviation (over all treatment groups) 
of the observed efficacy data at Week 24.  Imputed values for the Patient’s Global 
Assessment of Osteoarthritis will be rounded to integer values from 1 to 5.  Imputed values 
for WOMAC Pain and Physical Function will be truncated at 0 and 10.  One hundred 
imputation samples will be used, and the ANCOVA model described above will be used for 
each imputation dataset.  The final results will be calculated using the combined sets of 
results from each imputation dataset analysis.2
Additional analyses will explore the sensitivity of results to the effect of missing data on the 
co-primary efficacy endpoints.  The first analysis will use the same main effects ANCOVA 
model as described above, but with LOCF for missing data.  The second analysis will use the 
same main effects ANCOVA model as described above, but with BOCF for missing data.  
The third analysis will use Mixed Model for Repeated Measurements (MMRM) utilizing all 
observed data up to and including Week 24.
9.2.2. Analysis of Secondary Endpoints
Secondary efficacy endpoints will examine the change from Baseline to additional 
timepoints in the WOMAC Pain and Physical Function subscales, and the Patient’s Global 
Assessment of Osteoarthritis, using the multiple imputation for missing data procedure and 
analysis described above.  The change from Baseline in the Patient’s Global Assessment of 
Osteoarthritis to Weeks 2, 4, 8, 12,16, 24 and 32 will also be analyzed using the 
Cochran-Mantel-Haenszel test (stratified by the combinations of the two stratification 
factors).  Changes by each level of improvement will be summarized.  For this analysis 
imputation for missing data will used mixed BOCF/LOCF, as well as BOCF and LOCF 
separately. 
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Other secondary endpoints include the WOMAC Stiffness subscale, WOMAC Average score 
and WOMAC Pain subscale items (Pain When Walking on a Flat Surface, and Pain When 
Going Up or Down Stairs), conducted for the change from Baseline to Weeks 2, 4, 8, 12, 16, 
24 and 32.  Analysis of Average Pain in the index joint will be conducted for the change 
from Baseline to Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28 and 32.  The analysis of these 
endpoints will use the same ANCOVA analysis as described above for the co-primary 
endpoints, with multiple imputation for missing data.
The OMERACT-OARSI responder index, and subject response endpoints of improvement in 
the WOMAC Pain ≥30, 50, 70 and 90%, WOMAC Physical Function ≥30, 50, 70 and 90%, 
and improvement in the Patient’s Global Assessment of Osteoarthritis ≥2 will be analyzed 
for change from Baseline to Weeks 2, 4, 8, 12, 16, 24 and 32 using logistic regression for 
binary data, with model terms for Baseline WOMAC Pain subscale score, Baseline WOMAC 
Physical Function or Baseline Patient’s Global Assessment score, Baseline Diary Average 
Pain, index joint, Kellgren-Lawrence grade and treatment group.  The cumulative distribution 
of percent change to Weeks 16 and 24 in the WOMAC Pain subscale score and WOMAC 
Physical Function subscale score will be summarized for the response categories of 
reductions of >0%, ≥10 to 90% (in steps of 10%) and 100% (no reported pain or difficulties 
at timepoint of interest).  Imputation for missing data will use both LOCF and BOCF, where
imputation with BOCF will lead to the subject being assessed as a nonresponder for the 
response endpoint at a particular timepoint.  In addition, in order to closely match the 
primary imputation analysis, a mixed BOCF/LOCF imputation for response endpoints will be 
used.  In this analysis BOCF imputation (ie, a subject would be a nonresponder) would be 
used for missing data due to discontinuation for reasons of lack of efficacy, adverse event or 
death up to the timepoint of interest, and LOCF imputation would be used for missing data 
for any other reason.
The incidence and number of days per week of rescue medication use will be analyzed for 
Weeks 2, 4, 8, 12, 16, 24 and 32, and the amount of rescue medication use per week will be 
analyzed for Weeks 2, 4, 8, 12 16 and 24.  The incidence of use of rescue medication will be 
analyzed using logistic regression for binary data, with model terms for Baseline WOMAC 
Pain subscale score, Baseline Diary Average Pain, index joint, Kellgren-Lawrence grade and 
treatment group.  The number of days and amount of rescue medication (mg dosage of 
acetaminophen) will be analyzed using the Negative Binomial model, with model terms of 
Baseline WOMAC Pain subscale score, Baseline Diary Average Pain, index joint, 
Kellgren-Lawrence grade, and treatment group.  Estimated levels of rescue medication use 
will be shown for each treatment group, and the ratio (with 95% CI) for comparisons versus 
placebo will be shown.  Imputation for missing rescue medication data will use LOCF only.  
The incidence and number of days of rescue medication use will be summarized up to 
Week 32, and the amount of rescue medication taken in a week summarized up to Week 24. 
The incidence of and time to withdrawal due to lack of efficacy will also be analyzed for
discontinuation up to Week 24 (end of treatment period).  The time to discontinuation will be 
analyzed using the log-rank test, with Kaplan-Meier estimates of the time to discontinuation 
shown for selected percentiles, dependent on the level of discontinuation.  The expectation is 
that these would be the 1st, 2nd, 5th, 10th and 25th percentiles.  Other percentiles may be shown 
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if the level of discontinuation due to lack of efficacy as calculated using Kaplan-Meier 
procedure is sufficiently large.  The analysis of the incidence of discontinuation due to lack 
of efficacy will be made using logistic regression for binary data, with model terms for 
baseline WOMAC Pain subscale score, Baseline Diary Average Pain, index joint, 
Kellgren-Lawrence grade and treatment group.
A table showing number and percentage of subjects will summarize the response for each 
dimension (item) of the EQ-5D-5L at Baseline and Weeks 8, 16 and 24.  These summary 
tables will be shown by treatment group.  In addition, for each treatment and each time point 
assessed, descriptive statistics (mean, standard deviation, median, number of subjects) will 
characterize the five-item health status profile on the EQ-5D-5L in terms of the health utility 
score and the EQ-VAS.
A summary of the change from Baseline to Weeks 8, 16 and 24 in the WPAI:OA impairment 
scores will be shown by treatment group.
All data from mPRTI will be summarized by visit.  Two items of the mPRTI (patient 
willingness to use drug again; patient preference of drug versus prior treatment) will be 
analyzed using the Cochran-Mantel-Haenszel test (stratified by the combination of the two
stratification factors) at both Weeks 16 and 24.  For any analysis using the 
Cochran-Mantel-Haenszel test, if there are too few subjects in any stratification combination 
group then an unstratified test will be performed.  The HCRU data will be reported as 
outlined in the Statistical Analysis Plan
All endpoints up to Week 32 will be summarized (where available), and endpoints up to 
Week 32 will be analyzed.  Any efficacy data collected at the Week 32 visit will be excluded 
from summary and analyses of efficacy with the following exception: Any efficacy data 
collected at the Week 32 visit for subjects that have discontinued the study early, and the 
observations are within 10 weeks after the last dose (8 weeks plus a window of 2 weeks) can 
be included in the efficacy summaries and analyses for the appropriate efficacy window in 
which the data falls.
9.3. Safety Analysis
Adverse events, concomitant medications, laboratory safety tests, physical and neurological 
examinations, vital signs, electrocardiogram (ECG), the anti-drug antibody test will be 
collected for each subject during the study according to the Schedule of Assessments.  
Standard safety reporting tables will summarize and list the safety data. 
Separate adverse event summaries by treatment group for adverse events of decreased 
sympathetic function will be conducted.  More specifically, adverse events with the 
following preferred terms will be considered to represent adverse events of decreased 
sympathetic function:  Blood pressure orthostatic decreased, bradycardia, dizziness postural, 
heart rate decreased, orthostatic hypotension, presyncope, sinus bradycardia, syncope, 
anhidrosis, hypohidrosis, abdominal discomfort, diarrhea, early satiety, fecal incontinence, 
nausea, vomiting, ejaculation delay, ejaculation disorder, ejaculation failure, hypertonic 
bladder, micturition urgency, nocturia, urinary frequency, urinary hesitation, urinary 
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incontinence, respiratory distress and respiratory failure.  If necessary, this list of preferred 
terms may be adjusted for updates made to the MEDICAL DICTIONARY FOR DRUG 
REGULATORY AFFAIRS (MedDRA) dictionary versions used for reporting.
In addition to summaries of adverse events considered to represent adverse events of 
decreased sympathetic function noted above, adverse events of syncope, bradycardia, 
orthostatic hypotension, anhidrosis, or hypohidrosis are designated as adverse events of 
interest that will be reviewed by the unblinded E-DMC (See Section 9.6).
Selected adverse events of interest and common adverse events will be summarized using 
Risk Differences (with 95% confidence intervals) between each tanezumab group and 
placebo.  In addition, significance testing will be performed for adverse events of interest 
between each tanezumab group and placebo.  There will be no multiplicity adjustment for 
these significance tests. 
Incidence of orthostatic hypotension using postural changes in blood pressure, in addition to 
mean changes in postural blood pressure will be summarized.
The Survey of Autonomic Symptoms (SAS) scores will be summarized by treatment group 
for the total number of symptoms reported and total impact score.  The summary will be 
shown by visit, and for the change from Baseline.  
The Neuropathy Impairment Score (NIS) is the sum of scores over all 37 items from both the 
Left and Right side.  The change from baseline to each post-baseline visit in the NIS, (using 
LOCF for missing data), and to worst (largest) change from Baseline (over all post-Baseline 
visits) will be summarized, and analyzed using Cochran-Mantel-Haenszel test (stratified by 
the combinations of two stratification factors).  The NIS data, the neurological consultation 
data and the conclusion from neurological examination data will be reported.  The 
neurological consultation data will be summarized for all subjects, and for subjects with 
adverse events of abnormal peripheral sensation, which are described in the adverse event 
section above.  The “conclusion from the neurological examination” data will be summarized 
for each timepoint, and then a summary of the final assessment over all neurological 
examinations for each subject.
The incidence of subjects with any of the adjudication outcomes of rapidly progressive 
osteoarthritis (type 1 and type 2), subchondral insufficiency fracture (or SPONK), primary 
osteonecrosis, or pathological fracture, and for occurrence of total joint replacement will be 
shown by number of subjects treated and subject years of exposure (treatment plus follow up 
periods), for individual treatment groups and differences between tanezumab treatment 
groups and the placebo treatment group.
The change from Baseline to Weeks 24 and 48 in the Minimum Joint Space Width (JSW) for 
subjects with Kellgren-Lawrence grades of 2 or 3 in the index joint will be analyzed for 
subjects with measurements in the knee and hip separately.  The percentage of subjects with 
narrowing over a certain measurement will be shown, over the range of values from 0 
(ie, >0 mm, or any narrowing) to ≥2 mm, in addition to summary statistics of the mean (with 
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standard error) and median narrowing.  Significant progression of osteoarthritis will be 
defined using the Bland-Altman method,28 as proposed by OARSI-OMERACT.29
Progression will be defined as 1.96 times the within-subject standard deviation of the change 
in JSW.  The incidence of subjects with JSW narrowing greater than or equal to these values 
will be shown (with Kellgren-Lawrence grades of 2 or 3 in the index joint), and incidence 
analyzed using logistic regression for binary data, taking into account study site and baseline 
JSW as covariates.  This summary and analysis will be performed separately for subjects 
with osteoarthritis of the hip and knee.  These analyses will use the Week 24 End of 
Treatment/Early Termination data and then Week 48 End of Study/Early Termination 
regardless of the study day of assessment and/or where subjects have discontinued early from 
the study.  In the event of missing data, baseline data will not be carried forward for 
Radiographic data.  
9.3.1. Anti-Tanezumab Antibodies (ADA)
The following assessments of ADA data will be made:
•
A listing of the subjects who develop anti-tanezumab antibodies after treatment for each 
dose, and the proportion of subjects who develop anti-tanezumab will be summarized for 
each dose.
•
The PK profile will be examined for subjects with anti-tanezumab antibodies. 
9.4. Analysis of Other Endpoints
Pharmacokinetic Data and Tertiary Endpoints
Tanezumab concentrations will be measured to support the development of a SC population 
PK model that allows for the prediction of the tanezumab concentration over time in 
individuals.  In addition tanezumab concentrations will be measured to inform the 
immunogenicity profile of tanezumab.
All other summarization and analysis of tertiary endpoints will be described in the SAP.
9.5. 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 (refer to 
Section 7.4.5), total joint replacement, as well as investigator reported adverse events of 
osteonecrosis, rapidly progressive osteoarthritis, 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 (refer to Section 7.3.7).
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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 external E-DMC will be provided with a blinded summary of the Adjudication 
Committee’s review of events after each review meeting.
9.6. Data Monitoring Committee 
An independent, E-DMC has been 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.   Adverse 
events of syncope, bradycardia, orthostatic hypotension, anhidrosis or hypohidrosis 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.  The E-DMC will have 
written operating procedures and a Charter, including a specific description of the scope of 
their responsibilities.
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the Charter. If the blinded Adjudication Committee 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 the 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 the study 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. 
9.6.1. Protocol-Level Rules for Dosing Suspension/Safety Assessment
9.6.1.1. Serious Adverse Events
Tanezumab safety will be reviewed at two levels; blinded data reviews by Pfizer and 
unblinded reviews by the data safety monitoring board (DMC).  The E-DMC will review 
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unblinded safety data including adverse events and serious adverse events on a regular basis 
throughout the course of these studies.  Pfizer performs blinded review of all serious adverse 
event data (including those serious adverse events specified below) and a cumulative review 
on a monthly basis.  If blinded review notes a pre-specified serious adverse event occurring 
at a rate that could trigger the protocol-based dosing suspension rule (ie, at least 3 or more 
cases of a given pre-specified serious adverse event), an urgent, ad hoc assessment by the E-
DMC will be conducted.  The E-DMC will determine whether a protocol-based dosing 
suspension rule should be triggered. At the individual protocol-level, if a given pre-specified 
serious adverse event is reported in 3 more subjects in any individual tanezumab treatment 
group than for control group subjects, the protocol-based rule for dosing suspension will be 
triggered.
The pre-specified serious adverse events are: 
•
Sudden cardiac death or cardiac death.
•
Acute renal failure.
•
Anaphylactic shock or severe anaphylactic reaction.
•
Neuropathic joint or neuropathic arthropathy (ie, Charcot joint).
•
Peripheral neuropathy confirmed with objective findings such as treatment-emergent 
abnormalities on neurologic examination, nerve conduction abnormalities or biopsy 
findings consistent with peripheral neuropathy.
•
One of the events related to sympathetic dysfunction (orthostatic hypotension, 
bradycardia, syncope, anhidrosis, or hypohidrosis).
If a protocol-based rule for dosing suspension is triggered, it will result in suspension of 
further dosing of subjects in the study until a decision is reached regarding whether it is safe 
to resume dosing in some or all treatment groups or whether the study should be terminated 
completely.  This decision will be made by the Sponsor in consultation with the tanezumab 
E-DMC.  
If the protocol-based stopping rule is triggered, the E-DMC will consider the implications of 
this action on a program-level basis and formulate a recommendation whether it is safe to 
continue dosing (for some or all treatment groups) in other ongoing tanezumab clinical 
studies.  Decisions regarding stopping treatment in other ongoing tanezumab clinical studies 
will be made by the Sponsor in consultation with the E-DMC.
Factors that may be considered in making this decision in relation to serious adverse events 
or adjudicated clinically significant adverse events include:
•
Consideration of relationship of investigational product to the adverse event;
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•
Consideration of whether similar adverse events are occurring in other tanezumab studies 
with similar subject populations;
•
Dosage of tanezumab (2.5 mg or 5 mg) and distribution of adverse events across 
tanezumab dose arms;
•
Possible differences in the baseline demographics between treatment groups;
•
Use of concomitant medications;
•
Possible differences in baseline medical history and/or co-morbidities;
•
Duration of therapy (0-6 months, 6-12 months).
9.6.1.2. Events consistent with Hy’s Law
If two events are reported which are consistent with Hy’s Law in tanezumab-treated subjects, 
irrespective of dose across all ongoing osteoarthritis and chronic low back pain studies, 
dosing will be temporarily suspended in all studies until the relationship to investigational 
product is established for the given events which were consistent with Hy’s Law. If 
two events consistent with Hy’s Law are considered to be related to treatment with 
tanezumab or the cause cannot be determined, all dosing in the tanezumab osteoarthritis and 
chronic low back pain program may be stopped.  The E-DMC will determine whether the 
dosing suspension should be triggered.  Subsequently the E-DMC will formulate a 
recommendation whether all studies should be permanently terminated.  Decisions regarding 
permanently stopping treatment and terminating studies will be made by the Sponsor in 
consultation with the DMC.
9.6.2. Joint Safety Events
If the blinded Adjudication Committee identifies adjudicated events of rapidly progressive 
osteoarthritis type 2, subchondral insufficiency fractures (or spontaneous osteonecrosis of the 
knee [SPONK]), primary osteonecrosis, or pathological fracture occurring at a combined rate 
that could trigger the protocol-based stopping criteria, an urgent, ad hoc assessment of the 
events will be made by the External Data Monitoring Committee.  
The protocol (or treatment group) stopping rule has three components; the difference in the 
number of subjects with an adjudicated joint safety event, the exposure-adjusted risk 
difference (RD) and the exposure adjusted risk ratio (RR) between each tanezumab treatment 
group and the active comparator group.  The exposure-adjusted RD will be calculated as the 
difference in the ratios of the number of subjects with an adjudicated joint safety event 
divided by exposure (subject-years) between each tanezumab group and the comparator 
group.  The exposure-adjusted RR will be similarly calculated using the ratio of exposure 
adjusted event rates (number of subjects with an adjudicated joint safety event divided by 
exposure) for each tanezumab group relative to the comparator group.  The exposure will be 
calculated as the combined treatment and follow-up periods.
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If the RD 
 (ie, 
), and the RR is 
and the difference in the number of subjects with adjudicated events joint safety events 
for any tanezumab treatment group versus the comparator treatment group, the 
protocol-based stopping rule will be triggered.  If the protocol-based stopping rule is 
triggered, the E-DMC will formulate a recommendation whether it is safe to continue dosing 
in some or all treatment groups or whether the study should be terminated completely.  This 
decision will be made by Pfizer in consultation with the E-DMC.
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 
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CC
C
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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. 
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, according to 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 approval from the national 
competent authority before implementing a substantial amendment.
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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.
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 Good Clinical Practice (GCP) (ICH 1996), and the 
Declaration of Helsinki (World Medical Association 1996 and 2008). 
NOTE: For Sweden, 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 Good Clinical Practice (GCP) (ICH 
1996), and the Declaration of Helsinki1. 
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 in any other disclosures, except 
where required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, address,  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 documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements including applicable privacy laws.
The informed consent documents 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.
                                                
1The Declaration of Helsinki (World Medical Association 2013) will be followed except that the study 
drug (tanezumab) will not be made available to subjects after they have finished the study [NB Tanezumab will 
not be available to subjects after they have finished the study at all sites].
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The investigator must ensure that each study subject, or his or 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.
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
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.  
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 which 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 last scheduled 
procedure shown in the Schedule of Activities for the last participant.
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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, 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.
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 subjects 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 study 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. 
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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual subjects 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 the principle 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.
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 multi-center 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 (Clinical Study Agreement) 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 CSA.
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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Tanezumab Investigator Brochure.
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Brown MT, Murphy FT, Radin DM, et al. Tanezumab Reduces Osteoarthritic Knee 
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Brown MT, Murphy FT, Radin DM, et.al. Tanezumab reduces osteoarthritic hip pain: 
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Ekman EF, Gimbel JS, Bello AE, et.al. Efficacy and Safety of Intravenous Tanezumab 
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Pfizer Data on File A4091027 CSR approved 01 Feb 2012.
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Castro M. Placebo versus Best-Available-Therapy Control Group in Clinical Trials for 
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Ornetti P, et al. OARSI-OMERACT Definition of Relevant Radiographic Progression 
in Hip / Knee Osteoarthritis. Osteoarthritis and Cartilage 2009;17:856-63.
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pregnancy testing in clinical trials [Internet]. Germany: Heads of Medicines Agencies 
(HMA); 2014 [2014 Sep 15; cited 2015 Aug 12]. Available from: 
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Appendix 1. American College of Rheumatology (ACR) Classification Criteria for 
Osteoarthritis
1986 Osteoarthritis Knee Criteria28
Clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee.
Meets criteria 1, 2 and 3:
1. Knee pain;
2. Presence of at least 1 of the following 3:
•
Age greater than 50 years.
•
Morning stiffness less than 30 minutes in duration.
•
Crepitus.
3. Presence of osteophytes on X-ray.
Osteoarthritis Hip Criteria30
Combined clinical (history, physical examination, laboratory) and radiographic criteria for 
osteoarthritis of the hip, traditional format.
1. Hip pain;
2. AND at least 2 of the 3 following features:
•
Erythrocyte sedimentation rate (ESR) less than 20 mm/hour;
•
Radiographic femoral or acetabular osteophytes;
•
Radiographic joint space narrowing (superior, axial, and/or medial).
Because the presence of osteophytes on X-ray is a protocol requirement (defined by a 
Kellgren-Lawrence X-ray Grade of ≥2 in inclusion criteria #3), protocol defined requirement 
for diagnosis of osteoarthritis of the hip will be the presence of hip pain, presence of 
osteophytes on x-ray and either an ESR<20 mm/hour OR joint space narrowing on X-ray.
ESR testing may be conducted at the local laboratory.
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Appendix 2. American Society of Anesthesiologists (ASA) Physical Status Classification
ASA Physical Status Classification 
The ASA physical status classification system is used for assessing the fitness of patients 
before surgery.  In 1963 the American Society of Anesthesiologists (ASA) adopted the 
five-category physical status classification system;31 a sixth category was later added 
(http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Class
ification-System). 
1. A normal healthy patient.
2. A patient with mild systemic disease.
3. A patient with severe systemic disease.
4. A patient with severe systemic disease that is a constant threat to life.
5. A moribund patient who is not expected to survive without the operation.
6. A declared brain-dead patient whose organs are being removed for donor purposes.
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Appendix 3. Half-Lives of Prohibited Prior and Concomitant Medications
Half-Lives of NSAIDs and Other Analgesics
Use of analgesics (including marijuana, duloxetine and prescription or over-the-counter 
(OTC) NSAIDs irrespective of route, eg oral, topical or rectal) except acetaminophen / 
paracetamol is prohibited through Week 32 of the study beginning 48 hours prior to the start 
of the IPAP (the seven days prior to Randomization/Baseline (Day 1) or at the period of time 
prior to the start of the IPAP that is at least 5 times the half-life of the particular analgesic 
used, whichever is greater.  Products containing glucosamine sulfate and chondroitin sulfate 
should not be initiated during the study; however, subjects who have taken a stable dose of 
these products for at least 6 months prior to the Initial Pain Assessment Period will be 
allowed to continue their regimen. Note that a stable regimen of aspirin taken for cardiac 
prophylaxis at a dose of ≤325 mg/day is permitted throughout the study.
These lists are not all-inclusive.  The Physician’s Desk Reference provides half-life 
information.
HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
Analgesic
Half-life (hours)
Minimum Washout Period
Aspirin >325 mg/day
0.25
2 days
Azapropazone
15.0
4 days
Bromfenac
1.3-3.1
2 days
Capsaicin (cream, 
ointments, patches)
2.0
2 days
Carprofen
12.0
3 days
Celecoxib
11.0
3 days
Codeine
3.5
2 days
Diclofenac gels
1.9
2 days
Diclofenac
1.1
2 days
Diclofenac/misoprostol
2.4-9.0
2 days
Diflunisal
13.0
3 days
Dipyrone
2.0-5.0
2 days
Duloxetine
8 - 17
4 days
Etodolac
6.0
2 days
Fenbufen
11.0
3 days
Fentanyl
Contact study clinician
Fenoprofen
2.5
2 days
Flufenamic acid
1.4
2 days
Flurbiprofen
3.8
2 days
Hydrocodone
4.5
2 days
Hydromorphone
3.0
2 days
Ibuprofen
2.1
2 days
Indomethacin
4.6
2 days
Ketoprofen
1.8
2 days
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HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
Ketorolac
4.0-9.0
2 days
Lidocaine patch or EMLA
(lidocaine/prilocaine)
2.0 
2 days
Meclofenamate
2.0-4.0
2 days
Mefenamic acid
2.0
2 days
Meloxicam
16.0 to 20.0
5 days
Meperidine
3.7
2 days
Mexiletine
6.0-17.0 
4 days
Morphine
2.0
2 days
Nabumetone
26.0
6 days
Naproxen
14.0
3 days
Oxaprofen
40.0-50.0
11 days
Oxaprozin
58.0
13 days
Oxycodone
3.2
2 days
Oxycodone CR
8.0
2 days
Oxymorphone
7.3-9.4
2 days
Phenylbutazone
68.0
15 days
Piroxicam
57.0
12 days
Pirprofen
3.8
2 days
Propoxyphene
12.0
3 days
Salicylates
2.0-15.0
4 days
Sulindac
14
3 days
Suprofen
2.5
2 days
Tapentadol
4
2 days
Tenoxicam
60.0
13 days
Tiaprofenic acid
3.0
2 days
Tolmetin
1.0
2 days
Tramadol
5.9
2 days
Corticosteroids The following use of oral or intramuscular corticosteroids is prohibited 
through Week 32 of the study and: 1) within 30 days prior to the Initial Pain Assessment 
Period (the seven days prior to Randomization/Baseline) or, 2) at the period of time prior to 
the start of the Initial Pain Assessment Period that is at least 5 times the half-life of the 
particular corticosteroid used, whichever is greater or, 3) the anticipated need to start such 
during the study.  Intra-articular injection of corticosteroids within 12 weeks to the index 
joint or to any other joint within 30 days prior to the Initial Pain Assessment Period is 
PROHIBITED.  Topical, inhaled and intranasal corticosteroids are PERMITTED.
Corticosteroids
Generic
Brand
betamethasone
Celestone, Soluspan
Cortisone
dexamethasone
Decadron, Dexacort, Turbinaire
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fludrocortisone
Florinet
hydrocortisone
A-hydroCort, Cortef, Hydrocortone, Solu-Cortef
methylprednisolone
Medrol, Solu-Medrol
Prednisolone
Orapred, Prelone
Prednisone
Cortan, Deltasone, Medicorten
Hyaluronic Acid
Intra-articular hyaluronic acid injection to the index knee is prohibited within 30 days (or 
within 18 weeks for long-acting formulations such as Synvisc) of the Initial Pain Assessment 
Period and throughout the study.
Biologicals
Use of biologicals is prohibited within 3 months of the Initial Pain Assessment Period and 
during the study. 
The following lists are provided for your reference but may not be all-inclusive.  Refer to the 
Physician’s Desk Reference for exclusion determination of a particular agent.
TNFα Inhibitors
Generic
Brand
Adalimumab
Humira
Etanercept
Enbrel
Infliximab
Remicade
Use of live attenuated vaccines (with the exception of Flumist®Influenza Virus Vaccine Live, 
Intranasal or other inhaled live attenuated influenza vaccines and Pneumovax) is prohibited 
within 3 months of Initial Pain Assessment Period and during the study. 
The following lists are provided for your reference but may not be all-inclusive.  Refer to the
Physician’s Desk Reference for exclusion determination of a particular agent.
Live Attenuated Vaccines
Generic
Brand
BCG (for tuberculosis)
Not available in the US
Herpes zoster vaccine
Zostavax
Influenza, intranasal
FluMist
Measles
Attenuvax
Measles, Mumps, and Rubella (MMR)
MMR
Mumps
Mumpsvax
Oral poliovirus vaccine, oral
OPV (no longer available in the US)
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Live Attenuated Vaccines
Generic
Brand
Rotavirus, oral
RotaTeq
Rubella
Meruvax II
Smallpox
Dryvax (Not commercially available in 
the US)
Typhoid, oral
Vivotif Berna
Varicella zoster
Varivax
Yellow fever
YF-VAX
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Appendix 4. Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) NRS3.1 V5 US
English
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Appendix 5. Patient’s Global Assessment of Osteoarthritis
Patient’s Global Assessment of Osteoarthritis – Knee
Subjects will answer the following question when the knee is selected as index joint:
Considering all the ways your osteoarthritis in your knee affects you, how are you doing 
today?
Subjects will rate their condition using the following scale: 
Grade
Description
1 – Very Good
Asymptomatic and no limitation of normal activities
2 – Good 
Mild symptoms and no limitation of normal activities
3 – Fair 
Moderate symptoms and limitation of some normal activities
4 – Poor 
Severe symptoms and inability to carry out most normal activities
5 – Very Poor
Very severe symptoms which are intolerable and inability to carry out all 
normal activities
Patient’s Global Assessment of Osteoarthritis – Hip
Subjects will answer the following question when the hip is selected as index joint:
Considering all the ways your osteoarthritis in your hip affects you, how are you doing 
today?
Subjects will rate their condition using the following scale: 
Grade
Description
1 – Very Good
Asymptomatic and no limitation of normal activities
2 – Good 
Mild symptoms and no limitation of normal activities
3 – Fair 
Moderate symptoms and limitation of some normal activities
4 – Poor 
Severe symptoms and inability to carry out most normal activities
5 – Very Poor
Very severe symptoms which are intolerable and inability to carry out all 
normal activities
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Appendix 6. Work Productivity and Activity Impairment Questionnaire: Osteoarthritis 
of the Knee or Hip V2.0 (WPAI:OA)
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Appendix 7. EuroQol 5 Dimension (EQ-5D-5L)
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Appendix 8. Neuropathy Impairment Score (NIS) Sample
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Appendix 9. Patient Health Questionnaire (PHQ-9)
Administration of the PHQ-9 is not mandatory but may be used by the investigator to assess 
the severity of depression.  The severity score is the sum of questions 1-9 only.  A score of 
15 or higher on questions 1 through 9 indicates severe depression.  If used the PHQ-9 should 
be stored in the subject file.  The results of this instrument will not be entered into a database, 
nor will it be analyzed.
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Appendix 10. Adjudication Categories
Adjudication 
Category
Adjudicated Condition
1
Primary Osteonecrosis
2
Worsening Osteoarthritis
2a
Rapidly Progressive Osteoarthritis (type-1 or type-2)
2b
Normal progression of osteoarthritis
2c
Not enough information to distinguish between rapidly progressive osteoarthritis and 
normal progression of osteoarthritis
3
Subchondral insufficiency fracture
4
Pathologic fracture
5
Other (with diagnosis specified)
6
Not enough information to specify a diagnosis 
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Appendix 11. Survey of Autonomic Symptoms (SAS)22
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Appendix 12. Patient Reported Treatment Impact Assessment-Modified (mPRTI)
PATIENT REPORTED TREATMENT IMPACT ASSESSMENT
Overall, how satisfied are you with the drug that you received in this study?
Please Check (X) ONE only:
(5) Extremely satisfied
(4) Satisfied
(3) Neither satisfied nor dissatisfied
(2) Dissatisfied
(1) Extremely dissatisfied
PATIENT GLOBAL PREFERENCE ASSESSMENT
Before enrolling in this clinical trial, what is the current or most recent treatment you were receiving for your 
osteoarthritis pain?
Please Check (X) ONE only:
(1) Injectable prescription medicines
(2) Prescription medicines taken by mouth 
(3) Surgery
(4) Prescription medicines and surgery
(5) No treatment
Overall, do you prefer the drug that you received in this study to the treatment you received before this clinical 
trial?
Please Check (X) ONE only:
(1) Yes, I definitely prefer the drug that I am receiving now
(2) I have a slight preference for the drug that I am receiving now
(3) I have no preference either way
(4) I have a slight preference for my previous treatment
(5) No, I definitely prefer my previous treatment
PATIENT WILLINGNESS TO USE DRUG AGAIN ASSESSMENT
In the future, would you be willing to use the same drug that you have received in this study for your 
osteoarthritis pain?
Please Check (X) ONE only:
(1) Yes, I would definitely want to use the same drug again
(2) I might want to use the same drug again
(3) I am not sure
(4) I might not want to use the same drug again
(5) No, I definitely would not want to use the same drug again
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Appendix 13. Abbreviations
This is a list of abbreviations that may or may not be used in the protocol.  
Abbreviation
Term
Ab
antibody
ACR
American College of Rheumatology
ADA
anti-drug antibody
AE
adverse event
AEMPS
Agency on Medicinal Products and Medical Devices
ALARA
As Low As Reasonably Achievable
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASA
American Society of Anesthesiologists
AST
aspartate aminotransferase
BID
twice a day
BMI
body mass index
BOCF
baseline observation carried forward
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
C1M
C-terminal neoepitope of type I collagen
CPK
creatine phosphokinase
CRF
case report form
CR
controlled release
CRA
Clinical Research Associate
 
CSA
clinical study agreement
CT
computed tomography
CTA
clinical trial application
CTS
carpal tunnel syndrome
CYP
cytochrome enzyme system
DAAP
United States Food and Drug Administration Division of 
Analgesia, Anesthetic, and Addiction Products
DAI
Dosage andAdministration Instructions
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
E-DMC
External Data Monitoring Committee
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EDTA
edetic acid (ethylenediaminetetraacetic acid)
EIU
exposure in-utero
EQ-5D-5L
EuroQol 5 Dimension
ER
extended release
ESR
erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiation Protection
IND
Investigational New Drug application
INR
International Normalized Ratio
IgG
immunoglobulin G
IgG2
immunoglobulin G Type 2
IPAP
Initial Pain Assessment Period
IRB
institutional review board
IL
interleukin
IL-1β
Interleukin-1 beta
IRT
interactive response technology
ITT
intent to treat
IUD
intrauterine device
IUS
Intrauterine system
IV
intravenous 
JSW
joint space width
LDH
lactate dehydrogenase
LFT
liver function test
LOCF
Last Observation Carried Forward
LSLV
last subject last visit 
LSMean
least squared mean
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MHRA
Medicines and Healthcare prodcuts Regulatory Agency
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MMRM
mixed model for repeated measures
mPRTI
Patient Reported Treatment Impact assessment-modified
MMR
measles, mumps and rubella
mSv
millisievert
MVPA
moderate to vigorous physical activity
N/A
not applicable
NGF
nerve growth factor
NGFI
nerve growth factor inhibitor
NIS
Neuropathy Impairment Score
NNH
number needed to harm
NNT
number needed to treat
NRS
numeric rating scale
NSAID
non-steroidal anti-inflammatory drug
NSC
Neuropathy Symptom Change
NYHA
New York Heart Association
OA
osteoarthritis
OMERACT-OARSI
Outcome Measures in Rheumatology – Osteoarthritis Research 
Society Initiative
OTC
over-the-counter
PCD
primary completion date
PD
pharmacodynamic
PEI
Paul Ehrlich Institute
PGA
Patient Global Assessment
PHQ-9
Patient Health Questionnaire 
PK
pharmacokinetic
PO
oral administration (per os)
PT
prothrombin time
PTH
parathyroid hormone
QD
once daily
QID
four times a day
QT
in electrocardiography, the time corresponding to the beginning 
of depolarization to repolarization of the ventricles
QTc
in electrocardiography, the time corresponding to the beginning 
of depolarization to repolarization of the ventricles, corrected for 
heart rate
QTcB
QT corrected for heart rate using Bazett’s formula
QTcF
QT corrected for heart rate using Fridericia’s formula
RD
risk difference
RNA
ribonucleic acid
RPOA
rapidly-progressive osteoarthritis
RR
risk ratio
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I
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SAE
serious adverse event
SAS
Survey of Autonomic Symptoms
SC
subcutaneous
SOA
schedule of activities
SPONK
spontaneous osteonecrosis of the knee
SRSD
single reference safety document
TNF-α
tumor necrosis factor alpha
trkA
tropomyosin receptor kinase A
ULN
upper limit of normal
US
United States
VAS
visual analog scale
WOMAC
Western Ontario and McMaster University Osteoarthritis Index
WPAI:OA
Work Productivity and Activity Impairment Questionnaire: 
Osteoarthritis 
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Appendix 14. Lifestyle Guidelines for Subjects from Sites in Sweden
For sites in Sweden, all female subjects who are of childbearing potential and are sexually 
active and at risk of pregnancy must agree to use one (1) highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for 112 days (16 weeks) after the last dose of investigational product.  The investigator or his 
or her designee, in consultation with the subject, will confirm that the subject has selected the 
most appropriate method 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 one 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 (SOA) 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 contraception methods are discontinued or if pregnancy is known or suspected in 
the subject or the subject’s partner. 
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:32
1. Established use of hormonal methods of contraception is allowed provided the subject 
plans to remain 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 ovulation*:
•
oral
•
injectable
•
implantable
*Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action is not 
accepted as a highly effective method.
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2. Correctly placed intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS). 
3. Bilateral tubal occlusion.
4. Vasectomised partner provided that the partner is the sole sexual partner of the trial 
participant and that the vasectomised 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.
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Appendix 15. France Appendix
This appendix applies to study sites located in France.
1. GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the Study will 
complete the Pfizer GCP Training or equivalent before performing Study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the Study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
2. Investigational Product
No subjects or third-party payers will be charged for investigational product.
3. Inspections
The investigator(s) will notify Pfizer or its service provider immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with Pfizer or its service provider to prepare the study site for the inspection and will allow 
Pfizer or its service provider (if not prohibited by law) to be present during the inspection. 
The study site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the subject's medical records.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its service provider.  Before response 
submission to the regulatory authorities, the investigator will provide Pfizer or its service 
provider with an opportunity to review and comment on responses to any such findings.  
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