Clinical trial NCT02709486
Conditions: Osteoarthritis, Hip Osteoarthritis, Knee
Keywords: Osteoarthritis, pain, tanezumab.
Sponsor: Pfizer
Start date: 2016-03-02; Completion date: 2018-11-14
Enrollment: 849 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Tanezumab is a monoclonal antibody that binds to and inhibits the actions of nerve growth factor (NGF). The Nerve Growth Factor Inhibitor (NGFI) class may offer an important breakthrough in the treatment of chronic pain and is under clinical investigation for the treatment of pain associated with osteoarthritis or other chronic pain conditions.

The 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.

Detailed description:
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).

Week 24 is the landmark analysis in this study. Subjects who do not complete the Double-blind Treatment period will enter and complete the 24-week Early-termination follow-up period.

Arms: arm 1: Investigational product arm 2: Investigational product arm 3: Investigational product
Interventions: intervention 1: Tanezumab intervention 2: Tanezumab intervention 3: Placebo
Intervention descriptions: intervention 1: 2.5 mg intervention 2: 5 mg intervention 3: Placebo

Protocol documents:
Prot_000.pdf: 
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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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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Gimbel J, Kivitz A, Bramson C, N et al. Long-term safety and efficacy of tanezumab as 
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Castro M. Placebo versus Best-Available-Therapy Control Group in Clinical Trials for 
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Huda W, Gkanatsios NA. Radiation dosimetry for extremity radiographs. Health Phys. 
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Okkalides D, Fotakis M. Patient effective dose resulting from radiographic 
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Wall BF, Hart D. Revised radiation doses for typical X-ray examinations. Report on a 
recent review of doses to patients from medical X-ray examinations in the UK by 
NRPB. Br J Radiol. 1997;70:437-9.
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Blake GM, Naeem M, Boutros M. Comparison of effective dose to children and adults 
from dual X-ray absorptiometry examinations. Bone. 2006;38:935-42.
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Dyck PJ, Litchy WJ, Lehman KA, et al. Variables influencing neuropathic endpoints: 
The Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology 1995; 
45(6):1115-21.
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28.
Altman R, Asch E, Bloch D, et al. The American College of Rheumatology criteria for 
the classification and reporting of osteoarthritis of the knee. Arthritis Rheum 1986;
29:1039-49. 
29.
Ornetti P, et al. OARSI-OMERACT Definition of Relevant Radiographic Progression 
in Hip / Knee Osteoarthritis. Osteoarthritis and Cartilage 2009;17:856-63.
30.
Altman R, Alarcón G, Appelrouth D, et al. The American College of Rheumatology
criteria for the classification and reporting of osteoarthritis of the hip. Arthritis; Rheum
1991; 34:505-14.
31.
Dripps RD. New classification of physical status. Anesthesiol. 1963;24:111.
32. Clinical Trial Facilitation Group. Recommendations related to contraception and 
pregnancy testing in clinical trials [Internet]. Germany: Heads of Medicines Agencies 
(HMA); 2014 [2014 Sep 15; cited 2015 Aug 12]. Available from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf
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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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SAMPLE
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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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CCI
CCI
CCI
CCI
CCI
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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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CCI
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CCI
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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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CCI
CCI
CC
I
CCI
CCI
CCI
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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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CCI
CCI
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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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SAP_001.pdf: 
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Protocol A4091057
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
Statistical Analysis Plan 
(SAP)
Version:
4.0 (Final)
Date:
21-DEC-2018
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................9
2.1. Study Objectives .......................................................................................................9
2.1.1. Primary Objective.........................................................................................9
2.1.2. Secondary Objective.....................................................................................9
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................11
3.1. Primary Endpoint(s) ................................................................................................11
3.2. Secondary Endpoint(s) ............................................................................................11
3.2.1. Efficacy Measures ......................................................................................11
3.3. Other Endpoints.......................................................................................................14
3.3.1. Pharmacokinetic and Pharmacodynamic Measures....................................14
3.4. Baseline Variables...................................................................................................14
3.4.1. Covariates ...................................................................................................14
3.5. Safety Endpoints .....................................................................................................15
3.5.1. Adverse Events...........................................................................................15
3.5.2. Vital Signs ..................................................................................................17
3.5.3. Total Joint Replacement and Surgical Endpoints.......................................17
3.5.4. Neurological Endpoints ..............................................................................18
4. ANALYSIS SETS ...............................................................................................................18
4.1. Full Analysis Set .....................................................................................................18
4.2. Per Protocol Analysis Set........................................................................................18
4.2.1. Major Deviations Assessed Prior to Randomization..................................19
4.2.2. Major Deviations Assessed Post-Randomization.......................................19
4.3. Safety Analysis Set..................................................................................................20
4.4. Other Analysis Sets .................................................................................................20
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................20
5.1. Hypotheses and Decision Rules ..............................................................................20
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5.1.1. Statistical Hypotheses.................................................................................20
5.1.2. Statistical Decision Rules ...........................................................................20
5.2. General Methods .....................................................................................................22
5.2.1. Analyses for Binary Data............................................................................24
5.2.2. Analyses for Continuous Data....................................................................25
5.2.3. Analyses for Categorical Data....................................................................29
5.2.4. Analyses for Time to Event Data................................................................30
5.3. Methods to Manage Missing Data ..........................................................................30
6. ANALYSES AND SUMMARIES ......................................................................................34
6.1. Primary Endpoint(s) ................................................................................................34
6.2. Secondary Endpoint(s) ............................................................................................34
6.3. Other Endpoint(s)....................................................................................................34
6.3.1. Pharmacokinetics........................................................................................34
6.4. Subset Analyses.......................................................................................................35
6.5. Baseline and Other Summaries and Analyses.........................................................35
6.5.1. Concomitant Medications and Non-Drug Treatments................................36
6.6. Safety Summaries and Analyses .............................................................................36
6.6.1. Adverse Events...........................................................................................37
6.6.2. Vital Signs ..................................................................................................39
6.6.3. Neurological Results...................................................................................39
6.6.4. Immunogenicity..........................................................................................40
6.6.5. Joint Safety Events .....................................................................................40
7. INTERIM ANALYSES.......................................................................................................40
7.1. Introduction .............................................................................................................40
7.2. Interim Analyses and Summaries............................................................................41
8. REFERENCES ....................................................................................................................42
9. APPENDICES .....................................................................................................................43
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ................................................5
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LIST OF FIGURES
Figure 1.
Study Design.........................................................................................................10
Figure 2.
Graphical Multiple Testing Procedure for Strong Control of Type I Error..........21
APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES........................................................43
Appendix 2. DATA DERIVATION DETAILS ......................................................................53
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................53
Appendix 3. STATISTICAL METHODOLOGY DETAILS..................................................56
Appendix 3.1. Further Details of Interim Analyses.................................................................61
Appendix 3.2. Further Details of the Statistical Methods........................................................61
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study A4091057 is based on the Protocol 
Amendment 2 dated 10Feb2016.
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1.0
(14JUL2016)
Not 
Applicable
Not Applicable
2.0
(26SEP2018)
Clarified abbreviation, synonym, definition across this 
document; 
Clarified the day of baseline of IAP under Section 2.2;
Amend the period to summarize about selected safety 
analysis is based on treatment and safety follow-up 
separately under Section 2.2, Section 3.5.1, Section 3.5.2;
Removed Week 32 of some categorical efficacy endpoints 
under Section 3.2;
Clarified the baseline definition of NRS score using the last 
3 values under Section 3.4;
Moved last two sentences of source data definition of 
statistical model and the summary of randomization system 
vs. CRF from Section 3.4 through Section 3.4.1;
Added WOMAC baseline as covariate in model about 
rescue medication and removed the site as random effect 
from the same model under Section 3.4.1;
Added explanation of covariate for incidence of treatment 
discontinuation under Section 3.4.1;
Removed the interaction analysis of corresponding baseline, 
index joint, KL grade under Section 3.4.1;
Removed a sensitivity analysis without covariate under 
Section 3.4.1;
Added to summarize about orthostatic hypotension under 
Section 3.5.2; 
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Removed to summarize about postural change in DBP/SBP 
under Section 3.5.2;
Removed some analysis of composite endpoints and 
re-categorized the adjudication outcome under Section 
3.5.3;
Removed gender subgroup analysis of neurological 
endpoints under Section 3.5.4; 
Updated the timing to decide how patients who randomized 
but received incorrect treatment for safety from “prior to 
database lock” to “before unblinding” under Section 4;
Clarified the process about per protocol population
definition under Section 4.2; 
Updated the criteria of major deviation assessed prior to 
randomization under Section 4.2.1;
Added an criteria about mismatch between CRF and 
electric tablet and updated criteria for non-NSAID under 
Section 4.2.2;
Removed other analysis set under Section 4.4;
Added estimand definition under Section 5.2;
Clarified general time points to be measured and on-off 
treatment detail under Section 5.2;
Removed description of sensitivity analysis about 
ANCOVA (LOCF and BOCF) and MMRM in section of 
primary analysis of co-primary endpoint under Section 
5.2.2;
Amended MMRM using multiple imputation data and 
added MMRM using observed data (regardless of on-off 
treatment) up to week 24 as sensitivity analyses under 
Section 5.2.2;
Removed interaction analysis except for treatment by 
country and treatment by study site and removed unadjusted 
analysis under Section 5.2.2;
Added sensitivity analysis to evaluate missing sentence for 
Spanish translation under Section 5.2.2;
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Removed analysis of other time point of primary endpoints 
defined as secondary endpoint using multiple imputation 
and added analysis from day 1 through day 7 of average 
pain under Section 5.2.2;
Removed the description of ANCOVA for dairy pain due to 
duplicated sentence under Section 5.2.2;
Added additional WPAI analysis under Section 5.2.2;
Removed CMH analysis of patient global assessment under 
Section 5.2.3;
Updated analyses of mPRTI under Section 5.2.3;
Removed time to joint safety analysis under Section 5.2.4;
Clarified to apply multiple imputation to time points other 
than primary (week 24), updated seeds for multiple 
imputation, added to how to impute WOMAC each items, 
clarified to apply using standard methods (Little & Rubin, 
2002), clarified how to handle the multiple data within 
same time window, and clarified only to use the last 3 data 
for baseline calculation of IPAP under Section 5.3;
Updated PK analysis and merged Section 6.3.1 through 
6.3.3 as Section 6.3.1;
Removed subset analysis about TJR under Section 6.4; 
Added diabetes status as baseline characteristics under 
Section 6.5;
Removed some analyses (AE/SAE of patient-years, 
sympathetic neuropathy consults, depressed sympathetic 
functions, AEs of APS, plots of start and stop day of 
APS/DFS/Odema peripheral, summary of start day and 
duration of APS/DFS/Odema peripheral, summary of 
demographic details, etc…) under Section 6.6;
Updated duration period in some summary table under 
Section 6.6;
Added summary of days of NSAID use, mg dose of NSAID 
under Section 6.6;
Updated the cut-off % for tier 2 AE from 1% to 3%, and 
removed graphs of AE and risk difference under Section 
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6.6.1;
Clarified AE summary definition and added to summarize 
during safety follow-up for selected AEs under Section 
6.6.1; 
Removed to summarize mean change from baseline in 
postural blood pressure under Section 6.6.2;
Clarified neurologic data summaries under Section 6.6.3;
Removed to analyze joint some safety events like events per 
1000 patients years of exposure, and removed to analyze 
joint space width under Section 6.6.5;
Removed all analyses about joint space width under Section 
6.6.5;
Updated adjudicated events to summarize for SMC under 
Section 7.2;
Removed the link of EQ 5D under Section 8;
Updated analysis under Appendix 1 based on amendments 
before section 7; 
Removed the window of end of study, added additional 
window of 16 +/- 4 weeks past the date of the last SC dose, 
added some specific endpoints window, EQ-5D-5L, WPAI: 
OA, HCRU, and mPRTI, updated the definition of baseline 
calculation to use last 3 non-missing pain score, and 
updated time windows of dairy pain after week 24 under 
Appendix 2.1.
Added to collect HCRU during last 8 week prior to baseline 
description under Appendix 3 to keep consistent with the 
corresponding CRF.
Updated to analyze rescue medication under Appendix 3.
3.0
(13DEC2018)
Added gatekeeping strategy for co-primary and key 
secondary endpoints under Section 5.1.2 and added 
references under Section 8;
Clarified how to summarize p-value of Spanish interaction 
subgroup under Section 5.2.2;
Removed “site” from fixed effect in the model of 
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exploratory analysis under Appendix 1.
4.0
Removed one sentence of introductory sentence under 
Section 6.6.1; 
Added the definition of windowing under Section 6.6.5.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicised. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A4091057.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
2.1.1. Primary Objective
Demonstrate superior efficacy of tanezumab 5 mg and 2.5 mg administered subcutaneously 
(SC) every 8 weeks versus placebo at Week 24.
2.1.2. Secondary Objective
Evaluate the safety of tanezumab 2.5 mg SC and 5 mg SC.
2.2. Study Design
The study design is summarized in the diagram below.
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Figure 1.
Study Design
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 (Day -7 through Day -1)).
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The end of treatment period is at Week 24, with the safety follow-up period up to Week 48.  
The primary time point for efficacy is Week 24.  The period of interest for most safety results 
is the treatment period.  Selected safety results will be provided separately for the safety
follow-up and for the combined overall study period comprising the treatment and safety 
follow-up periods.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
•
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.
Baseline values will be those from the Baseline window as described in Appendix 2.1.
3.2. Secondary Endpoint(s)
3.2.1. 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, and 24.
The OMERACT-OARSI responder index at Week X utilizes the change from Baseline to 
Week X in the WOMAC Pain subscale, the WOMAC Physical Function Subscale and the 
PGA of Osteoarthritis (using appropriate imputation where necessary for any components).  
According to this definition, a patient is classified as a responder if, either:
•
The improvement from Baseline to Week X was ≥50% and ≥2 points in either the 
WOMAC Pain or Physical Function subscales, OR
•
At least 2 of the following 3 were true:
•
The improvement from Baseline to Week X was ≥20% and ≥1 point in the 
WOMAC Pain subscale;
•
The improvement from Baseline to Week X was ≥20% and ≥1 point in the 
WOMAC Physical Function subscale;
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•
The improvement from Baseline to Week X ≥20% and ≥1 point in the PGA of 
Osteoarthritis (note: from the 5-point Likert scale, any change of ≥1 
corresponded to a change of ≥20%).
•
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, and 24.
•
Treatment Response: Reduction in the WOMAC Physical Function subscale of ≥30%, 
≥50%, ≥70% and ≥90% at Weeks 2, 4, 8, 12, 16, and 24.
•
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, and 24.
•
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.
The WPAI:OA impairment scores are listed below:
•
Percent work time missed due to Osteoarthritis.
•
Percent impairment while working due to Osteoarthritis.
•
Percent overall work impairment due to Osteoarthritis.
•
Percent activity impairment due to Osteoarthritis.
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The calculation of these endpoints is described in Appendix 3.
•
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.
The Baseline and Weeks 8, 16, and 24 responses in the five dimensions (mobility; self-care; 
usual activities; pain/discomfort; anxiety/depression) and overall health utility score from the 
EuroQol 5 Dimensions (EQ-5D-5L), and the EQ-VAS will be summarized by treatment 
group.  This summary will use observed data only (no imputation for missing data).  The 
overall health utility score is calculated using the EuroQol value sets, and is described in 
Appendix 3.
An additional question, called the EQ-VAS asks the patient to rate their health today using a 
VAS scale from 0 (the worst health you can imagine) to 100 (the best health you can 
imagine).  This will be summarized along with the health utility score. 
•
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 24.
The three endpoints derived from this questionnaire are described below:
Patient satisfaction.  This comes from the question “Overall, how satisfied are you with 
the drug that you received in this study?”.  This is rated on a 5 point Likert scale from 1 
(‘Extremely dissatisfied’) to 5 (‘Extremely satisfied’). 
Patient willingness to use drug again.  This comes from the question “In the future, 
would you be willing to use the same drug that you have received in this study for your 
osteoarthritis pain?”.  This is rated on a 5 point Likert scale from 1 (‘Yes, I would 
definitely want to use the same drug again’) to 5 (‘No, I definitely would not want to 
use the same drug again’).
Patient preference of drug versus prior treatment.  This comes from the question 
“Overall, do you prefer the drug that you received in this study to the treatment you 
received before this clinical trial?”. This is rated on a 5 point Likert scale from 1 (‘Yes, 
I definitely prefer the drug I am receiving now’) to 5 (‘No, I definitely prefer my 
previous treatment’).
•
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.
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3.3. Other Endpoints
3.3.1. Pharmacokinetic and Pharmacodynamic Measures
•
Plasma tanezumab concentrations.
•
Serum NGF assessment.
•
Serum and urine osteoarthritis biomarker concentrations.
3.4. Baseline Variables
Baseline is generally defined as the last observation prior to first receipt of study drug, within 
the baseline window as defined in Appendix 2.1.
For analysis of diary pain intensity scores for the index joint, baseline is defined as the mean 
average daily Pain NRS score using the last 3 values during the 7 days of the Initial Pain
Assessment Period prior to Randomization/Day 1.
The stratification variables are 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).
3.4.1. Covariates
For all models analyzing the continuous primary and secondary efficacy endpoints (except 
rescue medication) the corresponding Baseline value will be used as a covariate, in addition 
to Baseline diary average pain.  Study site will be fitted as a random effect in the ANCOVA 
models. The randomization stratification variables of index joint (hip or knee) and highest 
Kellgren-Lawrence grade (2, 3 or 4) will be included as fixed effects.
A listing of subjects with mis-matches between the stratification variables entered at 
randomization and the case report form data (including central lab data for 
Kellgren-Lawrence grade) will be provided.  In analysis models, the strata entered at 
randomization will be used, but for descriptive summarization of the population and 
identification of subgroups, the strata as indicated on the case report form data will be used.
For the models analyzing the amount and number of days of rescue medication use the model 
will include terms for Baseline WOMAC Pain, Baseline diary average pain, and stratification 
factors.
The analysis of the incidence of treatment discontinuation due to lack of efficacy will include 
… model terms for Baseline WOMAC Pain subscale score, Baseline diary average pain 
score, index joint, Kellgren-Lawrence grade, and treatment group. 
For categorical/binary response endpoints relating to WOMAC Pain and PGA, the 
corresponding Baseline WOMAC Pain or PGA value will be used as a covariate in the 
analysis model, in addition to the stratification parameters of index joint and highest 
Kellgren-Lawrence grade, as well as Baseline diary average pain.  For the OMERACT 
response endpoint, the Baseline WOMAC Pain subscale score and Baseline diary average 
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pain score will be used as covariates in the analysis model, in addition to the stratification 
parameters of index joint and highest Kellgren-Lawrence grade. 
Additional analyses of the three co-primary endpoints will examine the treatment interactions 
with Study site, and Country.
3.5. Safety Endpoints
•
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.
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to a given treatment if:
•
The event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment (for example, during the baseline or run-in 
period), or
•
The event was seen prior to the start of treatment but increased in severity during 
treatment.
The effective duration of treatment is determined by the lag time.  Any event occurring 
within the lag time, whether this occurs during a break in treatment or at the end of treatment, 
is attributed to the corresponding treatment period. An infinite lag will be used for the study,
meaning any treatment-emergent AE reported in the database will be included in tables of 
AEs up to end of study.
The adverse events of Abnormal Peripheral Sensation (APS) are defined in the table below. 
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Allodynia
Neuritis
Axonal neuropathy
Neuropathy peripheral
Burning sensation
Paraesthesia
Carpal Tunnel Syndrome
Paraesthesia oral
Decreased Vibratory Sense
Peripheral sensorimotor neuropathy
Demyelinating polyneuropathy
Peripheral sensory neuropathy
Dysaesthesia
Polyneuropathy
Formication
Polyneuropathy chronic
Hyperaesthesia
Sensory disturbance
Hyperpathia
Sensory loss
Hypoaesthesia
Thermohypoaesthesia
Hypoaesthesia oral
Sciatica
Intercostal neuralgia
Tarsal Tunnel Syndrome
Neuralgia
Adverse Events of Sympathetic Nervous System are defined in the table below.
Abdominal discomfort
Micturition urgency
Anal incontinence
Nausea
Anhidrosis
Nocturia
Blood pressure orthostatic decreased
Orthostatic hypotension
Bradycardia
Pollakiuria
Diarrhoea
Presyncope
Dizziness postural
Respiratory distress
Early satiety
Respiratory failure
Ejaculation delayed
Sinus bradycardia
Ejaculation disorder
Syncope
Ejaculation failure
Urinary hesitation
Heart rate decreased
Urinary incontinence
Hypertonic bladder
Vomiting
Hypohidrosis
A smaller set of the above Adverse Events (to be called AEs of Decreased Sympathetic 
Function) may also be summarized.  These are defined below.
Anhidrosis
Orthostatic hypotension
Bradycardia
Syncope
Hypohidrosis
The lists given above may be updated depending on any additional adverse events observed 
in any tanezumab study.  There are a number of summaries based on these groupings of 
adverse events.
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A 3-tier approach will be used to summarize AEs.  Under this approach, AEs are classified 
into 1 of 3 tiers. Different analyses will be performed for different tiers.  A description of the 
three tiers and analyses are given in Section 6.6.1. 
All summaries of adverse events will be shown for adverse events that begin or worsen from 
the first SC dose (treatment-emergent) up to the end of the treatment period.  In addition a 
selection of adverse event tables will be produced for the safety follow-up period and for the 
whole period up to the end of the study, including the treatment period and safety follow-up 
period.
3.5.2. Vital Signs
The incidence of orthostatic hypotension at each visit, at any treatment period visit (including 
unscheduled visits), and at any safety follow-up period (including unscheduled visits), will be
summarized.  The definition of orthostatic hypotension is:
•
For patients with Baseline supine systolic Blood Pressure ≤150 mmHg: 
•
Reduction in sBP (standing minus supine) ≥20, OR
•
Reduction in dBP (standing minus supine) ≥10.
•
For patients with Baseline supine systolic Blood Pressure >150 mmHg: 
•
Reduction in sBP (standing minus supine) ≥30, OR
•
Reduction in dBP (standing minus supine) ≥15.
An additional summary will be provided of outcomes of assessment resulting from an 
incident of orthostatic hypotension or other events of interest using data from both the CRF 
database and the consultations database, as appropriate.
3.5.3. Total Joint Replacement and Surgical Endpoints 
A summary of adjudication outcomes (including – outcomes of rapidly progressive 
osteoarthritis (type-1 only), rapidly progressive osteoarthritis (type-2 only), rapidly 
progressive osteoarthritis (type-1 or type-2 combined), subchondral insufficiency fracture, 
primary osteonecrosis, and pathological fracture) and total joint replacements will be 
provided.
Reporting of total joint replacement events including surgery and recovery will be described 
in a separate Statistical Analysis Plan for Study 1064.  Corresponding data from Studies 
1056, 1057 and 1058 will be reported under study 1064, as well as patients who enter study 
1064 from studies 1059, 1061, and 1063 due to those studies closing out.
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3.5.4. Neurological Endpoints 
The Neuropathy Impairment Score (NIS) is the sum of scores over all 37 items from both the 
Left and Right side.  Items 1-24 are scored on a 0-4 scale (0, 1, 2, 3, 3.25, 3.5, 3.75, 4) and 
items 25-37 are scored on a 0-2 scale (0, 1, 2).  The possible range of the NIS is 0-244.
The Survey of Autonomic Symptoms (SAS) is a 12 item (11 for females) questionnaires.  
From this the total number of symptoms (0-12 for males and 0-11 for females) will be 
calculated.  Where a patient has a symptom, the impact of that symptom is then rated from 1 
(‘not at all’) to 5 (‘a lot’).  The total impact score is calculated using this 1-5 scale, with 0 
assigned where the patient does not have the particular symptom.  The range for the total 
impact score is 0-60 for males and 0-55 for females. 
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
If a subject was:
•
Randomized but not treated, then that subject will be excluded from all efficacy and 
safety analyses.
•
Treated but not randomized, then by definition that subject will be excluded from the 
efficacy analyses, but will be reported under the treatment they actually received for 
all safety analyses.
•
Randomized but received incorrect treatment, then that subject will be reported under 
their randomized treatment group for all efficacy analyses, but will be evaluated on a 
case-by-case basis for presentation for safety analyses.  Decisions will be made 
before unblinding. 
4.1. Full Analysis Set
The intent to treat (ITT) analysis set is the primary analysis set for efficacy analyses.  It 
consists of all randomized subjects who received at least one dose of SC study medication 
(either tanezumab or placebo SC).  This analysis set is used in the presentations of all 
efficacy data, and all data listings, and is labeled as the ‘ITT Analysis Set’ or ‘ITT 
Population’.
4.2. Per Protocol Analysis Set 
The per-protocol (PP) analysis set is the secondary efficacy analysis set.  It is defined as all 
subjects in the ITT analysis set who are not major protocol deviators (which would 
potentially affect efficacy).  The criteria for major protocol deviators are described below in 
Sections 4.2.1 and 4.2.2.  The identification of specific subjects included and excluded (and 
reason for exclusion) for this analysis set will be made and documented prior to unblinding.  
Protocol deviations for the PP analysis set will be obtained from the collected list of 
potentially important protocol deviations, and this list will comprise deviations identified 
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from review of programmed potentially important protocol deviation listing and study 
monitoring.  This analysis set is used in a specific sensitivity analysis of the co-primary 
efficacy endpoints, and is labeled as the ‘Per Protocol Population’.
Any other major deviation which is not pre-specified below, but results in a subject being 
excluded from the PP analysis set, will be specified in the protocol deviations document 
which is completed prior to unblinding.
The following protocol deviations are defined as ‘major’ and would exclude a subject from 
the PP analysis set.  These deviation criteria can be split into those assessed prior to 
randomization relating to the protocol inclusion and exclusion criteria, and those assessed 
post randomization. 
4.2.1. Major Deviations Assessed Prior to Randomization
•
Inclusion criteria: #3-5.
•
Exclusion criteria: #3, 4 (if any of the following conditions are in the index joint: 
severe chondrocalcinosis, other arthropathies [eg, rheumatoid arthritis], systemic 
metabolic bone disease [eg, pseudogout, Paget’s disease, metastatic calcifications], 
primary or metastatic tumor lesions, stress or traumatic fracture), 10, 14, 15, 16 (if 
index joint was involved), 17.
•
Randomization criteria: #1, 3-6. Note, subjects with missing Baseline data for any of 
the co-primary endpoints would not meet the randomization/inclusion criteria for 
Baseline co-primary endpoints and so would be defined as a deviation according to 
these criteria.
4.2.2. Major Deviations Assessed Post-Randomization
•
Mismatch in specification of index joint in the CRF vs. electronic tablet for WOMAC 
data collection.
•
Rescue medication taken within 24 hours prior to the Week 24 visit.
•
Prohibited medications that could affect pain and function assessments (protocol 
section 5.7.1) taken (i) within 48 hours prior to Week 24 visit for non-NSAID 
medications (or any use if long-acting, eg, Synvisc), or (ii) within 48 hours prior to 
Week 24 visit or within the wash-out period specified by Appendix 3 of the protocol, 
for NSAID medications.
In addition, unforeseen major protocol deviations may be added to this list. However the 
final definition of this criteria and the per-protocol population will be made prior to 
unblinding of this study.
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4.3. Safety Analysis Set
The safety analysis set is defined as all subjects treated with tanezumab or placebo SC (see 
beginning of Section 4 for further details).  This analysis set will be labeled as the ‘Safety
Analysis Set’ or ‘Safety Population’ in the corresponding data analyses and summary 
presentations.
4.4. Other Analysis Sets
Not applicable. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Statistical Hypotheses
The treatment comparisons being made in this study are tanezumab 2.5 mg and 5 mg versus 
placebo.  For these treatment comparisons, the null and alternative hypotheses are shown 
below (note μTREATMENT relates to the mean change from Baseline for the specified treatment 
group).  All tests will be 2-sided.
Null Hypotheses
H0: 
0
PLACEBO
2.5mg
  
TANEZUMAB
=
−μ
μ
H0: 
0
PLACEBO
5mg
  
TANEZUMAB
=
−μ
μ
Alternative Hypotheses
H1: 
0
PLACEBO
2.5mg
  
TANEZUMAB
≠
−μ
μ
H1: 
0
PLACEBO
5mg
  
TANEZUMAB
≠
−μ
μ
The hypotheses for other types of analyses (eg, for the binary response endpoints) would be 
similar to those shown above.
5.1.2. Statistical Decision Rules
In addition to three co-primary endpoints in Section 3.1, three secondary endpoints of 
subjects with ≥50% reduction from baseline in WOMAC Pain at Week 24, change from 
baseline to Week 2 in the WOMAC Pain subscale, and change from baseline to Week 1 in 
average pain score in the index knee or hip, are identified as key secondary endpoints.  The 
testing of these co-primary endpoints and key secondary endpoints will follow the graphical 
approach of gate keeping strategy proposed by Bretz et al (2011)2, as depicted in the 
following figure.  This will be implemented to control the family-wise type I error rate of 
5% (two-sided), and this graphical approach is a closed testing procedure; hence, it strongly 
controls the family-wise error rate (Alosh et al. 2014).1
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Figure 2.
Graphical Multiple Testing Procedure for Strong Control of Type I Error
As initial step of three co-primary endpoints, these are represented by a single graphical node 
per dose, and this is equivalent to step-down testing strategy.  The step-down testing will first 
test tanezumab 5 mg versus placebo, and if statistically significant (p≤0.05) will then test 
tanezumab 2.5 mg versus placebo.  Finally, the particular tanezumab dose 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.
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If the null hypothesis is not rejected in the above graphical multiple testing procedure, no 
further testing is conducted as the α for that test is considered “spent” and cannot be passed 
to other endpoints.  The testing process continues as long as at least one null hypothesis can 
be rejected at its assigned α-level.  Each time a null hypothesis is rejected, the graph is 
updated to reflect the reallocation of α assigned to that hypothesis, which is considered 
“recycled” (Alosh et al. 2014).1  This iterative process of updating the graph and reallocating 
α is repeated until all key secondary hypotheses have been tested or when no remaining 
hypotheses can be rejected at their corresponding α level.
The primary analysis will be that with the multiple imputation approach (see below for 
details), and thus the overall type I error is controlled for each of the two doses (2.5 mg and 
5 mg) since all three co-primary endpoints need to be significant for a single dose.  The 
overall type I error of the study is also controlled given the step-down testing strategy for 
each of the endpoints.  Control of the family wise type I error rate accounting for multiplicity 
of contrasts will only apply to the three co-primary endpoints (model with the primary 
imputation analysis) and three key secondary endpoints. 
Regardless of the outcome of the primary analyses and three key secondary endpoints, the 
secondary endpoints will be tested.  No adjustment for multiple comparisons will be made 
for the secondary efficacy, and for the safety endpoints.  The α-level for each hypothesis test 
for the secondary and exploratory analyses will be 5%.
5.2. General Methods 
Subjects will be randomized at Baseline to one of three treatment groups: placebo SC, 
tanezumab 2.5 mg SC, or tanezumab 5 mg SC.  These will be labeled as placebo, tanezumab 
2.5mg, and tanezumab 5mg for the three treatment groups respectively. 
A modified treatment-policy estimands strategy is applied as the main strategy to assess 
effectiveness of tanezumab.  Data collected will be included for efficacy assessment 
regardless of rescue medication being used or not.
The general study design for efficacy, as depicted below, includes a planned treatment period 
through the Week 24 visit, and a planned 24-week post-treatment safety follow-up period.  
Efficacy data planned to be collected during this post-treatment safety follow-up period are 
intended to have efficacy measures contemporaneous to safety observations during this 
period.  They are not intended to assess treatment effects or compare treatment groups. All 
endpoints up to Week 32 will be summarized (where available), and endpoints up to Week 24
will be analyzed. 
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1057 study visits/analysis windows
Week
B
2
4
8
12
16
24
32
48
Study Day
1
15 29
57
85
113
169
225
337
Completer
x
x
x
x
x
x
x
x 
Drop after 
week 8 dose
x
x
x
x
x 
ET1
x ET2
Drop after 
day 1 dose
x
x
x
x 
ET1
x
ET2
B is baseline, x is collection of most efficacy endpoints, and ET is “Early Termination Visit.”
The method and definition of reporting windows for assigning efficacy data to particular time 
points is described in Appendix 2.1.
All efficacy assessments during the treatment period are made on the analysis windows 
defined in Appendix 2.1. Using these windows we find the analysis window for a patient’s 
last subcutaneous (SC) dose.  Any data included in a window that is up to 8 weeks from this 
last SC dose window is ‘on-treatment’, and any data included in a window that is more than 
8 weeks after the last SC dose window is ‘off-treatment’.  Data in on-treatment analysis 
windows will be used in summaries and analyses, while data in off-treatment analysis 
windows will be excluded from all summaries and analyses of treatment period efficacy data, 
ie, up to Week 24.
For example, the table below shows on-treatment and off-treatment windows for the planned 
collection visits for the WOMAC data during the treatment period:
Last SC Dose 
Analysis Window
On-treatment Analysis 
Window Data 
Off-treatment Analysis 
Window Data
Baseline
Weeks 2, 4, 8
Weeks 12, 16, 24
Week 2
Weeks 2, 4, 8
Weeks 12, 16, 24
Week 4
Weeks 2, 4, 8, 12
Weeks 16, 24
Week 8
Weeks 2, 4, 8, 12, 16
Week 24
Week 12
Weeks 2, 4, 8, 12, 16
Week 24
Week 16
Weeks 2, 4, 8, 12, 16, 24
None
Week 24
Weeks 2, 4, 8, 12, 16, 24
None
Efficacy data at Week 32 is planned to be off-treatment so will not be subject to the above 
handling, ie, all available data in the Week 32 window will be used in summaries.
Efficacy data collected via subject diary (NRS pain scores and rescue medication use) are 
collected daily or weekly, not at study visits.  Diary efficacy data will be considered 
on-treatment if it is collected up to 12 weeks (84 days) after the last SC dose.  Diary efficacy 
data collected more than 12 weeks (84 days) after the last SC dose will be considered 
off-treatment and excluded from summaries and analyses of treatment period efficacy data, 
ie, for presentation up to Week 24.
Diary data after Week 24 is planned to be off-treatment so will not be subject to the above 
handling, ie, all available data after Week 24 window will be used in summaries.
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A summary of all analyses is given in Appendix 1.  In all tables the treatment group ordering 
will be: placebo, tanezumab 2.5mg, tanezumab 5mg.  Unless otherwise specified, efficacy 
analyses use the ITT analysis set only.
5.2.1. Analyses for Binary Data
Binary response parameters, and the incidence of rescue medication use and treatment 
discontinuation due to lack of efficacy will be analyzed using logistic regression for binary 
data, with covariates described in Section 3.4.1.  Output will show the number and 
percentage of subjects in each response category, and odds ratios (with 95% confidence 
intervals) for the treatment comparisons shown in Section 5.1.1.
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, and 24 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 WOMAC Pain 
for OMERACT-OARSI responder index), 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 (‘Insufficient Clinical 
Response’ on the End of Treatment Subject Summary Case Report form), adverse event or 
death up to the timepoint of interest, and LOCF imputation would be used for missing data 
for any other reason.
The use of BOCF for missing data implies subjects with missing data are included in the 
analysis as non-responders.  Similarly the use of LOCF in the case where subjects have no 
post-Baseline data (and Baseline would be carried forward) again implies those subjects are 
included in the analysis as non-responders.
The incidence … of rescue medication use 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... Imputation for 
missing rescue medication data will use LOCF only.  The incidence … of rescue medication 
use will be summarized up to Week 32... 
The incidence of…treatment withdrawal due to lack of efficacy will also be analyzed for
discontinuation up to Week 24 (end of treatment period)... The analysis of the incidence of 
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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.  Discontinuation in the 
post-treatment safety follow-up period will not be included in this endpoint for analysis, but 
will be summarized as part of the safety tables.
5.2.2. Analyses for Continuous Data
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 
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.
The primary analysis set is the Intent to Treat analysis set.  These three primary endpoint 
analyses will be used to assess the primary objective of the study.
The mixed model ANCOVA, with multiple imputation, will also be used with other 
continuous change from Baseline endpoints for landmark (single time point) analyses.  The 
model will include the covariates described in Section 3.4.1, including study site as a random
effect.  Estimates of treatment effects and pair wise treatment comparisons will be based on 
least squares means (LS means) and 95% confidence intervals (CI) will be provided. 
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A number of sensitivity analyses will be performed on the primary efficacy endpoints in 
order to assess the robustness of the conclusions for the primary objective.  These relate to 
the analyses for missing data and the analysis population, the homogeneity of the results 
across factors that may influence efficacy, and for a secondary analysis of the PGA.  The 
analyses described below will not be subject to the testing strategy described for multiple 
comparisons of the primary analyses.  As such, assessment of all treatment comparisons will 
be made independent of results over the three co-primary endpoints or the two treatment 
comparisons for each analysis.
Primary Endpoint Sensitivity Analyses
The ITT analysis set is used in the analyses numbered 2 and 3 below, and Per-Protocol 
analysis set used in analysis number 1 below.
1. Per-Protocol Analysis Set
The primary analysis using multiple imputation described above will be repeated, but using 
the Per-Protocol analysis set in place of the ITT analysis set.  This analysis will assess the 
robustness of the efficacy conclusions to subjects who have more strictly adhered to protocol 
inclusion and exclusion criteria, and to protocol defined study procedures.
2. Alternative Missing Data Analyses
There are four additional analyses that will assess the robustness of the efficacy conclusions 
to the choice of multiple imputation as the primary method for accounting for missing data. 
In the first and second analyses, the primary ANCOVA analysis model described above will 
be repeated, but using BOCF and LOCF respectively for missing data (note these are single 
imputation analyses).
The third sensitivity analysis for the primary endpoints will use a mixed model repeated 
measures analysis using the observed and imputed data up to Week 24 from the primary 
multiple imputation analysis, with covariate terms for Time (study week, treated as a 
categorical variable), Treatment Group and Time-by-Treatment interaction, as well as the 
covariates described in Section 3.4.1.  The unstructured covariance will be used in the 
modeling of the within-subject errors in the analysis.  Even though this is a sensitivity 
analysis for the primary endpoints, estimates for the time points of Weeks 2, 4, 8, 12, and 16, 
in addition to Week 24 will be shown from this analysis.  See Appendix 2.1 for details on 
windows.
The forth sensitivity analysis for the primary endpoints will use a mixed model repeated 
measures analysis using all observed data up to Week 24 (ie, retrieved dropout), with 
covariate terms for Time (study week, treated as a categorical variable), Treatment Group 
and Time-by-Treatment interaction, as well as the covariates described in Section 3.4.1.  The 
unstructured covariance will be used in the modeling of the within-subject errors in the 
analysis.
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A summary of the missing data pattern will be shown for the WOMAC Pain and Physical 
Function subscales and the PGA over Baseline and Weeks 2, 4, 8, 12, 16, and 24.  This 
summary will show the incidence of subjects with each pattern of observed and missing data 
over these visits and endpoints.  This summary will be shown overall, and split by treatment 
group.
3. Interaction Analyses
Interaction analyses will be performed for the co-primary endpoints, exploring the effect of
Study site and Country.  These analyses will fit the covariate terms described in Section 3.4.1
(except for use of Study site as a covariate in the Country interaction analysis, where Country 
will be used instead [as a fixed term], in addition to the interaction term of treatment group 
by factor.  The Treatment by Study site interaction term will be fitted as a random effect. 
The interaction of Treatment with Study site will be fitted as a random effect (in addition to 
Study site itself), with the resulting estimated treatment differences being shown for the 
largest (pertaining to enrollment) study sites to illustrate the level of consistency of treatment 
benefit across the larger study sites.  The study sites to be examined in this way will be any 
site with an average of four or more subjects per treatment group within the site, which for 
this study relates to any site with 12 or more subjects in total.  This assessment will be made 
prior to unblinding, therefore a study site in this group may still have fewer than four subjects 
in one or more of the treatment groups, however that site will still be included in this 
summary of efficacy of the largest study sites.  To aid the interpretation of the treatment-site 
and treatment-country interactions, a summary of the efficacy data for each co-primary 
endpoint by treatment group will be shown for the sites with ≥12 subjects and also for the 
countries with ≥15 subjects over all treatment groups.
Other time points for the primary efficacy measure
The ANCOVA model described above for the co-primary endpoints, using covariates of
Baseline score, Baseline diary average pain, Index Joint, Highest KL grade (2, 3 or 4) and 
Treatment, with Study Site as a random variable, will be used in the analysis of WOMAC 
Pain, WOMAC Physical Function and PGA for the change from Baseline to Weeks 2, 4, 8, 
12, and 16.  This analysis will be produced using multiple imputation, and BOCF and LOCF 
for missing data.
The MMRM analysis described above will also analyze results for the secondary time points 
of Weeks 2, 4, 8, 12 and 16, for the co-primary efficacy endpoints.
Exploratory Analyses of WOMAC Physical Function Subscale
For WOMAC physical functions questionnaire from Q  through Q
, the 90 subjects 
answered them with missing last sentence 
 
 in Spanish version until January 5 2017.  To evaluate the 
impact of this missing sentence, the following analysis about WOMAC physical function
subscale will be conducted.
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•
The mixed model ANCOVA, with multiple imputation, will be conducted with 
change from baseline to week 24.  The model will include the covariates described in 
Section 3.4.1 (including study site as random effects), the subgroup of missing last 
sentence (See the below bullet for definition), and the interaction of treatment by the 
subgroup of missing last sentence (p-value of interaction term will be calculated by 
imputation and will be summarized.).  There are two categories of this subgroup 
defined as below sub-bullets;
•
If a subject answered questionnaires with full sentence at both baseline and 
post-baseline (week 24), then the subject will be categorized as “the subject who 
answered them with full sentence”. 
•
If a subject answered questionnaires with missing last sentence but answered 
them with full sentence at week 24 or if a subject answered questionnaires with 
missing last sentence at baseline and at week 24, then the subject will be 
categorized as “the subject who answered them with missing last sentence”. 
•
Descriptive statistics of change from baseline of each treatment group at week 24
visit will be summarized using the same subgroup categories of ANCOVA. 
•
Descriptive statistics of raw value of each treatment group at baseline and at week 24
will be summarized using the same subgroup categories of ANCOVA. 
Secondary Endpoint Analyses
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,and 24.  Analysis of Average Pain in the index joint will be conducted for the change from 
Baseline to Days 1, 2, 3, 4, 5, 6, and 7 and to Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24.  
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, and using the additional 
covariate of baseline diary average pain score.
The rescue medication data will be converted to Weekly scores for the week prior to the 
timepoint of interest.  Calculation of the endpoints is described in Appendix 3.
The … number of days per week of rescue medication use will be analyzed for Weeks 2, 4, 8, 
12, 16, and 24, and the amount of rescue medication use per week will be analyzed for 
Weeks 2, 4, 8, 12 16 and 24…  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.  In this model the error term is defined with 
a negative binomial distribution, and ‘log’ is used as the link function.  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.  For this analysis, Baseline data will not be carried forward in the 
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case of a post-Baseline observation not being available for use in LOCF.  The … 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. 
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.  This summary will use observed data only (no 
imputation for missing data).  The calculation of these endpoints is described in Appendix 3.
The summary will show number and % of subjects with a decrease, no change, and an 
increase in score for the change from Baseline to Week 8, 16, and 24 as well as descriptive 
statistics (mean, standard deviation, median, number of subjects) of the change in addition to 
the individual time points of Baseline and Week 8, 16, and 24.  The 4 WPAI parameters will 
be analyzed using the ANCOVA model described above for the primary endpoint using 
covariates of the corresponding Baseline score, Baseline diary average pain, Index Joint, 
Highest KL grade (2, 3 or 4), and Treatment, with Study Site as a random variable.
The Health Care Resource Utilization (HCRU) at Baseline, Weeks 32 and 48 will be 
summarized.
5.2.3. Analyses for Categorical Data
The change from Baseline in the Patient’s Global Assessment of Osteoarthritis to Weeks 2, 4, 
8, 12, 16, and 24 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, as well as any improvement (change<0), and any worsening (change>0).  
For this analysis imputation for missing data will used mixed BOCF/LOCF, as well as 
BOCF and LOCF separately.  The mixed BOCF/LOCF analysis at Week 24 will provide a 
sensitivity analysis for the primary analysis of the PGA.
All data from mPRTI will be summarized by visit.  Three items of the mPRTI (patient 
satisfaction, patient willingness to use drug again; patient preference of drug versus prior 
treatment in Section 3.2.1) 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 CMH test, if there are too few subjects in any stratification 
combination group (defined as <15 subjects in any of the 6 combinations of stratification 
factors) then an unstratified test will be performed.
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The change from Baseline in the NIS will be analyzed using a Cochran-Mantel-Haenszel 
(CMH) test for ‘row mean scores differ’, using change from Baseline categories as the scores 
in the analysis, and stratified by the combined levels of the stratification factors.  Output will 
show number and percentage of subjects whose NIS score worsened (change>0), improved 
(change<0) or had no change, in addition to the mean (with standard deviation) and median 
change, and minimum and maximum change.  This analysis will be performed for the two 
treatment comparisons separately, and shown by visit and worst change (largest change from 
baseline to any post-baseline visit), and by last change (summary statistics only). 
5.2.4. Analyses for Time to Event Data
The … time to treatment 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, in addition to the minimum and 
maximum time to discontinuation.  Other percentiles may be shown if the level of 
discontinuation due to lack of efficacy as calculated using Kaplan-Meier procedure is 
sufficiently large...
A plot of the time to discontinuation (failure) will be shown using the Kaplan-Meier 
estimates.  Only treatment discontinuation up to the end of treatment period (Week 24 visit or 
early discontinuation) will be used in this analysis.  Discontinuation due to lack of efficacy 
after the end of treatment visit will be included in the standard safety tables.  Time to event 
for discontinued subjects (discontinuing for reasons other than lack of efficacy) prior to the 
Week 24 visit uses censoring at the time of discontinuation.  Imputation of time to event for 
completed subjects or discontinued subjects (for any reason) post Week 24 visit uses 
censoring at the Week 24 visit time point.
5.3. Methods to Manage Missing Data
The three co-primary efficacy endpoints are the changes from Baseline to Week 24 in the
WOMAC Pain subscale, the WOMAC Physical Function subscale, and the Patient Global 
Assessment of Osteoarthritis. 
The primary analysis of the co-primary endpoints will use multiple imputation for missing 
data at Week 24 (where the method for imputation will be dependent on the reason for 
missing data) followed by the ANCOVA analysis with the model described below for the 
multiple imputed datasets.  The imputation strategies are described in the following table.
While the table describes the multiple imputation strategy specifically for the Week 24 time 
point, multiple imputation analysis at other time points will use the same strategy but with 
the appropriate time point, eg, ‘Week 2,’ substituted for ‘Week 24’ in the table below.  
Efficacy data missing from windows after the Week 24 window, eg, Week 32, will not be 
imputed for any summary or analysis unless otherwise indicated.
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Type of Missing Data
Imputation Method
Missing data resulting from discontinuation 
due to Death, Adverse Events (AEs) or 
Insufficient Clinical Response (Lack of 
Efficacy, LoE) prior to or during the Week 
24 visit reporting window*.
Multiple imputations will be created by 
sampling from a normal distribution based on 
the subject’s baseline score and the standard 
deviation (over all treatment groups) of the
observed efficacy data at Week 24 over all 
ITT subjects. This is a multiple imputation 
version of BOCF single imputation method.  
[Seeds 1, 3, and 5 below].
Missing data for other reasons, ie,
•
Subject did not discontinue on or before 
Week 24 (includes discontinuation for 
any reason after the end of the Week 24 
visit reporting window*)
•
Subject discontinued for a different 
reason prior to or during the Week 24 
visit reporting window*.
Multiple imputations will be created by 
sampling from a normal distribution based on 
the subject’s last score and the standard 
deviation (over all treatment groups) of the
observed efficacy data at Week 24 over all 
ITT subjects. For example if last observation 
for a subject is at Week 12, then the 
imputation sample for that subject is created 
using the subjects Week 12 observation and 
the standard deviation of the Week 24 
observations for all subjects.  Note, a 
subject’s last observation may be the Baseline 
observation.  This is a multiple imputation 
version of LOCF single imputation method.  
[Seeds 2, 4, and 6 below].
* See Appendix 2.1 for a definition of the reporting windows
The imputation of baseline-like data for subjects with missing data due to discontinuation 
due to Death, AE or LoE is intended to impute conservative efficacy values for those 
subjects who discontinue because of a reason that is considered to be a poor outcome for the 
subject, and so a poor outcome is imputed.  For those subjects with missing data that is likely 
to not be related to treatment group, the intention is that missing data should be imputed 
based on a ‘missing at random’ assumption taking into account the subject’s previous 
available data.
One hundred imputed datasets will be used in the analysis of ANCOVA.  In order to 
pre-define the analysis (and not to allow the results to change if run again), the following 
seeds will be used in the creation of the multiple imputed data: WOMAC scores: [1] 
10001-10100 and [2] 20001-20100; PGA scores: [3] 30001-30100 and [4] 40001-40100; and 
diary pain scores: [5] 50001-50100 and [6] 60001-60100.  Imputed Week 24 data for the 
PGA will be rounded to integer scores in the range 1 to 5.  Imputed Week 24 data for the 
WOMAC subscale and Average scores, and for the dairy pain scores <0 and >10 will be 
truncated to 0 and 10, respectively.  Imputed Week 24 data for the WOMAC items of Pain 
when Going Up or Down Stairs and Pain when Walking on a Flat Surface will be rounded to 
integer scores in the range of 0 to 10.  The ANCOVA analysis described in Section 5.2.2
(with covariates in Section 3.4.1) will be used for each imputation dataset, and the overall 
results will be calculated to take account of the variability both within and between 
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imputation datasets using standard methods (Little & Rubin, 2002), which are described in
Appendix 3.2.  This analysis will be used for the co-primary efficacy endpoints at Week 24, 
plus secondary analyses at other time points, and also for a range of secondary efficacy 
endpoints at all time points up to Week 24.  When using the multiple imputation method 
described above for time points earlier than Week 24, then the reason for missing data is 
assessed up to the end of the window for that particular time point (see Appendix 2.1).
Four additional methods will explore the sensitivity of the effect of missing data.  The first 
method of Baseline Observation Carried Forward (BOCF) for missing data at the primary 
time point of Week 24 will impute the subject’s Baseline value for the Week 24 time point, 
and therefore a zero change from baseline.  If a subject’s baseline data is also missing then 
that subject’s data remain missing for the post-baseline time point, and the patient would 
effectively be excluded from the analysis.  The second method of Last Observation Carried 
Forward (LOCF) for missing data at the primary time point of Week 24 will impute the 
subject’s last observed data value for the efficacy endpoint. With LOCF, if a subject is 
missing all post-baseline efficacy data for a given efficacy endpoint, then baseline will be 
carried forward (if baseline is also missing then the subject would have no contributing data 
to be included in the analysis, and again effectively be excluded from the analysis).  In both 
the BOCF and LOCF imputation analyses, the same main effects ANCOVA model as 
described below will be used.  The third method will use Mixed Model for Repeated 
Measurements (MMRM) utilizing the datasets created by the multiple imputation process up 
to and including Week 24 (see Appendix 2.1 for details on windows; if multiple observations 
are within a window, only the single observation selected for analysis by the windowing 
algorithm will be used in the MMRM analysis).  The fourth method will use MMRM 
utilizing all available data up to and including Week 24, including data considered 
off-treatment (retrieved dropout).
Analyses of the three co-primary endpoints at secondary time points will use the BOCF and 
LOCF imputation methods for missing data, and use the same (main effects) ANCOVA 
model as described for the primary analyses.
The responder endpoints will be analyzed using logistic regression for binary data, using both 
BOCF and LOCF separately for missing data of the response endpoint at a particular time 
point.  Imputation using BOCF will lead to the subject being assessed as a non-responder.  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 non-responder) would be used for missing data due to discontinuation for 
reasons of lack of efficacy, adverse event or death up to the time point of interest, and LOCF 
imputation would be used for missing data for any other reason.
Note, if Baseline is missing then the subject data for the change from Baseline will be set to 
missing for all efficacy analyses for that parameter.  A subject who has a missing baseline
score will be missing for the response criteria for endpoints where the response is based on 
one parameter. The OMERACT-OARSI responder index is based on 3 parameters.  It is set 
to missing if two or three out of these three parameters are missing at baseline (per its 
definition, a response can be still be achieved if only one parameter is missing, regardless of 
which one it is). 
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The individual WOMAC subscales are calculated of the mean of the individual items (5 for 
Pain, 17 for Physical Function and 2 for Stiffness). 
 
 
 
  The WOMAC Average score is 
calculated as the mean of the three WOMAC subscale scores of Pain, Physical Function and 
Stiffness.  
 
issing WOMAC subscale or WOMAC Average scores will be subject to the 
imputation method of the analysis as described above. 
For the analysis of the rescue medication endpoints, missing data is imputed for daily 
missing scores first, and then the last available weekly score (after daily missing data is 
imputed) will be used for subsequent missing weekly scores, as described below. While 
subjects are still in the study any missing data will be imputed by carrying forward the last 
recorded daily data up to Week 24 (LOCF daily data).  Where there is no record of rescue 
medication being taken on a study day, and the subject has not completed or discontinued 
from the study, then the last daily rescue medication observation will be carried 
forward. Imputation using the daily data will occur up to the end of the last week when the 
subject is in the study (see Appendix 2.1 for definitions of the last study day in each 
week). For example if a subject discontinues on study day 10, then data up to the end of 
Week 2 will be imputed in this way. The weekly scores for the rescue medication endpoints 
can then be calculated for each week the subject is in the study. Rescue medication 
endpoints are summarized and analyzed using LOCF, and so the last weekly score for the 
rescue medication will be used for LOCF after the subject has discontinued from the study 
(note, imputation is taken from the last week with non-missing data and not necessarily from 
the last available study week, eg, if Week 8 is missing then Week 7 data can be used). The 
baseline observation will not be carried forward in the case where a post-baseline observation 
is not available for the LOCF imputation.  In the example above, the subject who 
discontinued in Week 2 (Study Day 10) will have their Week 2 value used as the LOCF 
value for all Weeks 3-24.  The BOCF imputation rule will not be used for the subject because 
rescue medication is collected during the Initial Pain Assessment Period only (days -7 to -1) 
and subjects should not be taking rescue medication within 24 hours of the Baseline visit (so 
part of day -1), therefore Baseline rescue medication use is not an accurate reflection of 
subjects true Baseline use of rescue medication.  Imputation of weekly diary data after 
Week 24 will not be performed.
The electronic diary data are a mix of daily and weekly average pain assessments for the 
index hip or knee, although the recall assessment period is the past 24 hours for both daily 
and weekly assessments.  A weekly mean score will be calculated from the available daily 
pain scores where that is available.  Any missing daily pain scores will be left as missing in 
the weekly pain score calculated.  If there are no non-missing observations then the weekly 
score will be missing.  The Baseline mean will be calculated using the last 3 values during 
the 7 days of the Initial Pain Assessment Period (IPAP) prior to Randomization/Day1.  The 
weekly pain scores (either calculated from the daily scores when available or directly from 
the weekly pain assessments) will then be utilized for the multiple imputation, and the LOCF 
and BOCF imputations in the standard way.  Note, for the weekly pain score, a pain score
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being carried forward with LOCF might not be a visit week assessment (eg, carry forward 
Week 3 for missing Week 4 data even though there is no scheduled Week 3 visit).  For the 
purposes of the imputation analyses, where there is no post-baseline observation available to 
carry forward, then the baseline score carried forward will be the baseline average pain score, 
being the mean of the last 3 pain scores in the baseline assessment period.  If there are less 
than 3 baseline pain scores then the baseline is calculated over the remaining non-missing 
values.
Missing values in standard summaries of AEs, lab values, vital signs and ECGs will be 
handled per Pfizer standard algorithms.  For the analysis of NIS the baseline observation will 
not be carried forward in the case where a post-baseline observation is not available for the 
LOCF imputation.
The Baseline diary average pain is used in the analysis of most endpoints as described in
Section 3.4.1.  However if a patient has a missing value for this covariate then to avoid 
exclusion of the patient for the endpoint then a Baseline value will be imputed as the 
patient’s WOMAC Pain subscale score.  This imputed value will not be used in the analysis 
of the Average Pain from the diary, but as a covariate for other endpoints. 
6. ANALYSES AND SUMMARIES
A summary of the details of the efficacy analyses is presented in tabular format in 
Appendix 1.
6.1. Primary Endpoint(s)
See Appendix 1.
6.2. Secondary Endpoint(s)
See Appendix 1.
6.3. Other Endpoint(s)
6.3.1. Pharmacokinetics
The following reporting of PK data will be done using all available data:
•
A listing of all plasma tanezumab concentrations sorted by subject, active treatment 
group and nominal time post dose.  The listing of concentrations will also include the 
actual times post dose.
•
A descriptive summary of the plasma tanezumab concentrations based on nominal 
time post dose for each treatment group.
•
Pharmacodynamics (NGF)
Serum samples from a subset of patients will be run in the bioanalytical assays for the NGF 
related proteins (total NGF, bound NGF, proNGF, soluble p75). 
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The NGF related protein concentrations will be reported in summary tables and figures and 
will be part of the A4091057 study CSR.  The data analysis of the NGF related protein 
concentrations will be described in a separate Population Modeling Analysis Plan and the 
results will be reported in a separate Population Modeling Analysis Report.
The following reporting of NGF concentration data will be done in the CSR:
•
A listing of individual total NGF, relative percent bound NGF, proNGF/total NGF
and soluble p75 concentrations in serum sorted by subject, active treatment group and 
nominal time post dose.  The listing of concentrations will also include the actual 
times post dose.
•
A descriptive summary (mean, SD, SE, 95% CI, median, min, max) of the total NGF, 
relative percent bound NGF, proNGF/total NGF and soluble p75 concentrations in 
serum based on nominal time post dose for each treatment group.
•
Box plot of either total NGF, relative percent bound NGF, proNGF/total NGF and 
soluble p75 concentrations over time by treatment.
•
Osteoarthritis Biomarkers
Biomarker concentrations will be measured in subjects with any of the joint safety 
adjudication outcomes of rapidly progressive osteoarthritis (type 1 and type 2), subchondral 
insufficiency fracture, primary osteonecrosis, or pathological fracture, and for occurrence of 
total joint replacement due to normal progression of OA.  In addition, control subjects (no 
AEs) to these cases will be analyzed for biomarker concentrations and will be identified 
based on matching duration of treatment. The biomarker concentrations will be reported in 
summary tables and figures in a report separate from the A4091057 study CSR. The data 
analysis of the osteoarthritis biomarker concentrations will be described in a separate 
Statistical Analysis Plan and the results will be reported in a separate report which will 
address the biomarker results in a combined fashion across OA studies A4091056, A4091057, 
and A4091058.
6.4. Subset Analyses 
Separate tables will be produced for subjects in the ITT analysis set in Japanese sites.  These 
tables will be defined prior to the unblinding of the study.
6.5. Baseline and Other Summaries and Analyses
The following non-standard baseline tables will be included:
•
A summary of baseline characteristics, including index joint, Kellgren-Lawrence 
grade of the index joint (for subjects with Hip and Knee OA separately then overall), 
highest Kellgren-Lawrence grade for each subject, WOMAC subscales at Baseline 
and Screening (for Pain subscale only), diabetes status (from medical history and/or 
pre-treatment HbA1c ≥6.5%), and the PGA at Baseline.  This summary will also 
include a summary of the number of subjects who are ≥75 years old.
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6.5.1. Concomitant Medications and Non-Drug Treatments
Summaries of various classes of concomitant medications based on Case Report Form 
classifications will be provided, eg, treatments for bone metastasis, non-NSAID and NSAID 
medications (shown separately).
6.6. Safety Summaries and Analyses
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. 
Pfizer standard safety data presentations will be made for demography data, discontinuation 
data, adverse event data, laboratory test data, vital signs data and ECG data.
The following non-standard safety tables will also be included:
•
Summary of number of subjects treated by country and treatment group.
•
Incidence and severity of Adverse Events leading to discontinuation.
•
Summary of AEs, Incidence of AEs, Incidence of AEs leading to discontinuation and 
summary of Serious AEs will be shown for the whole study period (including the 
safety follow-up period).
•
Summary of evidence of neurological examination abnormalities by visit and final 
assessment, and incidence of neurological findings over consecutive visits.  Further 
details of this summary are given below.
•
Summary of final outcome of neurological consultation.  Further details of this 
summary are given below. 
•
Summary of the Incidence of sympathetic neuropathy based on investigator 
assessment and, if performed, expert consultant assessment.
•
‘Incidence and severity’ tables of treatment-emergent adverse events of Abnormal 
Peripheral Sensation (APS) and Sympathetic Nervous Function, as defined above.  
Other adverse events may be added to these groupings if they are observed in this 
study or other studies in the tanezumab program.
•
Summary table and listing of inclusion and exclusion criteria that are not met by 
subjects who were screened (but not randomized).
•
Summary of discontinuation by treatment group and reason, and study week of 
discontinuation for the treatment period (Weeks 1-2, 3-4, 5-8, 9-12, 13-16, 17-20, 
21-24, ≥24) ) and for the safety follow-up period (Weeks 1-8, 9-16, 17-24, >24).
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•
A summary of the maximum increase from baseline in the sitting systolic and 
diastolic blood pressure.  The categories used are: (systolic BP) only decreases or no 
change, >0 to 10, >10-20, >20-30, >30, and (diastolic BP) only decreases or no 
change, >0 to 10, >10-20, >20.
•
A summary of the maximum decrease from baseline in the sitting systolic and 
diastolic blood pressure.  The categories used are: (systolic BP) <-30, -30 to <-20, -20 
to <-10, -10 to <0, only increases or no change, and (diastolic BP) <-20, -20 to 
<-10, -10 to <0, only increases or no change.
•
A summary of the change from baseline to last observation in the sitting systolic and 
diastolic blood pressure.  The categories used for these summaries are: (systolic BP) 
≤-40, >-40 to -30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to <10, 10-<20, 20-<30, 
30-<40, ≥40, and (diastolic BP) ≤-30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to <10, 
10-<20, 20-<30, ≥30.
•
A summary of incidence of subjects with confirmed orthostatic hypotension, for each 
visit and any post-baseline incidence of orthostatic hypotension. 
•
A summary of discontinuation up to End of Treatment period, and up to End of Study 
period.
•
Incidence of musculoskeletal physical examination at screening.
•
Summary of the Survey of Autonomic Symptoms (SAS) number of symptoms 
reported and total symptom impact score, at each visit, and for the change from 
Baseline score.
•
Summary of concomitant medications for Osteoarthritis for non-NSAID and NSAID 
medications (shown separately).
•
Summary of number of days of NSAID use per dosing interval (eg, Day 1 to Week 8,
Week 8 to Week 16, Week 16 to Week 24) and for the first 8-week interval in the 
safety follow-up period.  This will show the number and percentage of subjects in an
interval that exceeded the limit of 10 days of NSAID use.  If an interval exists, the 
visits will be used to define the interval, otherwise calendar time will be used. A 
summary of average number of days of NSAID use will be displayed by interval.  
Also, a summary of the overall number of days of NSAID use from Day 1 to Week 
32 will be shown, as well as the number and percentage of subjects who exceeded the 
limit of 40 days of NSAID use during this interval.
•
Summary of failed drug treatments for protocol qualification, with reasons for 
discontinuation.
6.6.1. Adverse Events
Adverse Events of Abnormal Peripheral Sensation will be summarized. The Survey of
Autonomic Symptoms (SAS) scores will be summarized for the total number of symptoms
reported and total impact score, by visit and for the change from Baseline.
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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 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.
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.
For the 3-tier adverse event reporting, tier 1 adverse events are defined in the tanezumab 
Safety Review Plan, and this definition of tier-1 adverse events for the report of study 1057
tables will be finalized prior to the unblinding of this study.
Tier 2 AEs are those with a frequency of ≥3% in any treatment group and that are not in tier 
1.
Tier 3 AEs are those not in Tier 1 or Tier 2, and will be summarized using standard Pfizer 
data standards tables, where all Adverse Events will be included (ie, Tier 3 AEs will not be 
shown separately).
Adverse events within tier 1 and 2 will be summarized using Risk Differences between each 
tanezumab group and placebo, together with 95% confidence interval, using exact methods.  
Significance tests will be performed for tanezumab versus placebo comparisons using exact 
methods for the tier 1 AEs.  There will be no multiplicity adjustment for these significance 
tests.  These tables will be produced for the comparisons of tanezumab 2.5 mg versus 
placebo and tanezumab 5 mg versus placebo.
The following footnote will be used in the Tier 1 AE tables: “P-values and confidence 
intervals are not adjusted for multiplicity and should be used for screening purpose only.  
95% Confidence intervals are provided to help gauge the precision of the estimates for Risk 
Difference.  Risk Difference is computed as ‘Tanezumab 2.5 mg versus placebo’ and 
‘Tanezumab 5 mg versus placebo’.  Exact methods are used for 95% confidence intervals 
and significance tests”.  Similarly the following footnote will be used in the Tier 2 AE tables: 
“Confidence intervals are not adjusted for multiplicity and should be used for screening 
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purpose only.  95% Confidence intervals are provided to help gauge the precision of the 
estimates for Risk Difference. Risk Difference is computed as ‘Tanezumab 2.5 mg versus 
placebo’ and ‘Tanezumab 5 mg versus placebo’.  Exact methods are used for 
95% confidence intervals.”  
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events.  Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation.  The 3-tier approach facilitates this exploratory analysis.
All summaries of adverse events will be shown for adverse events that begin or worsen after 
the first dose of study drug (treatment-emergent) up to the end of the treatment period.  In 
addition a selection of adverse event tables will be produced for the off-study medication 
safety follow-up period, and some will be produced for the whole period up to the end of the 
study, including the treatment period and safety follow-up period.
6.6.2. Vital Signs
Incidence of orthostatic hypotension using postural changes in blood pressure…, will be 
summarized.
6.6.3. Neurological Results
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 the last and the 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, last change from Baseline 
will be analyzed).  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….  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 change from Baseline in the NIS for Weeks 2, 4, 8, 12, 16, 24, 32 and 48 will be 
analyzed using a CMH test (stratified by the combined levels of the stratification factors) 
with change scores.  Missing data will be imputed using LOCF only.  For this analysis, 
Baseline data will not be carried forward in the case of a post-Baseline observation not being 
available for use in LOCF.  An additional analysis will use the change from Baseline to the 
largest (worst) post-Baseline value.
The “conclusion from the neurological examination” data will be summarized for each time 
point and the last subject assessment.  In addition the persistence of any neurological 
examination finding will be summarized, showing the incidence of subjects with new or 
worsened neurological examination abnormality (both clinically significant only and also for 
any finding) for 2, 3, 4, and ≥5 consecutive visits.
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6.6.4. Immunogenicity
The following assessments of anti-drug antibody (ADA) data will be made:
•
A listing of individual serum ADA results sorted by treatment group, subject ID and 
planned visit. The listing will also include the actual test date/times. 
•
The proportion of subjects who test positive (ie, develop anti-tanezumab antibodies) 
and negative for treatment-emergent ADA presence will be summarized by treatment 
group and planned visit. The summary will also include the proportion of subjects 
who test positive and negative overall for treatment-emergent ADA in the study.
•
Subjects who develop treatment-emergent anti-tanezumab antibodies will be 
evaluated for the presence of anti-tanezumab neutralizing antibodies, and individual 
results will be listed.
•
Individual subjects who develop treatment-emergent antibodies will be evaluated for 
potential ADA impact on the individual’s PK, NGF, efficacy and safety profile. 
6.6.5. Joint Safety Events
The incidence of subjects with any of the adjudication outcomes of rapidly progressive
osteoarthritis (type 1 and type 2), subchondral insufficiency fracture, 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.
Events will be included in summaries if they occur up to the end of the safety follow-up 
period or 26 weeks (planned duration of the follow-up period + 2 weeks) after the end of the 
treatment period, whichever is later.
For the joint safety event analyses, the observation period is defined as the time from first SC
dose to study completion or discontinuation for subjects who did not have an event, or time
from first SC dose to the earliest event for subjects who did have at least one event.
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 listed for subjects 
with measurements in the knee and hip separately. 
7. INTERIM ANALYSES
7.1. Introduction
Interim analysis is planned for safety as described in the following sections.
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7.2. Interim Analyses and Summaries
Safety data will be subject to regular and ongoing reporting and review throughout the study.  
The details of these interim analyses will be documented in a separate Statistical Analysis 
Plan.  Review of the safety data will be by the tanezumab external Data Monitoring 
Committee (E-DMC).
A blinded Adjudication Committee will be convened and asked to review all possible or 
probable joint-related safety events identified by the Central Reader (rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fractures, primary osteonecrosis, 
or pathological fracture), total joint replacement as well as investigator reported adverse 
events of osteonecrosis, rapidly progressive osteoarthritis, subchondral insufficiency fracture 
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.  A 
stopping rule relating to a set of adjudicated outcomes has been defined, and is described 
below.
If the blinded Adjudication Committee identifies adjudicated events of rapidly progressive 
osteoarthritis type 2, subchondral insufficiency fracture…, 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.
The protocol (or treatment group) stopping rule will be based on the assessment of the 
number of subjects with adjudicated events of interest (rapidly progressive osteoarthritis type 
2, subchondral insufficiency fractures…, primary osteonecrosis, or pathological fracture) 
during the course of the study.  Assuming the rate of adjudicated events in the placebo group 
is no more than 
 if adjudicated events of interest are reported in 
 
 subjects in any tanezumab treatment group than for the placebo treatment group, a 
treatment-group or protocol-based stopping rule will be triggered. If the rate of events in the 
placebo treatment group is higher than 
 the appropriate threshold 
number of events (subjects) for the stopping rule will be reassessed. 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.
A separate set of dosing suspension rules for specified Serious Adverse Events and events 
consistent with Hy’s Law are described in Section 9.6.1 of the protocol.
Programming and review of unblinded outputs will be performed by individuals independent 
of the study team.
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CCI
CCI
CCI
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8. REFERENCES 
1.
Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical 
trials. Statist. Med. (2014):33:693–713.
2.
Bretz F, Posch M, Glimm E, Klingmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures usingweighted Bonferroni, Simes, or 
parametric tests Biometrical Journal. 53(2011) 6, 894–913.
3.
EuroQol Group.  EuroQol: a new facility for the measurement of health related quality 
of life. Health Policy 1990; 16:199-208.
4.
Little RJ & Rubin DB (2002).  Statistical Analysis with Missing Data.  New Jersey: 
Wiley.
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9. APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES
Note: BL=Baseline
Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
Change from Baseline to Week 24 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Primary 
Analysis 
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Primary 
Analysis 
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Primary 
Analysis 
Change from Baseline to Week 24 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Study Site, 
Treatment Group, Study Site x 
Treatment Group (Study site and 
interaction as random effects)
Multiple 
Imputation
Additional 
(Interaction) 
Analysis
Change from Baseline to Week 24 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Country, Treatment 
Group, Country x Treatment Group.
Multiple 
Imputation
Additional 
(Interaction) 
Analysis
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Study Site, 
Treatment Group, Study Site x 
Treatment Group (Study site and 
interaction as random effects)
Multiple 
Imputation
Additional 
(Interaction) 
Analysis
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
Multiple 
Imputation
Additional 
(Interaction) 
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
grade (2, 3 or 4), Country, Treatment 
Group, Country x Treatment Group.
Analysis
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Study Site, 
Treatment Group, Study Site x 
Treatment Group (Study site and 
interaction as a random effect)
Multiple 
Imputation
Additional 
(Interaction) 
Analysis
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Country, Treatment 
Group, Country x Treatment Group
Multiple 
Imputation
Additional 
(Interaction) 
Analysis
Change from Baseline to Week 24 in 
WOMAC Pain subscale
PP
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Sensitivity 
Analysis (Per 
protocol)
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
PP
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Sensitivity 
Analysis (Per 
protocol)
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis
PP
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Sensitivity 
Analysis (Per 
protocol)
Change from Baseline to Week 24 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
BOCF
Sensitivity 
Analysis
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
BOCF
Sensitivity 
Analysis
Change from Baseline to Week 24 in
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
BOCF
Sensitivity 
Analysis
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
Change from Baseline to Week 24 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
LOCF
Sensitivity 
Analysis
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
LOCF
Sensitivity 
Analysis
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
LOCF
Sensitivity 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, 16 and 24 in WOMAC Pain subscale
ITT
MMRM
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Time, Treatment 
Group, Time x Treatment Group 
(Study site as a random effect)
Multiple 
Imputation 
Sensitivity 
Analysis for 
Week 24 
(Secondary 
Endpoint 
Analysis for 
other time 
points)
Change from Baseline to Weeks 2, 4, 8, 
12, 16 and 24 in WOMAC Physical 
Function subscale
ITT
MMRM
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Time, Treatment 
Group, Time x Treatment Group 
(Study site as a random effect)
Multiple 
Imputation 
Sensitivity 
Analysis for 
Week 24 
(Secondary 
Endpoint 
Analysis for 
other time 
points)
Change from Baseline to Weeks 2, 4, 8, 
12, 16 and 24 in Patient Global 
Assessment of Osteoarthritis
ITT
MMRM
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Time, Treatment 
Group, Time x Treatment Group 
(Study site as a random effect)
Multiple 
Imputation 
Sensitivity 
Analysis for 
Week 24 
(Secondary 
Endpoint 
Analysis for 
other time 
points)
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
Change from Baseline to Weeks 2, 4, 8, 
12, 16 and 24 in WOMAC Pain subscale
ITT
MMRM
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Time, Treatment 
Group, Time x Treatment Group 
(Study site as a random effect)
All Observed 
Data Including 
Off-Treatment
Sensitivity 
Analysis for 
Week 24 
(Secondary 
Endpoint 
Analysis for 
other time 
points)
Change from Baseline to Weeks 2, 4, 8, 
12, 16 and 24 in WOMAC Physical 
Function subscale
ITT
MMRM
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Time, Treatment 
Group, Time x Treatment Group 
(Study site as a random effect)
All Observed 
Data Including 
Off-Treatment
Sensitivity 
Analysis for 
Week 24 
(Secondary 
Endpoint 
Analysis for 
other time 
points)
Change from Baseline to Weeks 2, 4, 8, 
12, 16 and 24 in Patient Global 
Assessment of Osteoarthritis
ITT
MMRM
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Time, Treatment 
Group, Time x Treatment Group 
(Study site as a random effect)
All Observed 
Data Including 
Off-Treatment
Sensitivity 
Analysis for 
Week 24 
(Secondary 
Endpoint 
Analysis for 
other time 
points)
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group, 
Spanish flag , Spanish flag x 
Treatment Group (Study site as 
random effects)
Multiple 
Imputation
Exploratory 
analysis about 
interaction
regarding the
missing 
sentence in 
Spanish 
questionnaires
Change from Baseline to Weeks 2, 4, 8, 
12, 16, and 24 in Patient Global 
Assessment of Osteoarthritis
ITT
CMH test 
Treatment Group [1]
Mixed 
BOCF/LOCF
Sensitivity 
Analysis for 
PGA
Change from Baseline to Weeks 2, 4, 8, 
ITT
CMH test 
Treatment Group [1]
BOCF
Sensitivity 
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
12, 16, and 24 in Patient Global 
Assessment of Osteoarthritis
Analysis for 
PGA
Change from Baseline to Weeks 2, 4, 8, 
12, 16, and 24 in Patient Global 
Assessment of Osteoarthritis
ITT
CMH test 
Treatment Group [1]
LOCF
Sensitivity 
Analysis for 
PGA
Change from Baseline to Week 24 in 
WOMAC Pain subscale, shown by site 
(sites with n≥12)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive 
summary for 
interaction 
analysis
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale, 
shown by site (sites with n≥12)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive 
summary for 
interaction 
analysis
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis, shown by site (sites with 
n≥12)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive 
summary for 
interaction 
analysis
Change from Baseline to Week 24 in 
WOMAC Pain subscale, shown by 
country (countries with n≥15)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive 
summary for 
interaction 
analysis
Change from Baseline to Week 24 in 
WOMAC Physical Function subscale, 
shown by country (countries with n≥15)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive 
summary for 
interaction 
analysis
Change from Baseline to Week 24 in 
Patient Global Assessment of 
Osteoarthritis, shown by country 
(countries with n≥15)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive 
summary for 
interaction 
analysis
Missing data pattern for WOMAC Pain 
subscale for Baseline and Weeks 2, 4, 8, 
12, 16 and 24
ITT
None (summary)
NA
Observed Data
Supportive 
summary for 
missing data
Missing data pattern for WOMAC 
Physical Function subscale for Baseline 
and Weeks 2, 4, 8, 12, 16 and 24
ITT
None (summary)
NA
Observed Data
Supportive 
summary for 
missing data
Missing data pattern for Patient Global 
ITT
None (summary)
NA
Observed Data
Supportive 
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
Assessment of Osteoarthritis for Baseline
and Weeks 2, 4, 8, 12, 16 and 24
summary for 
missing data
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8,
12, and 16 in WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
BOCF
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
LOCF
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in WOMAC Physical Function 
subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in WOMAC Physical Function 
subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
BOCF
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in WOMAC Physical Function 
subscale
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
LOCF
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in Patient Global Assessment 
of Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in Patient Global Assessment 
of Osteoarthritis
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
BOCF
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, and 16 in Patient Global Assessment 
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
LOCF
Secondary 
Endpoint 
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
of Osteoarthritis
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Analysis
The OMERACT-OARSI response at 
Weeks 2, 4, 8, 12, 16, and 24  
ITT
Logistic Regression
BL Score (WOMAC Pain), BL diary 
average pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group
Mixed 
BOCF/LOCF
Secondary 
Endpoint 
Analysis
The OMERACT-OARSI response at
Weeks 2, 4, 8, 12, 16, and 24  
ITT
Logistic Regression
BL Score (WOMAC Pain), BL diary 
average pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group
BOCF
Secondary 
Endpoint 
Analysis
The OMERACT-OARSI response at 
Weeks 2, 4, 8, 12, 16, and 24  
ITT
Logistic Regression
BL Score (WOMAC Pain), BL diary 
average pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group
LOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with reduction of 
>30/50/70/90% from Baseline to Weeks 2, 
4, 8, 12, 16, and 24 in the WOMAC Pain 
subscale 
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
Mixed 
BOCF/LOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with reduction of 
>30/50/70/90% from Baseline to Weeks 2, 
4, 8, 12, 16, and 24 in the WOMAC Pain 
subscale 
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
BOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with reduction of 
>30/50/70/90% from Baseline to Weeks 2, 
4, 8, 12, 16, and 24 in the WOMAC Pain 
subscale 
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
LOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with reduction of 
>30/50/70/90% from Baseline to Weeks 2, 
4, 8, 12, 16, and 24 in the WOMAC 
Physical Function subscale 
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
Mixed 
BOCF/LOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with reduction of 
>30/50/70/90% from Baseline to Weeks 2, 
4, 8, 12, 16, and 24 in the WOMAC 
Physical Function subscale 
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
BOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with reduction of 
>30/50/70/90% from Baseline to Weeks 2, 
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
LOCF
Secondary 
Endpoint 
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
4, 8, 12, 16, and 24 in the WOMAC 
Physical Function subscale 
grade (2, 3 or 4), Treatment Group
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 2, 4, 8, 12, 16, and 24 in the 
Patient Global Assessment of 
Osteoarthritis  
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
Mixed 
BOCF/LOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 2, 4, 8, 12, 16, and 24 in the 
Patient Global Assessment of 
Osteoarthritis  
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
BOCF
Secondary 
Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 2, 4, 8, 12, 16, and 24 in the 
Patient Global Assessment of 
Osteoarthritis  
ITT
Logistic Regression
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
LOCF
Secondary 
Endpoint 
Analysis
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline 
to Weeks 16 & 24 in the WOMAC Pain 
subscale
ITT
None (summary and 
plot)
NA
Mixed 
BOCF/LOCF
Summary of 
secondary 
endpoint
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline 
to Weeks 16 & 24 in the WOMAC Pain 
subscale
ITT
None (summary)
NA
BOCF
Summary of 
secondary 
endpoint
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline 
to Weeks 16 & 24 in the WOMAC Pain 
subscale
ITT
None (summary)
NA
LOCF
Summary of 
secondary 
endpoint
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline 
to Weeks 16 & 24 in the WOMAC 
Physical Function subscale
ITT
None (summary and 
plot)
NA
Mixed 
BOCF/LOCF
Summary of 
secondary 
endpoint
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline
to Weeks 16 & 24 in the WOMAC 
ITT
None (summary)
NA
BOCF
Summary of 
secondary 
endpoint
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
Physical Function subscale
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline 
to Weeks 16 & 24 in the WOMAC 
Physical Function subscale
ITT
None (summary)
NA
LOCF
Summary of 
secondary 
endpoint
Change from Baseline to Weeks 2, 4, 8, 
12, 16, and 24 in the WOMAC Stiffness 
subscale 
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, 16, and 24 in the WOMAC Average 
Score
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, 16, and 24 in the WOMAC Item: Pain 
When Walking on a Flat Surface
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
12, 16, and 24 in the WOMAC Item: Pain 
When Going Up or Down Stairs
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Change from Baseline to Days 1, 2, 3, 4, 
5, 6, 7, and to Weeks 1, 2, 3, 4, 6, 8, 10, 
12, 16, 20, and 24 in the weekly average 
pain score in the index joint
ITT
ANCOVA
BL Score, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group (Study site as a 
random effect)
Multiple 
Imputation
Secondary 
Endpoint 
Analysis
Time to treatment discontinuation due to
lack of efficacy (up to Week 24)
ITT
Log-Rank (with 
KM estimates) 
Treatment Group
Observed 
Secondary 
Endpoint 
Analysis
Incidence of treatment discontinuation due 
to lack of efficacy (up to Week 24)
ITT
Logistic Regression
BL WOMAC Pain, BL diary average 
pain, Index Joint (Knee/Hip), Highest 
KL grade (2, 3 or 4), Treatment Group 
Observed
Secondary 
Endpoint 
Analysis
Incidence of rescue medication use during 
Weeks 2, 4, 8, 12, 16, and 24
ITT
Logistic Regression
BL WOMAC Pain, BL diary average 
pain, Index Joint (Knee/Hip), Highest 
KL grade (2, 3 or 4), Treatment Group 
LOCF
Secondary 
Endpoint 
Analysis
Number of days of rescue medication use 
during Weeks 2, 4, 8, 12, 16, and 24
ITT
Negative Binomial 
Model
BL WOMAC Pain, BL diary average 
pain, Index Joint (Knee/Hip), Highest 
LOCF
Secondary 
Endpoint 
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates
Missing 
Data
Objective
KL grade (2, 3 or 4), Treatment Group
Analysis
Amount (mg) of rescue medication taken 
during Weeks 2, 4, 8, 12, 16 and 24
ITT
Negative Binomial 
Model
BL WOMAC Pain, BL diary average 
pain, Index Joint (Knee/Hip), Highest 
KL grade (2, 3 or 4), Treatment Group
LOCF
Secondary 
Endpoint 
Analysis
EQ-5D-5L dimensions (Mobility; 
Self-care; Usual activities; 
Pain/Discomfort; Anxiety/Depression), 
EQ-VAS and Overall Health Utility at 
Baseline and Weeks 8, 16 and 24
ITT
Summary
NA
Observed
Secondary 
Endpoint
Analysis
mPRTI endpoints (willingness to re-use; 
patient preference; patient satisfaction) at 
Weeks 16 and 24)
ITT
CMH test
Treatment Group [1]
Observed
Secondary 
Endpoint 
Analysis
WPAI endpoints (% work time missed; % 
impairment while working; % overall 
work impairment; % activity impairment) 
at Weeks 8, 16, and 24
ITT
ANCOVA
BL Score, BL diary average pain, 
Index Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), Treatment Group
(Study site as a random effect)
Observed
Secondary 
Endpoint 
Analysis
Healthcare Resource Utilization at 
baseline, weeks 32 and 48
ITT
Descriptive 
Summary
Treatment group
Observed
Secondary 
Endpoint 
Analysis
Change from baseline to Weeks 2, 4, 8,
12, 16, 24, 32, and 48 in the NIS score, 
and Change from Baseline to Worst 
post-Baseline NIS score
ITT
CMH test
Treatment Group [1]
LOCF (Weeks 
8, 16, 24, 32, 
40 & 48), 
Worst
post-baseline 
score
Safety Endpoint 
Analysis
Survey of Autonomic Symptoms (SAS), 
number of symptoms and total impact 
score (by visit and change from Baseline)
ITT
Summary
NA
Observed, 
Safety Endpoint
Analysis
[1] CMH test will be stratified by the levels of the combined stratification parameters (6 levels).  If there are <15 subjects in any combined stratification level 
then the CMH test will be unstratified.
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Appendix 2. DATA DERIVATION DETAILS
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Study visits are planned at Screening, Baseline and then at post-baseline Weeks 2, 4, 8, 12, 
16, 24, 32 and 48.  If a subject discontinues from the trial then there will be an Early 
Termination Follow-Up period and for those who refuse, ideally, an Early termination visit.  
To account for this visit and any early or late scheduled visits (compared to the target study 
days) we define ‘windows’ to be able to allocate each efficacy observation to a single 
specific study visit.  For the assessments made at each planned study visits (eg, WOMAC 
subscales, Patient Global Assessment of Osteoarthritis etc.) these visit windows are shown 
below.  When multiple observations occur in a visit window, the observation closest to the 
protocol specified target day will be used, noting that the latter will be used in the case of a 
tie.
If multiple observations occur on a same day, an averaged value on the day will be used. 
Visit
Target Study Day
Window
Screening [1]
Variable (up to 37 days 
prior to baseline visit)
[No lower limit, Day -8]
Baseline
1 (defined as initial day of 
study drug administration)
[-7,1]
Week 2
15
[2,22]
Week 4
29
[23,43]
Week 8
57
[44,71]
Week 12
85
[72,99]
Week 16
113
[100,141]
Week 24
169
[142,197]
Week 32
225
[198, 253]
[1] Only efficacy data collected at screening is WOMAC Pain subscale
One additional window will be created relative to the date of last SC dose for summaries of 
efficacy data collected beyond the planned treatment period.  This window will include data 
from 16 +/- 4 weeks past the date of the last SC dose.  The target day is 113 days after the 
last SC dose, with a window of [85, 141] days after the last SC dose.  If multiple 
observations occur in this visit window, the observation closest to the specified target day 
will be used, noting that the latter will be used in the case of a tie.
For the assessments not made at each planned study visit, broader visit windows are shown 
below.  When multiple observations occur in a visit window, the observation closest to the 
protocol specified target day will be used, noting that the latter will be used in the case of a 
tie.
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EQ-5D-5L
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[-7, 1]
Week 8
57
[2, 85]
Week 16
113
[86, 141]
Week 24
169
[142,197]
WPAI: OA
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[-7,1]
Week 8
57
[2, 85]
Week 16
113
[86, 141]
Week 24
169
[142,197]
HCRU
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[no lower limit, 1]
Week 32
225
[2, 281]
Week 48
337
[282, no upper limit]
mPRTI
Visit
Target Study Day
Window
Week 16
113
[2, 141]
Week 24
169
[142, 197]
For the average pain in the index joint, the data are collected daily via electronic diary up to 
the end of Week 24, and thereafter Weekly up to Week 48.  Data up to Week 24 will be 
reported as part of the efficacy assessment (summary up to Week 32; analysis up to 
Week 24). 
The Baseline score of IPAP is the mean of the last three non-missing pain scores over study 
days -7 to -1.  If fewer than 3 are available between study days -7 and -1, the baseline will be 
the mean of the available scores.
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The table below describes the visit days for each week (Weeks 1-24).  All available 
on-treatment diary data in each of the weekly intervals will be used to calculate the mean 
daily pain score for that study week.
Study 
Week
Days
Study 
Week
Days
Study 
Week
Days
1
1-7
9
57-63
17
113-119
2
8-14
10
64-70
18
120-126
3
15-21
11
71-77
19
127-133
4
22-28
12
78-84
20
134-140
5
29-35
13
85-91
21
141-147
6
36-42
14
92-98
22
148-154
7
43-49
15
99-105
23
155-161
8
50-56
16
106-112
24
162-168
After the Week 24 visit, pain scores are captured only once week in the diary.  These are
grouped in 4-week interval using visit windows as shown below.  If a subject comes in late 
for a Week 24 visit (or weekly diary is not activated at the visit), and so has daily diary data 
collected past Day 168, these data will be averaged with any data obtained weekly for any 
given interval.  All available on- or off-treatment data will be used for these windows after 
the planned treatment period.
Summary 
Week
Includes 
Weeks
Days
28
25 - 28
169 - 196
32
29 - 32
197 - 224
36
33 - 36
225 - 252
40
37 – 40
253 - 280
44
41 – 44
281 - 308 
48
45 - 48
309 - 336
One additional window will be created relative to the date of last SC dose for summaries of 
diary pain scores collected beyond the planned treatment period.  This window will be 
identified as 16 Weeks Post Last Dose, and will include the average of all data from 13 to 16 
weeks (85 to 112 days)_past the date of the last SC dose. All available on- or off-treatment 
data will be used for this window after the planned treatment period. 
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Appendix 3. STATISTICAL METHODOLOGY DETAILS 
Health State Utility of the EQ-5D-5L
The EQ-5D-5L contains five questions that measure the following dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each of the five 
dimensions has five levels: (1) no problems; (2), slight problems; (3) moderate problems; (4) 
severe problems; and (5) extreme problems. 
The health utility scores are defined for every possible set of outcome combinations of the 
five dimensions for the following countries:
•
Denmark, France, Germany, Japan, the Netherlands, Spain, Thailand, UK, US and 
Zimbabwe.
It is intended that this study will recruit subjects from the following countries:  
•
Austria, Bulgaria, Finland, France, Germany, Hungary, Italy, Japan, Poland, Portugal, 
Romania, Slovakia, Spain, Sweden, UK.
Some of these may not actually recruit or treat subjects, and other countries may be added.  
As there is a mismatch between countries where subjects are being recruited and the 
currently available EQ-5D-5L health utility scoring, we will assign subjects to the following 
scoring countries based on the following assignments.
EQ-5D Scoring Country
Study Recruitment Country
Denmark
Finland, Sweden
France
France, Italy
Germany
Austria, Bulgaria, Germany, Hungary, 
Poland, Romania, Slovakia
Japan
Japan
The Netherlands
-
Spain
Spain, Portugal
Thailand
-
UK
UK
US
-
Zimbabwe
-
If more EQ-5D-5L utility scores become available or other countries are added, then this 
assignment may be modified.
The health utility for a patient with no problems in all 5 items is 1 for all countries (except 
for Zimbabwe where it is 0.9), and is reduced where a patient reports greater levels of 
problems across the five dimensions.  The minimum score for the scoring countries to be 
used in this study ranges from -0.654 (Spain) to -0.111 (Japan).
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WPAI:OA Endpoints
The tables below summarize the 6 questions of the WPAI:OA questionnaire, and the four 
endpoints of the effect of impairment on activity and impairment.
Question
Question Wording
Scoring
1
Are you currently employed? [if No skip 
to question 6]
Yes, No
2
During the past seven days, how many 
hours did you miss from work due to 
problems associated with your OA of the 
knee or hip
number of hours (free text)
3
During the past seven days, how many 
hours did you miss from work because of 
any other reason, such as vacation, 
holidays, time off to participate in this 
study?
number of hours (free text)
4
During the past seven days, how many 
hours did you actually work (if ‘0’ skip to 
Question 6)
number of hours (free text)
5
During the past seven days, how much did 
your OA of the knee or hip affect 
productivity while you were working?
0 to 10 scale with 0 being ‘No effect 
on my work’ and 10 being 
‘Completely prevented me from 
working’
6
During the past seven days, how much did 
your OA of the knee or hip affect your 
ability to do your regular daily activities, 
other than work at a job?
0 to 10 scale with 0 being ‘No effect 
on my daily activities’ and 10 being 
‘Completely prevented me from 
doing my daily activities’
WPAI endpoint
Calculation
Percent activity impairment due to 
Osteoarthritis
Q6*10
Percent impairment while working due to 
osteoarthritis
Q5*10
Percent overall work impairment due to 
osteoarthritis
100
10
5
4
2
2
1
4
2
2
×
⎪⎭
⎪⎬
⎫
⎪⎩
⎪⎨
⎧
⎟
⎠
⎞
⎜
⎝
⎛⎥
⎦
⎤
⎢
⎣
⎡
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
−
+
+
Q
Q
Q
Q
Q
Q
Q
Percent work time missed due to 
Osteoarthritis
4
2
2
Q
Q
Q
+
*100
Healthcare Resource Utilization (example using 3 month recall—8 week recall is also 
used in study)
Question
Response
Scoring
During the last 3 months (or during 
last 8 weeks) what services did you 
Number of Visits
Response not selected = 
0
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Question
Response
Scoring
receive directly related to your 
osteoarthritis?
•
Primary Care Physician;
•
Neurologist;
•
Rhematologist;
•
Physician Assistant or 
Nurse Practioner;
•
Pain Specialist;
•
Orthopedist;
•
Physical Therapist;
•
Chiropractor;
•
Alternative Medicine or 
Therapy;
•
Podiatrist;
•
Nutritionist/Dietician;
•
Radiologist;
•
Home healthcare services;
•
Other;
Number of visits = 
1-999
During the past 3 months (or 
during last 8 weeks), have you 
visited the emergency room due to 
your osteoarthritis?
Yes, No
No = 0
Yes = 1
How many times?
Number of visits
0-999 
During the past 3 months (or 
during last 8 weeks), have you 
been hospitalized due to your 
osteoarthritis?
Yes, No
No = 0
Yes = 1
How many nights in total did you 
stay in hospital due to your 
osteoarthritis in the last 3 months
(or during last 8 weeks)?
Number of Nights
0-999 (max should be 
92)
Did you use these aids or devices 
Did not use any 
Did not use any aids or 
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Question
Response
Scoring
to help you in doing things because 
of your osteoarthritis in the last 3 
months (or during last 8 weeks)?
•
Walking Aid;
•
Wheelchair;
•
Devices or utensils to help 
you dress, eat or bathe;
•
Other.
aids or devices
Never, rarely, 
sometimes, often, 
always
devices = 0
Device not selected = 0
Never = 1
Rarely = 2
Sometimes = 3
Often = 4
Always = 5
Did you quit your job because of 
your osteoarthritis?
Yes, No
No = 0
Yes = 1
Not applicable = 2
How long ago did you quit your 
job because of your osteoarthritis?
Years and Months
0-99 Years and 0-99 
Months (should be max 
of 11 months)
Rescue Medication Endpoints
Rescue medication data is collected daily using an electronic system up to Week 24, and 
Weekly after Week 24 and up to Week 48.  Daily and Weekly collected data will be assigned 
to a specific study week for summary and reporting.  The assignment of daily and weekly 
data to weeks will use the same principle as described above in Appendix 2.1 for the daily 
and weekly index joint pain data. 
The incidence of rescue medication use will look for any incidence in the week of interest 
(collected through daily or weekly diary data).  The number of days of RM use (using daily 
and weekly data) and the total amount taken (using daily data up to Week 24 only) over the 
week will be calculated for the assigned week algorithm described above. 
Imputation is described in Section 5.3 above.  Imputation occurs for daily data up to Week 24
where the subject is in the trial and up to the end of that particular week.
An example of imputation and calculating the three endpoints using the daily diary data is 
shown below.
Example of calculating rescue medication data from Daily Diary Data (Subject does not 
discontinue)
In this example, a subject has a Week 2 visit on study day 14 (slightly earlier than the 
nominal day 15).  Study days 8-14 would represent Week 2 data.
Using the Week 2 interval described above for a subject, ie, study days [8-14], we have the 
following rescue medication example data
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The amount taken and number of days of rescue medication use is adjusted for the duration 
of the Weekly interval. 
Study Day (Week)
Number of Doses of 
RM taken [1]
Number of Doses of 
RM taken [1] with 
LOCF imputation
8 (Week 2)
2
2
9 (Week 2)
Missing
2 [2]
10 (Week 2)
0
0
11 (Week 2)
1
1
12 (Week 2)
Missing
1 [2]
13 (Week 2)
2
2
14 (Week 2)
0
0
[1] 500mg tablets of acetaminophen (If a site dispenses different dosage as rescue medication, the dosage will 
be used.); [2] Using LOCF imputation for missing data
For this subject the following data will be calculated for Week 2:
•
Incidence of rescue medication taken in Week 2: Yes.  Rescue medication taken on 
days 8, 9 (imputed), 11, 12 (imputed), 13.
•
Number of days of rescue medication use in Week 2:   5.  For days 8-14 we have 
rescue medication taken on days 8, 9 (imputed), 11 and 12 (imputed), and 13. 
•
Amount (mg) of rescue medication use in Week 2: For days 8-14 we have the number 
of doses taken of 2, 2 (imputed), 0, 1, 1 (imputed), 2 and 0.  The number of doses 
taken for the 7 day period is 8, making the amount of acetaminophen dosage of 
4000 mg.
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Example of calculating rescue medication data from Daily Diary Data (Subject 
discontinues)
In this example, a subject discontinues on study day 62, a few days after a Week 8 visit 
(which was on study day 60).  The Week 5-8 data is calculated as described above (eg,
Week 8 using days [50, 56]).  The subject has rescue medication data as shown below.
Study Day (Week)
Number of Doses of 
RM taken [1]
Number of Doses of 
RM taken [1] with 
LOCF imputation
57 (Week 9)
1
1
58 (Week 9)
1
1
59 (Week 9)
Missing
1 [2]
60 (Week 9)
Missing
1 [2]
61 (Week 9)
Missing
1 [2]
62 (Week 9)
Missing
1 [2]
63 (Week 9)
Missing
1 [2]
[1] 500mg tablets of acetaminophen (If a site dispense different dosage as rescue medication, the dosage will be 
used.); [2] Using LOCF imputation for missing data
Week 9 is calculated as days 57 to 63.  The data up to the end of the last week the subject 
was in the trial is imputed using LOCF as shown above.  Therefore the Week 9 scores are 
then used to impute the Weekly data for summary and analysis for Weeks 10 to 24.
As above the incidence of rescue medication for Week 9 would be ‘Yes’.  The number of 
days of rescue medication use would be 7, and the average dose would be 
7/7*7*500=3500mg for this week.
Appendix 3.1. Further Details of Interim Analyses
Details of the ongoing review of safety data (including joint safety events) are given in a 
separate statistical analysis plan for the Data Monitoring Committee.
Appendix 3.2. Further Details of the Statistical Methods
A description of the combination of the ANCOVA results from each of the multiple imputed 
datasets is given below, and taken from Little & Rubin (2002), page 86-7.
In this analysis we have defined the number of imputations (D) to be 100.
The treatment estimates for individual treatment groups and treatment contrasts are defined 
as 
iθ for 
D
i
K
1
=
.  The combined estimate is 
∑
=
=
D
i
i
D
D
1
1
θ
θ
.  The variability of the 
combined estimate contains components of both Within- (W) and Between- (B) imputation 
dataset variability.  These are shown below:
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∑
=
=
D
i
i
D
W
D
W
1
1
and 
(
)
∑
=
−
−
=
D
i
D
i
D
D
B
1
2
ˆ
1
1
θ
θ
where 
i
W is the variance for the parameter 
iθ .
The total variance for 
D
θ is shown below:
D
D
D
B
D
D
W
T
1
+
+
=
.
The test statistic (
)
D
D
T
θ
θ −
has a t-distribution with 
*
v degrees of freedom, which is defined 
below:
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
=
obs
v
v
v
ˆ
1
1
*
,
using
(
)
(
)
.
1
1
ˆ
1
ˆ
1
ˆ
1
1
1
1
3
2
D
D
D
com
com
com
D
obs
D
D
T
B
D
v
v
v
v
B
W
D
D
v
⎟
⎠
⎞
⎜
⎝
⎛+
=
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
−
=
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
+
−
=
+
γ
γ
This distribution can be used to construct the test statistics and 95% confidence intervals for 
θ.
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