Clinical trial NCT02609828
Conditions: Bone Metastasis Cancer Pain
Keywords: Metastatic cancer bone pain Multiple myeloma
Sponsor: Pfizer
Start date: 2015-10-28; Completion date: 2021-06-25
Enrollment: 156 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether tanezumab is effective in the treatment of cancer pain due to bone metastasis in patients already taking background opioid therapy.

Detailed description:
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group Phase 3 study in cancer subjects requiring treatment with background opioids for pain due to bone metastasis.

Approximately 144 subjects will be randomized to one of 2 treatment groups in a 1:1 ratio (approximately 72 subjects per group). Subjects will receive a total of 3 subcutaneous injections, separated by 8 weeks in addition to background opioids administered throughout the study.

Treatment groups will include: 1. Placebo SC (matching tanezumab SC) in addition to background opioid therapy. 2. Tanezumab 20 mg SC in addition to background opioid therapy.

The study consists of three periods: Pre-Treatment (up to 37 days), Double-Blind Treatment (24 weeks) and Safety Follow-up (24 weeks).

Arms: arm 1: Tanezumab 20 mg subcutaneously arm 2: Placebo matched to active treatment subcutaneously
Interventions: intervention 1: Tanezumab
Intervention descriptions: intervention 1: Subcutaneous study treatment (tanezumab 20 mg or matched placebo) dosed at 8 week intervals.

Protocol documents:
Prot_000.pdf: 
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF THE
SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB (PF-04383119) IN 
SUBJECTS WITH CANCER PAIN PREDOMINANTLY DUE TO BONE 
METASTASIS RECEIVING BACKGROUND OPIOID THERAPY
Compound:
PF-04383119
Compound Name:
Tanezumab
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2013-002223-42
Protocol Number:
A4091061
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
Amendment 4
14 June 2018
Rationale for Protocol Amendment 4. Added 
background and rationale for key changes in 
Amendment 4.
Study Design and Study Treatments. Updated 
to reflect enrolment and revised statistical 
methods.
Statistical Methods. Interim analysis and final 
sample size revised.
Section 3. Study Design. Figure 1. Revised to 
reflect change in sample size. Updated to 
reflect change to interim analysis and sample 
size. 
Section 4.2. Exclusion Criteria. Criterion 5. 
Prohibited medications revised.
Section 4.2. Exclusion Criteria. Criterion 16c. 
Updated for clarification.
Section 4.4. Lifestyle Guidelines. Clarification 
of contraception method 5. Sexual abstinence 
added.
Section 5.5. Administration. Clarification of 
medication error added.
Section 5.6. Investigational Product Storage. 
Clarification of medication error added.
Section 5.8.1.1. Prohibited Background Opioid 
Treatment. Clarification added regarding 
prohibited opioids.
Section 5.8.1.3. Restrictions on Use of 
Treatments for Underlying Cancer or Bone 
Metastasis. Clarification regarding prohibited 
medication added.
Section 5.8.2.3. Permitted Concomitant 
Treatments for Underlying Cancer or Bone 
Metastasis. Updated to reflect revised 


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prohibited medications.
Section 9.1. Sample Size Determination. 
Interim analysis and sample size revised.
Section 9.2.1. Primary Endpoint Analysis. 
Clarification added.
Section 9.6. Interim Analysis. Interim analysis 
and sample size revised.
Section 9.7.1.1. Serious Adverse Events. 
Pre-specified serious adverse events revised.
Section 9.7.1.2. Events consistent with Hy’s 
Law. Hy’s Law section added.
Appendix 1. List of Abbreviations. Updated to 
reflect terms added.
 
 
Appendix 8. Restrictions on Prior and 
Concomitant Medications. Opioids. 
Clarification added regarding prohibited 
opioids.
Appendix 8. Restrictions on Prior and 
Concomitant Medications.  Chemotherapeutic, 
Radiopharmaceutical or Radiotherapy, Anti-
Cancer Hormonal Treatments. Updated to 
reflect revised prohibited medications.
Appendix 8. Restrictions on Prior and 
Concomitant Medications.  Biologics. 
Clarification added regarding prohibited 
medications.
Amendment 3
02 February 2017
Rationale for Protocol Amendment 3. Added 
to provide background and rationale for key 
changes in Amendment 3.
Protocol Summary. Background and Rationale. 
Updated to include background on prior 
studies.
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Objectives and Endpoints. Primary objective 
revised to remove tanezumab 10 mg dose 
comparison. Secondary objective revised to 
remove tanezumab 10 mg dose comparison.
Study Design and Study Treatments. Updated 
to reflect removal of tanezumab 10 mg dose 
arm.
Statistical Methods. Updated to reflect removal 
of tanezumab 10 mg dose arm.
Table 1. Pre-Treatment, Double-Blind & 
Safety Follow-Up Schedule of Activities &
Table 2. Early Termination Schedule of 
Activities. Footnotes updated to reflect 
changes to protocol activities.
Section 1.2.5. Dose Selection Rationale. 
Updated to reflect removal of tanezumab 10 
mg dose arm and include information on prior 
studies.
Section 1.2.8. Rationale for Population. 
Updated to include rationale for expanding 
primary tumor types.
Section 1.2.9. Benefit vs Risk for the Study 
Population. Updated to reflect removal of 
tanezumab 10 mg dose arm and expanding 
tumor types.
Section 2.1.1. Primary Objective. Updated to 
reflect removal of tanezumab 10 mg dose arm.
Section 2.1.2. Secondary Objective. Updated 
to reflect removal of tanezumab 10 mg dose 
arm.
Figure 1. Study Design. Figure updated to 
reflect revised study design without tanezumab 
10 mg dose arm.
Section 3. Study Design. Updated to reflect 
removal of tanezumab 10 mg dose arm.
Section 4.1. Inclusion Criteria, Item 4. Body 


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weight revised.
Section 4.1. Inclusion Criteria, Item 5. Primary 
cancer types expanded.
Section 4.1. Inclusion Criteria, Item 6. Imaging 
modality requirement for bone scan 
confirmation of bone metastasis revised.
Section 4.1. Inclusion Criteria, Item 13. 
Criterion for adequate renal function revised 
and clarified.
Section 4.2. Exclusion Criteria, Item 3. 
Clarification of test process.
Section 4.2. Exclusion Criteria, Item 5; Section 
5.8.; Section 6.2.2.2. Dose stability window 
requirement for concomitant treatments for 
underlying cancer or bone metastasis revised. 
Restrictions on use clarified.
Section 4.2. Exclusion Criteria, Item 6. 
Exclusionary window requirement for receipt 
of radiopharmaceutical treatment or 
radiotherapy for treatment of bone metastasis 
revised.
Section 4.2. Exclusion Criteria, Item 7. Dose 
stability window requirement for concurrent 
adjuvant analgesics revised.
Section 4.2. Exclusion Criteria, Item 9. 
Clarification regarding diagnostic criteria for 
shoulder osteoarthritis added.
Section 4.2. Exclusion Criteria, Item 12. 
Clarification regarding permitted radiographic 
findings added.
Section 4.2. Exclusion Criteria, Item 16. 
Clarification regarding diagnosis of 
paraneoplastic syndrome added.
Section 4.2. Exclusion Criteria, Item 28. 
Exlusionary time period for participation in 
other studies updated.


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Section 5.1. Allocation to Treatment. Updated 
to reflect removal of tanezumab 10 mg dose 
arm.
Sections 5.3, 6.2.2.1, and 7.1.2. Clarification 
regarding capture of background opioid use
added.
Section 5.4.1.2. Placebo for Tanezumab and 
Section 5.4.2. Preparation and Dispensing. 
Updated to reflect removal of tanezumab 10 
mg dose arm.
Section 5.6. Investigational Product Storage. 
Temperature monitoring of Investigational 
Product Storage updated.
Sections 5.8.1 and 6.2.2.2. Use of prohibited 
concomitant treatments including opioid, non-
opioid, other and underlying cancer or bone 
metastasis therapies revised.
Section 5.8.2. Use of permitted concomitant 
treatments including non-opioid, anticancer 
therapies revised. Clarification regarding use 
and reimbursement of standard of care 
analgesia added.
Section 6.1. Re-screening process revised. 
Clarification regarding inclusion/exclusion 
criteria assessment, and Screening activities
added.
Section 6.1.1.1.1. Assessment of Inclusion and 
Exclusion Criteria. Updated to reflect 
permitted bone metastasis imaging.
Section 6.1.1.2.2. Schedule Screening X rays 
of Major Joints. Clarification added regarding 
Screening x-ray assessments.
Section 6.1.1.2.4. Adjustment of Background 
Opioid Regimen. Clarification added regarding 
Screening activities.
Section 6.2.2.2. Concomitant Treatment for 
Underlying Cancer or Bone Metastasis. 
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concomitant treatments.
Section 6.3. Safety Follow-Up Period. Updated 
to reflect changes to permitted concomitant 
treatments.
Section 6.4. Subject Withdrawal/Early 
Termination. Clarification added regarding 
permitted concomitant treatments.
Section 7.1.1.2. Non-index Site(s) of Cancer 
Pain Assessment. Typographical error 
corrected.
Section 7.1.2. Subject Daily/Weekly Opioid 
Medication Use. Clarification added regarding 
recording opioid use.
Section 7.2.4. Eastern Cooperative Oncology 
Group (ECOG) Performance Status. 
Completion of assessment updated.
Section 7.4.4. Evaluation and Follow-Up for 
Increased, Severe Persistent Joint Pain. 
Clarification added regarding evaluation and 
follow-up for subjects who report new or 
worsened joint pain.
Section 9.1. Sample Size Determination. 
Updated to reflect removal of tanezumab 10 
mg dose arm.
Section 9.2. Efficacy Analysis. Updated to 
reflect removal of tanezumab 10 mg dose arm.
Section 9.2.1. Primary Endpoint Analysis. 
Updated to reflect removal of tanezumab 10 
mg dose arm. Definition of secondary efficacy 
population (Per Protocol) updated.
Section 9.3.4. Opioid Use and Opioid Adverse 
Effects Analysis. Updated to reflect plan for 
data analysis of discontinued tanezumab 10 mg 
dose arm.
Section 9.4. Safety Analysis. Updated to 
reflect plan for data analysis of discontinued 


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tanezumab 10 mg dose arm.
Section 16. References. Updated to reflect 
additional references.
Section 101. Substudy Introduction. 
Clarification added regarding protocol-
required procedures.
Section 104.2. Life Style Guidelines. 
Clarification regarding contraception 
requirements in the substudy added.
Section 106.1. Baseline Visit (Last Visit in 
Study A4091061 or when Notified of TJR 
Surgery). Clarification added regarding 
assessments. 
Tables 1 & 2. Main table and footnote text 
revised in line with changes to protocol. 
Appendix 1. List of Abbreviations. Updated to 
reflect additional imaging modality.
Appendix 4. American College of 
Rheumatology (ACR) Classification Criteria 
for Osteoarthritis. Clarification added 
regarding ESR testing.
 
 
Appendices 7 and 8. Guidance regarding 
analgesics and concomitant medications 
updated in line with changes to protocol.
Administrative clarifications and typographical 
corrections have been incorporated throughout. 
Amendment 2
02 November 2015
Sections 4.2 and 5.8.2.3. In Japan only, 
chemotherapies associated with peripheral 
neuropathy are prohibited from Screening to 
Week 32.
Sections 3, 6.3 and 6.3.2, and Schedule of 
Activities, Table 1. Week 40 will be a clinic 
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visit for subjects in Japan.
Sections 6, 6.2.2.4 and 7.3.9, and Schedule of 
Activities, Table 1. At Week 16, subjects in 
Japan will have X-rays of joints; typo 
correction. 
Section 7.3.9.1. Radiation exposure has been 
added for subjects in Japan. 
Appendix 18. For France Contrat Unique has 
been added. 
Amendment 1
18 August 2015
Section 4.1. Inclusion Criteria, item 16. Update 
to contraceptive requirements.
Section 4.2. Exclusion Criteria, item 29.  
Update to contraceptive requirements.
Section 4.4. Lifestyle Guidelines. Update to 
acceptable methods of contraception.
Section 16. References. Addition of citation 
for contraception methods.
Section 104.2. Life Style Guidelines. Update to 
contraceptive requirements.
Appendix 1. List of Abbreviations. Addition of 
intrauterine system (IUS).
Original protocol
10 April 2015
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of regulatory authorities, institutional review boards/ethics committees (IRBs/ECs), 
etc.  


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RATIONALE FOR PROTOCOL AMENDMENT 3
Background
The original A4091061 protocol was issued with a version date of 10 April 2015. The 
protocol was subsequently amended as follows:

Amendment 1, 18 August 2015: in response to comments received during assessment 
of the initial clinical trial application (CTA) for A4091061 via the European Union 
(EU) Voluntary Harmonisation Procedure (VHP684 [VHP2015072]), the protocol 
was amended with respect to contraceptive requirements. 

Amendment 2, 2 November 2015: the schedule of activities for subjects in Japan was 
modified following comments received from the Pharmaceuticals and Medical 
Devices Agency (PMDA).
Study Status
As of 1 January 2017, a total of 54 investigational sites have been opened in the following 
countries: Australia, Austria, Czech Republic, Hungary, Japan, Poland, Romania, Slovakia, 
South Korea, Spain and United Kingdom (UK).
The A4091061 protocol achieved first subject first visit (FSFV) in October 2015. As of 1 
January 2017, only 17 of the required 255 subjects have been randomized, and, moreover, no
subjects were randomized during October or November 2016.
In summary, there have been extensive recruitment challenges with this study to date, despite 
the Sponsor’s efforts to train investigators and motivate sites. In order to address these 
challenges, the protocol has been amended (Amendment 3) in order to optimize clinical and 
operational feasibility, with details provided below.
Amendment 3
The most common reason cited by study investigators for the slow enrollment, thereby 
making the study so difficult to conduct, was that several of the entry criteria were 
unnecessarily restrictive. Therefore, Amendment 3 includes modifications to the entry 
criteria in order to more accurately reflect the real-world population and the clinical 
management of patients with metastatic bone pain. These modifications are intended to make 
the study operationally feasible while still maintaining benefit-risk for the recruited subjects.  
Key changes include:

Removal of the restriction on permitted primary tumor types to allow any primary tumor 
type so long as there is a documented bone metastasis. 

Less restrictive body weight and renal function inclusion criteria.


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
Expansion of acceptable imaging modalities for demonstration of a bone metastasis.

Broader permitted concomitant medications for cancer therapies, and less restrictive 
timeframe for use both prior to randomisation and also during weeks 8-24 of the double 
blind treatment period (i.e. after the primary endpoint data have been collected).
Removal of 10 mg dose treatment arm
During the process of amending the protocol, the utility of including the 10 mg dose arm was 
reassessed.
In the previous cancer pain study (A4091003), tanezumab at 10 mg did not demonstrate a 
significant improvement versus placebo on the primary efficacy endpoint of the change from 
Baseline to Week 6 in the daily average pain intensity.  However, there was evidence of 
efficacy for tanezumab 10 mg in post-hoc subgroup analyses of subjects with Baseline pain 
scores >5 and Baseline opioid use below the median value for the study (60 mg/day in 
morphine equivalents).  Also, in subjects with Baseline pain scores >5 irrespective of 
Baseline opioid use, a meaningful treatment difference was demonstrated, indicating that it 
may be possible to demonstrate tanezumab efficacy in subjects with painful bone metastasis 
under different study conditions. 
Considering the preliminary evidence for tanezumab 10 mg efficacy in cancer pain subjects, 
it was hypothesized that study A4091061 would provide confirmatory evidence of efficacy 
for the 10 mg dose in the current study. However, since the original A4091061 protocol was 
written, a study with another nerve growth factor (NGF) inhibitor, fulranumab, has been 
published which also failed to demonstrate a treatment benefit in the primary endpoint of 
pain intensity in cancer pain1.
Although the fulranumab data have not yet appeared in a peer-reviewed journal, given the 
totality of the available clinical data on NGF inhibition in cancer pain, the observation that 
higher doses of tanezumab are needed in certain pain models to provide clinically significant 
efficacy (e.g. painful diabetic neuropathy vs. chronic lower back pain vs. osteoarthritis), good 
tolerability in previous cancer pain trials and the very slow enrollment rate with the current 
study design, further investigation of tanezumab at the lower dose of 10 mg will not be 
conducted. Therefore, the revised study will only investigate the higher dose of 20 mg for 
which the Sponsor considers there is a reasonable probability of achieving clinically relevant 
efficacy in cancer pain without additional risk. Subjects who have been randomized to the 10 
mg dose treatment arm, and who are in the double-blind treatment period at the time of 
implementation of Amendment 3, will be administered 20 mg for any remaining doses.
Summary
The changes incorporated into Amendment 3, which have been based upon feedback from 
investigators, optimize benefit-risk for the subjects and more accurately reflect standard of 
care clinical practice in the real world. The changes maintain high standards of scientific 
integrity and are essential in order to enable study execution. Cancer pain is an area of 
significant unmet medical need, and therefore Amendment 3 is proposed to overcome study 


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obstacles, as described, and to facilitate potential delivery to patients of a new drug, should 
the study yield positive results.  
RATIONALE FOR PROTOCOL AMENDMENT 4
The changes incorporated into Amendment 4 reflect feedback provided by the United States 
(US) Food and Drug Administration (FDA) in May 2018.
Interim Analysis and final sample size modifications have been made in order to facilitate 
futility or efficacy decision-making.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................21
LIST OF FIGURES .................................................................................................................21
APPENDICES .........................................................................................................................21
1. INTRODUCTION ...............................................................................................................38
1.1. Mechanism of Action/Indication.............................................................................38
1.2. Background and Rationale ......................................................................................38
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain...........................38
1.2.2. Description of Investigational Product.......................................................38
1.2.3. Overview of Bone Metastasis and Metastatic Bone Pain...........................38
1.2.4. Overview of Clinical Studies......................................................................40
1.2.4.1. Efficacy in Cancer Pain Studies................................................40
1.2.4.2. Safety in Cancer Pain Studies ...................................................41
1.2.5. Dose Selection Rationale............................................................................41
1.2.6. Rationale for Placebo Treatment ................................................................42
1.2.7. Rationale for Opioid Background...............................................................43
1.2.8. Rationale for Population.............................................................................43
1.2.9. Benefit vs Risk for the Study Population ...................................................43
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................44
2.1. Objectives................................................................................................................44
2.1.1. Primary Objective.......................................................................................44
2.1.2. Secondary Objective...................................................................................44
2.2. Endpoints.................................................................................................................44
2.2.1. Primary Endpoint........................................................................................44
2.2.2. Secondary Endpoints ..................................................................................44
2.2.2.1. Efficacy Measures.....................................................................44
2.2.2.2. Opioid Use and Opioid Adverse Effects Measures...................45
2.2.2.3. Safety Measures ........................................................................46
3. STUDY DESIGN.................................................................................................................47
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4. SUBJECT SELECTION......................................................................................................48
4.1. Inclusion Criteria.....................................................................................................48
4.2. Exclusion Criteria....................................................................................................50
4.3. Randomization Criteria ...........................................................................................54
4.4. Lifestyle Guidelines ................................................................................................54
4.5. Sponsor’s Qualified Medical Personnel..................................................................56
5. STUDY TREATMENTS.....................................................................................................56
5.1. Allocation to Treatment ..........................................................................................57
5.2. Breaking the Blind ..................................................................................................57
5.3. Subject Compliance.................................................................................................58
5.4. Investigational Product Supplies.............................................................................58
5.4.1. Dosage Form(s) and Packaging..................................................................58
5.4.1.1. Tanezumab ................................................................................58
5.4.1.2. Placebo for Tanezumab.............................................................58
5.4.2. Preparation and Dispensing........................................................................59
5.5. Administration.........................................................................................................59
5.6. Investigational Product Storage ..............................................................................59
5.7. Investigational Product Accountability...................................................................60
5.7.1. Destruction of Investigational Product Supplies ........................................60
5.8. Concomitant Treatment(s).......................................................................................60
5.8.1. Concomitant Treatment Prohibited During the Study................................60
5.8.1.1. Prohibited Background Opioid Treatment ................................60
5.8.1.2. Prohibited Non-opioid Analgesics ............................................61
5.8.1.3. Restrictions on Use of Treatments for Underlying Cancer 
or Bone Metastasis ............................................................................62
5.8.1.4. Other Prohibited Medications ...................................................63
5.8.2. Permitted During the Study ........................................................................63
5.8.2.1. Background Opioid Treatment..................................................63
5.8.2.2. Permitted Non-opioid Analgesics .............................................64
5.8.2.3. Permitted Concomitant Treatments for Underlying Cancer 
or Bone Metastasis ............................................................................64
5.8.2.4. Other Permitted Medications ....................................................65
5.8.2.5. Standard of Care Analgesia (after Week 8) ..............................65


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5.8.2.6. Standard of Care Treatment for Underlying Cancer or 
Bone Metastasis (after Week 8) ........................................................66
6. STUDY PROCEDURES .....................................................................................................66
6.1. Pre-Treatment Period ..............................................................................................67
6.1.1. Screening Period.........................................................................................67
6.1.1.1. Activities Performed at the Screening Visit..............................67
6.1.1.2. Screening Activities Initiated at the End of the Initial 
Screening Visit in Subjects Meeting Criteria up to That Point .........68
6.1.2. Baseline Assessment Period (BAP, Days -5 to -1).....................................69
6.2. Double-Blind Treatment Period..............................................................................70
6.2.1. Randomization Clinic Visit ........................................................................70
6.2.1.1. Pre-Randomization....................................................................70
6.2.1.2. Randomization ..........................................................................70
6.2.1.3. Dosing (Day 1)..........................................................................71
6.2.1.4. Post-dosing................................................................................71
6.2.2. Double Blind Treatment Period..................................................................71
6.2.2.1. Background Opioid Use............................................................71
6.2.2.2. Concomitant Treatment for Underlying Cancer or Bone 
Metastasis ..........................................................................................72
6.2.2.3. IRT (Subject Diary)...................................................................72
6.2.2.4. Routine Clinic Visits (Week 2 and Week 4).............................72
6.2.2.5. Dosing Visits (Week 8 and Week 16).......................................72
6.2.2.6. Phone Contact Visits (Week 12 and Week 20).........................73
6.2.2.7. Week 24 Clinic Visit (End of Double-Blind Treatment) ..........73
6.3. Safety Follow-Up Period.........................................................................................73
6.3.1. Week 32 Clinic Visit ..................................................................................74
6.3.2. Phone Contacts (Weeks 28, 36, 40, and 44); for Japan only, Week 40 
Clinic Visit.......................................................................................................74
6.3.3. Week 48 Clinic Visit (End of Study)..........................................................74
6.4. Subject Withdrawal/Early Termination ..................................................................74
6.4.1. Early Termination Follow-Up Procedures..................................................76
6.4.1.1. Early Termination Visit 1 (~8 Weeks after Last Dose of 
SC Study Medication) .......................................................................77


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6.4.1.2. Early Termination Telephone Contacts 1 and 2 (~12 
Weeks and ~20 Weeks after Last Dose of SC Study 
Medication)........................................................................................77
6.4.1.3. Early Termination Visit 2 (~16 Weeks after Last Dose of 
SC Study Medication) .......................................................................77
6.4.1.4. Early Termination Visit 3 (~24 Weeks after Last Dose of 
SC Study Medication) .......................................................................77
6.5. Procedures for Subjects Undergoing Joint Replacement ........................................77
7. ASSESSMENTS..................................................................................................................77
7.1. Subject IRT Assessments........................................................................................78
7.1.1. Daily/Weekly Pain IRT Assessments.........................................................78
7.1.1.1. Index Bone Metastasis Cancer Pain Site Assessment...............78
7.1.1.2. Non-Index Site(s) of Cancer Pain Assessment .........................78
7.1.1.3. Joint Pain Assessments..............................................................79
7.1.2. Subject Daily/Weekly Opioid Medication Use ..........................................79
7.1.3. Concomitant NSAID Use ...........................................................................79
7.2. Study Visit Efficacy Assessments and Other Instruments......................................80
7.2.2. Opioid-Related Symptom Distress Scale....................................................80
7.2.3. Patient’s Global Assessment of Cancer Pain (PGA of Cancer Pain) .........80
7.2.4. Eastern Cooperative Oncology Group (ECOG) Performance Status.........80
7.3. Safety Assessments .................................................................................................81
7.3.1. Cancer History............................................................................................81
7.3.2. General Physical Examination....................................................................81
7.3.3. Musculoskeletal History and Physical Examination ..................................81
7.3.4. Laboratory Safety Assessments..................................................................81
7.3.4.1. Blood tests.................................................................................82
7.3.4.2. Urinalysis and Urine Toxicology..............................................82
7.3.4.3. Pregnancy Testing.....................................................................83
7.3.4.4. Serum FSH Testing ...................................................................83
7.3.5. Vital Signs ..................................................................................................83
7.3.6. 12-Lead Electrocardiograms.......................................................................84
7.3.7. Orthostatic Blood Pressure Measurement ..................................................84
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7.3.9. Radiographic Assessments .........................................................................85
7.3.9.1. Radiation Exposure ...................................................................86
7.3.11. Anti-Drug Antibody Testing (ADA) ........................................................88
7.4. Triggered Requirements and Subject-Level Stopping Rules ..................................89
7.4.1. Dysesthesia/Allodynia ................................................................................89
7.4.2. Hypersensitivity or Injection Site Reactions ..............................................89
7.4.3. Orthostatic Hypotension and Sympathetic Function Adverse Events........89
7.4.4. Evaluation and Follow-Up for Increased, Severe Persistent Joint Pain .....92
7.4.5. Central Reader and Subject-Level Stopping Criteria for Possible or 
Probable Joint Safety Events ...........................................................................92
7.4.6. Procedures for Subjects Undergoing Joint Replacement............................93
8. ADVERSE EVENT REPORTING......................................................................................97
8.1. Adverse Events........................................................................................................97
8.2. Reporting Period .....................................................................................................98
8.3. Definition of an Adverse Event...............................................................................98
8.4. Medication Errors....................................................................................................99
8.5. Abnormal Test Findings..........................................................................................99
8.6. Serious Adverse Events.........................................................................................100
8.6.1. Protocol-Specified Serious Adverse Events.............................................101
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................101
8.7. Hospitalization ......................................................................................................102
8.8. Severity Assessment..............................................................................................103
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8.9. Causality Assessment............................................................................................103
8.10. Exposure During Pregnancy................................................................................104
8.10.1. Additional Postnatal Development Follow-Up ......................................105
8.11. Occupational Exposure .......................................................................................105
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal/Early Termination) ..............................................................................105
8.13. Eliciting Adverse Event Information ..................................................................106
8.14. Reporting Requirements......................................................................................106
8.14.1. Serious Adverse Event Reporting Requirements ...................................106
8.14.2. Nonserious Adverse Event Reporting Requirements .............................106
8.14.3. Medical Device Reporting Requirements...............................................106
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ..............107
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................107
9.1. Sample Size Determination...................................................................................107
9.2. Efficacy Analysis ..................................................................................................108
9.2.1. Primary Endpoint Analysis.......................................................................108
9.2.2. Secondary Efficacy Endpoint Analysis ....................................................109
9.3.4. Opioid Use and Opioid Adverse Effects Analysis ...................................111
9.4. Safety Analysis......................................................................................................111
9.5. External Adjudication Committee.........................................................................112
9.6. Interim Analysis ....................................................................................................113
9.7. Data Monitoring Committee .................................................................................114
9.7.1. Protocol-Level Rules for Dosing Suspension/Safety Assessments..........115
9.7.1.1. Serious Adverse Events...........................................................115
9.7.1.2. Events consistent with Hy’s Law............................................116
9.7.1.3. Joint Safety Events..................................................................116
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................116
11. DATA HANDLING AND RECORD KEEPING ...........................................................117
11.1. Case Report Forms/Electronic Data Record .......................................................117
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11.2. Record Retention.................................................................................................117
12. ETHICS............................................................................................................................118
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................118
12.2. Ethical Conduct of the Study ..............................................................................118
12.3. Subject Information and Consent........................................................................118
12.4. Subject Recruitment ............................................................................................119
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................119
13. DEFINITION OF END OF TRIAL.................................................................................120
13.1. End of Trial in a Member State...........................................................................120
13.2. End of Trial in All Other Participating Countries...............................................120
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................120
15. PUBLICATION OF STUDY RESULTS........................................................................120
15.1. Communication of Results by Pfizer ..................................................................120
15.2. Publications by Investigators ..............................................................................121
16. REFERENCES ................................................................................................................123
101. SUBSTUDY INTRODUCTION ...................................................................................161
101.1. Rationale for Selected Patient Reported Outcomes ..........................................161
101.2. Interactive Web Response System ....................................................................162
102. SUBSTUDY OBJECTIVE AND ENDPOINTS ...........................................................162
102.1. Objective ...........................................................................................................162
102.2. Endpoints...........................................................................................................162
103. SUBSTUDY STUDY DESIGN ....................................................................................163
104. SUBSTUDY SUBJECT SELECTION..........................................................................164
104.1. Inclusion Criteria...............................................................................................165
104.2. Life Style Guidelines.........................................................................................165
104.3. Sponsor Qualified Medical Personnel...............................................................166
105. SUBSTUDY STUDY TREATMENTS.........................................................................166
105.1. Concomitant Medication(s)...............................................................................166
106. SUBSTUDY STUDY PROCEDURES.........................................................................166
106.1. Baseline Visit (Last Visit in Study A4091061 or when Notified of TJR 
Surgery) ...................................................................................................................167
106.1.1. Activities at the Baseline Visit: ............................................................167


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106.2. Day of Surgery (Day 1 + 10 days) ....................................................................168
106.3. Week 4 (Day 29 5 days).................................................................................168
106.4. Week 8 (Day 57 5 days).................................................................................169
106.5. Week 12 (Day 85 5 days)...............................................................................169
106.6. Week 16 (Day 113 5 days).............................................................................170
106.7. Week 20 (Day 141 5 days).............................................................................171
106.8. Week 24 (Day 169 5 days).............................................................................171
106.9. Subject Withdrawal/Early Termination ............................................................171
107. SUBSTUDY ASSESSMENTS......................................................................................172
107.1. Surgeon’s Assessment of Procedural Difficulty ...............................................172
107.2. Pathology Specimens ........................................................................................173
107.3. Telephone-based Assessments ..........................................................................173
107.3.1. Adverse Events.....................................................................................173
107.3.2. Concomitant Analgesic Medication .....................................................174
107.3.3. Physical Rehabilitation Activities.........................................................174
107.3.4. Additional or Corrective Procedures ....................................................174
107.4. Web-based Assessments ...................................................................................174
107.4.1. Overall Satisfaction with Joint Replacement Surgery..........................174
107.4.2. Pain in Replaced Joint ..........................................................................175
107.4.3. Assessment of Functional Activity.......................................................175
107.4.3.1. WOMAC .............................................................................176
107.4.3.2. The Shoulder Pain and Disability Index (SPADI) ..............176
108. SUBSTUDY ADVERSE EVENT REPORTING .........................................................177
109. SUBSTUDY DATA ANALYSIS/STATISTICAL METHODS...................................177
109.1. Sample Size Determination...............................................................................177
109.2. Analysis of Endpoints .......................................................................................177
109.3. Data Monitoring Committee (DMC).................................................................178
109.4. External Adjudication Committee.....................................................................178
110. SUBSTUDY QUALITY CONTROL AND QUALITY ASSURANCE ......................178
111. SUBSTUDY DATA HANDLING AND RECORD KEEPING ...................................178
112. SUBSTUDY ETHICS ...................................................................................................178
113. SUBSTUDY DEFINITION OF END OF TRIAL.........................................................179


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114. SUBSTUDY SPONSOR DISCONTINUATION CRITERIA......................................179
115. SUBSTUDY PUBLICATION OF STUDY RESULTS................................................179
116. SUBSTUDY REFERENCES ........................................................................................179
LIST OF TABLES
Table 1.
Pre-Treatment, Double-Blind & Safety Follow-Up Schedule of Activities.........28
Table 2.
Early Termination Schedule of Activitiesa ...........................................................35
Table 3.
Stratification Randomization Scheme ..................................................................57
Table 4.
Orthostatic Blood Pressure Changes and Orthostatic Hypotension 
Definition..............................................................................................................85
Table 5.
Schedule of Activities.........................................................................................159
LIST OF FIGURES
Figure 1.
Study Design.........................................................................................................47
Figure 2.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events...............91
APPENDICES
Appendix 1. List of Abbreviations.........................................................................................128
Appendix 2. Adjudication Categories....................................................................................132
Appendix 3. Eastern Cooperative Group (ECOG) Performance Status ................................133
Appendix 4. American College of Rheumatology (ACR) Classification Criteria for 
Osteoarthritis.......................................................................................................134
Appendix 6. American Society of Anesthesiologists (ASA) Physical Status 
Classification ......................................................................................................137
Appendix 7. Half-Lives of NSAIDs and Other Analgesics...................................................138
Appendix 8. Restrictions on Prior and Concomitant Medications ........................................140
Appendix 9. Daily/Weekly Pain IRT Assessments ...............................................................147
Appendix 11. Opioid-Related Symptom Distress Scale........................................................150
Appendix 12. Patient Global Assessment of Cancer Pain.....................................................151
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PROTOCOL SUMMARY
BACKGROUND AND RATIONALE
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.  Information 
regarding development of tanezumab in non-cancer patient populations can be found in the 
tanezumab investigator brochure2 and in publically-available documents prepared for the 
United States (US) Food and Drug Administration (FDA) Arthritis Advisory Committee 
meeting on March 12, 2012.3 4,5.
The rationale for treatment of tanezumab in subjects with metastatic bone pain is provided by 
the rich innervation of bone by NGF-responsive neurons,33 the pathologic elevation of NGF 
and NGF-responsive neurons in bone metastases,33 results of preclinical studies 
demonstrating metastatic bone pain efficacy with the murine precursor antibody to 
tanezumab (MAb 911) and results of tanezumab clinical studies in musculoskeletal and 
visceral pain conditions.2
The efficacy of tanezumab in subjects with painful bone metastasis has been evaluated in 
Study A4091003, which was a randomized, double-blind, placebo-controlled, parallel group 
study in subjects with cancer pain due to bone metastasis who were receiving background 
treatment with opioids.43  In addition, subjects who had been randomized and treated in 
Study A4091003, and who wished to receive open-label tanezumab therapy, could roll over 
to Study A4091029, a safety extension study designed to investigate the safety and 
maintenance of effect of tanezumab 10 mg. 44  In Study A4091003, a total of 59 patients were 
treated with either a single intravenous (IV) dose of tanezumab 10 mg (N=29) or placebo 
(N=30). In Study A4091029, a total of 41 patients were treated with tanezumab 10 mg IV.
A positive outcome for the primary efficacy endpoint for Study A4091003 (ie, a statistically 
significant change from Baseline to Week 6 in the daily average pain intensity) was not 
achieved, although the mean decrease from Baseline in the tanezumab 10 mg IV treatment 
group was numerically greater than that for the placebo treatment group. The change from 
Study A4091003 Baseline in average pain was maintained up to Week 24 in A4091029 for 
all subjects.  For the 6 subjects who had received placebo in Study A4091003, the average 
pain score in A4091029 subsequently worsened from Week 24 to Week 40 (back to the 
Study A4091003 Baseline pain level).  However for subjects who had received tanezumab 
10 mg in Study A4091003, the improvement in average pain was further maintained to 
Week 40 of Study A4091029.
Although an acceptable safety profile was seen in the previous studies in this patient 
population, efficacy has not yet been robustly demonstrated, hence further evaluation of 
benefit-risk is required in Study A4091061.


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OBJECTIVES AND ENDPOINTS
Primary and Secondary Objectives
The primary objective of Study A4091061 is to demonstrate superior analgesic efficacy of 
tanezumab 20 mg subcutaneous (SC) versus matching placebo SC at Week 8 in subjects with 
cancer pain predominantly due to bone metastasis receiving background opioid therapy. 
The secondary objective is to evaluate the safety of tanezumab 20 mg SC versus matching 
placebo SC in subjects with cancer pain predominantly due to bone metastasis receiving 
background opioid therapy.
Primary and Secondary Endpoints
The primary efficacy endpoint is the change from Baseline to Week 8 in the daily average 
pain intensity Numeric Rating Scale (NRS) score in the index bone metastasis cancer pain 
site.
The secondary endpoints are as follows:
Efficacy Measures
•
Change from Baseline to Weeks 1, 2, 4, 6, 12, 16 and 24 in the daily average pain 
intensity NRS score in the index bone metastasis cancer pain site.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily worst pain 
intensity NRS score in the index bone metastasis cancer pain site.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the weekly average 
pain intensity NRS score in non-index cancer pain sites.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the weekly worst pain 
intensity NRS score in non-index cancer pain sites.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily average pain 
intensity NRS score in the non-index visceral cancer pain sites.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily worst pain 
intensity NRS score in the non-index visceral cancer pain sites.
 
 
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•
Response as defined by a ≥30%, ≥50%, ≥70%, and ≥90%, reduction from Baseline in 
the daily average and daily worst pain intensity NRS score in the index bone 
metastasis cancer pain site at Weeks 1, 2, 4, 6, 8, 12, 16 and 24.
•
Change from Baseline in Patient’s Global Assessment of Cancer Pain at Weeks 2, 4, 
8, 16 and 24. 
•
Response as defined by an improvement of ≥2 points in Patient's Global Assessment 
of Cancer Pain at Weeks 2, 4, 8, 16 and 24. 
 
 
Opioid Use and Opioid Adverse Effects Measures
•
Average daily total opioid consumption (in mg of morphine equivalent doses) at 
Weeks 1, 2, 4, 6, 8, 12, 16 and 24.
•
Average number of doses of rescue medication required per week at Weeks 1, 2, 4, 6, 
8, 12, 16 and 24.
•
Change from Baseline in the weekly Opioid-Related Symptom Distress Scale at 
Weeks 2, 4, 8, 16 and 24.
Safety Measures
•
Adverse events.
•
Standard safety assessments (safety laboratory testing [chemistry, hematology], 
sitting vital signs, electrocardiogram [ECG, 12-lead]).
•
Orthostatic (supine/standing) blood pressure assessments.
•
Weight measurements.
•
Physical examinations.
•
Joint safety adjudication outcomes.
•
Total joint replacements.
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•
Anti-drug antibody (ADA) assessments.
STUDY DESIGN AND STUDY TREATMENTS
The study is designed with a post-randomization study duration of 48 weeks and will consist 
of three periods: Pre-Treatment, Double-Blind Treatment and 6-month Safety Follow-Up.  
The Pre-Treatment Period lasting 5-37 days will be used to determine subject eligibility, 
followed by a Double-Blind Treatment Period lasting 24 weeks (Days 1-169) and a 6-month 
Safety Follow-Up Period ending with the End of Study Visit at Week 48 (Day 337).  
The protocol was initially designed to include 3 treatment groups (tanezumab 20 mg SC, 
tanezumab 10 mg SC, and placebo), and was amended (Amendment 3) after study start to 
discontinue the tanezumab 10 mg dose arm. It is estimated that approximately 11 subjects in 
total were randomized to receive tanezumab 10 mg SC prior to implementation of 
Amendment 3.
Following implementation of Amendment 3, subjects were randomized in a 1:1 ratio
(planned 85 subjects/arm) to one of two treatment arms: tanezumab 20 mg SC or matching 
placebo SC, each administered in addition to background opioids. Subjects who had been 
randomized to the 10 mg dose treatment arm and who were in the double-blind treatment 
period at the time of implementation of Amendment 3 were administered 20 mg for any 
remaining doses.
STATISTICAL METHODS
The primary efficacy endpoint is the change from Baseline to Week 8 in the average daily 
pain intensity in the index bone metastasis cancer pain site measured by the 11 point pain 
intensity Numerical Rating Scale (NRS) where scores range from 0-10.  Baseline is defined 
as the mean average daily pain NRS score during the Baseline Assessment Period prior to 
randomization.  The Week 8 pain intensity value is the mean of the daily average pain 
intensity scores for the 7 days prior to the Week 8 visit.
The primary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model, with model terms for Baseline score, the stratification variables, Baseline opioid use, 
region and treatment group.  The stratification variables are (i) tumor aggressiveness 
(assessed by Eastern Cooperative Group [ECOG] performance status and 
(ii) presence/absence of concomitant anticancer treatment (eg, chemotherapy or hormonal 
therapy or anti-hormonal therapy).
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The primary analysis of the primary endpoint 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.  Refer to Section 9.2 for details.
Data from subjects initially randomized to the tanezumab 10 mg treatment group will be 
summarized but not included in analyses of efficacy. A Group Sequential Design with a 
single interim analysis will be used for the assessment of futility and of efficacy of the 
primary efficacy parameter.
The interim analysis will be performed when at least 50% (36 from each treatment group) of 
subjects have completed or discontinued prior to Week 8. Based on current enrollment, it is 
expected that the interim analysis will include approximately 36 to 45 subjects per treatment 
group.
Based on data from the previous cancer pain study (A4091003), and not accounting for the 
assessment of futility and efficacy at the interim analysis, a sample size of approximately 
72 subjects per treatment group is required to achieve 85% power to demonstrate statistical 
significance (using the 2-sided 5% significance level), in the treatment comparison of 
tanezumab 20 mg + opioid versus placebo + opioid.  Taking into account for the assessment 
of non-binding futility and efficacy at the interim analysis, the same sample size is expected 
to achieve 80 to 85% power.    
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 be 
asked to review all joint-related safety events resulting in total joint replacement and/or 
discontinuation from the study as well as adverse events reported as osteonecrosis, rapidly 
progressive osteoarthritis, or other events suggestive of abnormal joint destruction.  The 
Adjudication Committee will have written operating procedures and a Charter, including a 
specific description of the scope of their responsibilities.
EXTERNAL 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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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 management of cancer pain.
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.6,7  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, particularly in states of allodynia and 
hypersensitivity, following a variety of insults such as Freund’s adjuvant, carrageenan,
surgical incision or administration of cytokines.7,8  Together these observations suggest that 
NGF may play a role in pain secondary to inflammation or injury.
1.2.2. Description of Investigational Product
Tanezumab is a humanized immunoglobulin G Type 2 (IgG2) monoclonal antibody, derived 
from a murine precursor 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.9,10  Tanezumab is highly potent in sequestering NGF and preventing interaction 
with the trkA or p75 receptors.2
1.2.3. Overview of Bone Metastasis and Metastatic Bone Pain
With improved medical treatment of many cancers, patients are living longer, which places 
them at increased risk to develop metastatic disease.  The skeleton is the third most common 
target of metastatic cancer and can be the one of the earliest sites affected.11
Cancers of the breast and prostate are particularly likely to spread to bone; about 70% of 
patients who die from these diseases have evidence of skeletal involvement at autopsy.  
Carcinomas of the thyroid, kidney, and bronchus also often cause bone metastasis with a 
postmortem incidence of 30% to 40%, but, by contrast, tumors of the gastrointestinal tract do 
so rarely, affecting only about 5% of patients dying from these malignancies.  Given the high 
prevalence of carcinomas of the breast, prostate, and lung, it is estimated that these cancers 
probably account for more than 80% of cases of metastatic bone disease.12
For many patients, metastatic bone cancer is a chronic condition, with survival from the time 
of diagnosis varying significantly among the various tumor types.  For bone metastasis from 
prostate and breast and in multiple myeloma, median survival time from diagnosis is 
measurable in years.  For advanced lung cancer, it is usually measured in months.13


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Pain associated with cancer is a substantial problem that negatively impacts patients’ quality 
of life, especially as emerging therapies directed against the underlying cancer have begun to 
prolong patient survival.  While pain can result from a number of causes, bone metastasis is 
the most common cause of cancer pain, occurring in 60 to 84% of patients14,15  More than 
70% of patients with bone metastasis report moderate to severe pain that has a significant 
impact on their functional status and quality of life.14,16,17
Treatment of bone metastasis is primarily palliative, in order to relieve pain, prevent 
development of pathological fractures and improve mobility and function.18,19  Conventional 
treatment uses a multidisciplinary approach including local radiotherapy to the painful area 
along with systemic treatment (hormone therapy or chemotherapy or radioisotopes) and 
supportive care such as analgesic therapy, corticosteroids and bisphosphonates.20 21  
Unfortunately, chronic pain resulting from bone metastasis is relatively resistant to 
analgesics; therefore, its management remains a challenge for clinicians.16,18
The basic approach to cancer pain treatment was designed by the World Health Organization 
(WHO) in 198622 and was subsequently revised in 1996.23  This approach uses a 3-step 
analgesic ladder in which patients begin treatment with non-opioids and move up the ladder 
to mild opioids and finally to strong opioids if their pain is not sufficiently controlled by 
analgesic treatments in the first step(s) of the ladder.  Since the initial WHO publication, 
other groups have issued guidelines for management of cancer.24,25,26,27  Overall there has 
been increasing use of opioids for management of cancer pain and opioids remain the 
mainstay for treatment of moderate to severe cancer pain.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer-related bone pain has 
been questioned since the evidence in the medical literature is poor.  In addition, there is a 
possibility that NSAIDs and cyclooxygenase (COX)-2 inhibitors could affect bone health by 
inhibiting COX enzymes which reduce synthesis of prostaglandins.18  
Recent investigations have shown that opioids may impair bone metabolism and chronic 
opioid users have an increased risk of fractures.18,28  In addition, recent publications seem to 
hint that opioids may have a possible role in tumor progression.29  
Despite the widespread use of opioids, results of a recent systematic review current literature 
for randomized controlled trials of opioids for management of cancer pain noted the level of 
evidence for pain relief was only fair for transdermal fentanyl and was poor for morphine, 
tramadol, oxycodone, methadone and codeine.30 A 10-year validation study of the World 
Health Organization analgesic ladder in 199531 suggested that 76% of patients could achieve 
good pain relief using the principles of the ladder, a further 12% achieved satisfactory 
efficacy and 12% had inadequate efficacy.  Unfortunately, subsequent studies suggest that 
these results are not achieved in clinical practice and that much cancer pain continues to be 
poorly controlled.32  
The issues described above support the need for better treatments for patients suffering from 
metastatic bone pain.


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1.2.4. Overview of Clinical Studies
A total of 32 clinical studies involving over 11,000 subjects have been conducted with 
tanezumab as of September 2013.  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 IV (intravenous) or SC administration for the relief of the signs and 
symptoms of osteoarthritis alone or in combination with 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.2  
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 brochure,2 in publically-available documents prepared for the United 
States (US) Food and Drug Administration (FDA) Arthritis Advisory Committee meeting on 
March 12, 20123,4,5 and in external publications of individual studies.37,38,39,40,41,42
1.2.4.1. Efficacy in Cancer Pain Studies
1.2.4.1.1. Study A4091003
The efficacy of tanezumab in subjects with painful bone metastasis has been evaluated in 
Study A4091003, which was a randomized, double-blind, placebo-controlled, parallel group 
study in subjects with cancer pain due to bone metastasis who were receiving background 
treatment with opioids.43  In Study A4091003, a total of 59 subjects were treated with either a 
single IV dose of tanezumab 10 mg (N=29) or placebo (N=30). 
A positive outcome for the primary efficacy endpoint for Study A4091003 (ie, the change 
from Baseline to Week 6 in the daily average pain intensity) was not achieved.  Although the 
mean decrease from Baseline in the tanezumab 10 mg IV treatment group was numerically 
greater than that for the placebo treatment group, the difference was estimated to be -0.26 
(95% CI: -1.18, 0.66) and was not statistically significant (p=0.569).
Post-hoc subgroup analyses indicated that subjects with high Baseline pain scores (>5) in 
combination with low total weekly opioid use (60.5 morphine equivalents) may yield the 
largest treatment difference from placebo.  In this subgroup, the estimated treatment 
difference between tanezumab 10 mg and placebo was -2.72 (95% CI: -5.11, -0.33), and this 
difference was statistically significant (p=0.027).  In another subgroup analysis, subjects with 
Baseline pain scores >5 (irrespective of Baseline opioid use) had an estimated treatment 
difference between tanezumab 10 mg and placebo of -1.67 (95% CI: -3.41, 0.08) with 
p=0.061 when using Baseline Observation Carried Forward (BOCF) imputation at Week 8.  
Refer to the tanezumab investigator brochure for additional details.2


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1.2.4.1.2. Study A4091029
Study A4091029 was a safety extension study designed to investigate the safety and efficacy 
of tanezumab 10 mg intravenous (IV) in subjects with pain due to bone metastasis who had 
been randomized and treated in the double-blind parent Study A4091003 and who wished to 
receive open-label tanezumab therapy. 
The change from Study A4091003 Baseline in average pain was maintained up to Week 24 
in A4091029 for all subjects.  For the 6 subjects who received placebo in Study A4091003, 
the average pain score in A4091029 subsequently worsened from Week 24 to Week 40 (back 
to the Study A4091003 Baseline pain level).  However for subjects who received tanezumab 
10 mg in Study A4091003, the improvement in average pain was further maintained to 
Week 40 of Study A4091029.44
1.2.4.2. Safety in Cancer Pain Studies
1.2.4.2.1. Study A4091003
In Study A4091003 (N=59), the incidence of subjects with adverse events was comparable 
between the tanezumab 10 mg treatment group (62.1%) and in the placebo treatment group 
(60.0%).  One subject in the tanezumab 10 mg treatment group (disease progression; 3.3%) 
and one subject in the placebo treatment group (embolic stroke; 3.4%) discontinued from the 
study due to an adverse event.  The incidence of serious adverse events was higher in the 
tanezumab 10 mg treatment group (24.1%) compared with the placebo treatment group 
(13.3%).  Three subjects in total died during the study, 2 (6.9%) in tanezumab 10 mg and 
1 (3.3%) in placebo treated subjects.  The causes of death for subjects in the tanezumab 
10 mg treatment group were disease progression and acute cardiac failure and for the subject 
in the placebo treatment group the cause of death was disease progression.  None of the 
deaths were considered by the investigator to be related to study medication.  Refer to the 
tanezumab Investigator Brochure for additional details.2
1.2.4.2.2. Study A4091029
In A4091029,44 (N=41) the incidence of adverse events was comparable to (though 
marginally greater than) the adverse event incidence for tanezumab-treated subjects in the 
parent Study A4091003.43  Nausea was the most common adverse event and is a well-known 
side effect of opiates which most of the subjects were taking as background analgesia and 
thus that adverse event was likely caused by the opiates.  In addition, the incidence of serious 
adverse events (including death) and discontinuations due to adverse events was greater in 
A4091029 than in A4091003, and reflected the progression of the underlying cancer. In 
A4091029 there were no reported events of osteonecrosis or total joint replacements.44  Refer 
to the tanezumab Investigator Brochure for additional details.2
1.2.5. Dose Selection Rationale
In Study A4091003, tanezumab 10 mg administered as a single intravenous infusion in 
subjects with painful bone metastasis despite background opioid treatment did not 
demonstrate a significant improvement versus placebo in average daily pain scores at the 
Week 6 primary endpoint.  However, there was evidence of efficacy for tanezumab 10 mg in 
post-hoc subgroup analyses of subjects with Baseline pain scores >5 and Baseline opioid use 


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below the median value for the study (60 mg/day in morphine equivalents).  Also, in subjects 
with Baseline pain scores >5 irrespective of Baseline opioid use, a meaningful treatment 
difference was demonstrated, indicating that it may be possible to demonstrate tanezumab 
efficacy in subjects with painful bone metastasis under different study conditions. 
Within the tanezumab program, there has been a demonstration that different doses of 
tanezumab may be needed for optimal efficacy, depending on the pain condition under study.  
For example, tanezumab 10 mg dose levels were needed to achieve comparable levels of 
efficacy in chronic lower back pain study A4091012 vs 5 mg in Phase 3 osteoarthritis 
studies.  In a small proof of concept study in subjects with painful diabetic neuropathy 
(A4091031), a single subcutaneous injection of tanezumab 20 mg demonstrated efficacy vs 
placebo at Week 8. There is no evidence that more frequent dosing would be beneficial in 
cancer pain compared to other disease states.
The tanezumab 20 mg every 8 weeks dose regimen was studied in Study A4091012.  
Although it was associated with higher frequencies of adverse events and withdrawals due to 
adverse events than the lower tanezumab doses, the incidence of serious adverse events was 
comparable to placebo for all tanezumab doses and tanezumab was considered to be 
generally safe and well-tolerated in this study.  In Study A4091031, tanezumab 20 mg was 
considered to be generally safe and well tolerated.
Based on the results of the studies noted above there has been precedence for efficacy with 
the tanezumab 20 mg dose.  Because the performance of tanezumab 10 mg in A4091003 was 
not convincingly robust, the current study will explore the efficacy of tanezumab 20 mg in 
the population of subjects with painful bone metastasis despite background opioid treatment.  
Although the primary endpoint is at Week 8, this study has a 24-week double-blind treatment 
duration to evaluate safety and maintenance of efficacy during 6 months of treatment in this 
study population.
1.2.6. 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.45  In this study 
SC placebo is used to blind investigators and subjects as to whether or not SC tanezumab has 
been administered.  Although minimal analgesic efficacy is expected from placebo treatment, 
some placebo-treated subjects may experience a beneficial effect on well-being.  Background 
opioid medication (both around the clock [ATC] and immediate release [IR] opioids) will be 
provided to all subjects to maintain Baseline pain relief throughout the study.


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1.2.7. Rationale for Opioid Background
Unfortunately, finding effective analgesia for cancer pain due to bone metastasis is 
challenging and subjects with bone metastasis frequently require opioid treatment once 
non-opioids have failed to provide adequate pain relief.  In this clinical setting, the use of 
background opioids allows a comparison of tanezumab vs placebo in a manner that allows 
determination of efficacy and safety of tanezumab in subjects with metastatic bone pain.
1.2.8. Rationale for Population
Bone tissue is richly innervated by NGF- responsive neurons.  More than 80% of all sensory 
nerve fibers that innervate the bone are trkA-positive, whereas only 30% of the sensory nerve 
fibers innervating skin are trkA-positive.33
In addition, studies of prostate tumor cells injected into bone suggest NGF is pathologically 
elevated in these tumors and that the source of increased NGF release is not tumor cells but 
rather tumor-associated stromal, inflammatory and immune cells, which frequently account 
for 10–80% of the cells comprising the tumor mass.  NGF released by these cells can induce 
a 10- to 70-fold increase in density of trkA positive sensory nerve fibers in the bone 
marrow.33  Thus, in the presence of NGF-releasing tumor, there is a further enrichment of 
NGF-responsive neurons in bone.
Preclinical studies of the murine precursor antibody to tanezumab (MAb 911) in both 
prostate and sarcoma models of bone cancer showed the anti-NGF antibody was more 
effective than or equivalent to acute morphine therapy in reducing bone cancer pain-related 
behavior in mice.34,35
In summary, the rich innervation of bone by NGF-responsive neurons, pathologic elevation 
of NGF and NGF-responsive neurons in bone metastasis, preclinical studies demonstrating 
metastatic bone pain efficacy with MAb 911 and tanezumab clinical study results together 
provide the rationale to study tanezumab in subjects with metastatic bone pain.
As the pain generated by bone metastasis is thought to have the same pathophysiologic 
mechanism,36 the potential effect of tanezumab on metastatic bone pain should be similar, 
regardless of underlying tumor type.
1.2.9. Benefit vs Risk for the Study Population
As noted in Sections 1.2.4.1 and 1.2.8, there is rationale for studying tanezumab in patients 
with painful bone metastasis based on the biology of bone innervation and bone metastasis, 
preclinical studies in animals with bone metastasis in which anti-NGF treatment 
demonstrated analgesia and two Phase 2 clinical tanezumab studies in subjects with painful 
bone metastasis.  The population selected for this study is subjects with moderate to severe 
cancer pain predominantly due to bone metastasis who have had inadequate pain relief with 
opioids and who are seeking effective treatment options. 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 cancer pain that is more severe or treatment-resistant and who 
have limited treatment options remaining.


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In Study A4091003, there was some evidence of efficacy of tanezumab 10 mg in this 
population, but the pre-specified primary efficacy endpoint was not achieved.  Therefore, in 
this study, a higher dose arm (tanezumab 20 mg) is being studied, and is considered to be 
generally safe and well-tolerated (see Section 1.2.5.).  
In order to reduce risk in this population, subjects with symptomatic osteoarthritis of the 
knees, hips or shoulders will be excluded from participation.  Additional risk mitigation 
measures that have been developed as an outgrowth of the joint-related safety analyses to 
reduce the risk of rapidly progressive osteoarthritis are included in this study, along with 
additional assessments of sympathetic nervous system safety.
In addition, exclusion of subjects with poor Eastern Cooperative Oncology Group (ECOG) 
Performance Status47  (used as a surrogate measure of tumor aggressiveness), or safety 
laboratory findings, supports appropriate benefit-risk in this patient population and across 
tumor types. 
Complete information for tanezumab may be found in the Single Reference Safety Document 
(SRSD), which for this study is the Investigator Brochure.2
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective

Demonstrate superior analgesic efficacy of tanezumab 20 mg SC versus matching
placebo SC at Week 8 in subjects, with cancer pain predominantly due to bone 
metastasis, receiving background opioid therapy. 
2.1.2. Secondary Objective

Evaluate the safety of tanezumab 20 mg SC versus matching placebo SC in subjects,
with cancer pain predominantly due to bone metastasis, receiving background opioid 
therapy. 
2.2. Endpoints
2.2.1. Primary Endpoint

Change from Baseline to Week 8 in the daily average pain intensity in the index bone 
metastasis cancer pain site.
2.2.2. Secondary Endpoints
2.2.2.1. Efficacy Measures

Change from Baseline to Weeks 1, 2, 4, 6, 12, 16 and 24 in the daily average pain 
intensity NRS score in the index bone metastasis cancer pain site.

Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily worst pain 
intensity NRS score in the index bone metastasis cancer pain site.


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•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the weekly average 
pain intensity NRS score in non-index cancer pain sites.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the weekly worst pain 
intensity NRS score in non-index cancer pain sites.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily average pain 
intensity NRS score in the non-index visceral cancer pain sites.
•
Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily worst pain 
intensity NRS score in the non-index visceral cancer pain site.
 
 
•
Response as defined by a ≥30%, ≥50%, ≥70%, and ≥90% reduction from Baseline in
the daily average and daily worst pain intensity NRS score in the index bone 
metastasis cancer pain site at Weeks 1, 2, 4, 6, 8, 12, 16 and 24.
•
Change from Baseline in Patient’s Global Assessment of Cancer Pain at Weeks 2, 4, 
8, 16 and 24. 
•
Response defined as an improvement of ≥2 points in Patient's Global Assessment of 
Cancer Pain at Weeks 2, 4, 8, 16 and 24. 
 
 
2.2.2.2. Opioid Use and Opioid Adverse Effects Measures
•
Average daily total opioid consumption (in mg of morphine equivalent doses) at 
Weeks 1, 2, 4, 6, 8, 12, 16 and 24.
•
Average number of doses of rescue medication required per week at Weeks 1, 2, 4, 6, 
8, 12, 16 and 24.
•
Change from Baseline in the weekly Opioid-Related Symptom Distress Scale at 
Weeks 2, 4, 8, 16, and 24.
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2.2.2.3. Safety Measures
•
Adverse events.
•
Standard safety assessments (safety laboratory testing [chemistry, hematology], 
sitting vital signs, ECG [12-lead]).
•
Orthostatic (supine/standing) blood pressure assessment.
•
Weight measurements.
•
Physical examinations.
•
Joint safety adjudication outcomes.
•
Total joint replacements.
•
Anti-drug antibody (ADA) assessments.
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3. STUDY DESIGN
Figure 1.
Study Design
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group 
Phase 3 study in cancer subjects requiring treatment with background opioids for pain due to 
bone metastasis.  
The protocol was initially designed to include 3 treatment groups (tanezumab 20 mg SC, 
tanezumab 10 mg SC, and placebo), and was amended (Amendment 3) after study start to 
discontinue the tanezumab 10 mg dose arm. It is estimated that approximately 11 subjects in 
total were randomized to receive tanezumab 10 mg SC prior to implementation of 
Amendment 3.
Following implementation of Amendment 3, subjects were randomized in a 1:1 ratio 
(planned 85 subjects/arm) to one of two treatment arms: tanezumab 20 mg SC or matching 
placebo SC, each administered in addition to background opioids. Subjects who had been 
randomized to the 10 mg dose treatment arm and who were in the double-blind treatment 
period at the time of implementation of Amendment 3 were administered 20 mg for any 
remaining doses.
In protocol Amendment 4, the sample size has been reduced.  A total of 155 subjects will be 
randomized.  This comprises 144 subjects (72/treatment arm) randomized to receive 
tanezumab 20 mg SC or matching placebo SC plus an estimated 11 subjects previously 
randomized to receive tanezumab 10 mg SC. 
Subjects will receive a total of 3 SC injections, separated by 8 weeks in addition to 
background opioids administered throughout the study: Treatment groups will include:  
1. Placebo SC (matching tanezumab SC) in addition to background opioid therapy. 


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2. Tanezumab 20 mg SC in addition to background opioid therapy.
The study is designed with a post-randomization duration of 48 weeks and will consist of 
three periods: Pre-Treatment (up to 37 days), Double-Blind Treatment (24 weeks) and 
6-month Safety Follow-Up (24 weeks).  The Pre-Treatment Period will include a Screening 
Period (lasting up to 32 days) with washout of prohibited study medication and stabilization 
of background opioid regimen prior to a 5-day Baseline Assessment Period.  
Confirmation of radiographic eligibility by a central radiologist based on protocol-defined
x-rays will take place during the Pre-Treatment period.  The study is designed such that post 
randomization, contacts with subjects are made approximately every 4 weeks through the end 
of the Safety Follow-Up period.  The Double-Blind Treatment Period consists of 6 in-clinic 
visits (including 3 dosing visits) and 2 phone contact visits.  Because of the long half-life of 
tanezumab (approximately 21 days), the End of Double-Blind Treatment visit takes place
8 weeks after the last dose of SC medication is administered.  The Safety Follow-Up period 
begins with the completion of the End of Treatment visit and includes 4 phone contacts and 
2 additional in-clinic visits, with the exception of sites in Japan where 3 phone contacts and 3 
additional in-clinic visits will occur.  Refer to Section 6 for the procedures to be performed 
during the study.
Changes from Baseline in pain intensity in the index bone metastasis site and non-index 
cancer pain sites, along with other measures of efficacy and safety will address the primary 
and secondary study objectives. Refer to Section 7 for descriptions of the efficacy and safety 
assessments to be performed during the study.
Stratification variables are (i) tumor aggressiveness (assessed by Eastern Cooperative Group 
[ECOG] performance status and (ii) presence/absence of concomitant anticancer treatment 
(eg, chemotherapy or hormonal therapy or anti-hormonal therapy).  Stratification by ECOG 
performance status will balance treatment groups with respect to tumor aggressiveness to 
minimize imbalances in tumor-specific safety findings.  Stratification based on 
presence/absence of concomitant anticancer treatment will control for potential confounding 
effects of anticancer treatment on efficacy.  Refer to Section 9 for details regarding sample 
size determination and stratification. 
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 this study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
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:


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1. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
2. Subject is willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures.
3. Male or female, 18 years of age.
4. Weight is 40 kg at Screening;
5. Subject has cancer diagnosed as having metastasized to bone or has multiple 
myeloma.
6. Imaging confirmation of bone metastasis at Screening or within 120 days prior to the 
Screening visit according to local standard of care (eg, via bone scan, magnetic 
resonance imaging (MRI), computed tomography (CT) scan, or positron emission 
tomography-computed tomography (PET-CT) scan). 
7. Subject is expected to require daily opioid medication throughout the course of the 
study.
8. Subject willing to not use prohibited medications (including NSAIDs) throughout the 
duration of the study (refer to Section 5.8.1 for details regarding prohibited 
concomitant medications).
9. Average Pain Score 5 at Screening for the index bone metastasis cancer pain site
(refer to Section 6.1.1).
10. Patient’s Global Assessment of Cancer Pain must be “fair”, “poor” or “very poor” at 
Screening.
11. Eastern Cooperative Oncology Group (ECOG) Performance Status Score47 of 0, 1, or 
2 at Screening (refer to Appendix 3). 
12. Adequate bone marrow function at Screening (confirmed by a repeat test if needed), 
as defined by:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9.0 g/dL.
13. Adequate renal function at Screening (confirmed by a repeat test if needed), as 
defined by:
a.
Estimated glomerular filtration rate 30 mL/min as calculated by the Central 
Laboratory, and 


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b. Urinary protein <2+ by urine dipstick performed by the Central Laboratory.  If 
dipstick is 2+, then 24 hour urinary protein <2 g per 24 hours.
14. Adequate liver function at Screening (confirmed by a repeat test if needed), as 
defined by:
a.
Total serum bilirubin 1.5 x upper limit of normal (ULN); 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
2.5 x ULN (5.0 x ULN if there is tumor involvement in the liver); 
c.
Alkaline phosphatase 5 x ULN.
15. International Normalized Ratio (INR) or prothrombin time (PT) <1.5 x ULN at 
Screening (confirmed by a repeat test if needed), provided the subject is not being 
treated with anticoagulant medication.  For subjects being treated with anticoagulants, 
the INR should be within the range recommended for the specific clinical indication.
16. 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. 
17. Female subjects who are not of childbearing potential (ie, must meet at least one of 
the following criteria): 

Have undergone documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Achieved postmenopausal 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.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. The subject’s pain is related to an oncologic emergency such as bowel 
obstruction/perforation, spinal cord compression, epidural metastasis, or fracture or 
impending fracture of weight bearing bone.
2. The subject has brain metastasis or leptomeningeal metastasis.
3. Presence of hypercalcemia at Screening (confirmed by a repeat test if needed), 
defined as albumin-corrected serum calcium concentration of 12 mg/dL.  If 


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measured albumin is <4.5 gm/dL, corrected calcium (mg/dL) = measured calcium 
(mg/dL) + 0.8 x (4.5 gm/dL-measured albumin in gm/dL).
4. The subject’s pain is primarily classified as neuropathic, visceral or unknown in 
nature, has resulted from prior cancer therapy, is due to infection or is otherwise not 
predominantly related to a bone metastasis.
5. Systemic treatment for the primary malignancy or bone metastasis, including 
chemotherapy, hormonal treatment (eg, gonadotropin-releasing hormone (GnRH)
agonists or antagonists), bisphosphonates and denosumab started within 30 days of 
the first day of the Baseline Assessment Period.
Chemotherapies associated with peripheral neuropathy (ie, paclitaxel, docetaxel, 
oxaliplatin, cisplatin, vincristine, thalidomide or bortezomib48), are prohibited during 
study period from 30 days prior to the first day of the Baseline Assessment Period to 
Week 48.
6. Receipt of radiopharmaceutical treatment or radiotherapy for treatment of bone 
metastasis within 30 days of the first day of the Baseline Assessment Period.  
Subjects who are candidates for external beam radiotherapy for painful bone 
metastasis should not be considered for this study in lieu of external beam 
radiotherapy.
7. Initiation or unstable dose of concurrent adjuvant analgesics such as single-agent 
acetaminophen (paracetamol), serotonin norepinephrine reuptake inhibitors (SNRI),  
tricyclic antidepressants, anticonvulsant medication, corticosteroids, or muscle 
relaxants within 30 days of the start of the Baseline Assessment Period.
8. Diagnosis of osteoarthritis of the knee or hip as defined by the American College of 
Rheumatology (ACR) combined clinical and radiographic criteria (refer to
Appendix 4); Radiographic criteria will be assessed by the Central Reader.
9. Subjects with symptoms and radiographic findings (eg, joint space narrowing, 
osteophytes) consistent with osteoarthritis in the shoulder.
10. History of significant trauma or surgery to a major joint (eg, hip, knee or shoulder) 
within one year prior to Screening.
11. A history of osteonecrosis or osteoporotic fracture (ie, a subject with a history of 
osteoporosis and a minimally traumatic or atraumatic fracture). 
12. Radiographic (x-ray) 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 fracture, 4) spontaneous osteonecrosis of 
the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.  
NOTE: 


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
Necrosis of the bone secondary to radiotherapy (ie, osteoradionecrosis) and in 
relation to metastatic disease of the bone (ie, involving the tumor-bone interface) 
is allowable.  

Vertebral pathologic fracture with less than 50% vertebral body destruction and 
no spinal canal compromise is allowable.

A treated (eg, fixation) and resolved pathologic fracture of a non-weight bearing 
bone (eg, humerus) is allowable if not involving a major joint.
13. Signs and symptoms of clinically significant cardiac disease including but not limited 
to:
a.
Ischemic cardiac disease (eg, unstable angina, myocardial infarction) in the 
6 months prior to Screening; 
b. Surgery or stent placement for coronary artery disease in the 6 months prior to 
Screening;
c.
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; 
d. Resting tachycardia (heart rate 120) or resting bradycardia (heart rate 45) on 
ECG at Screening; 
e.
Any other cardiovascular illness that in the opinion of the investigator would 
render a subject unsuitable to participate in the study. 
14. Subjects who have evidence of orthostatic hypotension based upon replicate 
orthostatic blood pressure measurements at Screening or at Baseline prior to 
randomization (refer to Section 7.3.7).  If orthostatic blood pressure change cannot be 
determined (eg, unable to establish a stable supine systolic and diastolic blood 
pressure) that subject is not eligible for the study.
15. Diagnosis of a transient ischemic attack in the 6 months prior to Screening or 
diagnosis of stroke with residual deficits (eg, aphasia, substantial motor or sensory 
deficits), that would preclude completion of required study activities.
16. History, diagnosis, or signs and symptoms of clinically significant neurological 
disease including but not limited to:
a.
Alzheimer’s disease or other types of dementia;
b. Clinically significant head trauma within the past year;
c.
Peripheral neuropathy or autonomic neuropathy; (Note: Subjects with a stable, 
chemotherapy-induced peripheral polyneuropathy over the 6 months prior to 


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Screening will be considered eligible provided they are no longer being treated 
with chemotherapy associated with peripheral neuropathy (ie, paclitaxel, 
docetaxel, oxaliplatin, cisplatin, vincristine, thalidomide or bortezomib48).  
Subjects with confirmed cancer-induced neuropathy or paraneoplastic neuropathy 
should be excluded. 
d. Epilepsy or seizure disorder with seizure within 2 years of Screening;
e.
Myopathy;
f.
Brain or leptomeningeal metastasis.
18. Subjects with a past history of carpal tunnel syndrome (CTS) with signs or symptoms 
of CTS in the one year prior to Screening.
19. The subject has a history of significant alcohol, analgesic, or narcotic substance abuse 
within the six months prior to Screening.
20. Planned surgical procedure during the duration of the study.
21. Subjects considered unfit for surgery, defined as Grade >3 on the American Society 
of Anesthesiologists (ASA) physical classification system for surgery (refer to
Appendix 6) or subjects who would not be willing to undergo joint replacement 
surgery if required.
22. Subject has known hypersensitivity to opioids or an underlying medical condition 
contraindicating opioid use.
23. Subject has a history of allergic or anaphylactic reaction to a therapeutic or diagnostic 
monoclonal antibody or IgG-fusion protein.
24. Previous exposure to exogenous nerve growth factor or to an anti-nerve growth factor 
antibody.
25. Presence of drugs of abuse (except for opioids or cannabinoids, as allowed per 
protocol), prescription medications without a valid prescription or other illegal drugs 
in the urine toxicology screen obtained at Screening.
26. Positive Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) tests at 
Screening indicative of current infection.
27. Subjects who are investigational site staff members directly involved in the conduct 
of the trial 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.
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28. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
30 days (or 90 days for investigational biologics) before Baseline Assessment Period 
and/or during study participation.
29. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential who are unwilling or unable to use one (1) highly 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.
30. 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
The following criteria must be met to be eligible for randomization:
1. There have been 3 IR rescue episodes per day for breakthrough pain from Day -3 to 
Day -1 during the Baseline Assessment Period.
2. The mean value of the average daily pain scores for the index bone metastasis cancer 
pain site from Day -5 to Day -1 during the Baseline Assessment Period must be 5;
Subjects must complete interactive response technology (IRT) pain assessments on at 
least 3 of the 5 days during the Baseline Assessment Period.
3. There are no intolerable opioid side effects in the judgment of the subject from Day -3 to 
Day -1 during the Baseline Assessment Period.
4. The Patient’s Global Assessment of Cancer Pain must be “fair”, “poor” or “very poor” at 
the Baseline Visit.
5. Radiologic eligibility must have been confirmed by the Central Reader during the 
Screening Period, Baseline Assessment Period or at the Baseline Visit.
4.4. Lifestyle Guidelines
Subjects should maintain their normal daily routine, including stable doses of permitted 
medications and exercise program.  Subjects are also permitted to 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 the surgery whenever possible.  Subjects 
who undergo joint replacement or arthroplasty will be discontinued from study treatment and 
followed in a substudy as described in Appendix 16.


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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 oneof 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;49
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.
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the 
study treatments) may obviate the need for contraception ONLY if this is the 
preferred and usual lifestyle of the subject.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the study manual.
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 number, 
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 
subjects 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 only used 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 
study team for advice on medical questions or problems that may arise during the study.  The 
contact center 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).




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only be broken 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 report form (CRF).
5.3. Subject Compliance
All doses of SC investigational product will be administered by the appropriately designated 
study staff at the investigational site.  Tanezumab SC or matching placebo SC dosing will be 
recorded on the appropriate CRF.  Because tanezumab or matching placebo will be 
administered by site staff, subject compliance with SC treatment is not anticipated to be an 
issue. 
Compliance with background opioid therapy from Day 1 to Week 8 will be calculated within 
the IRT for one regimen. If more than one concomitant opioid is used, manual calculation by 
the sponsor will be undertaken to determine background opioid therapy dose.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Tanezumab and matching placebo for tanezumab will be supplied by the sponsor or designee.
Tanezumab drug product and matching placebo for SC administration will be supplied in a 
single-use pre-filled syringe (PFS) that should be stored refrigerated at 2-8C. 
5.4.1.1. Tanezumab
Tanezumab 20 mg is presented as a sterile solution for subcutaneous administration, 
packaged in a glass PFS.  Each PFS contains a sufficient amount of tanezumab to provide the 
intended dose of drug at a concentration of 20 mg/mL.  Each PFS is packaged in an 
individual carton.  Each PFS has a unique container number.
Tanezumab 10 mg is presented as a sterile solution for subcutaneous administration, 
packaged in a glass PFS.  Each PFS contains a sufficient amount of tanezumab to provide the 
intended dose of drug at a concentration of 10 mg/mL.  Each PFS is packaged in an 
individual carton.  Each PFS has a unique container number.
5.4.1.2. Placebo for Tanezumab
Placebo for tanezumab is presented as a sterile solution for subcutaneous administration, 
packaged in a matching glass PFS.  Each PFS is packaged in an individual carton.  Each PFS
has a unique container number.
Only tanezumab 20 mg and matching placebo for tanezumab will be supplied following 
implementation of protocol Amendment 3. Subjects randomized to the 10 mg dose treatment 
arm and who are in the double-blind treatment period at the time of implementation of 
Amendment 3 will be administered 20 mg for any remaining doses. Subjects who are 
randomized following implementation of protocol Amendment 3 will receive either 
tanezumab 20 mg or matching placebo.


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5.4.2. Preparation and Dispensing
See the Drug Administration Instructions (DAI) for instructions on how to prepare 
tanezumab SC and matching 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.
5.5. 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 in facilities which can handle allergic reactions.  All subjects will receive 1 mL of study 
medication 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. 
o Subcutaneous injection administered via any route other than subcutaneous (i.e. 
intramuscular, intravenous), is a medication error.
o Syringe (medical device) malfunction is a medication error (e.g.syringe/plunger breaks 
during administration).
Refer to section 8.4 Medication Errors for additional information.
Full dosage and administration instructions will be provided in the Pharmacist Manual.  All 
local/state/federal laws must be complied with in assigning administration duties.
5.6. Investigational Product Storage 
The Pharmacy Manual will provide complete details on storage and handling.
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational 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.  Tanezumab and 
matching placebo will be shipped and stored at a temperature between 2and 8C and 
protected from light. 
Storage conditions stated in the single reference safety document (ie, the Investigator 
Brochure) may be superseded by the storage conditions stated in the 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 


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applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active evaluation for 
excursions should be available. The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations. 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 labeled storage 
conditions, 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 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.
The dispensing or administration of expired, quarantined, or improperly stored medication 
without prior approval from Pfizer Pharmaceutical Sciences (e.g. investigational product 
storage temperature excursion where subject was dosed with unacceptable drug per 
Pharmaceutical Sciences) is a medication error.
Refer to section 8.4 Medication Errors for additional information.
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
5.7. Investigational Product Accountability 
The investigator or designated personnel must maintain adequate records documenting the 
receipt, use, loss, or other disposition of the drug supplies. 
5.7.1. 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.
5.8. Concomitant Treatment(s)
5.8.1. Concomitant Treatment Prohibited During the Study
5.8.1.1. Prohibited Background Opioid Treatment
The following opioids are not permitted in this study:


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butorphanol*
meperidine*
nalbuphine*
pentazocine*
propoxyphene **
opioids in combination with non-opioids (such as acetaminophen or 
NSAIDs)***
* Use not recommended by NCCN Guidelines27; 
** Withdrawn from some major markets due to safety concerns
*** Opioids in combination with acetaminophen may be permitted as standard of care analgesia 
from Week 8 onwards. Opioid-NSAID combinations are prohibited throughout the study until 
at least 16 weeks have passed since the last dose of study medication (Week 32 or Early 
Termination Visit 2).
Permitted background opioid regimens are described in Section 5.8.2.1.
5.8.1.2. Prohibited Non-opioid Analgesics
The use of analgesics (other than background opioids and permitted uses described in 
Sections 5.8.2) is prohibited throughout the study beginning 48 hours (or 5 half-lives, 
whichever is longer) prior to the start of the Baseline Assessment Period and ending at 
Week 8.  
Use of NSAIDs and COX-2 selective inhibitors, both prescription or over-the-counter (OTC) 
is prohibited through Week 32 except for occasional use.  Management of subjects’ NSAID 
use is described below (Section 5.8.1.2.1). Intra-articular injection of corticosteroids to any 
major joint within 30 days prior to the Baseline Assessment Period through Week 32 is 
prohibited.  
Unless the following drugs were started at least 30 days prior to the first day of the Baseline 
Assessment Period and are maintained at a stable dose, use of concurrent adjuvant analgesics 
such as single-agent acetaminophen (paracetamol), serotonin norepinephrine reuptake 
inhibitors (SNRI), tricyclic antidepressants, anticonvulsant medication, corticosteroids, or 
muscle relaxants is prohibited through Week 8. 
Refer to Appendix 7: Half-Lives of NSAIDs and Other Analgesics, for a detailed washout 
schedule for analgesic medications.  Sites must consult product labeling and conduct a taper 
according to the product instructions if a taper is required. 
5.8.1.2.1. Guidelines for Management of Subjects Reporting NSAID Use
Limited concomitant use of prescription or OTC NSAIDs may be allowed on an occasional 
basis for self-limiting conditions not related to cancer pain.  However, they must not be taken 
within 48 hours of a study visit where efficacy assessments are being collected.  Study 
management should be contacted for approval prior to use whenever possible, and all doses 
and days of use must be recorded on the concomitant analgesic CRF. 
NSAID use should not exceed a total of 36 days between Day 1 (Baseline) and Week 32 and
the aggregate usage of NSAIDs during any one dosing interval (defined as the period of 
8 weeks between 2 SC doses) should not exceed 10 days. 


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Subjects who report concomitant use of prescription or OTC NSAIDs during the study prior 
to Week 32 will be managed as per the following guidelines: 

Subjects who report concomitant use of NSAID should be interviewed by study site 
personnel to determine the reason for use and if the subject anticipates being able to 
comply with concomitant medication restrictions in the future.  Subjects who indicate 
they are taking NSAIDs because of insufficient cancer pain relief or who indicate that 
they cannot or will not be able to comply with concomitant medication restrictions 
will be withdrawn from study treatment and entered in the Early Termination 
Follow-Up period (refer to Section 6.4).

Subjects who reported greater than 10 days (aggregate total) of concomitant NSAID 
use (any dosage of NSAIDs) in a SC dosing interval and who after counseling report 
further concomitant NSAID use should be withdrawn from study treatment and 
entered in the Early Termination Follow-Up period (refer to Section 6.4).
After Week 32, there are no restrictions on NSAID use provided the NSAID dosing is 
prescribed according to its approved label.
Subjects will be instructed that many over-the-counter medications contain NSAIDs and to 
be aware of this during their selection of OTC medications.  Subjects who report concomitant 
NSAID use will be requested to provide details of the usage (dosage and reasons for use) 
which will be recorded in the appropriate concomitant medication case report form (CRF). 
5.8.1.3. Restrictions on Use of Treatments for Underlying Cancer or Bone Metastasis
Monoclonal antibodies used for the treatment of underlying cancer (eg, bevacizumab 
(Avastin), trastuzumab (Herceptin), panitumumab (Vectibix)) or bone metastasis (eg, 
denosumab (Prolia, Xgeva)) are generally permitted if ongoing at stable dose regimen at least 
30 days prior to the first day of the Baseline Assessment Period (see Section 5.8.2.3). 
However, monoclonal antibody therapies associated with clinically significant peripheral or 
autonomic neuropathy or joint-related adverse effects or those based on chimeric or murine 
antibodies (eg, cetuximab (Erbitux)) are prohibited within 90 days of the start of the Baseline 
Assessment Period and during the study until Week 32. Monoclonal antibody therapies 
which are not specifically listed as permitted (see Appendix 8) should be discussed with the 
study clinician on a case-by-case basis.
Small molecule inhibitors (eg, erlotinib (Tarceva), sunitinib (Sutent), lapatinib (Tykerb)) 
used in the treatment of underlying cancer or bone metastasis are permitted (except for 
bortezomib) if at a stable dose regimen at least 30 days prior to the first day of the Baseline 
Assessment Period. 
If during the double-blind treatment period prior to Week 8, the subject’s underlying cancer 
or bone metastasis progresses so as to require a new chemotherapy regimen, new 
concomitant bisphosphonates, new concomitant hormonal anti-cancer treatment, or initiation 
of radiotherapy to sites of bone metastasis, the subject should be withdrawn from study 
treatment (eg, due to disease progression) and entered in the Early Termination Follow-Up 
period (refer to Section 6.4). Between Week 8 to Week 32, if treatment for underlying cancer 


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or bone metastasis needs to be initiated or changed (refer to Section 5.8.2.3), the study 
clinician should be informed so that guidance may be provided as to whether the subject 
should be withdrawn from study treatment and entered in the Early Termination Follow-Up 
period. After the Week 32 visit, standard of care treatment may be prescribed as appropriate, 
without prior consultation with the study clinician.  
5.8.1.4. Other Prohibited Medications
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 
start of the Baseline Assessment Period will be allowed to continue their regimen.  
Cell/gene therapies, investigational therapies, or tumor necrosis factor alpha (TNF-)
inhibitors (eg, adalimumab, etanercept, infliximab) are generally prohibited and must not be
taken within 90 days prior to start of the Baseline Assessment Period or during the study until 
Week 32. For further guidance, refer to Appendix 8 or contact study monitor or study 
clinician.
Live attenuated vaccines must not have been taken within 90 days prior to the Baseline 
Assessment Period and are prohibited during the study.  FlumistInfluenza Virus Vaccine 
Live, Intranasal or other inhaled influenza vaccines (in regions where these vaccines are 
approved) is the only exception of a live attenuated vaccine that will be permitted during the 
study. 
5.8.2. Permitted During the Study
5.8.2.1. Background Opioid Treatment
The following oral or transdermal background opioid medications are permitted throughout 
the study:
buprenorphine
levorphanol
tapentadol
codeine
methadone
tramadol
fentanyl
morphine
hydrocodone
oxycodone
hydromorphone
oxymorphone
Tamper-resistant or opioid abuse-deterrent formulations (which may contain both an opioid 
agonist and an opioid antagonist) such as the following are permitted, for example:

Embeda [morphine ER + naltrexone].

Opana ER [oxymorphone ER with a crush-resistant matrix].

Remoxy [oxycodone ER in highly viscous liquid gelatin capsule]). 
Targin (ie, oxycodone/naloxone for opioid induced constipation) is also permitted.


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Background opioids should consist of a fixed regimen of around-the-clock (ATC) opioid(s)
plus supplemental “as needed” (rescue) doses of an immediate-release (IR) opioid as 
determined by the investigator and subject according to accepted clinical guidelines for 
opioid use. Refer to Section 6 for procedures regarding background opioids during the study.
5.8.2.2. Permitted Non-opioid Analgesics
Concurrent adjuvant analgesics such as SNRIs, tricyclic antidepressants, anticonvulsant 
medication, single-agent acetaminophen (paracetamol) 3 grams/day for 3 days or less per 
week, corticosteroids, or muscle relaxants are allowed provided these drugs were started at 
least 30 days prior to start of the Baseline Assessment Period and are maintained at a stable 
dose through Week 8.  With the exception of NSAIDs and intra-articular corticosteroids, 
standard of care analgesia is permitted starting at Week 8 (refer to Section 5.8.2.5 and 6.3).
Use of NSAIDs or intra-articular corticosteroids as part of standard of care analgesia is 
permitted beginning 16 weeks after the last dose of subcutaneous study medication.
Occasional use of acetaminophen (paracetamol) (eg, 3 grams/day for 3 days or less per 
week) for pain conditions other than cancer pain is permitted. 
In certain circumstances, occasional use of usually-prohibited analgesics (eg, NSAIDs) may 
be permitted.  Such circumstances could include outpatient diagnostic procedures 
(eg, colonoscopy, dental procedures) or limited accidental injury (eg, ankle sprains, minor 
fractures, minor burns/sunburns).  Refer to Section 5.8.1 for limitations and prohibitions on 
these analgesics.  Subjects should also be counseled to avoid scheduling prospective 
procedures such that pain medications would be needed within 48 hours of a study visit.  
Limited use of oral, intramuscular or intravenous corticosteroids for non-analgesic purposes 
such as prophylaxis or treatment of chemotherapy-induced nausea and vomiting is permitted. 
However, they must not be taken within 48 hours of a study visit where efficacy assessments 
are being collected.  Topical, inhaled and intranasal corticosteroids are permitted.  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. 
5.8.2.3. Permitted Concomitant Treatments for Underlying Cancer or Bone Metastasis
Concomitant anticancer treatment of the subject’s underlying primary cancer or bone 
metastasis is permitted as follows:

Concomitant chemotherapy, other than paclitaxel, docetaxel, oxaliplatin, cisplatin, 
vincristine, thalidomide and bortezomib or those expressly prohibited (see Appendix 8), 
is allowable provided it was ongoing for at least 30 days before the first day of the 
Baseline Assessment Period.  It is acceptable for the regimen to complete at any time 
after Randomization.

Paclitaxel, docetaxel, oxaliplatin, cisplatin, vincristine, thalidomide and 
bortezomib  are not permitted from 30 days prior to the first day of the 
Baseline Assessment Period to Week 48.


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
A subject with chemotherapy-induced peripheral neuropathy can be enrolled 
provided the neuropathy has been stable over the 6 months prior to the start of 
the Baseline Assessment Period and the subject is no longer being treated with 
a chemotherapy agent associated with peripheral neuropathy.  

Monoclonal antibody therapies used in the treatment of underlying cancer or bone 
metastasis are allowed (with some exceptions; refer to Section 5.8.1.3 ) if part of a stable 
dose regimen started at least 30 days prior to the first day of the Baseline Assessment 
Period. It is acceptable for the regimen to complete at any time after Randomization; 
however, if new treatment is initiated prior to Week 8, the subject should be withdrawn 
from study treatment. Refer to Appendix 8.

Monoclonal antibody therapies associated with clinically significant 
peripheral or autonomic neuropathy or joint-related adverse effects or those 
based on chimeric or murine antibodies (eg, cetuximab (Erbitux)) are 
prohibited within 90 days of the start of the Baseline Assessment Period and 
during the study until Week 32. Refer to Section 5.8.1.3. 

Small molecule inhibitors used in the treatment of underlying cancer or bone metastasis 
(eg, erlotinib (Tarceva), sunitinib (Sutent)) are permitted (except for bortezomib) during 
the study if initiated at least 30 days prior to the first day of the Baseline Assessment 
Period and maintained at stable dose during the double-blind treatment period to at least 
Week 8.

Blood and blood products for transfusion are allowed throughout the study.

Concomitant hormonal anti-cancer treatment (eg, GnRH agonists or antagonists, 
anti-androgens or anti-estrogens) is allowable if treatment has been ongoing at stable 
dose for at least 30 days prior to the first day of the Baseline Assessment Period and bone 
pain still is severe enough to meet inclusion criteria.  Post-Baseline, the concomitant 
hormonal anti-cancer treatment dose regimen should remain stable through at least 
Week 8.
5.8.2.4. Other Permitted Medications
Medications for other (non-cancer, non-pain) conditions are permitted.  Dose adjustments 
(includes starting a new therapy) during the study can be made if required, and recorded on 
the concomitant medication CRF.
Daily low dose aspirin (325 mg as per local prescribing practice) therapy for cardiovascular 
prophylaxis is permitted without restriction.
5.8.2.5. Standard of Care Analgesia (after Week 8)
With the exception of NSAIDs or intra-articular corticosteroids, beginning at Week 8 (or 
Early Termination Visit 1), the investigator may prescribe standard of care analgesia for 
subjects intending to complete the 24-week Safety Follow-Up period.  In this study, standard 
of care analgesia refers to treatments approved by FDA (for US subjects) or another 


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applicable Health Authority (for non-US subjects) to relieve the cancer pain.  These 
medications may include opioids, topical analgesics, capsaicin products  and are prescribed at 
the discretion of the investigator. 
Standard of care analgesia may include NSAIDs or intra-articular corticosteroids, but these 
agents should not be re-instituted on a regular basis until at least 16 weeks have passed since 
the last dose of study medication (Week 32 or Early Termination Visit 2), in order to ensure 
tanezumab has been eliminated and to minimize joint safety risk.  Standard of care analgesics 
are not considered study medication but will be reimbursed by Pfizer from Randomization, if 
allowed per local regulation, while the subject is participating in the study. Cancer or bone 
metastasis therapies are not reimbursed by Pfizer.
5.8.2.6. Standard of Care Treatment for Underlying Cancer or Bone Metastasis (after 
Week 8)
Between Week 8 to Week 32, if treatment for underlying cancer or bone metastasis needs to 
be initiated or changed (refer to Section 5.8.2.3), the study clinician should be informed so 
that guidance may be provided as to whether the subject should be withdrawn from study 
treatment and entered in the Early Termination Follow-Up period. Following Week 32, 
cancer or bone metastasis treatment may be instituted in accordance with standard of care 
without prior consultation of the study clinician.
6. STUDY PROCEDURES 
Refer to Schedule of Activities Table 1 and Table 2 for the lists of procedures to be 
performed throughout 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.  If possible, each subject’s 
clinic visits should be conducted at approximately the same time of day.
Subjects should be thoroughly instructed on completion of the scales/instruments via IRT 
prior to completing them the first time (at Screening for PGA of Cancer Pain
; at 
Baseline for 
 OR-SDS
questionnaires).  No coaching or other 
interpretative assistance should be given to subjects during completion of these 
questionnaires. 
The windows for study visits (in clinic and phone contacts) are ±3 days for the Week 2 to 
Week 16 visits, ±5 days for the Week 20 to Week 28 visits, and ±7 days for the Week 32 to 
Week 48 visits.  Study visits should be scheduled with reference to the study drug dosing 
date as much as possible.  Subject scheduling issues should be brought to the attention of the 
study monitor for resolution.  Dosing visits should occur no earlier than 7 weeks from the 
previous injection.  The visit window for the Week 24 x-rays is ±30 days from the nominal 
time point of the visit.  The Week 48 x-rays should be obtained within a ±30 day visit 
window, preferably prior to the Week 48 visit, but if possible, no more than 14 days after the 
Week 48 visit. In Japan only, the Week 16 x-rays may be obtained up to 7 – 21 days before 
the Week 16 visit (Week 14 ± 7 days).
CCI
CCI
CCI


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6.1. Pre-Treatment Period
The Pre-Treatment Period of the study consists of a Screening Period lasting  ≤32 days and a 
Baseline Assessment Period lasting 5 days. Subjects with a Pre-treatment Period lasting
longer than 37 days eg, due to scheduling delays, should be discussed with the study team
prior to Randomization. Subjects may be permitted to re-screen eg, due to resolution of 
exclusionary condition, with prior agreement of the study team.
Prior to entering the study, subjects must have been diagnosed with cancer and have 
moderate to severe pain due to bone metastasis despite treatment with an allowable regimen 
of opioids.
6.1.1. Screening Period
Although it is generally expected that most Screening activities will occur at the initial 
Screening visit, additional visits during the Pre-Treatment period may be required in order to 
perform protocol-required activities (eg, repeat laboratory testing, imaging scheduling, 
subject diary IRT set-up).
6.1.1.1. Activities Performed at the Screening Visit
6.1.1.1.1. Assessment of Inclusion and Exclusion Criteria
After obtaining informed consent at Screening, the investigator will obtain information and 
perform activities listed in the Schedule of Activities.  Refer to Schedule of Activities 
Table 1 for an all-inclusive list of procedures to be performed at the Screening Visit and 
Section 7 for descriptions of the assessments.
Subjects requiring background regimens of a number of oral or transdermal opioids will be 
eligible.  Refer to Section 5.8 for permitted and prohibited background opioid regimens.
If imaging (eg, bone scan) is not available within 120 days of the Screening visit for 
confirmation of the presence of bone metastasis, the subject will undergo appropriate 
imaging confirmation during the Screening Visit or Screening Period according to local 
standard of care.  It is generally expected that confirmation will take place at the Screening 
Visit, prior to setting the subject up with an IRT subject diary, unless the imaging 
confirmation of bone metastasis (if required) cannot be performed at the Screening Visit or if 
further testing is needed.  In this case, the subject diary IRT set-up will be finalized after 
confirmation has taken place.
6.1.1.1.2. Subject Completion of Screening Assessments
IRT will be used by the subject to complete assessments as described in the Schedule of 
Activities Table 1 (eg, PGA of cancer pain,
assessments of pain at cancer sites and pain 
in major joints). Refer to Section 7 for details of these assessments.
Site staff will instruct the subject on completion of the initial IRT assessments and the 
subject will then complete these assessments independently. 
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6.1.1.1.3. Selection of Index Bone Metastasis Site and Non-index Cancer Pain Sites
At the initial Screening Visit, the subject will record an initial average and worst daily pain 
score with an 11-point numerical rating scale (NRS) via IRT for the most painful site of bone 
metastasis (the index bone metastasis cancer pain site) and for up to 2 other (non-index) sites 
of cancer pain (which could be due to bone metastasis pain or other types of cancer pain).  
The investigator will confirm that the site identified by the subject as the most painful site 
corresponds to a site of bone metastasis.  
If the investigator is unable to confirm this, but considers that such confirmation could be 
made based upon additional imaging information (eg, bone scan, MRI), then such additional 
imaging is permitted. In this case, subject diary IRT set-up should be deferred until after 
confirmation has taken place.
For the other non-index sites of cancer pain selected by the subject, the investigator will 
confirm that the pain at each site is due to cancer or cancer treatment (eg, chemotherapy 
induced peripheral neuropathy) and whether in his/her judgment the cancer pain for each site 
is primarily somatic, neuropathic or visceral in nature.  Once the index and non-index sites 
are identified and confirmed, the IRT will indicate the location(s) the subject selected when 
the subject is subsequently asked to provide pain ratings.
Appendix 15 provides a scenario example of how a subject might select painful sites at 
Screening using a body diagram (with confirmation by the investigator).
6.1.1.2. Screening Activities Initiated at the End of the Initial Screening Visit in 
Subjects Meeting Criteria up to That Point
6.1.1.2.1. Washout of Prohibited Pain Medications
The Screening Period will include the discontinuation and washout of all prohibited pain 
medications (eg, NSAIDs) for at least 5 times the elimination half-life prior to the Baseline 
Assessment Period. 
6.1.1.2.2. Schedule Screening X-rays of Major Joints
At the initial Screening Visit, the subject will have provided an average pain score (scored 
with an 11-point NRS via IRT) for the shoulders, hips and knees and any other joint for 
which a radiograph is to be obtained.  The investigator will indicate whether or not pain 
reported in the major joints noted above is considered related to cancer or cancer treatment. 
The subject will then be scheduled for x-rays of each of the subject’s knees, hips, and 
shoulders.  All x-rays will be evaluated by a Central Reader to determine the subject’s 
radiographic eligibility for the study.  Other major joints exhibiting signs or symptoms 
suggestive of osteoarthritis should also be imaged.  The average pain score, recorded by the 
subject at the Screening visit via IRT, for the shoulders, hips and knees (and any other joint 
for which a radiograph is obtained) will be reviewed by the Central Reader with the x-rays.  
Refer to Section 7.3.9 for details regarding x-ray evaluation.  Subjects with clinical and 
radiographic evidence of osteoarthritis of the knee, hip or shoulder or other pre-specified 
joint abnormalities (as described in Exclusion Criteria) will be excluded from study 
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6.1.1.2.3. Instruct Subject on Completion of Daily/Weekly IRT Assessments (Subject 
Diary)
Site staff will instruct the subject on completion of daily/weekly IRT assessments.  During 
the Pre-Treatment Period, the subject will use the IRT to record average and worst daily pain 
scores each day for the index bone metastasis cancer pain site and each week for non-index 
cancer pain sites, based on a 24-hour recall period.  (Refer to Section 7.1.1 for details 
regarding pain assessments.)  Each day during the Pre-Treatment Period the subject will also 
record via IRT the amount of opioid taken and whether s/he is having intolerable opioid side 
effects. 
6.1.1.2.4. Adjustment of Background Opioid Regimen
During the Pre-Treatment Period, the total daily dose of a fixed regimen of ATC opioid(s)
plus supplemental “as needed” (rescue) doses of IR opioid will be determined by the 
investigator and subject according to accepted clinical guidelines for opioid initiation and 
adjustment, such as the National Comprehensive Cancer Network (NCCN) Clinical Practice 
Guidelines in Oncology: Adult Cancer Pain.46 The purpose is to determine the optimal total 
daily dose of opioid medication using a stable ATC regimen of opioids and IR opioids as 
needed for breakthrough pain.  Each day the subject will record via IRT (subject diary) the 
amount of ATC and IR opioids taken, the number of times rescue medication was taken, and 
whether or not opioid pain medication side effects are tolerable.
Based on subject responses recorded in the IRT, study site personnel will contact (eg, by 
telephone call) the subject as needed for the purposes of determining and prescribing an 
optimal regimen of background opioids.  Opioid dose recommendations will be made based 
on accepted clinical guidelines.
Doses may be changed at each assessment during the Pre-Treatment Period (no more often 
than daily).  Doses need not be changed if the investigator chooses to observe the subject 
longer at a given dose, if side effects are tolerable, or if the ATC regimen is considered to be 
stable and tolerable and the subject is able to enter the Baseline Assessment Period.  
Investigators and subjects should be aware that subjects on a stable opioid regimen who meet 
the criteria for randomization during the Baseline Assessment Period will need to continue 
on the opioid regimen with minimal dosage increases permitted for the first 8 weeks of the 
Double-Blind Treatment Period.
Note: In the event that Screening activities cannot be completed within 32 days of signing 
informed consent (eg, due to unavoidable delays in scheduling), investigators should contact 
the study team to confirm whether the subject may continue in the study and if additional 
steps are required (eg, re-consent of subject, repeat of study procedures).
6.1.2. Baseline Assessment Period (BAP, Days -5 to -1)
The purpose of the Baseline Assessment Period is to determine the Baseline pain value for 
each subject and to document that the subject’s background opioid regimen is sufficiently 
robust to minimize the need for opioid IR rescue but also tolerable as judged by the subject.  
These data will confirm that Randomization Criteria 1, 2 and 3 have been met.  Refer to 
Section 4.3 for Randomization Criteria details.


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Subjects who remain eligible and who are tolerating a stable ATC regimen of opioids can 
begin the Baseline Assessment Period approximately 5 days prior to the Baseline (Day 1) 
randomization visit. 
During the Baseline Assessment Period, the subject will record daily pain scores for his/her 
cancer pain sites and opioid medication use via the IRT (refer to Section 7.1.1).  The daily 
average pain score in the index bone metastasis site and daily opioid use collected via IRT 
should be reviewed by study site staff to assess compliance with the subject diary and need 
for dose adjustments. Each day the subject will record via IRT (subject diary) the amount of 
ATC and IR opioid taken, the number of times rescue medication was taken, and whether or 
not opioid pain medication side effects are tolerable.
Note:  In the event a subject misses an assessment day in this Baseline Assessment Period, 
the schedule may be adjusted to acquire the 5 days of assessment entry into the IRT.  Study 
sites will monitor the IRT reports for compliance with diary recordings and rescue 
medication use and reschedule those subjects who fail to provide at least the final 3 days of
diary data (Day -3 to Day -1).
6.2. Double-Blind Treatment Period
The day after the 5-day Baseline Assessment Period is complete, eligible subjects will be 
randomized and enter the 24-week 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 6 clinic visits (Day 1 and Weeks 2, 4, 8, 16, and 24) and 
2 telephone contacts (Weeks 12 and 20) between site staff and study subjects.  Week 8 and 
Week 16 are dosing visits.
6.2.1. Randomization Clinic Visit
6.2.1.1. Pre-Randomization
Full eligibility prior to randomization includes (but is not limited to) radiographic 
confirmation of bone metastasis, confirmation of Randomization Criteria (including those 
regarding Baseline PGA criteria and confirmation of Central Reader eligibility for each hip, 
knee and shoulder x-ray), confirmation of appropriate washout of concomitant medications 
and confirmation that no adverse events occurred since signing informed consent that would 
render the subject ineligible for randomization.  
Refer to the Schedule of Activities Table 1 for the activities which should be completed prior
to randomization to confirm eligibility for randomization.
6.2.1.2. Randomization
Subjects must satisfy all Inclusion, Exclusion and Randomization Criteria to be eligible for 
randomization. Refer to Sections 4.1, 4.2, and 4.3, respectively. 
Following confirmation of eligibility, subjects will be randomized via an IRT system, which 
will assign a randomization number to the subject


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6.2.1.3. Dosing (Day 1)
After randomization, subjects will receive a single SC injection of blinded study medication 
according to the treatment assigned by the IRT system (refer to Section 5.1).
The administration of study drug 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 study drug administration should be discontinued 
immediately and permanently.  No other dosage modifications are allowed.
6.2.1.4. Post-dosing
Subjects will be observed for adverse events including signs and symptoms of 
hypersensitivity or injection reactions in the clinic for a minimum of 1 hour after 
administration of SC study medication.
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 after 
leaving the clinic.

If not done before, female subjects of child bearing potential will be reminded of 
contraceptive requirements.
6.2.2. Double Blind Treatment Period
6.2.2.1. Background Opioid Use
After randomization and through Week 8, all subjects will continue to take the opioid 
regimen or morphine equivalent dose used during the Baseline Assessment Period.  The 
average of the total daily opioid doses (ATC + IR) taken during the Baseline Assessment 
Period will be used as the Baseline total daily opioid dose. 
Beginning on Day 1 and through Week 8, the average total daily dose of opioids between 
study clinic visits should not exceed the Baseline total daily morphine equivalent opioid dose 
by more than 10%.  Subjects who require an opioid dose more than 10% greater than the 
Baseline total daily opioid dose should discontinue the Double-Blind Treatment Period for 
insufficient clinical response or disease progression ( per investigator’s judgment) and enter 
the 6-month Safety Follow-Up period (refer to Section 6.4).  Opioid dose reduction will be 
allowed if the subject experiences intolerable opioid side effects, if pain decreases or if the 
subject requests dose reduction.  Once reduced, the opioid dose may be re-increased if 
needed for pain relief, but should not exceed the Baseline total daily morphine equivalent 
opioid dose by more than 10%.  
Following the Week 8 clinic visit, subjects will remain on the opioid regimen used during the 
Baseline Assessment Period but will be allowed to change formulation, increase or decrease
the amount of their background opioid medication without restriction if the investigator 


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considers such changes are necessary.  Opioid reductions and increases will be done using 
accepted clinical guidelines (refer to Section 6.1.1.2.4).
6.2.2.2. Concomitant Treatment for Underlying Cancer or Bone Metastasis
Beginning at Week 8, additional changes to underlying cancer or bone metastasis therapy or 
pain treatment regimen may be initiated by the investigator to provide standard of care 
treatment (with the exception of NSAIDs) if determined appropriate (refer to Section 
5.8.2.6).  If treatment is initiated or changed between Week 8 to Week 32, the study clinician 
should be informed so that guidance may be provided as to whether the subject should be 
withdrawn from study treatment and entered in the Early Termination Follow-Up period.
6.2.2.3. IRT (Subject Diary)
Beginning with the Pre-Treatment Period and through Week 8, the subject will record via 
IRT (subject diary) average and worst daily pain scores each day for the index bone 
metastasis cancer pain site, the amount of background opioid taken each day, and will record 
average and worst daily pain scores each week using a 24-hour recall period for non-index 
cancer pain site(s).
After Week 8 and through Week 24, each of these assessments will be collected weekly 
using a 24-hour recall (see Section 7.1.1).
Beginning with the Pre-Treatment Period and through Week 48, each week the subject will 
be asked via IRT if he or she experienced new onset or increased pain in a major joint (refer 
to Section 7.1.1.3).  If the subject reports new onset or increased pain in a major joint 
(Post-Baseline), the subject will be asked to rate his/her pain in that joint on an 11-point 
NRS, using a 24-hour recall period and to rate his/her pain in that joint for the remainder of 
the study.  Subjects with severe, persistent joint pain will have more detailed evaluations to 
investigate this (refer to Section 7.4.4). 
On a weekly basis from Baseline (Day 1) and through Week 48, the subject will also be 
asked via IRT to record the number of days of NSAID use in the past week.  Details of the 
NSAID use will be collected by the site (eg, via phone contact) as described in Section 7.1.3.
6.2.2.4. Routine Clinic Visits (Week 2 and Week 4)
The subject will return for clinic visits at Week 2 and Week 4 to be assessed for efficacy and 
safety. Refer to Schedule of Activities Table 1 for the procedures to be performed at the 
Week 2 and Week 4 Visits.
6.2.2.5. 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 study medication, 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
6.2.1.3 and 6.2.1.4.


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NOTE: In Japan only, confirmation of continued radiographic eligibility from the Central 
Reader is required before Week 16 dosing.  The X-rays (knees, hips and shoulders, and any 
other major joint imaged at Screening or at-risk joint identified during the study period) may 
be obtained up to 7 – 21 days before the Week 16 visit (Week 14 7 days) in order to allow 
confirmation of continued radiographic eligibility from the Central Reader.
6.2.2.6. Phone Contact Visits (Week 12 and Week 20)
The subject will be contacted by telephone at Week 12 and 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 12 
and Week 20 Phone Contacts.

At the Week 20 phone call, schedule Week 24 x-rays, to occur preferably prior to the
Week 24 visit but if possible, no more than 30 days after the Week 24 clinic visit.
6.2.2.7. 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.  Given the design of this study, which includes a 24 week Safety 
Follow-Up period during which subjects no longer receive study medication and 
receive standard-of-care treatment from Week 8, additional investigational product at 
the conclusion of the study will not be provided.

Only subjects who complete the Week 24 assessments will be considered to have 
completed the Double-Blind Treatment Period.  
6.3. Safety Follow-Up Period
Subjects who enter the Safety Follow-Up period after completion of the Double-Blind 
Treatment period and the Week 24 visit will be followed for an additional period of
24 weeks. This will include 2 clinic visits (Weeks 32 and 48) and 4 telephone contacts 
(Weeks 28, 36, 40 and 44) between site staff and enrolled subjects. For Japan only, the 
Week 40 visit will be in-clinic. 
During the Safety Follow-Up period (after the Week 24 visit), the subject will no longer 
report cancer pain scores in the IRT (subject diary) for purposes of efficacy assessments.  
The subject will only provide a weekly assessment of joint pain (shoulders, hips and knees) 
and any NSAID use via IRT using a 24-hour recall period through Week 48.
From Week 24 to Week 32, the subject will continue to use opioids for cancer pain treatment 
(which as noted in Schedule of Activities Table 1 (footnote l) may have been liberalized 


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beginning as early as Week 8).  Any needed opioid dose adjustments during this period 
should continue to follow accepted clinical guidelines (as described in Section 6.1.1.2.4).
If needed, beginning at Week 32, treatment with NSAIDs may proceed without restriction, 
but within approved label instructions. 
At Week 48, the subject will return for the final End-of-Study clinic visit.  At this visit, all 
End-of-Study procedures are to be completed, including general physical
x-rays of each knee, hip and shoulder, laboratory assessments and other safety 
assessments as described in the Schedule of Activities.  X-rays of each shoulder, hip and 
knee as well as any additional joint that was imaged at Screening or identified as at risk 
during the study will be obtained.  These images will be sent to the blinded Central Reader 
for review.
6.3.1. Week 32 Clinic Visit
The subject will return for a clinic visit at Week 32 to be assessed for safety.  Refer to 
Schedule of Activities Table 1 for the procedures to be performed at the Week 32 Visit.
6.3.2. Phone Contacts (Weeks 28, 36, 40, and 44); for Japan only, Week 40 Clinic Visit
The subject will be contacted by telephone at Weeks 28, 36, 40 and 44 to review adverse 
events, concomitant medications, compliance with daily/weekly IRT entries and, at Week 28 
phone call only, to remind female subjects of contraceptive requirements.
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Weeks 28, 
36, 40 and 44 Phone Contacts.
At the Week 44 phone call, schedule Week 48 x-rays, to occur preferably prior to the 
Week 48 visit but if possible, no more than 14 days after the Week 48 Clinic Visit.
Note: In Japan only, subjects will return for a clinic visit at Week 40 to review adverse 
events, concomitant medications, compliance with daily/weekly IRT entries. Refer to 
Schedule of Activities Table 1 for the procedures to be performed at the Week 40 clinic visit.
6.3.3. Week 48 Clinic Visit (End of Study)
The subject will return for the end of study clinic visit at Week 48 to be assessed for safety.  
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 48 
(End of Study) Clinic Visit.
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.  In any circumstance, every effort should be made to document subject outcome, if 
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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 study medication. 
If the study medication and the allowable background opioid regimen are not providing 
acceptable pain relief during the double-blind treatment period, the subject should be 
withdrawn from study treatment (eg, due to lack of efficacy or disease progression per the 
investigator’s judgment) and entered in the Early Termination Follow-Up period. 
Subjects discontinuing from treatment (prior to Week 24), either at their request or at the 
decision of the investigator, will be asked 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 monthly 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 
cancer pain sites and for major joints via IRT, weekly, until 16 weeks after the subject’s last 
dose of SC study treatment (for cancer pain scores) and through the end of the 24 Week 
Safety Follow-Up period (for joint pain scores). 
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 study medication.
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/her or persons previously 
authorized by subject to provide this information.  Subjects should notify the investigator 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 from further treatment with study drug only 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 three documented contacts (via phone calls, faxes, and/or emails) as well 
as lack of response by subject to one registered mail letter.  All attempts should be 


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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 investigator’s 
use of 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 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). 
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 (corresponding 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 analgesia with NSAIDs or intra-articular corticosteroids 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.
Subjects entered in the Early Termination Follow-Up period will be able to take background 
opioid medication daily up to the Early Termination Follow-Up period Visit 3 (which occurs 
24 weeks after the last dose of SC study treatment.
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 7.3.9).  X-rays should be submitted to 
imaging Central Reader. 
Refer to the Early Termination Schedule of Activities Table 2.


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6.4.1.1. Early Termination Visit 1 (~8 Weeks after Last Dose of SC Study Medication)
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 1.
6.4.1.2. Early Termination Telephone Contacts 1 and 2 (~12 Weeks and ~20 Weeks
after Last Dose of SC Study Medication)
The subject will be contacted by telephone twice (~12 weeks and ~20 weeks after the last 
dose of SC study medication) to review adverse events, concomitant medications, 
compliance with daily/weekly IRT entries and, at Telephone contact 1, 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 x-rays, to occur preferably prior to the Early Termination 
Visit 3 but if possible, no more than 14 days after the Early Termination Visit 3.
6.4.1.3. Early Termination Visit 2 (~16 Weeks after Last Dose of SC Study Medication)
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 Visit 3 (~24 Weeks after Last Dose of SC Study Medication)
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.
6.5. Procedures for Subjects Undergoing Joint Replacement
Subjects who have undergone or plan to undergo total joint replacements or other 
arthroplasty procedure during the study will be discontinued from study treatment.  
Follow-up procedures for these subjects are described in Section 7.4.6.  In addition, subjects 
who undergo total knee, hip or shoulder joint replacement surgery during the study 
(Double-Blind Treatment Period or Safety Follow-Up Period) will be followed for 24 weeks 
after the procedure as part of a separate substudy, described in Appendix 16, provided the 
subject consents.
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 that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.


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7.1. Subject IRT Assessments
The subject IRT assessments described in this section should be completed in the evenings if 
possible.
7.1.1. Daily/Weekly Pain IRT Assessments
Average pain and worst pain in the index bone metastasis cancer pain site, non-index cancer 
pain sites and average pain in painful major joints will be assessed by the subject at 
approximately the same time each day (or each week) with an 11-point Numeric Rating Scale 
(NRS) ranging from 0 (no pain) to 10 (worst possible pain) captured through IRT.  The 
subjects should describe their pain in the painful site during the past 24 hours by choosing the 
appropriate number from 0 to 10.  
Subjects will record diary entries in an electronic IRT tool.  Although the subject is 
responsible for completing the diary, the site personnel have a number of responsibilities 
related to the IRT including:

Assigning, setting up and collecting the IRT devices.

Instructing subjects on IRT diary use and transmission of data.

Reviewing subject’s IRT (subject diary) during the Screening period (including Baseline 
Assessment Period) and at each study visit (including phone contact visits) to ensure 
completeness (eg, by using the IRT vendor’s trial manager).  Questioning subjects for 
missing entries and retrain as appropriate.  If the issue is technical, work with the subject 
and/or the IRT vendor to address the problem.

Reviewing daily and weekly (as applicable) IRT (subject diary) entries.
7.1.1.1. Index Bone Metastasis Cancer Pain Site Assessment
At Screening, subjects will be asked to identify the most painful site of bone metastasis via
IRT.  This site will be considered the index bone metastasis cancer pain site.  Subjects will be 
asked to record daily pain ratings for the index bone metastasis cancer pain site as described 
below. 
Average pain and worst pain in the index bone metastasis cancer pain site will be assessed by 
the subject at Screening and daily during the Pre-Treatment Period to the Week 8 Visit, and 
then will be assessed weekly using a 24-hour recall period beginning after the Week 8 visit 
through Week 24 (and weekly during the Early Termination Follow-Up Period, as shown in 
Table 2). Refer to Appendix 9 to see examples of the questions the subject will be asked.
7.1.1.2. Non-Index Site(s) of Cancer Pain Assessment
At Screening, subjects will be asked via the IRT whether they are experiencing cancer pain in 
site(s) other than the index bone metastasis cancer pain site.  If so, they will be prompted to 
identify up to 2 other site(s), which will be considered a non-index cancer pain site(s).  If the 
subject has more than 2 other painful cancer pain sites, he or she should select the 2 sites 
which are most painful as the non-index cancer pain sites.  Subjects will rate their average 


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pain and worst pain for each site(s) with an 11-point Numeric Rating Scale ranging from 
0 (no pain) to 10 (worst possible pain) during the past 24 hours. 
Assessment of pain in non-index site(s) of cancer pain will be performed weekly during the 
Pre-Treatment Period to the Week 24 Visit (and weekly during the Early Termination 
Follow-Up Period up to the visit that occurs 16 weeks after the last dose of SC study 
medication was administered).  Refer to Appendix 9 to see examples of the questions the 
subject will be asked.
7.1.1.3. Joint Pain Assessments
Pain in each shoulder, hip and knee and any additional major joint that will be imaged at 
Screening (refer to Section 7.3.9), will be assessed via IRT at the Screening Visit using the 
11-point NRS scale noted below.  These joint pain assessments are conducted for joint safety 
purposes, not for efficacy assessments. Refer to Appendix 9 to see an example of the 
question the subject will be asked.
Thereafter, on a weekly basis beginning during the Pre-Treatment Period and through 
Week 48 (or Early Termination as described in Section 6.4), the subject will also be asked
via IRT if he or she experienced new onset or increased pain in any major joint.  If a subject 
responds that he or she has experienced increased pain in a 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 for the remainder of the study. 
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. 
7.1.2. Subject Daily/Weekly Opioid Medication Use
Background opioid medication use will be collected in the IRT (subject diary) and in the 
CRF if dual concomitant opioids are used.  The subject is to record dosing information 
pertinent to his/her ATC opioid medication and rescue opioid medication for the past 
24 hours.  Background opioid medication use will be assessed daily via IRT during the
Pre-Treatment Period to the Week 8 Visit and then will be assessed weekly using a 24-hour 
recall period beginning after the Week 8 Visit through Week 24 Visit. 
7.1.3. Concomitant NSAID Use
Use of over-the-counter or prescription NSAID use will be collected weekly via IRT from 
the Baseline (Day 1) visit until the Week 48 visit (or if the subject discontinues treatment,
until 16 weeks after the last dose of SC study treatment).  Subject is to record the number of 
days of NSAID use in the past week using IRT.  Via telephone calls or at clinic visits, sites 
will interview the subject regarding their NSAID use and record the medication name, dose, 
and reason for use on a CRF.  The investigator or designee should closely monitor for 
concomitant NSAID use.  Subjects reporting concomitant NSAID use will be managed per 
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7.2. Study Visit Efficacy Assessments and Other Instruments
7.2.2. Opioid-Related Symptom Distress Scale
The Opioid-Related Symptom Distress Scale (OR-SDS) is a self-administered questionnaire 
that assesses frequency, severity, and level of bother of opioid-associated adverse effects 
(refer to Appendix 11). 
Pfizer developed the OR-SDS with the intent of specifically measuring the clinical benefit of 
the opioid-sparing treatment effect (refer to Appendix 11).  The OR-SDS was derived from 
the Memorial Symptom Assessment Scale developed for cancer pain.  The items were 
revised for opioid-related distress to include common adverse effects, based on literature and 
expert review, associated with use of opioid analgesics.
The OR-SDS will be completed by the subject via IRT during clinic visits (prior to SC 
dosing at dosing visits) as described in Schedule of Activities Table 1 and Table 2 and in 
Section 6). 
7.2.3. Patient’s Global Assessment of Cancer Pain (PGA of Cancer Pain)
The PGA of Cancer Pain is a global evaluation that utilizes a 5-point Likert scale with a 
score of 1 being the best (Very Good) and a score of 5 being the worst (Very Poor).  Refer to 
Appendix 12.  It is intended to provide a qualitative measurement of the subject’s impression 
of disease activity. Refer to Appendix 12 to see the question the subject will be asked.
The PGA of Cancer Pain will be completed by the subject via IRT during clinic visits as 
described in Schedule of Activities Table 1 and Table 2 and in Section 6. 
7.2.4. Eastern Cooperative Oncology Group (ECOG) Performance Status
Functional assessment tools based on performance, such as the Eastern Cooperative 
Oncology Group (ECOG) Performance Status,47 are validated and widely used tools in 
cancer care.  The ECOG Performance Status instrument is rated on a 5-point scale, with 
lower scores representing higher functional status.  Refer to Appendix 3.
The ECOG Performance Status will be completed via IRT as described in Schedule of 
Activities Table 1 and Table 2 and in Section 6. 
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7.3. Safety Assessments
7.3.1. Cancer History
Cancer history includes primary diagnosis, date of initial diagnosis, date of initial bone 
metastasis and treatment history.
7.3.2. General Physical Examination
Each subject will undergo a general physical examination at Screening, and Weeks 24 and 
48, or at Early Termination (as described in Section 6.4).
7.3.3. 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, crystalline disease, 
osteoporosis or osteopenia, joint injuries or other conditions. 
At Screening, the investigator will conduct a thorough musculoskeletal physical examination 
of all major joints.  The musculoskeletal physical exam 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.
In Japan only, Post-Baseline musculoskeletal physical examinations will also be performed at 
the Clinic Visits indicated in Schedule of Activities Table 1 and Table 2.
7.3.4. 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, Weeks 16, 
32 and 48 (or Early 
Termination):
Screening, Baseline, 
Weeks 16, 32 and 48 (or 
Early Termination):
Screening only:
Hemoglobin A1c
Serum FSH, if 
Screening only
(urine macro panel):
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7.3.4.3. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed at the Clinic Visits indicated in Schedule 
of Activities Table 1 and Table 2.  Serum pregnancy tests will be performed at Screening, 
Weeks 24 and 32 (and at Early Termination Visits 1 and 2 if applicable).  Urine pregnancy 
tests will be performed pre-dose at Baseline, Week 8 and Week 16.
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).  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 hCG test, the subject will be withdrawn from study medication but 
may remain in the study. 
Refer to Sections 6.4, 8.10 and 8.10.1 for guidance pertaining to subject withdrawal, 
exposure during pregnancy and additional post-natal follow-up, respectively.
7.3.4.4. Serum FSH Testing
Female subjects who are not of childbearing potential and who have not had a hysterectomy 
or bilateral oophorectomy and who have been amenorrheic for at least 1 year with no 
alternative pathological or physiological cause will undergo serum FSH testing to determine 
post-menopausal status.  A serum FSH level within the laboratory’s reference range for 
postmenopausal 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 serum FSH testing.
7.3.5. Vital Signs
Vital signs (including systolic blood pressure, diastolic blood pressure, and heart rate) will be 
collected as described in Schedule of Activities Table 1 and Table 2 and Section 6, after the 
subject has been in a sitting position for at least five minutes at each visit.


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7.3.6. 12-Lead Electrocardiograms
12-lead ECGs will be performed as described in Schedule of Activities Table 1 and Table 2
and Section 6 for determination of ECG-related eligibility and safety monitoring. 
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, QTcB, QTcF, RR intervals and 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 study drug.  In the event a clinically significant ECG 
abnormality is seen at a visit on a post treatment ECG, 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 on an ECG, exclusionary at 
Screening) 

Heart rate decrease from Screening of 25% with resulting heart rate <60 bpm.
Investigators should report adverse events of bradycardia for subjects who meet the ECG 
criteria listed above.
7.3.7. Orthostatic Blood Pressure Measurement
In addition to sitting vital sign measurements, orthostatic blood pressure measurements will 
be obtained using a standard manual sphygmomanometer at the clinic visits noted in 
Schedule of Activities Table 1 and Table 2 and Section 6. At each visit, blood pressure will 
be assessed in supine and standing positions.  Orthostatic vital blood pressure measurements 
will be obtained after collection of the sitting vital signs and before any required phlebotomy.  
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, 


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systolic and diastolic blood pressure will be measured and recorded for both timepoints.  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.
Table 4.
Orthostatic Blood Pressure Changes and Orthostatic Hypotension Definition
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 the subject should be excluded from study 
participation  
OR
>150 mmHg
≥30 mmHg systolic or
≥15 mmHg diastolic
Subjects who meet the criteria defining orthostatic hypotension as described in Table 4 at 
Screening or Baseline prior to randomization should be excluded from study participation.  
Subjects who meet criteria defining orthostatic hypotension at any post-Baseline clinic visit 
should follow the procedures described in Section 7.4.3.
7.3.9. Radiographic Assessments
Scheduled radiographic assessments (x-rays) of the knees, hips and shoulders will be 
obtained as described in the Schedule of Activities Table 1 and Table 2 and Section 6. 
Radiographic assessments of other major joints exhibiting signs or symptoms suggestive of 
osteoarthritis should also be imaged.  Any joint imaged at Screening or other at-risk joints 
identified during the study period should also be imaged at the same intervals as the knees, 
hips, and shoulders. 
It is recommended that the radiographs required at Screening be obtained as soon as possible 
after the initial Screening visit and at least two weeks prior to the Baseline visit to permit 
Central Reader review of the images and to establish subject eligibility for initial dosing in 
the study and taking into account that additional x-rays may be needed after review by the 
Central Reader.  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.  Radiographs 
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required for the Week 24 visit may be conducted up to 30 days before or after the visit.  
Radiographs required for the Week 48 visit may be conducted up to 30 days before or after 
the visit. These will be preferably scheduled before the Week 48 visit but if possible, no 
more than 14 days after the visit. In Japan only, the Week 16 x-rays may be obtained up to 
7 – 21 days before the Week 16 visit (Week 14 7 days).
For subjects discontinuing prior to the Week 48 visit, follow-up radiographs of the knees, 
hips and shoulders 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 the knees, 
hips and shoulders should be obtained 24 weeks (Early Termination Visit 3, Section 6.4.1.4) 
after the last dose of SC study treatment was administered.  Any joint imaged at Screening or 
other at risk joints identified during the study period should also be imaged at Early 
Termination Visits 1 and 3. 
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 facilitate 
assessment of joint space width measurement in the knee or hip, 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.  Central Readers will review the 
radiology images at Screening for assessment of eligibility including determination of 
identification of exclusionary joint conditions as defined in the tanezumab program imaging 
atlas such as osteoarthritis, rapidly progressive osteoarthritis, atrophic or hypotrophic hip 
osteoarthritis, subchondral insufficiency fractures, spontaneous osteonecrosis of the knee 
[SPONK], primary osteonecrosis, and pathological fractures.  After randomization, Central 
Readers will review radiology images obtained for diagnosis of joint conditions that would 
warrant further evaluation by the Adjudication Committee such as rapidly progressive 
osteoarthritis, subchondral insufficiency fractures, spontaneous osteonecrosis of the knee 
(SPONK), primary osteonecrosis or pathological fracture. 
For subjects who are identified with a possible or probable event described above 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.
7.3.9.1. Radiation Exposure
The International Commission on Radiation Protection (ICRP) has developed and applied the 
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 


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“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)
Knee57
0.036 mSv (Japan 0.048 mSv)
Hip55,56
2.60 mSv (Japan 3.47 mSv)
Shoulder55
0.06 mSv (Japan 0.08 mSv)
TOTAL
2.696 mSv (Japan 3.598 mSv)
The average subject exposure per radiograph is shown in the table above.  The total effective 
dose per subject in this study from these x-rays is expected to be approximately 
2.696 millisievert (mSv) (Japan 3.598 mSv).  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 necessary due to the quality of the initial x-ray 
images.  
 
 
 
 
 
 
  
 
 
 
 
 
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7.4. Triggered Requirements and Subject-Level Stopping Rules
The following rules will apply to individual subjects at the time of the 2nd and 3rd injection of 
SC study treatment.
7.4.1. Dysesthesia/Allodynia
Transient, resolved dysesthesia/allodynia: Administer SC study medication as planned as 
long as the condition has resolved before the next scheduled dose of SC study medication. 
Unresolved dysesthesia/allodynia: Withhold the SC study medication 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 study medication and will enter the 
Early Termination Follow-Up period (refer to Schedule of Activities Table 2 and 
Section 6.4). 
7.4.2. Hypersensitivity or Injection Site Reactions
If a severe hypersensitivity reaction or severe injection reaction occurs following the 
administration of SC study medication, study drug should be discontinued immediately and 
no further administrations of SC study medication will be allowed.  Subjects experiencing 
these types of reactions will enter the Early Termination Follow-Up Period (refer to Schedule 
of Activities Table 2 and 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 7.3.7 will be designated as a 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 7.3.7) 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 study 
medication should occur.  Figure 2 provides a flow diagram for the processes 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 study medication.


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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 7.3.7 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 7.3.6 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 study medication 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 study medication, 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 Schedule 
of Activities Table 2 and Section 6.4).  Subjects found to have a sympathetic autonomic 
neuropathy (Boxes I and L of flow diagram Figure 2) should not receive additional study 
medication 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


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7.4.4. Evaluation and Follow-Up for Increased, Severe Persistent Joint Pain
At Screening subjects will provide a daily average pain score (scored with an 11-point NRS 
via IRT) for the shoulders, hips and knees and any other joint for which a radiograph is 
obtained (refer to Section 7.1.1).
In addition, on a weekly basis beginning from Baseline through Week 48, the subject will be 
asked if he or she experienced new onset or increased pain in a major joint (refer to 
Sections 6.2.2.3 and 7.1.1.3). If a subject responds that he or she has experienced increased 
pain in a 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 by the investigator 
to determine the source of the subject’s pain and whether more comprehensive evaluation 
(eg, radiographic or MRI imaging, orthopedic consultation) of the subject is warranted.  An 
earlier evaluation of the subject can be made at the discretion of the investigator. 
At each study visit, systematic site review of the 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, or fractures will be evaluated by 
the site personnel. 
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 
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 Sections 7.4.5 and 9.5). 
7.4.5. Central Reader and Subject-Level Stopping Criteria for Possible or Probable 
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 


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period (refer to Schedule of Activities Table 2 and Section 6.4).  Note: At Screening, 
vertebral pathologic fracture with less than 50% vertebral body destruction and no spinal 
canal compromise is allowable.  Subjects with radiographic progression of vertebral 
pathologic fracture to ≥50% of the vertebral body or spinal canal compromise post-Screening 
will be withdrawn from treatment and enter the Early Termination Follow-Up period (refer to 
Schedule of Activities Table 2 and 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 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 1). 
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 9.7.1.
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 study treatment. 
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 substudy, described in Appendix 16, provided the subject 
consents.
Transition procedures into the substudy 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 substudy.  At the discontinuation visit, all procedures 
scheduled for the Week 24 and Week 48 visits should be completed.  In addition, if the 
subject terminates prior to the Week 24 visit, serum and plasma retention samples should 
be collected, and the
 OR-SDS, 
and PGA instruments should be 
completed.  Female subjects will be advised to continue their contraception regimen 
during a period of 112 days (16 weeks) after the last dose of SC study medication.  
Applicable substudy Baseline Visit activities should be completed on the same day as the 
Study A4091061 End of Treatment Visit. 
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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. 
SAEs 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.
AEs (serious and nonserious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the last subject 
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; 


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
Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page, and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the 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.


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE 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);

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 the section 
on Medical Device 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;


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
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 on Serious Adverse Event Reporting Requirements).
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 
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 values 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 preexisting 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 preexisting 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. 


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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, 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 
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 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);


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
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE 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 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 


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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;
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 a serious adverse event (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 preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death), the 
investigator should follow the procedures for reporting SAEs.


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
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.
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 adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the
investigator’s awareness, using the SAE eport 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 Case Report Form (CRF), however a copy of the 
completed SAE report form is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal/Early Termination)
Withdrawal due to AE 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.


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8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
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 time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious 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 


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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
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), 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
The primary efficacy endpoint is the change from Baseline to Week 8 in the average daily 
pain intensity in the index bone metastasis cancer pain site measured by the 11-point Pain 
Intensity NRS. 
From a prior study (A4091003), the assumed within-group standard deviation for the change 
from Baseline in the Average Pain NRS is 2.0.  The targeted mean treatment difference for 
tanezumab 20 mg SC + opioids versus placebo + opioids is -1.0.  A Group Sequential Design 
with a single interim analysis will be used for the assessment of futility and efficacy of the 
primary efficacy parameter (refer to Section 9.6 for details).
The interim analysis will be performed when at least 50% (36 from each treatment group) of 
subjects have completed or discontinued prior to Week 8. Based on current enrollment, it is 
expected that the interim analysis will include approximately 36 to 45 subjects per treatment 
group.
Based on data from the previous cancer pain study (A4091003), and not accounting for the 
assessment of futility and efficacy at the interim analysis, a sample size of approximately 
72 subjects per treatment group is required to achieve 85% power to demonstrate statistical 
significance (using the 2-sided 5% significance level), in the treatment comparison of 
tanezumab 20 mg + opioid versus placebo + opioid. Taking into account for the assessment 
of non-binding futility and efficacy at the interim analysis, the same sample size is expected 
to achieve 80 to 85% power.  


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9.2. Efficacy Analysis
Efficacy data from subjects randomized to the tanezumab 10 mg treatment group will be 
summarized but not included in analyses of efficacy.
9.2.1. Primary Endpoint Analysis
The primary efficacy endpoint is the change from Baseline to Week 8 in the daily average 
pain intensity in the index bone metastasis cancer pain site measured by the 11-point Pain 
Intensity Numerical Rating Scale (NRS), where scores range from 0-10.
Baseline is defined as the mean average daily Pain NRS score during the Baseline 
Assessment Period prior to Randomization (expected to be 5 days).  The Week 8 pain 
intensity value is the mean of the daily average Pain intensity scores for the 7 days prior to
the Week 8 visit.  If any of the seven Week 8 daily scores are missing then the Week 8 value 
will be calculated over the remaining observations.
The primary efficacy endpoint will be analyzed using an ANCOVA model, with model terms 
for Baseline score, the stratification variables, Baseline opioid use, region and treatment 
group.  The stratification variables are (i) tumor aggressiveness (assessed by Eastern 
Cooperative Group [ECOG] performance status and (ii) presence/absence of concomitant 
anticancer treatment (eg, chemotherapy or hormonal therapy or anti-hormonal therapy).
The primary analysis of the primary endpoint will use multiple imputation for missing data, 
to account for uncertainty around the unobserved 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 8 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 the placebo 
and tanezumab 20 mg treatment groups) of the observed efficacy data at Week 8.  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 subject’s last observed efficacy value and 
standard deviation (over the placebo and tanezumab 20 mg treatment groups) of the observed 
efficacy data at Week 8.  Imputed values will be truncated at 0 and 10, but not rounded.  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 significance level for the primary analysis of the primary endpoint at the interim and the 
final analysis will be determined in a way to have an overall two-sided 5% significance 
across analyses.  The boundary to declare efficacy at the interim or the final analysis will be 
determined using the Lan-DeMets alpha spending function with the O’Brien-Fleming style 
boundary (refer to Section 9.6 for details). The non-binding futility stopping rule will not 
influence the efficacy boundary.  
The primary efficacy population (Intent to Treat Set) is defined as all randomized subjects 
who received the Day 1 SC injection (either tanezumab SC or matching placebo SC).  A 


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secondary efficacy population (Per-Protocol) is defined as all subjects in the Intent to Treat 
Set who were not major protocol deviators.
9.2.2. Secondary Efficacy Endpoint Analysis
Unless otherwise stated, all data up to Week 24 will be summarized, and data for the 
specified time points up to Week 24 will be analyzed.
The change from Baseline for the daily average and worst pain intensity in the bone 
metastasis index cancer pain site will be summarized for each week from 1 to 24.  The 
change from Baseline to Weeks 1, 2, 4, 6, 8 (Worst Pain), 12, 16 and 24 will be analyzed 
using analysis of covariance (ANCOVA) as described above, using multiple imputation. 
A secondary analysis for the change from Baseline in the daily average pain scores will use a 
repeated measures mixed effects model, on the available data over Weeks 1 to 24.  Estimates 
for treatment groups and treatment difference for Weeks 1, 2, 4, 6, 8, 12, 16 and 24 will be 
shown.  Additional secondary analysis for the change from Baseline to Week 8 and 16 in the 
daily average pain will use single imputation Last Observation Carried Forward (LOCF) and 
Baseline Observation Carried Forward (BOCF) for missing data.
The mean of the subject’s average and worst pain in the non-index cancer sites, over all 
non-index sites (for up to 2 sites per subject) and for visceral non-index cancer sites will be 
calculated for Baseline and for each week, and for the change from Baseline.  The change 
from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in average and worst pain in the 
non-index cancer pain sites will be analyzed using analysis of covariance (ANCOVA) as 
described above, using multiple imputation.  An additional analysis will utilize only those 
sites where Baseline average/worst pain is at least 5.  If a subject has no nominated 
non-index sites (first analysis) or no nominated non-index sites where Baseline is at least 5 
(second analysis) then that subject would be excluded from the respective analysis.
Additional ANCOVA analyses with multiple imputation for the primary endpoint will be 
used to examine the interaction of treatment group with study site, Baseline pain score, type 
of primary cancer (eg, breast, lung, etc), Baseline opioid use and the stratification parameters. 
The change from Baseline to Weeks 2, 4, 8, 16, and 24 in the
 will also be 
summarized, and analyzed using the ANCOVA main effects model as described above with 
multiple imputation.
For the daily worst and average pain (in the index site) response efficacy endpoints (defined 
by a ≥30%, ≥50%, ≥70% and ≥90% change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 
24), will be summarized and analyzed using logistic regression for binary data, with model 
terms for Baseline average/worst pain subscale score, stratification variables, and treatment 
group.  Imputation for missing data will use both LOCF and BOCF, where imputation with 
BOCF will lead to the subject being assessed as a non-responder for the response endpoint at 
a particular time point.  Also, 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 
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9.3.4. Opioid Use and Opioid Adverse Effects Analysis
Opioid data from subjects randomized to the tanezumab 10 mg treatment group will only be 
summarized, and not included in statistical analyses of opioid use data.
Average daily opioid consumption (mg of morphine equivalent dosage) and average number 
of doses of rescue opioid consumption per week will be summarized for each week up to 
Week 24.  Percent change from Baseline in average daily opioid consumption will be 
analyzed using ANCOVA on the rank scores with treatment and the stratification variables as 
factors.  The average number of doses of rescue opioid consumption per week will be 
analyzed using a negative binomial model taking into account Baseline daily average pain 
and Baseline opioid use.
The number of doses of rescue medication per week will be summarized by treatment group 
for each week up to Week 24.  The total number of doses of rescue medication in Weeks 1, 2, 
4, 8, 16, and 24 will be analyzed using a negative-binomial regression model using the 
log-total number of days of data collection as the subject offset variable.  The resulting 
analysis will show the estimated rate of opioids taken as rescue medication for each week.  
This estimated rate will be shown by treatment group with standard error and 95% CI.  The 
ratio of the opioid usage rate between tanezumab + opioid versus opioid alone will be shown 
(with standard error and 95% CI).
The Opioid-Related Symptom Distress Scale (OR-SDS) is a questionnaire on the frequency, 
severity and level of bother of 10 symptoms.  For each symptom the mean of the frequency, 
severity and bother is calculated to become the Multi-Domain Average (MDA).  These are 
the four dimensions for each symptom.  The mean of each dimension over all symptoms is 
calculated to become the frequency, severity, bother and MDA composite scores.  Each of 
the four dimensions will be summarized by treatment and treatment difference for the 
10 symptoms and the overall composite, a total of 44 sets of summary measures.  The MDA 
for each symptom and the four dimensions for the composite score will be analyzed for each 
time point.  The analysis of this data will use a mixed effects repeated measures model and 
show analysis results for the change from Baseline to Weeks 2, 4, 8, 16, and 24.
9.4. Safety Analysis
Adverse events, concomitant medications, laboratory safety tests, physical and 
vital signs, ECGs, 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. 
Safety data from subjects randomized to the tanezumab 10 mg treatment group will be 
included in safety summaries and listings.
Adverse Events of Abnormal Peripheral Sensation will be summarized.  
Separate adverse event summaries by treatment group for adverse events of decreased 
sympathetic function will be conducted.  More specifically, adverse events with the 
CCI
CCI
CCI
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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 (refer to Section 9.7).
Selected adverse events of interest and common adverse events will be summarized using 
Risk Differences (with 95% confidence intervals) between the tanezumab 20 mg group and 
placebo.  In addition, significance testing will be performed for adverse events of interest 
between the tanezumab 20 mg 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.
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. 
Individual subjects with positive ADA results will be evaluated for potential impact on the 
individual’s pharmacokinetic, efficacy and safety profile.
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 
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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 
joint-related safety events resulting in total joint replacement and/or discontinuation from the 
study as well as adverse events reported as osteonecrosis, rapidly progressive osteoarthritis, 
or other events suggestive of abnormal joint destruction.  These will include, but will not be 
limited to events identified for adjudication by the Central Reader (refer to Section 7.3.9).
Refer to Appendix 2 for adjudication categories and conditions that could result based on a 
subject’s case assessment by the Adjudication Committee.
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.
After each review meeting, the Adjudication Committee’s blinded summary of events will be 
provided to the External Data Monitoring Committee (E-DMC).
9.6. Interim Analysis
The study is designed as a Group Sequential Design using a single interim analysis.  The 
purpose of the interim analysis is to assess the non-binding futility and the evidence of 
efficacy of the primary efficacy parameter.  
The interim analysis will be performed when at least 50% (36 from each treatment group) of 
subjects have completed or discontinued prior to Week 8. Based on current enrollment, it is 
expected that the interim analysis will include approximately 36 to 45 subjects per treatment 
group.
The non-binding futility stopping boundary will be defined using EAST version 6.3.1 (Cytel 
inc.), using the conditional power of 10% (based on estimated delta/sigma) boundary, for a 
one-sided assessment of futility.  The efficacy stopping boundary will be defined using the 
same software, using the Lan-DeMets Beta alpha spending function with the 
O’Brien-Fleming style boundary, for a one-sided assessment of efficacy. 
The analysis will be conducted by a statistician outside of Pfizer, with all details of the 
treatment allocation, analysis and results unknown to all within Pfizer or the contract 
research organization (CRO) performing the final analysis programming.  In the situation 
where the futility or efficacy stopping rule is met, then the statistician will convey the results 
of the interim analysis to a senior statistician within Pfizer (but outside the study team) to 
repeat and ratify the analysis.  The decision to stop the study will be made by Pfizer.  Results 
of the interim analysis will not be known to anybody in the study team until the formal 
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Before any interim analysis is initiated, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind as per Pfizer’s standard 
operating procedures (SOPs) will be documented and approved in an Interim Analysis 
charter.  In addition, the analysis details must be documented and approved in an interim 
analysis SAP or final SAP.
Once all subjects have completed the Week 24 Visit, a data-cut may be produced, and the 
study may be reported for efficacy data.  This would be an unblinded analysis of the final 
efficacy data, although patients and investigators would remain blinded throughout the 
remainder of the trial.  Safety data would continue to be collected for the remaining subjects 
in the trial, up to the end of Week 48.  A final analysis of safety data would also be produced 
for all subjects for the total study duration.  Any joint safety events will continue to be 
adjudicated in a blinded manner. 
9.7. Data Monitoring Committee 
This study will use an External Data Monitoring Committee (E-DMC) which 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 that 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 
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9.7.1. Protocol-Level Rules for Dosing Suspension/Safety Assessments
9.7.1.1. Serious Adverse Events
Tanezumab safety will be reviewed at two levels; blinded data reviews by Pfizer and 
unblinded reviews by the E-DMC.  The E-DMC will review 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 
placebo-treated 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);
•
Autonomic or peripheral neuropathy confirmed with objective findings such as 
treatment-emergent abnormalities on
nerve conduction 
abnormalities or biopsy findings consistent with peripheral neuropathy.
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.  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 study medication to the adverse event;
•
Consideration of whether similar adverse events are occurring in other tanezumab studies 
with similar subject populations;
•
Dosage of tanezumab (10 mg or 20 mg) and distribution of adverse events across 
tanezumab dose arms;
•
Possible differences in the Baseline demographics between treatment groups;
•
Use of concomitant medications;
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
Possible differences in Baseline medical history;

Study medications other than tanezumab;

Duration of therapy (0-6 months, 6-12 months).
9.7.1.2. 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 tanezumab studies, dosing will be 
temporarily suspended in all studies until the relationship to study drug is established. 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 pain program may be 
stopped.
9.7.1.3. 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 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 (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 (or spontaneous osteonecrosis of the knee 
[SPONK]), 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 6 per 
1000 patient-years, if adjudicated events of interest are reported in 3 or more 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 6 per 1000 patient-yrs the appropriate threshold number of events 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.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits 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 


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audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent,
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or 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 investigator’s 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 


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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, and telephone call reports).  The records should 
be retained by the investigator according to the International Conference on Harmonisation 
(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 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 (IRB)/Ethics Committee (EC)
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 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 GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.


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When study data is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subject 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.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
Given the design of this study, which includes a 24 week safety followup period during 
which subjects no longer receive study medication and instead receive standard-of-care 
treatment, providing additional investigational product at the conclusion of the study is not 
feasible.
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 that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, CTA) and ethics application in the Member State.  
Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State 
is not a reason for premature termination but is considered a normal conclusion to the study 
in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as database lock.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, 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 all Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 


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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.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
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 multicenter 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.


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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the 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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16. REFERENCES
1.
Slatkin N, Zaki N, Wang S, et al. Efficacy, safety, and tolerability of fulranumab as 
adjunctive therapy for cancer-related pain: a randomized, double-blind, placebo-
controlled, multicenter study. Support Care Cancer 2015; 23 (Suppl 1): Abstr 03-01-O.
2.
Tanezumab Investigator Brochure.
3.
Pfizer. TANEZUMAB ARTHRITIS ADVISORY COMMITTEE BRIEFING 
DOCUMENT. February 8, 2012; In; 2012. 
URL:http://www.fda.gov/AdvisoryCommittees/Calendar/ucm286556.htm?utm_source=
fdaSearch&utm_medium=website&utm_term=March 12, 2012&utm_content=1.Access 
Date: April 4, 2012.
4.
Hertz S, Fields E. Addendum to the Background Package for the March 12, 2012, AAC 
Meeting, Regarding the Agency Adjudication of Cases of Joint Replacements Occurring 
in Clinical Trials of Anti-NGF Agents. In; March 2, 2012. 
URL:http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Ar
thritisDrugsAdvisoryCommittee/ucm295201.htm. Access date: April 4, 2012.
5.
Rappaport BA. FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation 
and Research: Background Materials. February 13,2012.
URL:http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Ar
thritisDrugsAdvisoryCommittee/ucm295201.htm. Access date: April 4, 2012.
6.
Bennett DLH, McMahon SB, Rattray, et al. Nerve growth factor and sensory nerve 
function. In “Pain and Neurogenic Inflammation”, eds. SD Brain and PK Moore. 
Birkhauser, Basel. 1999.
7.
Woolf CJ, Safieh-Garabedian B, Ma QP, et al. Nerve growth factor contributes to the 
generation of inflammatory sensory hypersensitivity. Neuroscience 1994; 62:327-31.
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CCI
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EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FSFV
first subject first visit
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase
GnRH
gonadotropin-releasing hormone
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiation Protection
ID
identification
IND
Investigational New Drug application
INR
International Normalized Ratio
IgG
immunoglobulin G
IgG2
immunoglobulin G Type 2
IRB
institutional review board
IL
interleukin
IR
immediate release
IRT
interactive response technology
ITT
intent to treat
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous 
IWRS
interactive web response system
LDH
lactate dehydrogenase
LFT
liver function test
LOCF
Last Observation Carried Forward
LSLV
last subject last visit 
LSMean
least squared mean
MAb 911 
murine precursor antibody to tanezumab
MDA
Multi-Domain Average
MMR
measles, mumps and rubella
MRI
magnetic resonance imaging
mSv
millisievert
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NGF
nerve growth factor
CCI
CCI
CCI
CCI


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VAS
visual analog scale
WHO
World Health Organization
WOMAC
Western Ontario and McMaster University Osteoarthritis Index




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Appendix 3. Eastern Cooperative Group (ECOG) Performance Status
ECOG Performance Status47
Grade
ECOG Performance Status Definition
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physical strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed 
or chair.
5
Dead.


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Appendix 4. American College of Rheumatology (ACR) Classification Criteria for 
Osteoarthritis
1986 Osteoarthritis Knee Criteria53
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 Criteria54
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).
ESR testing may be conducted at the local laboratory or at the study site by appropriately-
trained staff using an approved test kit; prior ESR test results from a local laboratory may 
also be used provided they have been performed within 30 days of Screening.


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Appendix 6. 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; a sixth category was later added.  These 
are:
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 7. Half-Lives of NSAIDs and Other Analgesics
Other than background opioids (refer to Section 5.8.2.1) and certain permitted non-opioid 
analgesics (refer to Section 5.8.2.2), the use of any other analgesic is prohibited throughout 
the study, beginning 48 hours prior to the start of the Baseline Assessment Period (the five
days prior to Randomization/Baseline) or at the period of time prior to the start of the 
Baseline Assessment Period that is at least 5 times the half-life of the particular analgesic 
used, whichever is greater.  Half-lives of the analgesics included below are shown for 
reference and do not mean that it is prohibited, unless it is described in Section 5.8.1.1.  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
1.1
2 days
Diclofenac/misoprostol
2.4-9.0
2 days
Diflunisal
13.0
3 days
Dipyrone
2.0-5.0
2 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
Ibuprofen
2.1
2 days
Indomethacin
4.6
2 days
Ketoprofen
1.8
2 days
Ketorolac
4.0-9.0
2 days


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HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
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
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
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
Tenoxicam
60.0
13 days
Tiaprofenic acid
3.0
2 days
Tolmetin
1.0
2 days
Tramadol
5.9
2 days
Diclofenac gels 
1.9
2 days


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Appendix 8. Restrictions on Prior and Concomitant Medications
Medications for non-cancer, non-pain conditions are permitted throughout the study.  Dose 
adjustments (including starting a new therapy) during the study can be made if required, and 
recorded on the concomitant medication CRF.
Some restrictions apply to certain prior and concomitant medications including those used in 
the treatment of the underlying cancer, bone metastasis or pain.
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, or discuss with 
the study monitor or study clinician.
Opioids:
The following opioids are not permitted in this study:
butorphanol*
meperidine*
nalbuphine*
pentazocine*
propoxyphene **
opioids in combination with non-opioids (such as acetaminophen or 
NSAIDs)***
* Use not recommended by NCCN Guidelines27; 
** Withdrawn from some major markets due to safety concerns
*** Opioids in combination with acetaminophen may be permitted as standard of care analgesia 
from Week 8 onwards. Opioid-NSAID combinations are prohibited throughout the study until
at least 16 weeks have passed since the last dose of study medication (Week 32 or Early 
Termination Visit 2).
Refer to 5.8.1.1.
NSAIDs & COX-2 selective inhibitors:
Use of NSAIDs and COX-2 selective inhibitors, both prescription or over-the-counter (OTC) 
is prohibited during the study until Week 32 except for occasional use.  
Limited concomitant use of prescription or OTC NSAIDs may be allowed on an occasional 
basis for self-limiting conditions not related to cancer pain.  However, they must not be taken 
within 48 hours of a study visit where efficacy assessments are being collected.  NSAID use 
should not exceed a total of 36 days between Day 1 (Baseline) and Week 32 and the 
aggregate usage of NSAIDs during any one dosing interval (defined as the period of 8 weeks 
between 2 SC doses) should not exceed 10 days. 
Management of NSAID use is described in Section 5.8.1.2.1. Washout period guidance is 
provided in Appendix 7. 
Daily low dose aspirin (325 mg as per local prescribing practice) therapy for cardiovascular 
prophylaxis is permitted without restriction.
Adjuvant analgesics:


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Use of concurrent adjuvant analgesics is permitted if started at least 30 days prior to the first 
day of the Baseline Assessment Period and maintained at a stable dose. These may include:
single-agent acetaminophen (paracetamol), serotonin norepinephrine reuptake inhibitors 
(SNRI), tricyclic antidepressants, anticonvulsant medication, corticosteroids, or muscle 
relaxants. Treatment should not be initiated within 30 days of the start of the Baseline 
Assessment Period or during the study until at least Week 8.  
Other analgesics:
The use of other analgesics (other than background opioids and permitted uses described in 
Section 5.8.2) is prohibited throughout the study beginning 48 hours (or 5 half-lives, 
whichever is longer) prior to the start of the Baseline Assessment Period and ending at 
Week 8.  
Refer to Appendix 7: Half-Lives of NSAIDs and Other Analgesics, for a detailed washout 
schedule for analgesic medications.  Sites must consult product labeling and conduct a taper 
according to the product instructions if a taper is required. 
Herbal, homeopathic, and naturopathic remedies:
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 
start of the Baseline Assessment Period will be allowed to continue their regimen.  
Corticosteroids:
Unless they were started at least 30 days prior to the first day of the Baseline Assessment 
Period and are maintained at a stable dose, oral or intramuscular corticosteroids used as 
concomitant analgesics are prohibited from the start of the Baseline Assessment Period 
through Week 8.
Oral or intramuscular corticosteroids used as concomitant analgesics starting less than
30 days prior to the Baseline Assessment Period must be washed out during the Screening 
Period for a period of at least 48 hours or 5 times the half-life of the particular corticosteroid 
(whichever is greater) before starting the Baseline Assessment Period.  Intra-articular 
injection of corticosteroids to any major joint within 30 days prior to the Baseline
Assessment Period through Week 32 is prohibited.  
Limited use of oral, intramuscular or intravenous corticosteroids for non-analgesic purposes 
such as prophylaxis or treatment of chemotherapy-induced nausea and vomiting is permitted.  
Topical, inhaled and intranasal corticosteroids are permitted.  Refer to Section 5.8.2.2 for 
details.
Corticosteroid
Permitted
Prohibited
Oral or intramuscular 
corticosteroids used as concomitant 
analgesics
If started at least 30 days prior to 
the first day of the Baseline 
Assessment Period and maintained 
at a stable dose
If started within 30 days of the first 
day of the Baseline Assessment 
Period. Washout is required prior 
to the first day of the Baseline 
Assessment Period, and further use 


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is prohibited until Week 8
Oral, intramuscular or intravenous 
corticosteroids for non-analgesic 
purposes such as prophylaxis or 
treatment of chemotherapy-induced 
nausea and vomiting  
Limited use is permitted
-
Intra-articular injection to any 
major joint 
Allowable after Week 32
Prohibited within 30 days prior to 
the Baseline Assessment Period 
through to Week 32
Topical, inhaled and intranasal 
corticosteroids
Permitted throughout study
-
Examples of Corticosteroids
Generic
Brand
betamethasone
Celestone, Soluspan
cortisone
dexamethasone
Decadron, Dexacort, Turbinaire
fludrocortisone
Florinef
hydrocortisone
A-hydroCort, Cortef, Hydrocortone, Solu-Cortef
methylprednisolone
Medrol, Solu-Medrol
prednisolone
Orapred, Prelone
prednisone
Cortan, Deltasone, Medicorten
Chemotherapeutic, Radiopharmaceutical or Radiotherapy, Anti-Cancer Hormonal
Treatments
Concomitant chemotherapy is allowable, with some exceptions (see Section 5.8.2.3.),
provided it was ongoing for at least 30 days before the first day of the Baseline Assessment 
Period.  It is acceptable for the regimen to complete at any time after Randomization.  

A subject with chemotherapy-induced peripheral neuropathy can be enrolled provided the 
neuropathy has been stable over the 6 months prior to the start of the Baseline 
Assessment Period and the subject is no longer being treated with a chemotherapy agent 
associated with peripheral neuropathy (i.e. paclitaxel, docetaxel, oxaliplatin, cisplatin, 
vincristine, thalidomide and bortezomib).

Chemotherapies associated with peripheral neuropathy (i.e. paclitaxel, docetaxel, 
oxaliplatin, cisplatin, vincristine, thalidomide and bortezomib) are not permitted from 30 
days prior to the first day of the Baseline Assessment Period to Week 48 regardless of 
symptomatology.


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Receipt of radiopharmaceutical treatment or radiotherapy for treatment of bone metastasis 
within 30 days of the first day of the Baseline Assessment Period and through to Week 8 is 
not permitted.  
Concomitant hormonal anti-cancer treatment (eg, GnRH agonists or antagonists, anti-
androgens or anti-estrogens) is allowable if treatment has been ongoing at stable dose for at 
least 30 days prior to the first day of the Baseline Assessment Period. Post Baseline, the 
concomitant hormonal anti-cancer treatment dose regimen should remain stable until at least 
Week 8.
If prior to Week 8, the subject’s underlying cancer or bone metastasis progresses so as to 
require a new chemotherapy regimen, new concomitant bisphosphonates, new concomitant 
hormonal anti-cancer treatment, or initiation of radiotherapy to sites of bone metastasis, the 
subject should be withdrawn from study and entered in the Early Termination Follow-Up 
period (refer to Section 6.4). 
Following the Week 8 visit, standard of care treatments may be initiated (refer to Section 
5.8.2.3).
Criteria for Use of Chemotherapeutic, Radiopharmaceutical/ Radiotherapy or Hormonal Treatments*
Therapy
Permitted 
Prohibited 
Chemotherapy
(see below for criteria regarding 
biologics)
Allowable, with some exceptions 
(see Section 5.8.2.3.), if ongoing 
for at least 30 days before start of 
Baseline Assessment Period. 
If a new chemotherapy regimen is 
required prior to Week 8, subject 
should be withdrawn and entered 
in the Early Termination Follow-
Up period (refer to Section 6.4).
Chemotherapies associated with 
peripheral neuropathy (i.e. 
paclitaxel, docetaxel, oxaliplatin, 
cisplatin, vincristine, thalidomide 
and bortezomib) are not permitted 
from 30 days prior to the first day 
of the Baseline Assessment Period 
to Week 48 regardless of 
symptomatology.
Radiopharmaceutical treatment 
or radiotherapy for bone 
metastasis
Permitted if ≥30 days prior to first 
day of the Baseline Assessment 
Period.
Prohibited within 30 days of the 
first day of the Baseline 
Assessment Period through to
Week 8.  
If initiation of radiotherapy to sites 
of bone metastasis or new 
radiopharmaceutical regimen is 
required prior to Week 8, subject 
should be withdrawn and entered 
in the Early Termination Follow-
Up period (refer to Section 6.4).
Concomitant hormonal anti-
cancer treatment (eg, GnRH 
agonists or antagonists, anti-
androgens or anti-estrogens)
Permitted if ongoing at stable dose 
for ≥30 days prior to first day of 
Baseline Assessment Period. 
Post-Baseline, should remain stable 
until at least Week 8.
If initiation of new concomitant 


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hormonal anti-cancer treatment is 
required prior to Week 8, subject 
should be withdrawn and entered 
in the Early Termination Follow-
Up period (refer to Section 6.4).
*Following the Week 8 visit, standard of care treatments may be initiated (refer to Section 5.8.2.3).
Biologics
Monoclonal antibodies used for the treatment of underlying cancer or bone are generally 
permitted if ongoing at stable dose regimen at least 30 days prior to the first day of the 
Baseline Assessment Period (see Section 5.8.2.3.) and not meeting other exclusionary 
criteria. Standard of care treatments may be initiated following the Week 8 visit, if required.
Monoclonal antibody therapies associated with clinically significant peripheral or autonomic 
neuropathy or joint-related adverse effects or those based on chimeric or murine antibodies 
are prohibited within 90 days of the start of the Baseline Assessment Period and during the 
study until Week 32. 
Examples of permitted and prohibited monoclonal antibody therapies are provided in the 
following list for your reference but may not be all inclusive. Therapies which are not 
specifically listed should be discussed with the study clinician on a case-by-case basis. 
Small molecule inhibitors used in the treatment of underlying cancer or bone metastasis are 
permitted (except for bortezomib) if at a stable dose regimen at least 30 days prior to the first 
day of the Baseline Assessment Period. 
Cell/gene therapies, investigational therapies, or TNF-inhibitors are generally prohibited 
and must not be taken within 90 days prior to start of the Baseline Assessment Period or 
during the study until Week 32. 
Criteria for Use & Examples of Biologics
Biologic
Permitted
Generic (Brand)
Prohibited
Generic (Brand)
Monoclonal antibodies used in 
the treatment of underlying 
cancer or bone metastasis*
Permitted if not meeting exclusion 
criteria and at a stable dose 
regimen at least 30 days prior to 
the first day of the Baseline 
Assessment Period.
Eg, 
Bevacizumab (Avastin)
Trastuzumab (Herceptin)
Panitumumab (Vectibix)
Denosumab (Prolia, Xgeva)
Nivolumab (Opdivo)
Prohibited if associated with 
significant neurologic or 
musculoskeletal adverse effects or 
those based on chimeric or murine 
antibodies are prohibited from 
within 90 days of the start of the 
Baseline Assessment Period and 
for the duration of the study until 
Week 32.
Eg, 
Cetuximab (Erbitux)


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Pembrolizumab (Keytruda) 
Ramucirumab (Cyramza)
Ado-trastuzumab emtansine 
(Kadcyla)
Chemotherapies associated with 
peripheral neuropathy are not 
permitted from 30 days prior to the 
first day of the Baseline 
Assessment Period to Week 48
regardless of symptomatology.
Small molecule inhibitors used in 
the treatment of underlying 
cancer or bone metastasis
Permitted if at a stable dose 
regimen at least 30 days prior to 
the first day of the Baseline 
Assessment Period, except for 
bortezomib. 
Eg, 
Erlotinib hydrochloride (Tarceva)
Sunitinib (Sutent)
Lapatinib (Tykerb)
Prohibited if at unstable dose 
regimen or initiated within 30 days 
prior to the start of the Baseline 
Assessment Period.
Bortezomib is not permitted from 
30 days prior to the first day of the 
Baseline Assessment Period to 
Week 48.
TNFInhibitors
None permitted until Week 32
Prohibited within 90 days prior to 
start of the Baseline Assessment 
Period and during the study until 
Week 32.
Eg,
Adalimumab (Humira) 
Etanercept (Enbrel) 
Infliximab (Remicade)
Blood products
Blood transfusion
Eg, whole blood, platelets
Leukocyte growth factors 
Eg, Filgrastim (Neupogen)
Erythropoietin-stimulating agents
Eg, Epoetin alfa (Epogen)
-
Cell/gene therapies
None permitted
Prohibited within 90 days prior to 
start of the Baseline Assessment 
Period and during the study.
*Monoclonal antibody therapies which are not specifically listed as permitted or prohibited should be reviewed 
with the study clinician prior to enrollment.
Vaccines:
Inactivated viral or bacterial vaccines are permitted. Eg, Influenza  (Fluzone, Agriflu), 
Pneumococcus (Pneumovax), Tetanus, [reduced] Diphtheria (Td).
Use of live attenuated vaccines (with the exception of FlumistInfluenza Virus Vaccine 
Live, Intranasal or other inhaled live attenuated influenza vaccines) is prohibited within 90 
days of the start of the Baseline Assessment Period and during the study. 


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Prohibited Live Attenuated Vaccines
Generic
Brand
BCG (for tuberculosis)
Not available in the US
Herpes zoster vaccine
Zostavax
Measles
Attenuvax
Measles, Mumps, and Rubella (MMR)
MMR
Mumps
Mumpsvax
Oral poliovirus vaccine, oral
OPV (no longer available in the US)
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 9. Daily/Weekly Pain IRT Assessments
Index Bone Metastasis Cancer Pain Site Assessment
Average pain example question for the index bone metastasis cancer pain site:
Select the number that best describes your average pain in your <insert index site of bone 
metastasis pain> in the past 24 hours:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
Worst pain example question for the index bone metastasis cancer pain site:
Select the number that best describes your worst pain in your <insert index site of bone 
metastasis pain> in the past 24 hours:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
Non-index site(s) of Cancer Pain Assessment
Average pain example question for the non-index site(s) of cancer pain:
Select the number that best describes your average pain in your <insert non-index site of 
cancer pain> in the past 24 hours:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
Worst pain example question for the non-index site(s) of cancer pain:
Select the number that best describes your worst pain in your <insert non-index site of bone 
metastasis pain> 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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Joint Pain Assessments
Example question for major joints (each shoulder, hip and knee and any other major joint for 
which a radiograph is obtained):
Select the number that best describes your average pain in your < insert name and laterality 
of major joint> 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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Appendix 11. Opioid-Related Symptom Distress Scale
The subject will complete the following table detailing his/her experience with respect to the 
study medication taken for pain.
We have listed 10 symptoms below.  Read each one carefully.  If you have had the symptom during the 
past 24 hours, let us know how OFTEN you had it, how SEVERE it was usually and how much it 
DISTRESSED OR BOTHERED you by placing an “X” in the appropriate box.  If you DID NOT HAVE 
the symptom, please place an “X” in the box marked “Did not have”.
For the symptom “retching/vomiting” below, you will indicate the actual number of episodes you 
experienced.
During the last 24 hours, did you have any of the following?
Symptom
Did not
have
(If yes), how often 
did you have it?
Rarely
Occasionally
Frequently
Almost
Constantly
Slight
Moderate
Severe
Very Severe
Not at all
A little bit
Somewhat
Quite a Bit
Very Much
# of episodes
(If yes), how severe 
was it usually?
(If yes), how much did  it 
distress or bother you?
Fatigue
Drowsiness
Dizziness
Constipation
Itching
Difficulty with urination
Confusion
Retching/vomiting
Nausea
Inability to concentrate
Symptom
Did not
have
(If yes), how often 
did you have it?
Rarely
Occasionally
Frequently
Almost
Constantly
Rarely
Occasionally
Frequently
Almost
Constantly
Slight
Moderate
Severe
Very Severe
Not at all
A little bit
Somewhat
Quite a Bit
Very Much
# of episodes
(If yes), how severe 
was it usually?
(If yes), how much did  it 
distress or bother you?
Fatigue
Drowsiness
Dizziness
Constipation
Itching
Difficulty with urination
Confusion
Retching/vomiting
Nausea
Inability to concentrate




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Appendix 15. Example for Reporting Daily/Weekly NRS Pain Scores
As an example, assume that a subject has a painful bone metastasis (7 out of 10 average NRS 
rating) in the lower lumbar region.  In addition, the subject has a painful visceral metastasis 
in the right abdomen (4 out of 10 average NRS).  Finally, the subject has a mild, stable 
painful chemotherapy-induced peripheral neuropathy in both feet (3 out of 10 average NRS).
The subject may be shown a diagram on the IRT such as the one shown below to enable the 
subject to note the location of painful sites.  In this example, assume that the subject is able to 
select painful sites according to the number shown on the diagram.
At Screening, the subject will be asked to select the most painful site of bone metastasis pain, 
(which in the example diagram below would be site # 67) and to provide average and worst 
pain ratings for this site.  Once confirmed by the investigator, this will be the index site of 
bone metastasis cancer pain.
The subject will be asked via the IRT whether he or she is experiencing cancer pain in site(s) 
other than the index site of bone metastasis cancer pain.  If yes, the subject will be asked to 
specify up to 2 additional painful sites.  In this case, the subject will select site #1, (although 


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alternatively, site #2 could have been selected since the pain was equal in each foot), and 
site #15 as additional sites of pain and will provide average and worst pain ratings for each 
site.  Once confirmed by the investigator, these sites will be the non-index sites of cancer 
pain.
At Screening the investigator will confirm that the site identified by the subject as the most 
painful site corresponds to a site of bone metastasis (ie, the investigator will confirm the 
index bone metastasis cancer pain site).  In addition, for other non-index sites of cancer pain 
selected by the subject, the investigator will confirm that pain at each site is due to cancer or 
cancer treatment (eg, chemotherapy induced peripheral neuropathy) and will indicate 
whether in his/her judgment the cancer pain for each site is somatic, neuropathic or visceral 
in nature.
In this example at Screening, the investigator would confirm that the most painful site 
(site #67) is the index bone metastasis cancer pain site and would confirm that sites #1 
and #15 are non-index cancer pain sites.  The investigator would indicate site #1 represents 
neuropathic pain, and site #15 represents visceral pain.
After Screening, the IRT will be programmed to display either the index bone metastasis 
cancer pain site (for daily assessments) or both the index site and non-index sites of cancer 
pain (for weekly assessments) selected at Screening so the subject can provide pain ratings 
for these sites during the study.


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Appendix 16. Substudy for Subjects Undergoing Total Joint Replacement of the Hip, 
Knee or Shoulder
SUBSTUDY SUMMARY
Measures to better characterize the joint safety issue identified in 2010 have been developed 
and agreed with FDA.  The post-arthroplasty data collected within this substudy, when 
aggregated with similar data from other tanezumab clinical studies, fulfills one component of 
the agreed risk characterization measures and is an attempt to address the potential concern 
that subjects treated with tanezumab have a different post-surgical outcome than those not 
treated with tanezumab.  The total joint replacement data from completed tanezumab studies 
does not suggest a different post-surgical outcome in tanezumab treated subjects however 
those data were gathered retrospectively.  The types of endpoints to be assessed in this 
prospective substudy and the duration of this substudy have been agreed to with the FDA.  
Every effort will be made to enroll all A4091061 subjects who undergo a qualifying total 
joint replacement into this substudy however it is acknowledged that to a certain extent the 
population enrolled in this substudy will be 'self-selected' and thus there may be subjects with 
a qualifying total joint replacement who choose not to enter the substudy. 
This substudy is a long-term observational study of subjects from tanezumab Study 
A4091061 (regardless of treatment group) who undergo a total knee, hip or shoulder 
replacement during participation in the study (Treatment Period and Safety Follow-Up 
period).  If while the subject is participating in this substudy, the subject undergoes an 
additional total joint replacement surgery or the site becomes aware that an additional total 
joint replacement surgery has been scheduled for the subject, the subject will be requested to 
provide information on the additional total joint replacement surgery as well. Finally, any 
subject with a qualifying total joint replacement after the last subject completes the treatment 
period in study A4091061 may be followed in study A4091064 which is a separate study 
with a design similar to this substudy.
This substudy is designed with a total duration of subject follow-up of 24 weeks after the 
total joint replacement surgery.  There will be two methods of data collection utilized in this 
substudy: interview by site staff via the telephone and interactive web response system 
(IWRS) accessed by desktop, laptop or tablet computer (or paper if the subject has no access 
to the internet via a desktop, laptop or tablet computer).  Following the surgery, the subject 
will be contacted monthly via telephone by study site personnel to ascertain whether the 
subject has experienced any adverse events and to record any concomitant analgesic 
medications the subject is taking as well as the reason for the medication use.  An assessment 
of the subject’s overall satisfaction with their total joint replacement (IWRS), average pain in 
the replaced joint (IWRS), the subject’s level of function and activity in the replaced joint 
(IWRS) and physical rehabilitation activities (telephone interview) will be made at Weeks 4, 
12 and 24.  At Weeks 12 and 24, subjects will be queried during the telephone interview as to 
whether any additional or corrective procedures related to the total joint replacement are 
planned. 
All events of total knee, hip or shoulder replacement will be reviewed by the Joint Safety 
Adjudication Committee (Adjudication Committee) established for the tanezumab clinical 


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program.  This Committee will adjudicate in an independent and blinded fashion if the event 
is primary osteonecrosis, worsening OA (further sub-divided into rapidly progressive OA 
(RPOA) type 1 or type 2, normal progression of OA or not enough information to distinguish 
between RPOA and normal progression of OA), subchondral insufficiency fracture, 
pathologic fracture, other (with diagnosis specified) or not enough information to specify a 
diagnosis.  Prior to the Adjudication Committee’s review of a given event, Committee 
members will be provided with blinded, available source documentation of progress reports 
from the investigator, orthopedic consult reports, operative reports, the pathology report from 
the Central Laboratory, radiology reports, Dual Energy X-ray Absorptiometry (DEXA) 
reports, x-ray images and MRI for review.  In addition, blinded summaries of the following 
data from Study A4091061 will be provided to the Committee members for review for each 
event undergoing adjudication: demographic and Baseline characteristics, medical history 
and concomitant medications, study medication administration, non-drug treatments, subject 
disposition, efficacy data, adverse event information,
and a serious 
adverse event narrative (if applicable). 
Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons, and 
clinical research associates (CRAs) and staff directly involved with this substudy at Pfizer 
and its designees will be blinded to treatment assignment in Study A4091061.
The number of subjects who will enroll in this substudy is unknown but is estimated to be 
less than 25 subjects.  Also unknown is the distribution of subjects across treatment groups 
(ie, the treatment given in Study A4091061).  Therefore, it is predicted that there will be 
insufficient statistical power to perform statistical inferential analyses.  All analyses will be
descriptive in nature.  The data collected in this substudy will be combined with similar data 
collected in other tanezumab studies for further analysis.  These aggregate analyses will be 
reported separately.
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101. SUBSTUDY INTRODUCTION
Measures to better characterize the joint safety issue identified in 2010 have been developed 
and agreed with FDA.  The post-arthroplasty data collected within this substudy, when 
aggregated with similar data from other tanezumab clinical studies, fulfills one component of 
the agreed risk characterization measures and is an attempt to address the potential concern 
that subjects treated with tanezumab have a different post-surgical outcome than those not 
treated with tanezumab.  The total joint replacement data from completed tanezumab studies 
does not suggest a different post-surgical outcome in tanezumab treated subjects however 
those data were gathered retrospectively from previous studies.  The types of endpoints to be 
assessed in this prospective substudy and the duration of the substudy have been agreed to 
with the FDA.  Every effort will be made to enroll all Study A4091061 subjects who undergo 
a qualifying total joint replacement into this substudy however it is acknowledged that to a 
certain extent the population enrolled in this substudy will be 'self-selected' and thus there 
may be subjects with a qualifying total joint replacement who choose not to enter the 
substudy.
Every effort will be made to comply with all protocol required procedures however it is 
acknowledged that some protocol requirements could prove operationally difficult to 
complete. For example investigators may be notified of a subject's total joint replacement 
after the surgery and therefore baseline data are not available; the surgeon performing the 
total joint replacement surgery may be unable or unwilling to cooperate with requests to 
complete the Surgeon's Assessment of Procedural Difficulty; or local or national regulations 
may preclude provision of the pathology specimen. Any of these potential operational 
difficulties should not preclude a consenting subject from participating in the A4091061 
substudy. Every effort should be made to obtain any protocol-specified information that the 
subject and surgeon are able to provide.
101.1. Rationale for Selected Patient Reported Outcomes
Subject-based measures of health-related quality of life have increasingly been used by the 
orthopedic research community as a means to define a successful intervention.1  Subject 
reported outcomes typically assessed post-arthroplasty include overall satisfaction with the 
joint replacement, pain and function. 
The Self-Administered Patient Satisfaction Scale (SAPS) will be utilized to assess subject 
satisfaction with the joint replacement in this substudy.  The SAPS is a multidimensional, 
disease specific measure that evaluates subject satisfaction with the outcome of hip or knee 
arthroplasty and was designed to be used in conjunction with other clinical measures and 
functional health status instruments to evaluate the results of hip and knee arthroplasty.  The 
validity and reliability of the scale has been demonstrated.2  The scale consists of four items 
focusing on satisfaction with the extent of pain relief, improvement in ability to perform 
home or yard work, ability to perform recreational activities and overall satisfaction with 
joint replacement.
Average pain in the joint to be replaced (pre-surgery) and the replaced joint (post-surgery) 
will be assessed with an 11-point Numeric Rating Scale (NRS) ranging from zero (no pain) 
to 10 (worst possible pain).  The validity and reliability of the scale has been demonstrated.3


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The functional measures chosen for this substudy were those which have been shown to be 
valid, reliable and sensitive and in addition were region-specific and easy to administer.  
Subjects undergoing total knee or hip replacement will be asked to complete the Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with the knee or hip that 
was replaced serving as the “index joint”.  Subjects undergoing total shoulder replacement 
will be asked to complete the Shoulder Pain and Disability Index (SPADI).
The WOMAC is a self-administered condition-specific instrument which assesses pain, 
disability and joint stiffness in knee and hip osteoarthritis.  It is a valid, reliable and 
responsive measure of outcome in subjects with arthritis and has been used extensively.4,5,6
The SPADI is a self-administered questionnaire that was developed to measure the pain and 
disability associated with shoulder pathology in people with shoulder pain of 
musculoskeletal, neurogenic or undetermined origin.  The psychometric properties of the 
SPADI have been shown to be acceptable for research use and the SPADI has been 
recommended to assess outcomes in subjects undergoing shoulder arthroplasty.7,8  The 
instrument consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use.
101.2. Interactive Web Response System
To avoid a social desirability bias in the subject reported outcomes, an Interactive Web 
Response System (IWRS) will be utilized in this substudy.  Contingency plans will be in 
place to address system and/or connectivity issues with the IWRS. 
However, eligibility for this substudy does not require access to the internet via a desktop, 
laptop or tablet computer so, for those subjects without access to the internet via a desktop, 
laptop or tablet computer, paper versions of the assessments will be utilized.  Though not 
optimal, the use of two methods to collect subject reported outcomes will maximize the 
ability to capture information from all subjects who undergo a total knee, hip, or shoulder 
replacement surgery while participating in Study A4091061.  Additional considerations 
which mitigate the concerns about using two methods to collect subject reported outcomes in 
the same substudy include that this substudy has not been formally powered and all analyses 
will be descriptive rather than inferential.
102. SUBSTUDY OBJECTIVE AND ENDPOINTS
102.1. Objective
To describe the post-operative outcome of subjects who underwent a total knee, hip, or 
shoulder replacement while participating in Study A4091061 (Treatment Period and Safety 
Follow-Up period).
102.2. Endpoints
The following endpoints will be assessed in this substudy:


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
Surgeon’s Assessment of Procedural Difficulty: number and percentage of surgeries 
assessed as uneventful, minor complications or major complications.

Subjects’ overall satisfaction with surgery as assessed by the Self-Administered 
Patient Satisfaction (SAPS) Scale: number and percentage of subjects satisfied versus 
unsatisfied with their total joint replacement at Week 24.

Number and percentage of subjects with a post-surgical complication(s) up to 
Week 24 (derived from reported adverse events).

Number and percentage of subjects with additional or corrective procedures related to 
their total joint replacement up to Week 24.

Number and percentage of subjects participating in physical rehabilitation activities 
related to the replaced joint up to Week 24.

Change from Baseline to Week 24 in average pain in the replaced joint.

Change from Baseline to Week 24 in WOMAC Pain, Stiffness and Physical Function 
subscales in the replaced joint (subjects undergoing total hip or knee replacement 
surgery only).

Change from Baseline to Week 24 in the SPADI in the replaced shoulder (subjects 
undergoing total shoulder replacement surgery only).

Concomitant analgesic medication use.
103. SUBSTUDY STUDY DESIGN
This substudy is a long-term observational study of subjects from tanezumab Study 
A4091061 (regardless of treatment group) who undergo a total knee, hip or shoulder 
replacement during participation in the study (Treatment Period or Safety Follow-Up period). 
If while the subject is participating in this substudy, the subject undergoes an additional total 
joint replacement surgery or the site becomes aware that an additional total joint replacement 
surgery has been scheduled for the subject, the subject will be requested to provide 
information on the additional total joint replacement surgery as well. Finally, any subject 
with a qualifying total joint replacement after the last subject completes the treatment period 
in study A4091061 may be followed in study A4091064 which is a separate study with a 
design similar to this substudy.
This substudy is designed with a total duration of subject follow-up of 24 weeks after the 
total joint replacement surgery.  There will be two methods of data collection utilized in this 
substudy: interview by site staff via the telephone and IWRS accessed by desktop, laptop or 
tablet computer (or paper if the subject has no access to the internet via a desktop, laptop or 
tablet computer).  Following the surgery, the subject will be contacted monthly via telephone 
by study site personnel to ascertain whether the subject has experienced any adverse events 
and to record any concomitant analgesic medications the subject is taking as well as the 
reason for the medication use.  An assessment of the subject’s overall satisfaction with their 


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total joint replacement (IWRS), average pain in the replaced joint (IWRS), the subject’s level 
of function and activity in the replaced joint (IWRS) and physical rehabilitation activities 
(telephone interview) will be made at Weeks 4, 12 and 24.  At Weeks 12 and 24, subjects 
will be queried during the telephone interview as to whether any additional or corrective 
procedures related to the total joint replacement are planned. 
Any subject who expresses a desire to leave this substudy before 24 weeks of follow-up have 
been completed should be asked to complete all assessments scheduled for Week 24.
All events of total knee, hip or shoulder joint replacement will be reviewed by the Joint 
Safety Adjudication Committee (Adjudication Committee) established for the tanezumab 
clinical program.  This Committee will adjudicate in an independent and blinded fashion if 
the event is primary osteonecrosis, worsening OA (further sub-divided into rapidly 
progressive OA (RPOA) type 1 or type 2, normal progression of OA or not enough 
information to distinguish between RPOA and normal progression of OA), subchondral 
insufficiency fracture, pathologic fracture, other (with diagnosis specified) or not enough 
information to specify a diagnosis.  Prior to the Adjudication Committee’s review of a given 
event, Committee members will be provided with blinded, available source documentation of 
progress reports from the investigator, orthopedic consult reports, operative reports, the 
pathology report from the Central Laboratory, radiology reports, DEXA reports, x-ray 
images and MRI images for review.  Sites will be requested to submit required source 
documentation to the Endpoint Management Team as soon as possible, and ideally within 29 
± 5 days, after the total joint replacement surgery (ie, by the time the Week 4 visit occurs 
provided the source documentation has been completed).  In addition, blinded summaries of 
the following data from Study A4091061 will be provided to the Committee members for 
review for each event undergoing adjudication: demographic and Baseline characteristics, 
medical history and concomitant medications, study medication administration, non-drug 
treatments, subject disposition, efficacy data, adverse event information,
and a serious adverse event narrative (if applicable). 
The Adjudication Committee, in coordination with the E-DMC, is responsible for ongoing 
analysis of these outcomes and for informing the sponsor of recommendations made.
Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons, clinical 
research associates (CRAs) and staff directly involved with this substudy at Pfizer and its 
designee will be blinded to treatment assignment in Study A4091061.  The data collected in 
this substudy will be combined with similar data collected in other tanezumab studies for 
analysis.  Data analyses will be reported separately.
104. SUBSTUDY SUBJECT SELECTION
This substudy can fulfill its objectives only if appropriate subjects are enrolled.  The 
following eligibility criteria are designed to select subjects for whom the substudy is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this substudy is suitable for a particular subject. 
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104.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team (ie, the investigator or a sub-investigator) before subjects are 
included in this substudy.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
substudy:
1. Evidence of a personally signed and dated informed consent document indicating the 
subject (or a legal representative) has been informed of all pertinent aspects of the 
substudy.
2. Subject has been randomized and treated with SC study medication in tanezumab Study 
A4091061 and has completed the study or has been withdrawn from the study. 
3. Actual or planned total knee, hip or shoulder replacement surgery during Study
A4091061.  Note: additional procedures in a subject undergoing total joint replacement 
surgery (eg, revision of a previously replaced joint in addition to a new total joint 
replacement) will be allowed, but subjects undergoing solely sub-total arthroplastic 
procedures (eg, hemi-arthroplasty) will not be eligible.
4. Subject is willing and able to comply with scheduled visits and other substudy 
procedures. 
104.2. Life Style Guidelines 
All female subjects who are of childbearing potential and are sexually active and at risk for 
pregnancy, and who withdraw from Study A4091061 less than 16 weeks after the last 
dose of subcutaneous investigational product must agree to use one (1) method of highly 
effective contraception consistently and correctly until 112 days (16 weeks) after the last 
dose of subcutaneous investigational product. The investigator or his/or her designee, in 
consultation with the subject, will confirm the subject has selected the most appropriate form 
of contraception for the individual subject from the permitted list of contraception methods 
(see below), and instruct the subject in its consistent and correct use. Subjects need to affirm 
that they meet the criteria for correct use of the selected method of contraception. The 
investigator or his/her designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly according to the schedule of activities and document 
such conversation in the subject’s chart. In addition, the Investigator or his/or her designee 
will instruct the subject to call immediately if the selected birth control methods are 
discontinued or if pregnancy is known or suspected in the subject.Refer to Section 4.4 of the 
protocol for guidance on appropriate methods of contraception. 
There are no contraception requirements for sexually active female subjects of childbearing 
potential who withdraw from Study A4091061 more than 16 weeks after the last dose of 
subcutaneous investigational product.


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104.3. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for this 
substudy is documented in the study contact list located in the Study Manual (refer to 
Section 4.5 of the A4091061 protocol). 
105. SUBSTUDY STUDY TREATMENTS
This is an observational study of subjects who were randomized and treated in tanezumab 
Study A4091061 and who subsequently underwent a total knee, hip or shoulder replacement
during the Treatment or Safety Follow-Up period.  There are no study medications in this 
observational study. 
Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons, clinical 
research associates (CRAs) and staff directly involved with this substudy at Pfizer and its 
designees will be blinded to treatment assignment in Study A4091061.
105.1. Concomitant Medication(s)
No medications are specifically prohibited in this observational substudy. 
Subjects who enter into this substudy <16 weeks after their last dose of subcutaneous study 
medication in Study A4091061 will be advised to avoid chronic NSAID use or intra-articular 
corticosteroids, until at least 16 weeks has elapsed, if possible.
Subjects will be instructed to keep a record of concomitant analgesic medication usage 
(including dose, dosing regimen and reason for use).  This information will be recorded on 
the appropriate concomitant medication case report form (CRF) during the monthly 
telephone interviews.
106. SUBSTUDY STUDY PROCEDURES
Study visit windows are +10 days for activities related to the total joint replacement surgery 
and 5 days for activities performed on Weeks 4, 8, 12, 16, 20 and 24.  Site staff should 
make every effort to contact the subject within the defined visit window for Weeks 4, 8, 12, 
16, 20 and 24 however, data obtained outside of the visit window while a deviation, should 
still be recorded.  In the event that the activities related to a visit are performed within the 
extremes of the visit windows, following study visits and associated activities should be 
scheduled with reference to the total joint replacement surgery date.  Subject scheduling 
issues should be brought to the attention of study management for resolution. 
The investigator must make sure that delegations of responsibility to site staff for 
administering the IWRS or entering data into the IWRS are specifically documented using 
the appropriate forms and are based on documented evidence of adequate training in 
administration and use of the IWRS.  The investigator (or other site staff specifically 
delegated by the investigator) is responsible for regular monitoring of the compliance of the 
subjects with the required data entry by means of reports in the IWRS.  The IWRS will also 
be programmed to notify designated site staff when data has not been recorded within the 
requested timeframe.  Regardless of how the investigator delegates responsibility for 
administering the IWRS or entering data into the IWRS, the investigator remains responsible 


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for providing adequate supervision and oversight of the investigator’s colleagues, employees 
and any third parties as per FDA regulations and guidelines and Good Clinical Practice.
106.1. Baseline Visit (Last Visit in Study A4091061 or when Notified of TJR Surgery)
Baseline information for this substudy should be obtained as close as possible to, and prior 
to, the total joint replacement surgery.  The Baseline Visit may coincide with the last visit in 
Study A4091061 (End of Study or Early Termination Visit) or occur when the site is notified 
of a planned total joint replacement surgery.  Baseline Visit activities must be conducted at 
the clinical site. 
If a planned surgery is postponed such that more than 30 days has elapsed since the baseline 
pain and function assessments for the substudy were recorded, if possible, repeat assessments 
of pain and function should be recorded.
Subjects should be queried about their access to the internet via a desktop, laptop or tablet 
computer so as to determine the appropriate format for the subject reported outcomes of pain 
in the joint to be (or post-surgery, that has been) replaced, functional status and, post-surgery, 
satisfaction with surgery. 
Subjects with access to the internet via a desktop, laptop or tablet computer should be trained 
in the use of the IWRS and in their responsibilities for data entry in compliance with this 
substudy protocol.  IWRS technical support (Help Desk) will be available to the subject for 
the duration of the study.  Beginning with the Baseline Visit, subjects with access to the 
internet via a desktop, laptop or tablet computer should complete the aforementioned 
assessments via the IWRS.  In the event of internet connectivity issues at the Baseline Visit, 
paper versions of the assessments should be completed.
Only subjects without access to the internet via a desktop, laptop or tablet computer during 
this substudy should complete the aforementioned assessments on paper for the duration of 
the substudy.  Simple preference for the use of paper is not sufficient to allow its use by the 
subject who has access to the internet via a desktop, laptop or tablet computer during this 
substudy.
Except in unusual circumstances, subjects should not switch between paper-based and 
web-based completion of the subject reported outcome measures. 
Thorough instruction should be provided for completion of self-administered scales (subject 
reported outcomes) however, no coaching or other interpretative assistance should be given 
to the subject during the completion of the questionnaires. 
Telephone contact information should also be confirmed at the Baseline Visit.
106.1.1. Activities at the Baseline Visit:

Informed consent.

Review of inclusion criteria.


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
Record ongoing adverse events and concomitant analgesic medications.

Assessment of pain in the joint to be replaced (11-point NRS).

Assessment of functional status in the joint to be replaced (WOMAC for subjects 
undergoing total knee or hip replacement or SPADI for subjects undergoing total 
shoulder replacement).  NOTE: the WOMAC and SPADI should be completed in 
their entirety.

Subjects without access to the internet via a desktop, laptop or tablet computer should 
be provided with paper copies of the subject reported outcomes assessments.  
Subjects should be instructed on the timing of assessments and the need to return the 
assessments to the site as soon as possible, but no later than 5 days, after completion 
of the assessment.

Study site staff must contact the subject’s orthopedic surgeon to discuss the 
completion of the required forms and specimen collection and handling. The surgeon 
will be provided with the surgery related documents (Surgeon’s Assessment of 
Procedural Difficulty and instructions for the shipment of pathology specimens). 
Where possible study site staff should contact the surgeon to discuss required forms 
and specimen collection and handling.

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
study medication in Study A4091061, female subjects of child-bearing potential 
should be reminded of contraceptive requirements.
106.2. Day of Surgery (Day 1 + 10 days)
During this interval, sites should ensure receipt of a completed Surgeon’s Assessment of 
Procedural Difficulty and confirm that pathology specimens were shipped according to 
instructions.  Required source document collection (eg, operative report and discharge 
summary) should begin in this interval.
Sites will be requested to submit required source documentation to the Endpoint 
Management Team as soon as possible, and ideally within 29 5 days, after the total joint 
replacement surgery (ie, by the time the Week 4 visit occurs provided the source 
documentation has been completed).
106.3. Week 4 (Day 29 5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).


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
Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement); NOTE: the WOMAC and 
SPADI should be completed in their entirety.

Overall satisfaction with joint replacement surgery measured by the 
Self-Administered Patient Satisfaction Scale (SAPS).
At the conclusion of the telephone call, site staff should:

Remind subjects not utilizing the IWRS to return paper-based assessments to the site 
as soon as possible, but no later than 5 days, after completion of the assessment.

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
study medication in Study A4091061, remind female subjects of child-bearing 
potential of contraceptive requirements.

Confirm the approximate timing of the next telephone call.
106.4. Week 8 (Day 57 5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
study medication in Study A4091061, remind female subjects of child-bearing 
potential of contraceptive requirements.

Confirm the approximate timing of the next telephone call.
106.5. Week 12 (Day 85 5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.


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
Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).

Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.

Query for additional or corrective procedures related to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement); NOTE: the WOMAC and 
SPADI should be completed in their entirety.

Overall satisfaction with joint replacement surgery measured by the SAPS.
At the conclusion of the telephone call, site staff should:

Remind subjects not utilizing the IWRS to return paper-based assessments to the site 
as soon as possible, but no later than 5 days, after completion of the assessment.

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
study medication in Study A4091061, remind female subjects of child-bearing 
potential of contraceptive requirements.

Confirm the approximate timing of the next telephone call.
106.6. Week 16 (Day 113 5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous 
study medication in Study A4091061, remind female subjects of child-bearing 
potential of contraceptive requirements.

Confirm the approximate timing of the next telephone call.


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106.7. Week 20 (Day 141 5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

Confirm the approximate timing of the next telephone call.
106.8. Week 24 (Day 169 5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).

Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.

Query for additional or corrective procedures related to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement); NOTE: the WOMAC and 
SPADI should be completed in their entirety.

Overall satisfaction with joint replacement surgery measured by the SAPS.
At the conclusion of the telephone call, site staff should remind subjects not utilizing the 
IWRS to return paper-based assessments to the site as soon as possible, but no later than 
5 days, after completion of the assessment.
106.9. Subject Withdrawal/Early Termination 
Subjects may withdraw from this substudy 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. 


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If a subject cannot be contacted within the window for a scheduled visit, every effort should 
be made to contact the subject outside of the visit window.  If a subject is thought to be lost 
to follow-up, the site must attempt to contact the subject with a minimum of 3 documented 
phone call attempts and, if phone calls are unsuccessful, a certified letter sent to the subject.  
All attempts to contact the subject and information received during the contact attempts must 
be documented in the subject’s medical records.  In any circumstance, every effort should be 
made to document the subject’s outcome, if possible.  The investigator should inquire about 
the reason for withdrawal, follow-up with the subject regarding any unresolved adverse 
events, query for any new adverse events, query about concomitant analgesic medication use, 
physical rehabilitation activities or corrective procedures related to the joint replacement 
surgery and request that the subject complete the following assessments via the IWRS tool or 
via paper, as established at the Baseline Visit: 

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or 
SPADI for subjects with a total shoulder replacement) (WOMAC or SPADI).

Overall satisfaction with joint replacement surgery measured by the SAPS.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
107. SUBSTUDY ASSESSMENTS
Every effort should be made to ensure that the required procedures are completed as 
described.  However it is anticipated that from time to time there may be circumstances, 
outside of the control of the investigator that may make it unfeasible to perform a procedure.  
In these cases the investigator will take all steps necessary to ensure the safety and 
well-being of the subject.  When a required procedure cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he or she 
has taken to ensure that normal processes are adhered to as soon as possible.  The study team 
will be informed of these incidents in a timely fashion.
107.1. Surgeon’s Assessment of Procedural Difficulty
Following the total joint replacement surgery, the orthopedic surgeon performing the surgery 
will be asked to answer the following question:
“Taking into consideration the subject’s medical history and physical condition prior to 
surgery would you classify the operative procedure as:

Uneventful; or 

Minor complications; or

Major complications.


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If the category of minor or major complications is chosen, the surgeon will be requested to 
specify the complication(s).
107.2. Pathology Specimens
Surgeons will be requested to ship pathology specimens from the total joint replacement 
surgery to a Central Laboratory for analysis.  Detailed instructions for the shipping of 
pathology specimens will be provided.  Identification of specimens of adequate quality, 
preparation and histopathologic examination of the specimens will be performed in a 
standardized manner by the Central Laboratory under the direction of an expert orthopedic 
pathologist.  Pathology reports will generally be returned to the referring site within 
7-10 days following completion of the report by the Central Laboratory. 
107.3. Telephone-based Assessments
Post-surgery, subjects will be contacted monthly via telephone by study site personnel.
107.3.1. Adverse Events
At each post-surgery telephone contact, subjects will be queried for the occurrence of adverse 
events.  All adverse events reported by the subject must be recorded on the appropriate case 
report form (CRF).
Subjects reporting adverse events (any seriousness or severity) with preferred terms of 
bradycardia, syncope, orthostatic hypotension, anhidrosis or hypohidrosis should be further 
evaluated for the presence of sympathetic autonomic neuropathy.  Subjects will be referred 
CCI


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for neurologic or cardiologic evaluation depending on symptom presentation and the 
investigator’s assessment as to the specialist best able to evaluate the subject.
107.3.2. Concomitant Analgesic Medication
At each post-surgery telephone contact, subjects will be queried about concomitant analgesic 
medication usage including dose, dosing regimen and reason for use.  This information 
should be recorded on the appropriate case report form (CRF).
107.3.3. Physical Rehabilitation Activities
At the Week 4, 12 and 24 post-surgery telephone contacts, subjects will be queried for 
physical rehabilitation activities related to the replaced joint.  Specifically, subjects will be 
asked to respond yes or no to the following question:
“Are you participating in physical rehabilitation activities related to your replaced joint?”
Subjects will be queried for details if the answer to the question is yes.  This information 
should be recorded on the appropriate case report form (CRF).
107.3.4. Additional or Corrective Procedures
At the Week 12 and 24 post-surgery telephone contacts, subjects will be queried for 
additional or corrective procedures related to the total joint replacement surgery.  Specifically, 
subjects will be asked to respond yes or no to the following question:
“Have you been told by your orthopedic surgeon that additional or corrective procedures (for 
example a revision or implant replacement) are necessary for your total joint replacement?”
Subjects will be queried for details if the answer to the question is yes.  If necessary, the 
orthopedic surgeon may be contacted to confirm/expand upon the information regarding 
additional or corrective procedures.
107.4. Web-based Assessments
107.4.1. Overall Satisfaction with Joint Replacement Surgery
The Self-Administered Patient Satisfaction Scale (SAPS) evaluates subject satisfaction with 
the outcome of hip and knee arthroplasty and was designed to be used in conjunction with 
other clinical measures and functional health status instruments to evaluate the results of hip 
and knee arthroplasty. 
The scale consists of four items focusing on satisfaction with the extent of pain relief, 
improvement in ability to perform home or yard work, ability to perform recreational 
activities and overall satisfaction with joint replacement. 
Specifically, subjects will be asked to respond to the following questions:

How satisfied are you with the results of your surgery?

How satisfied are you with the results of your surgery for improving your pain?


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


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107.4.3.1. WOMAC
Subjects who will be proceeding to total knee or hip arthroplasty will be requested to 
complete all subscales of the WOMAC (ie, pain, physical function and stiffness) at Baseline 
and Weeks 4, 12, and 24 following total joint replacement surgery either via the IWRS or by 
paper if the subject does not have access to the internet via a desktop, laptop or tablet 
computer.  When completed on paper, the subject will be requested to return the assessment 
to the site but no later than 5 days, after completion of the assessment.
A copy of the WOMAC can be found in Appendix 17.
WOMAC Pain Subscale
The WOMAC Pain subscale is comprised of 5 questions regarding the amount of pain 
experienced due to OA in the index joint (selected study knee or hip) in the past 48 hours.  
For this study, the index joint (selected study knee or hip) is defined as the joint to be or 
that has been replaced.  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.
WOMAC Physical Function Subscale
The WOMAC Physical Function subscale is comprised of 17 questions regarding the degree 
of difficulty experienced due to arthritis in the index joint (selected study knee or hip) in the 
past 48 hours.  For this study, the index joint (selected study knee or hip) is defined as 
the joint to be or that has been replaced.  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.
WOMAC Stiffness Subscale
The WOMAC Stiffness subscale is comprised of 2 questions regarding the amount of 
stiffness experienced in the index joint (selected study knee or hip) in the past 48 hours.  For 
this study, the index joint (selected study knee or hip) is defined as the joint to be or 
that has been replaced.  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.
107.4.3.2. The Shoulder Pain and Disability Index (SPADI)
Subjects who will be proceeding to shoulder arthroplasty will be requested to complete both 
dimensions of the SPADI (ie, pain and function) at Baseline and Weeks 4, 12, and 24 
following total joint replacement surgery either via the IWRS or by paper if the subject does 


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not have access to the internet via a desktop, laptop or tablet computer.  When completed on 
paper, the subject will be requested to return the assessment to the site but no later than 
5 days, after completion of the assessment.
The SPADI consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use.  The scores from both 
dimensions are averaged to derive a total score from 0 (best) to 100 (worst).
A copy of the SPADI can be found in Appendix 18.
108. SUBSTUDY ADVERSE EVENT REPORTING
Refer to Section 8 of the A4091061 protocol.
109. SUBSTUDY DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for the summary and descriptive analyses of the data collected in this 
substudy 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.
109.1. Sample Size Determination
This substudy is designed to collect information sufficient to describe the post-operative 
outcome of subjects who underwent a total knee, hip, or shoulder replacement while 
participating in Study A4091061.  The number of subjects who will enroll in this substudy is 
unknown but is estimated to be less than 25 subjects.  Also unknown is the distribution of 
subjects across treatment groups (ie, the treatment given in Study A4091061).  Therefore, it 
is predicted that there will be insufficient statistical power to perform statistical inferential 
analyses.  All analyses will be descriptive in nature.  The data collected in this substudy will 
be combined with similar data collected in other tanezumab studies for further analysis.  
These aggregate analyses will be reported separately.
109.2. Analysis of Endpoints
Data from the substudy of subjects with total joint replacement of the knee, hip or shoulder 
will be presented at substudy Baseline or Day 1 (day of surgery) and each post-surgery visit 
using observed data (no imputation for missing data), and at Week 24 using Last Observation 
Carried Forward (LOCF) for missing data.  Data will be shown at the time points specified 
and also using change from (pre-surgery) Baseline where relevant.  Data will be shown 
overall, and split by treatment group.
For the Surgeon’s Assessment of Procedural Difficulty, the number and percentage of 
subjects in each category (Uneventful, Minor complications, Major complications) will be 
presented.  Complications reported by the surgeon will be listed. 


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For the Subject’s Overall Satisfaction with Surgery assessments (using the Self-Administered 
Patient Satisfaction scale, SAPS), the responses [score] for each category (Very Satisfied 
[100], Somewhat Satisfied [75], Somewhat Dissatisfied [50], Very Dissatisfied [25]) will be 
summarized for each of the four items.  The scale score is the un-weighted mean of the 
scores from the individual items, ranging from 25 to 100 per item with higher scores 
indicating greater satisfaction.  This total score will be summarized.  Reponses to the 
question “How satisfied are you with the results of your surgery?” will also be summarized 
as satisfied (very satisfied and somewhat satisfied categories combined) and dissatisfied 
(somewhat dissatisfied and very dissatisfied categories combined).
Similarly, the number and percentage of subjects who have required (i) additional or 
corrective procedures related to their total joint replacement and (ii) participating in physical 
rehabilitation activities related to their replaced joint will be presented.
Average pain (NRS) in the replaced joint for all subjects, WOMAC Pain, Stiffness and 
Physical Function sub-scale scores for subjects who had total knee or hip replacement and 
SPADI Pain, function and total score for subjects who had total shoulder replacement will be 
summarized (including change from substudy Baseline summaries).
The number and percent of subjects with specified post-surgical complications will be 
presented.  The list of post-surgical complications will be derived from reported adverse 
events and will consist of complications that are clinically significant and attributable to the 
total arthroplasty procedure eg, periprosthetic joint infection/wound infection, periprosthetic 
fracture, pulmonary embolism or sepsis/septicemia/shock.  Literature reported analyses of 
post-surgical complications9,10 will be used for guidance in developing the list of 
post-surgical complications.  The list of post-surgical complications will be developed prior 
to database lock. 
109.3. Data Monitoring Committee (DMC)
Refer to Section 9.7 of the A4091061 protocol.
109.4. External Adjudication Committee
External Adjudication Committee for the substudy will be as described for the main study.  
Refer to Section 9.5 of the A4091061 protocol.
110. SUBSTUDY QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Section 10 of the A4091061 protocol.
111. SUBSTUDY DATA HANDLING AND RECORD KEEPING
Refer to Section 11 of the A4091061 protocol.
112. SUBSTUDY ETHICS
Refer to Section 12 of the A4091061 protocol.


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113. SUBSTUDY DEFINITION OF END OF TRIAL
Refer to Section 13 of the A4091061 protocol.
114. SUBSTUDY SPONSOR DISCONTINUATION CRITERIA
Refer to Section 14 of the A4091061 protocol.
115. SUBSTUDY PUBLICATION OF STUDY RESULTS
Refer to Section 15 of the A4091061 protocol.
116. SUBSTUDY REFERENCES
1.
Beaton DE, and Schemitsch E. Measures of Health-Related Quality of Life and Physical 
Function. Clin Orth and Rel Research 413:2003; 90-105.
2.
Mahomed N, et al. The self-administered patient satisfaction scale for primary hip and 
knee arthroplasty. Arthritis 2011; doi:10.1155/2011/591253.
3.
Hawker GA, et al. Measures of adult pain. Arthritis Care Res 2011;63:S240-S252.
4.
Rolfson O, et al. Use of patient-reported outcomes in the context of different levels of 
data. J Bone Joint Surg Am 2011; 93 Suppl3(E):66-71.
5.
Beaton DE and Schemitsch E. Measures of health-related quality of life and physical 
function. Clin Orth Rel Res 2003; 413:90-105.
6.
Rogers JC and Irrgang JJ.  Measures of adult lower extremity function. Arthritis Care 
Res 2003;49:S67-S84.
7.
Angst F, et al. Measures of adult shoulder function.  Arthritis Care Res
2011;63:S174-S188.
8.
Roy J-S, MacDermid JC and Woodhouse LJ. Measuring shoulder function: a systemic 
review of four questionnaires. Arthritis Care Res 2009; 61:623-632.
9.
Grosso, LM et al., Hospital-Level Risk-Standardized Complication Rate Following 
Elective Primary Total Hip Arthroplasty and/or Total Knee Arthroplasty Measure 
Methodology Report 25 June 2012.
10.
Bohsali KI, Wirth MA and Rockwood CA. Complications of total shoulder arthroplasty. 
J Bone Joint Surgery 88:2006; 2279 – 2292.














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Appendix 18. The Shoulder Pain and Disability Index (SPADI)


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Appendix 19. 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.  

SAP_001.pdf: 
Protocol A4091061 (PF-04383119)  
Statistical Analysis Plan 
 
 
 
 PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
PROTOCOL A4091061 
 
 
 
 
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF THE 
SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB (PF-04383119) IN 
SUBJECTS WITH CANCER PAIN PREDOMINANTLY DUE TO BONE 
METASTASIS RECEIVING BACKGROUND OPIOID THERAPY 
 
 
 
STATISTICAL ANALYSIS PLAN  
(SAP) 
 
 
 
 
 
 
Version: 
 5.0 
Date:  
08 January 2021 


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TABLE OF CONTENTS  
LIST OF TABLES .....................................................................................................................4 
LIST OF FIGURES ...................................................................................................................4 
1. VERSION HISTORY ...........................................................................................................5 
2. INTRODUCTION ................................................................................................................6 
2.1. Study Objectives .......................................................................................................7 
2.1.1. Primary Objective ........................................................................................7 
2.1.2. Secondary Objective ....................................................................................7 
2.2. Study Design ............................................................................................................7 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9 
3.1. Primary Endpoint(s) .................................................................................................9 
3.2. Secondary Endpoint(s) .............................................................................................9 
3.2.1. Efficacy Measures ........................................................................................9 
3.2.2. Opioid Use and Opioid Adverse Effects Measures ...................................10 
 
 
3.4. Baseline Variables ..................................................................................................11 
3.4.1. Covariates ..................................................................................................11 
3.5. Safety Endpoints .....................................................................................................12 
3.5.1. Adverse Events ..........................................................................................12 
3.5.2. Vital Signs ..................................................................................................15 
3.5.3. Total Joint Replacement and Surgical Endpoints ......................................15 
4. ANALYSIS SETS ...............................................................................................................16 
4.1. Full Analysis Set.....................................................................................................16 
4.2. Potentially Important Protocol Deviations .............................................................17 
4.2.1. Major Deviations Assessed Prior to Randomization .................................17 
4.2.2. Major Deviations Assessed Post-Randomization ......................................17 
4.3. Safety Analysis Set .................................................................................................17 
 
5. GENERAL METHODOLOGY AND CONVENTIONS ...................................................18 
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5.1. Hypotheses and Decision Rules .............................................................................18 
5.1.1. Statistical Hypotheses ................................................................................18 
5.1.2. Statistical Decision Rules ..........................................................................18 
5.2. General Methods ....................................................................................................18 
5.2.1. A summary of all efficacy analyses is given in Appendix 1.  The 
treatment group ordering in these analyses outputs will be: Placebo,  
Tanezumab 20mg.   In outputs based on safety analysis set, the 
treatment ordering will be: Placebo, Tanezumab 10 mg, Tanezumab 
10/20 mg, Tanezumab 20 mg.  The Tanezumab 10/20 mg group 
includes subjects who have received both tanezumab 10 mg SC prior to 
Amendment 3 and tanezumab 20 mg SC after Amendment 3.Analyses 
for Binary Data ................................................................................................20 
5.2.2. Analyses for Continuous Data ...................................................................21 
5.2.3. Analyses for Categorical Data ...................................................................25 
5.3. Methods to Manage Missing Data ..........................................................................26 
6. ANALYSES AND SUMMARIES .....................................................................................30 
6.1. Primary Endpoint(s) ...............................................................................................30 
6.2. Secondary Endpoint(s) ...........................................................................................30 
 
 
6.5. Baseline and Other Summaries and Analyses ........................................................30 
6.5.1. Concomitant Medications and Non-Drug Treatments ...............................30 
6.6. Safety Summaries and Analyses ............................................................................31 
6.6.1. Adverse Events ..........................................................................................32 
6.6.2. Vital Signs ..................................................................................................34 
6.6.4. Immunogenicity .........................................................................................34 
6.7. Other Analyses .......................................................................................................35 
 
 
6.7.3. Joint Safety Events .....................................................................................35 
7. INTERIM ANALYSES ......................................................................................................36 
7.1. Introduction ............................................................................................................36 
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7.2. Interim Analyses and Summaries ...........................................................................36 
8. REFERENCES ....................................................................................................................38 
9. APPENDICES ....................................................................................................................39 
 
LIST OF TABLES 
Table 1 Summary of Major Changes in SAP Amendments ......................................................5 
 
LIST OF FIGURES 
Figure 1. 
Study Design ...........................................................................................................7 
 
APPENDICES 
Appendix 1. SUMMARY OF EFFICACY ANALYSES ........................................................39 
Appendix 2. DATA DERIVATION DETAILS ......................................................................47 
Appendix 2.1. Definition and Use of Visit Windows in Reporting .........................................47 
Appendix 3. STATISTICAL METHODOLOGY DETAILS ..................................................50 
Appendix 3.1. Further Details of Interim Analyses .................................................................50 
Appendix 3.2. Further Details of the Statistical Methods ........................................................50 
 
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1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study A4091061 is based on the Protocol 
Amendment 4 dated 14Jun2018.  
Table 1 Summary of Major Changes in SAP Amendments 
SAP 
Version 
Change 
Rationale 
1 
Not Applicable 
Not Applicable 
2 
Removed analyses 
involving 10 mg 
subcutaneous (SC) 
To be aligned with Protocol Amendment 3  
2 
Updated a few 
analyses 
To be aligned with program-level decisions.   
3 
Revised futility stop 
criterion and added 
efficacy stop 
criterion in the 
interim analysis; 
reduced the final 
sample size 
To be aligned with Protocol Amendment 4  
3 
Updated a few 
analyses and texts 
To be aligned with program-level decisions; 
Additionally, to implement clarifications, removal 
of redundant text, and correction of typos 
4 
Update analysis 
covariates related to 
randomization strata 
revise analysis model covariates to use the strata as 
indicated in the project database, due to a  high rate 
of mis-match between randomization strata and 
project database data  
5 
Updated analyses 
 
 
The definition of full analysis set is clarified to 
include all randomized subjects who were 
randomized to either tanezumab 20 mg or placebo 
SC and received at least one dose of SC study 
medication. Subjects randomized to tanezumab 10 
mg are excluded. 
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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 analgesic efficacy of tanezumab 20 mg SC versus matching placebo 
SC at Week 8 in subjects, with cancer pain predominantly due to bone metastasis, receiving 
background opioid therapy.  
2.1.2. Secondary Objective 
Evaluate the safety of tanezumab 20 mg SC versus matching placebo SC  in subjects, with 
cancer pain predominantly due to bone metastasis, receiving background opioid therapy.  
2.2. Study Design 
The study design is summarized in the diagram below. 
Figure 1. Study Design 
 
This is a randomized, double blind, placebo controlled, multicenter, parallel-group Phase 
3 study in cancer subjects requiring treatment with background opioids for pain due to bone 
metastasis. 
The protocol was initially designed to include 3 treatment groups (tanezumab 20 mg SC, 
tanezumab 10 mg SC, and placebo), and was amended (Amendment 3) after study start to 
discontinue the tanezumab 10 mg dose arm. It is estimated that approximately 11 subjects in 


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total were randomized to receive tanezumab 10 mg SC prior to implementation of 
Amendment 3. 
Following implementation of Amendment 3, subjects were randomized in a 1:1 ratio 
(planned 85 subjects/arm) to one of two treatment arms: tanezumab 20 mg SC or matching 
placebo SC, each administered in addition to background opioids. Subjects who had been 
randomized to the 10 mg dose treatment arm and who were in the double-blind treatment 
period at the time of implementation of Amendment 3 were administered 20 mg for any 
remaining doses. 
In protocol Amendment 4, the sample size has been reduced.  A total of 155 subjects will be 
randomized.  This comprises 144 subjects (72/treatment arm) randomized to receive 
tanezumab 20 mg SC or matching placebo SC plus an estimated 11 subjects previously 
randomized to receive tanezumab 10 mg SC.  
Subjects will receive a total of 3 SC injections, separated by 8 weeks in addition to 
background opioids administered throughout the study. Treatment groups will include:   
1. Placebo SC (matching tanezumab SC) in addition to background opioid therapy.  
2. Tanezumab 20 mg SC in addition to background opioid therapy. 
The study is designed with a post-randomization duration of 48 weeks and will consist of 
three periods: Pre-Treatment (up to 37 days), Double-Blind Treatment (24 weeks) and 
6-month Safety Follow-up (24 weeks).  The Pre-Treatment Period will include a Screening 
Period (lasting up to 32 days) with washout of prohibited study medication and stabilization 
of background opioid regimen prior to a 5-day Baseline Assessment Period (BAP).  
Confirmation of radiographic eligibility by a central radiologist based on protocol-defined 
x-rays will take place during the Pre-Treatment period.  The study is designed such that post 
randomization, contacts with subjects are made approximately every 4 weeks through the 
end of the Safety Follow-up period.  The Double-Blind Treatment Period consists of 
6 in-clinic visits (including 3 dosing visits) and 2 phone contact visits.  Because of the long 
half-life of tanezumab (approximately 21 days), the End of Double-Blind Treatment visit 
takes place 8 weeks after the last dose of SC medication is administered.  The Safety 
follow-up period begins with the completion of the End of Treatment visit and includes 
4 phone contacts and 2 additional in-clinic visits, with the exception of sites in Japan where 
3 phone contacts and 3 additional in-clinic visits will occur. 
Stratification variables are (i) tumor aggressiveness (assessed by Eastern Cooperative 
Group [ECOG] performance status and (ii) presence/absence of concomitant anticancer 
treatment (eg, chemotherapy or hormonal therapy or anti hormonal therapy). 
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 8.  The period of interest for most study drug 
associated safety results is the treatment period. Selected safety results will also be provided 


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separately for the safety follow-up period, and some results will be provided 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 8 in the daily average pain intensity in the index bone 
metastasis cancer pain site.   
Baseline is defined as the mean average daily pain NRS score during the Baseline 
assessment period prior to randomization (expected to be 5 days).  The Week 8 pain 
intensity value is the mean of the daily average pain intensity scores for the 7 days prior 
to the Week 8 visit.  See Appendix 2.1 for calculation details if the Week 8 visit is not on 
the scheduled Day 57.  If any of the seven Week 8 daily scores are missing then the Week 
8 value will be calculated over the remaining observations. 
3.2. Secondary Endpoint(s) 
3.2.1. Efficacy Measures 
• Change from Baseline to Weeks 1, 2, 4, 6, 12, 16 and 24 in the daily average pain 
intensity NRS score in the index bone metastasis cancer pain site. 
• Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily worst pain 
intensity NRS score in the index bone metastasis cancer pain site. 
• Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the weekly average pain 
intensity NRS score in non-index cancer pain sites. 
• Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the weekly worst pain 
intensity NRS score in non-index cancer pain sites. 
• Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily average pain 
intensity NRS score in the non-index visceral cancer pain sites. 
• Change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in the daily worst pain 
intensity NRS score in the non-index visceral cancer pain site. 
 
 
 
 
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• Response as defined by a ≥30%, ≥50%, ≥70%, and ≥90% reduction from Baseline in 
the daily average and daily worst pain intensity NRS score in the index bone 
metastasis cancer pain site at Weeks 1, 2, 4, 6, 8, 12, 16 and 24. 
• Change from Baseline (collected at Randomization visit) in Patient’s Global 
Assessment of Cancer Pain at Weeks 2, 4, 8, 16 and 24.  
• Response defined as an improvement of ≥2 points in Patient's Global Assessment of 
Cancer Pain at Weeks 2, 4, 8, 16 and 24.  
3.2.2. Opioid Use and Opioid Adverse Effects Measures 
• Average daily total opioid consumption (in mg of morphine equivalent doses) at 
Weeks 1, 2, 4, 6, 8, 12, 16 and 24. 
• Average number of doses of rescue medication required per week at Weeks 1, 2, 
4, 6, 8, 12, 16 and 24. 
• Change from Baseline in the weekly Opioid-Related Symptom Distress Scale at 
Weeks 2, 4, 8, 16, and 24. 
The Opioid-Related Symptom Distress Scale (OR-SDS) is a questionnaire on the 
frequency, severity and level of bother of 10 symptoms.  For each symptom the mean of 
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the frequency, severity and bother is calculated to become the Multi-Domain Average 
(MDA).  These are the four dimensions for each symptom.  The mean of each dimension 
over all symptoms is calculated to become the frequency, severity, bother and MDA 
composite scores.  
 
 
 
  
 
 
 
 
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 pain intensity scores, baseline is defined as the mean average daily Pain NRS score 
during the Baseline Assessment Period prior to Randomization (expected to be 5 days). It 
will be calculated as the mean of the  non-missing pain scores over study days -5 to -1.  If 
fewer than 5 are available between study days -5 and -1, the baseline will be the mean of the 
available scores. 
Baseline opioid use (daily amount) will be defined as the use during the 5-day Baseline 
Assessment Period. It will be calculated as the mean of the  non-missing opioid use values 
over study days -5 to -1.  If fewer than  5 are available between study days -5 and -1, the 
baseline will be the mean of the available values. 
Region will be used in statistical models.  Based on planned study countries, regions are 
anticipated to be Europe, Middle East, Latin America, Asia (including the single site in 
Australia). 
The stratification variables are (i) tumor aggressiveness (assessed by Eastern Cooperative 
Group [ECOG] performance status and (ii) presence/absence of concomitant anticancer 
treatment (eg, chemotherapy or hormonal therapy or anti hormonal therapy).   
3.4.1. Covariates 
For all models analyzing the continuous primary and secondary efficacy endpoints,  the 
corresponding Baseline value will be used as a covariate, together with the Baseline average 
pain intensity of the index pain site and baseline total opioid use (using morphine equivalent 
amount in mg).  Region will be fitted as a fixed effect in the ANCOVA models. The 
randomization stratification variables of tumor aggressiveness and presence/absence of 
concomitant anticancer treatment will also be included as fixed effects. 
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• A listing of subjects with mis-matches between the stratification variables entered at 
randomization and the case report form data will be provided.  In analysis models and 
descriptive summarization the strata as indicated in the project database data will be 
used. 
For the models analyzing the categorical/binary response efficacy endpoints, the model will 
include terms for Baseline average pain intensity of the index pain site, in addition to the 
stratification factors.   
For response endpoints relating to the Patients Global Assessment of Cancer Pain (PGA-CP), 
the Baseline PGA-CP will also be used as a covariate, in addition to Baseline average pain 
intensity of the index pain site and the fixed effect of the stratification factors  
For the models analyzing the amount of opioid consumption and number of doses of rescue 
medication use, the model will include terms for Baseline average pain intensity of the index 
pain site, stratification factors, and region. 
3.5. Safety Endpoints 
• Adverse events.  
• Standard safety assessments (safety laboratory testing [chemistry, hematology], 
sitting vital signs, ECG [12-lead]). 
• Orthostatic (supine/standing) blood pressure assessment. 
• Weight measurements. 
• Physical examinations. 
• Joint safety adjudication outcomes. 
• Total joint replacements. 
 
• Anti-drug antibody (ADA) assessments. 
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 screening or baseline 
assessment period), or 
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• the event was seen prior to the start of treatment but increased in severity during 
treatment. 


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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.  
Allodynia 
Axonal neuropathy 
Burning sensation 
Carpal tunnel syndrome 
Decreased Vibratory Sense 
Demyelinating polyneuropathy 
Dysaesthesia 
Formication 
Hyperaesthesia 
Hyperpathia 
Hypoaesthesia 
Hypoaesthesia oral 
Intercostal neuralgia 
 
Neuralgia 
Neuritis 
Neuropathy peripheral 
Paraesthesia 
Paraesthesia oral 
Peripheral sensorimotor neuropathy 
Peripheral sensory neuropathy 
Polyneuropathy 
Polyneuropathy chronic 
Sciatica 
Sensory disturbance 
Sensory loss 
Tarsal tunnel syndrome 
Thermohypoaesthesia 
 
 
Adverse Events of Sympathetic Nervous System are defined in the table below. 
Abdominal discomfort 
Anhidrosis 
Blood pressure orthostatic decreased 
Bradycardia 
Diarrhoea 
Dizziness postural 
Early satiety 
Ejaculation delayed 
Ejaculation disorder 
Ejaculation failure 
Anal incontinence 
Heart rate decreased 
Hypertonic bladder 
Hypohidrosis 
Micturition urgency 
Nausea 
Nocturia 
Orthostatic hypotension 
Presyncope 
Respiratory distress 
Respiratory failure 
Sinus bradycardia 
Syncope 
Pollakiuria 
Urinary hesitation 
Urinary incontinence 
Vomiting 
 


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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 
Bradycardia 
Hypohidrosis 
Orthostatic hypotension 
Syncope 
 
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. 
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 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 visit (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 (supine minus standing) ≥20 mmHg, OR 
• Reduction in dBP (supine minus standing) ≥10 mmHg 
• For patients with Baseline supine systolic Blood Pressure >150 mmHg:  
• Reduction in sBP (supine minus standing) ≥30 mmHg, OR 
• Reduction in dBP (supine minus standing) ≥15 mmHg 
An additional summary will be provided for outcomes of assessments resulting from an 
incident of orthostatic hypotension or other events of interest, using data from both the CRF 
database and the consultation 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 
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Reporting of total joint replacement events including surgery and recovery will be described 
in a separate Statistical Analysis Plan that will cover patients undergoing total joint 
replacement from Studies 1059, 1061 and 1063.   
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 modified intent to treat (mITT) analysis set is the primary analysis set for efficacy 
analyses.  It consists of all subjects who were randomized to either tanezumab 20 mg or 
placebo SC, and received at least one dose of SC study medication. Subjects randomized to 
tanezumab 10 mg prior to Amendment 3 are excluded from this set. This analysis set is used 
in the presentations of all efficacy data, and all data listings, and is labeled as the ‘mITT 
Analysis Set’ or ‘mITT Population’. 
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4.2. Potentially Important Protocol Deviations  
The number of patients with potentially important protocol deviations will be examined to 
assess their impact on the interpretation of the study results.  When necessary, the effect of 
protocol deviations may be examined by repeating the primary analysis using the 
per-protocol (PP) analysis set, defined as all subjects in the mITT analysis set who are not 
major protocol deviators (which would potentially affect efficacy).  Examples of major 
protocol deviators are described below in Section 4.2.1 and 4.2.2.   
4.2.1. Major Deviations Assessed Prior to Randomization 
• Inclusion criteria: #5-7, 9-11. 
• Exclusion criteria: #1 and 4-7  
• Randomization criteria: #1, 2, and 4 
4.2.2. Major Deviations Assessed Post-Randomization 
• Prohibited medications that could affect pain assessments (protocol section 5.8.1) for 
the Week 8 endpoint, for example: 
• dosing of opioids greater than protocol-specified criteria 
• new use or change to dose of non-opioid or adjuvant analgesics 
• new use or change to dose of anti-neoplastic or bone metastasis therapies 
outside protocol-specified criteria 
• inadequate washout period of pain medications 
• dosing of analgesia within 48 hours of diary completion 
 
4.3. Safety Analysis Set 
The safety analysis set is defined as all subjects treated with tanezumab or placebo SC, 
including subjects who received tanezumab 10 mg prior to Amendment 3.  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 
TJR Sub-study Analysis Set:  This analysis set includes all subjects who undergo total joint 
replacements of the hip, knee or shoulder during participation in the study.  


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5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Statistical Hypotheses 
The treatment comparison being made in this study is tanezumab  20 mg versus placebo.  
For the treatment comparison, 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. 
Comparison of tanezumab versus placebo will be made for data up to and including 
Week 24. 
Null Hypothesis 
H0: 
0
20mg
  
TANEZUMAB
=
−
PLACEBO
µ
µ
 
Alternative  Hypothesis 
H1: 
0
20mg
  
TANEZUMAB
≠
−
PLACEBO
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 
The Type I error rate (α-level) used in the assessment of  treatment comparison for the 
primary efficacy endpoint is two-sided 5%.   
Control of the type I error rate will only apply to the primary treatment comparison 
versus placebo for the average pain intensity of the index pain site at Week 8 (model 
with the primary imputation analysis).  The overall type I error rate will be allocated 
across the planned interim analysis and, if any stopping criteria are not met, the final 
analysis.  At each of the interim and the final analysis, the efficacy boundary will be 
defined using the Lan-DeMets alpha spending function with the O’Brien-Fleming style 
boundary.   
Regardless of the outcome of the analysis of the primary endpoint, other efficacy 
endpoints will be tested.  No adjustment for multiple comparisons will be made for these 
other efficacy endpoints, and for the safety endpoints.  The α-level for each hypothesis 
test for the secondary and exploratory analyses will be two-sided 5%. 
The planned interim analysis will also include the assessment of futility.  The non-
binding futility stopping boundary will be defined also using EAST software (Cytel inc.), 
using the conditional power of 10% (based on estimated delta/sigma) boundary.   
5.2. General Methods  
Subjects, including those randomized before Amendment 3, are  randomized at Baseline to 
one of three treatment groups: placebo SC, tanezumab 10 mg SC, or tanezumab 20 mg SC.  
These will be labeled as placebo, tanezumab 10 mg, and tanezumab 20 mg for the three 




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Last SC Dose  
Analysis Window 
On-treatment Analysis  
Window Data  
Off-treatment Analysis  
Window Data 
Baseline 
Weeks 2, 4, 8 
Weeks 16, 24 
Week 2 
Weeks 2, 4, 8 
Weeks 16, 24 
Week 4 
Weeks 2, 4, 8 
Weeks 16, 24 
Week 8 
Weeks 2, 4, 8, 16 
Week 24 
Week 16 
Weeks 2, 4, 8, 16, 24 
None 
Week 24 
Weeks 2, 4, 8, 16, 24 
None 
 
Efficacy data collected via subject diary (NRS pain scores and opioid medication use) are 
collected daily or weekly, not at study visits.  Opioid medications collected at study visits 
that were not recorded in the diary will be evaluated to determine if they were used as rescue 
medications.  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 presentations up to Week 24. 
5.2.1. A summary of all efficacy analyses is given in Appendix 1.  The treatment group 
ordering in these analyses outputs will be: Placebo,  Tanezumab 20mg.   In outputs 
based on safety analysis set, the treatment ordering will be: Placebo, Tanezumab 10 mg, 
Tanezumab 10/20 mg, Tanezumab 20 mg.  The Tanezumab 10/20 mg group includes 
subjects who have received both tanezumab 10 mg SC prior to Amendment 3 and 
tanezumab 20 mg SC after Amendment 3.Analyses for Binary Data 
Binary response parameters will be analyzed using logistic regression for binary data, with 
covariates described in Section 5.2.1.   Output will show the number and percentage of 
subjects in each response category, and odds ratios (with 95% CIs) for the treatment 
comparison shown in Section 5.1.1. 
For the daily worst and average pain (in the index site) response efficacy endpoints (defined 
by a ≥30%, ≥50%, ≥70% and ≥90% change from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 
24), will be summarized and analyzed using logistic regression for binary data, with model 
terms for Baseline average/worst pain subscale score, stratification variables, and treatment 
group.  Imputation for missing data will use both LOCF and BOCF, where imputation with 
BOCF will lead to the subject being assessed as a non-responder for the response endpoint 
at a particular time point.  Also, 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 the 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 
time point of interest, and LOCF imputation would be used for missing data for any other 
reason. 
The response parameter of an improvement of ≥2 in the Patient Global Assessment of Cancer 
Pain will be analyzed as described above using mixed BOCF/LOCF as described above for 


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missing data (using the covariates of Baseline Patient Global Assessment of Cancer Pain 
and Baseline daily average pain). 
The response endpoints of improvement in PGA-CP ≥2 and average and worst pain intensity 
≥30, 50, 70 and 90% improvements are analyzed using logistic regression with covariates as 
defined in Section 3.4.1,  at Weeks 1, 2, 4, 6, 8, 12 (pain intensity responses only), 16, and 
24.  These analyses use mixed BOCF/LOCF for missing data.  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. 
5.2.2. Analyses for Continuous Data 
Primary Analysis 
The primary efficacy endpoint will be analyzed using an ANCOVA model, with model terms 
for Baseline score, the stratification variables, Baseline opioid use (ie, morphine equivalent 
amount in mg), region and treatment group.  The stratification variables are (i) tumor 
aggressiveness (assessed by Eastern Cooperative Group [ECOG] performance status and 
(ii) presence/absence of concomitant anticancer treatment (eg, chemotherapy or hormonal 
therapy or anti hormonal therapy). 
The primary analysis of the primary endpoint will use multiple imputation for missing data, 
to account for uncertainty around the unobserved 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 8 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 the placebo 
and tanezumab 20 mg  groups) of the observed efficacy data at Week 8.  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 subject’s last observed efficacy value and standard 
deviation (over the placebo and tanezumab 20 mg groups) of the observed efficacy data at 
Week 8.  Imputed values will be truncated at 0 and 10, but not rounded.  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, based on the standard method (Little & Rubin, 
2002), which is described in Appendix 3. 
Primary Endpoint Sensitivity Analyses 
A number of sensitivity analyses will be performed on the primary efficacy endpoint 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, and the homogeneity of the results 
across factors that may influence efficacy.  The analyses described below will not be subject 


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to any multiplicity adjustment.   The mITT analysis set is used in the analyses numbered 2 to 
5 below, and Per-Protocol analysis set used in analysis number 1 below. 
(1) Per-Protocol Analysis Set 
When needed (see Section 4.2), the primary analysis described above will be repeated, but 
using the Per-Protocol analysis set in place of the mITT  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).  Note that this analysis along with the same analysis but at Week 16 is 
a part of secondary analyses; See the section “Secondary Endpoint Analyses” below. 
The third sensitivity analysis for the primary endpoint at Week 8 will use a mixed model 
repeated measures analysis using the observed and imputed data up to Week 8 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, and other 
covariates such as Baseline score, the stratification variables, Baseline opioid use (ie, 
morphine equivalent amount in mg) and  region.  The unstructured covariance will be used in 
the modeling of the within-subject errors in the analysis.  See Appendix 2.1 for details on 
windows.   
The fourth sensitivity analysis for the primary endpoint at Week 8 will use a mixed model 
repeated measures analysis using all observed data up to Week 8, with covariate terms for 
Time (study week, treated as a categorical variable), Treatment Group, and 
Time-by-Treatment interaction, and other covariates such as Baseline score, the stratification 
variables, Baseline opioid use (ie, morphine equivalent amount in mg) and  region.  The 
unstructured covariance will be used in the modeling of the within-subject errors in the 
analysis.   
A summary of the missing data pattern will be shown for the average pain intensity for 
Baseline and Weeks 1, 2, 4, 6, and 8.  This summary will show the incidence of subjects with 
each pattern of observed and missing data over these visits.  This summary will be shown 
overall, and split by treatment group. 
(3) Interaction Analyses 
Interaction analyses will be performed for the primary endpoint, exploring how these factors 
affected the treatment effect,  one at a time: region, baseline pain score, type of primary 


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cancer, baseline opioid use, tumor aggressiveness, or concomitant anticancer treatment.  
These analyses will fit the covariate terms including Baseline score, the stratification 
variables, Baseline opioid use (ie, morphine equivalent amount in mg), factor being explored 
and treatment group in addition to the interaction term of treatment group by factor.  All 
factors will be made into categorical variables and included as a fixed effect in the model.   
Baseline pain score and baseline opioid use will be categorized as ≤ median and > median. It 
is assumed that all regions will have 10 or more subjects. In the case where regions  have <10 
subjects, these regions will be collapsed into one category in the interaction analysis.  Similar 
approach will be used for other factors such as the primary cancer type.  To aid the 
interpretation of the treatment by factor interactions, a subgroup analysis within each factor 
level will be conducted with a point estimate and 95% CI to show how treatment effect 
varied by the factor. 
 (4) Analysis only including subjects who are randomized under protocol Amendment 3 
and 4 
In this study, the majority of subjects are randomized under Amendment 3 and 4.  It is 
estimated that only approximately 11 subjects had been randomized, prior to the time of 
Amendment 3, to receive tanezumab 10 mg SC.  To assess the impact of subjects who are 
randomized before Amendment 3 on the primary analysis result,  the primary analysis will be 
repeated with inclusion of only subjects who are randomized under protocol Amendent 3 
and 4. 
(5) Analysis only including data collected prior to the COVID-19 pandemic 
To assess the potential impact of COVID-19 on the study, the primary analysis will be 
repeated while only including data collected before March 11, 2020, the day when the World 
Health Organization designated COVID-19 as a global pandemic. For sites in China,  the 
analysis will only include data collected before January 9, 2020, the day when COVID-19 
was identified as the causative agent of outbreak in Wuhan by the China Center for Disease 
Control and Prevention.   
Secondary Endpoint Analyses 
The change from Baseline for the daily average and worst pain intensity in the bone 
metastasis index cancer pain site will be summarized for each week from 1 to 24.  The 
change from Baseline to Days 1, 2, 3, 4, 5, 6, and 7, and to Weeks 1, 2, 4, 6, 8 (Worst Pain), 
12, 16 and 24 will be analyzed using analysis of covariance (ANCOVA) as described above, 
using multiple imputation.  
A secondary analysis for the change from Baseline in the daily average pain scores will use a 
repeated measures mixed effects model, on the available data over Weeks 1 to 24.  Estimates 
for treatment groups and treatment difference for Weeks 1, 2, 4, 6, 8, 12, 16 and 24 will be 
shown.  Additional secondary analysis for the change from Baseline to Week 8 and 16 in the 


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daily average pain will use single imputation Last Observation Carried Forward (LOCF) 
and Baseline Observation Carried Forward (BOCF) for missing data. 
The mean of the subject’s average and worst pain in the non-index cancer sites, over all 
non-index sites (for up to 2 sites per subject) and for visceral non-index cancer sites will be 
calculated for Baseline and for each week, and for the change from Baseline.  The change 
from Baseline to Weeks 1, 2, 4, 6, 8, 12, 16 and 24 in average and worst pain in the 
non-index cancer pain sites will be analyzed using analysis of covariance (ANCOVA) as 
described above, using multiple imputation. For non-index visceral cancer sites, the 
ANCOVA will not be conducted if the number of available subjects is < 10.  An additional 
analysis will utilize only those sites where Baseline average/worst pain is at least 5.  If a 
subject has no nominated non-index sites (first analysis) or no nominated non-index sites 
where Baseline is at least 5 (second analysis) then that subject would be excluded from the 
respective analysis. Since some subjects have non-index sites without associated baseline 
pain scores, a sensitivity analysis will be conducted to examine the change from baseline or 
screening in weekly average pain intensity in the non-index cancer pain sites. 
Additional ANCOVA analyses with multiple imputation for the primary endpoint will be used 
to examine the interaction of treatment group with region, Baseline pain score, type of 
primary cancer (eg, breast, lung, etc), Baseline opioid use and the stratification parameters.  
The change from Baseline to Weeks 2, 4, 8, 16 and 24 in the Patient Global Assessment of 
Cancer Pain will be summarized by treatment group, and analyzed using ANCOVA as 
described above with multiple imputation.  A second analysis of this parameter will use 
Cochran-Mantel-Haenszel test for the change from Baseline to Weeks 2, 4, 8, 16 and 24. 
Daily Opioid Consumption and Doses of Rescue Medication Use 
Average daily opioid consumption (mg of morphine equivalent dosage) and average number 
of doses of rescue opioid consumption per week will be summarized for each week up to 
Week 24.  Percent change from Baseline in average daily opioid consumption will be 
analyzed using ANCOVA on the rank scores with treatment and the stratification variables 
as factors. Missing data will be imputed using LOCF.  The average number of doses of 
rescue opioid consumption per week will be analyzed using a negative binomial model taking 
into account Baseline daily average pain and Baseline opioid use.   
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The number of doses of rescue medication per week will be summarized by treatment group 
for each week up to Week 24.  The total number of doses of rescue medication per week in 
Weeks 1, 2, 4, 8, 16, and 24 will be analyzed using a negative-binomial regression model 
using the log-total number of days of data collection within the analysis week as the subject 
offset variable.  The resulting analysis will show the estimated rate of opioids taken as rescue 
medication for each week.  This estimated rate will be shown by treatment group with 
standard error and 95% CI.  The ratio of the opioid usage rate between tanezumab + opioid 
versus opioid alone will be shown (with standard error and 95% CI).   
In these models the error term is defined with a negative binomial distribution, and ‘log’ is 
used as the link function.  Output from these analyses will be the estimated amount of opioid 
use per day, and number of doses of rescue medication per week, in each treatment group, 
and (following the exponential back transformation) the ratio of medication use for the 
treatment comparison shown in Section 5.1.  The 95% CIs will be given for the estimates of 
both the individual treatment groups and the treatment group ratio. 
The Opioid-Related Symptom Distress Scale (OR-SDS) is a questionnaire on the frequency, 
severity and level of bother of 10 symptoms.  For each symptom the mean of the frequency, 
severity and bother is calculated to become the Multi-Domain Average (MDA).  These are 
the four dimensions for each symptom.  The mean of each dimension over all symptoms is 
calculated to become the frequency, severity, bother and MDA composite scores.  Each of the 
four dimensions will be summarized by treatment and treatment difference for the 
10 symptoms and the overall composite, a total of 44 sets of summary measures.  The MDA 
for each symptom and the four dimensions for the composite score will be analyzed for each 
time point.  The analysis of this data will use a mixed effects repeated measures model and 
show analysis results for the change from Baseline to Weeks 2, 4, 8, 16, and 24. 
5.2.3. Analyses for Categorical Data 
The proportion of subjects who have a reduction from Baseline to Weeks 8, 16 and 24 in 
average and worst pain of >0%, ≥10% to ≥90% (in steps of 10%), and =100% (ie, 
average/worst pain is 0) will be tabulated.  This will be shown using observed cases and 
mixed BOCF/LOCF as described above for missing data. The data on reduction from 
baseline to week 8 using mixed BOCF/LOCF will also be plotted.  Imputation with BOCF 
for subjects with missing data at that timepoint will lead to the subjects being assessed as 
non-responders for the response endpoint. 
The Cochran-Mantel-Haenszel (CMH) test will be performed for the PGA-CP, with 
additional summaries, for the change from Baseline to Weeks 2, 4, 8, 16, and 24.  Changes 
by each level of improvement will be summarized, as well as any improvement (change<0), 
any worsening (change>0).  This analysis will provide a sensitivity analysis for the 
ANCOVA analysis of the PGA.  The missing data imputation used for this analysis will be 
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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 combinations of stratification 
factors) then an unstratified test will be performed. 
5.3. Methods to Manage Missing Data 
The primary efficacy endpoint is the change from Baseline to Week 8 in the daily average 
pain intensity in the index bone metastasis cancer pain site.  The primary analysis of the 
primary endpoint will use multiple imputation for missing data at Week 8 (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 8 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 8’ in the table.  
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 
8 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 8 over all 
mITT subjects.  This is a multiple imputation 
version of BOCF single imputation method.  
[Seed 1 below] 
Missing data for other reasons, ie, 
• Subject did not discontinue on or before 
Week 8 (includes discontinuation for 
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 
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any reason after the end of the Week 
8 visit reporting window*) 
• Subject discontinued for a different 
reason prior to or during the Week 
8 visit reporting window*. 
observed efficacy data at Week 8 over all 
mITT subjects.  For example if last 
observation for a subject is at Week 5, then 
the imputation sample for that subject is 
created using the subject’s Week 
5 observation and the standard deviation of 
the Week 8 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.  [Seed 2 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 samples will be used in this analysis.  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: [1] 1001-1100; [2] 2001-2100.  Imputed Week 
8 data for the PGA-CP will be rounded to integer scores in the range 1 to 5.  Imputed Week 
8 data for the average and worst pain intensity and 
that are 
<0 and >10 will be truncated to 0 and 10, respectively.  Imputed Week 8 data for the
will be rounded to integer scores in the range 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 imputation datasets using standard methods (Little & Rubin, 2002), 
which are described in Appendix 9.3.2.  
This analysis will be used for the primary efficacy endpoint at Week 8, plus secondary 
analyses at other time points, and also for a range of secondary efficacy endpoints at all time 
points. When using the multiple imputation method described above for time points earlier or 
later than Week 8, then the reason for missing data is assessed up to the end of the window 
for that particular time point (see Appendix 9.2.1). 
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 8 will impute the subject’s Baseline value for the Week 8 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.  The second method of Last 
Observation Carried Forward (LOCF) for missing data at the primary time point of Week 
8 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 
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baseline will be carried forward (if baseline is missing then the subject would have no 
contributing data to be included in 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 8 (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 (including off-treatment data) up 
to and including Week 8. 
Analyses of the primary endpoint 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.   
For the calculation of the total Around The Clock (ATC) opioid consumption while subjects 
are still in the study, any missing ATC opioids data will be imputed by carrying forward the 
last recorded daily data up to Week 8 (LOCF daily data).  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 average ATC opioid consumption can then be calculated for each week the 
subject is in the study.  To derive the endpoint of weekly average total daily opioid 
consumption, add the respective weekly average daily rescue opioid consumption, which is 
calculated by dividing the observed total rescue opioid consumption by the number of days 
during the observation period. Percent change from baseline in this endpoint will be analyzed 
using ANCOVA on the rank scores. The last weekly score for the average total daily opioid 
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consumption will be used for weeks (LOCF weekly data) 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, e.g., if Week 8 is missing then Week 7 data 
can be used).   
For rescue opioids, the average daily number of doses at a week will be computed as the total 
number of doses observed divided by the number of days under observation for that week.  
The endpoint of average number of doses of rescue medication required per week will be 
analyzed with a negative binomial regression model, in which the response variable is the 
total number of doses during the week, and the offset variable is log of  the number of days 
under observation.      
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 3-8.  Imputation of weekly diary data (LOCF weekly data) after Week 
8 will use the last available weekly diary data score available.  
The electronic diary data is a mix of daily and weekly average pain assessments, 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 equivalent rules from the potential five values of 
the Baseline Assessment Period (BAP).  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 being carried forward with LOCF might 
not be a visit week assessment (eg, carry forward Week 3 for missing Week 4 data).  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 expected five pain scores in the baseline assessment period.  If any of 
the baseline average pain scores are missing (or there are fewer than 5 pain scores recorded) 
then the baseline is calculated over the remaining non-missing values. 
For the non-diary secondary endpoints based on
PGA-CP
 if data 
were not collected during the 5-day BAP period, the closest measurements prior to 
randomization can be used as baseline.  
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6.6. Safety Summaries and Analyses 
Adverse events, concomitant medications, laboratory safety tests, physical and 
examinations, vital signs, ECGs, 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 patients treated by region, 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 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 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, 17-24, 
>24), and for the safety follow-up period (Weeks 1-8, 9-16, 17-24, >24 
posttreatment). 
• 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 
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change, >0 to 10, >10 to 20, >20 to 30, >30, and (diastolic BP) only decreases or no 
change, >0 to 10, >10 to 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 to <20, 20 to <30, 
30 to <40, ≥40, and (diastolic BP) ≤-30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to 
<10, 10 to <20, 20 to <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 concomitant medications for cancer pain 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 who 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 36 days of NSAID use during this interval. 
• Summary of radiation or radiopharmaceutical therapy. 
6.6.1. Adverse Events 
Adverse Events of Abnormal Peripheral Sensation will be summarized.  
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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 the tanezumab 20 mg group and 
placebo.  In addition, significance testing will be performed for adverse events of interest 
between the tanezumab 20 mg 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 
1061 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 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  
tanezumab group and placebo, together with 95% confidence interval, using exact methods.  
Significance tests will be performed for the tier 1 adverse events.  There will be no 
multiplicity adjustment for these significance tests.  These summaries and analyses will also 
be provided for  subjects who are randomized only after Amendment 3, along with incidence 
and severity summary of treatment-emergent adverse events of Abnormal Peripheral 
Sensation (APS) and Sympathetic Nervous Function.  
The following footnote will be used in the 3-tier AE tables: “P-values and confidence 
intervals are not adjusted for multiplicity and should be used for screening purposes only.  
95% Confidence intervals are provided to help gauge the precision of the estimates for Risk 
Difference.  Risk Difference is computed as ‘Tanezumab 20 mg versus placebo’.  Exact 
methods are used for 95% confidence intervals and significance tests.”   


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 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. 
6.6.4. Immunogenicity 
The following assessments of 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.  
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7. INTERIM ANALYSES 
7.1. Introduction 
The following sections describe regular safety data monitoring as well as the single interim 
analysis to assess futility and the evidence of efficacy in the primary efficacy endpoint. 
7.2. Interim Analyses and Summaries 
Safety data monitoring 
Safety data will be subject to regular and ongoing reporting and review throughout the study.  
The details of these 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). 
Events relating to joint safety, including reported Osteonecrosis or events leading to Total 
Joint Replacement will be reviewed by a blinded expert adjudication panel.  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 fractures, 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 External Data 
Monitoring Committee (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 6 per 1000 patient-years, if adjudicated events of interest are reported in 
3 or more 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 6 per 1000 patient-yrs the appropriate threshold 
number of events 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. 
Separate sets of dosing suspension rules for specified Serious Adverse Events are described 
in Section 9.7.1.1 of the protocol. 
Programming and review of unblinded outputs will be performed by individuals independent 
of the study team. 
A single interim analysis for futility or efficacy 


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The study is designed as a Group Sequential Design using a single interim analysis.  The 
purpose of the interim analysis is to assess the non-binding futility and the evidence of 
efficacy of the primary efficacy parameter.   
The interim analysis will be performed when at least 50% (36 from each treatment group) of 
subjects have completed or discontinued prior to Week 8. Only subjects in countries with 
approval of protocol amendment 4 will be included in the interim analysis.  Based on current 
enrollment, it is expected that the interim analysis will include approximately 36 to 45 
subjects per treatment group who have completed or discontinued prior to Week 8.   
 
The non-binding futility stopping boundary will be defined using EAST (Cytel Inc.), using the 
conditional power of 10% (based on estimated delta/sigma) boundary, for a one-sided 
assessment of futility.  The efficacy stopping boundary will be defined using the same 
software, using the Lan-DeMets alpha spending function with the O’Brien-Fleming style 
boundary, for a one-sided assessment of efficacy.  The resulting stopping boundary z scores 
both for futility and efficacy will be determined by the proportion of subjects included in the 
interim analysis (over the 72 planned for the final sample size per treatment), i.e., 
information fraction.  
The analysis will be conducted by a statistician outside of Pfizer, with all details of the 
treatment allocation, analysis and results unknown to all within Pfizer or the contract 
research organization (CRO) performing the final analysis programming.  In the situation 
where the futility or efficacy stopping rule is met, then the statistician will convey the results 
of the interim analysis to a senior statistician within Pfizer (but outside the study team) to 
repeat and ratify the analysis.  The decision to stop the study will be made by Sponsor 
Management as defined in the Interim Analysis Charter.  Results of the interim analysis will 
not be known to anybody in the study team until the formal unblinding of the study at 
database lock. 
Before any interim analysis is initiated, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind as per Pfizer’s standard 
operating procedures (SOPs) will be documented and approved in an Interim Analysis 
charter.  In addition, the analysis details must be documented and approved in an interim 
analysis SAP. 
At the time when the SAP amendment 5 is issued, the planned single interim analysis has 
been performed according to the interim analysis SAP.  The interpretation of final analysis of 
the primary endpoint will take into account the type I error (alpha) spent at the interim 
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8. REFERENCES  
1. EuroQol Group.  EuroQol: a new facility for the measurement of health related quality of 
life. Health Policy 1990; 16:199-208. 
2. 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 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
Change from Baseline to Week 8 in daily 
average pain intensity in the index bone 
metastasis cancer pain site (aPI-IBM) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use 
Multiple 
Imputation 
Primary Analysis 
 
 
 
 
 
 
Change from Baseline to Week 8 in 
aPI-IBM 
PP 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL  opioid 
use 
Multiple 
Imputation 
Sensitivity Analysis 
(Per protocol) 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL  opioid 
use 
BOCF 
Sensitivity/ 
Secondary Analysis 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use 
LOCF 
Sensitivity/ 
Secondary Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
and 8 in aPI-IBM 
mITT 
MMRM 
BL Score, Time, Treatment Group, 
stratification factors, region, Time x 
Treatment Group, BL opioid use 
Multiple 
Imputation 
Data 
Sensitivity Analysis 
for Week 
8 (Secondary  
Analysis for other 
time points) 
Change from Baseline to Weeks 1, 2, 4, 6, 
and 8 in aPI-IBM 
mITT 
MMRM 
BL Score, Time, Treatment Group, 
stratification factors, region, Time x 
Treatment Group, BL opioid use 
Observed  
Data 
Sensitivity Analysis 
for Week 
8 (Secondary  
Analysis for other 
time points) 
Change from Baseline to Week 8 in aPI-
IBM based on data collected prior to 
January 9th, 2020 in China and prior to 
March 11th, 2020 everywhere else 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use 
Multiple 
Imputation 
Sensitivity Analysis 
to assess the 
potential impact of 
COVID-19 


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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in aPI-IBM 
mITT 
MMRM 
BL Score, Time, Treatment Group, 
stratification factors, region, Time x 
Treatment Group, BL opioid use 
Observed  
Data 
Secondary  Analysis 
Missing data pattern for aPI-IBM for 
Baseline and Weeks 1, 2, 4, 6, and 8 
mITT 
None 
(summary) 
NA 
Observed  
Data 
Supportive 
summary for 
missing data 
Change from Baseline to Week 8 in 
aPI-IBM (regions with n ≥ 10) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use,  region x Treatment Group 
Multiple 
Imputation 
Additional 
(Interaction) 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to Week 8 in 
aPI-IBM by baseline pain score (<= 
median, >median) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, Region, BL opioid 
use,  BL pain score category, BL pain 
score category x Treatment Group 
Multiple 
Imputation 
Additional 
(Interaction) 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM by type of primary cancer 
(breast, lung, etc.,) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, Region, BL opioid 
use,  type of cancer, type of cancer x 
Treatment Group 
Multiple 
Imputation 
Additional 
(Interaction) 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM by baseline opioid use (<= 
median, >median) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, Region, BL opioid 
use,  BL opioid use category, BL opioid 
use category x Treatment Group 
Multiple 
Imputation 
Additional 
(Interaction) 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM by tumor aggressiveness (ECOG 
performance status) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, Region, BL opioid 
use,  tumor aggressiveness, tumor 
aggressiveness x Treatment Group 
Multiple 
Imputation 
Additional 
(Interaction) 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM by concomitant anticancer 
treatment (presence/absence) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, Region, BL opioid 
use,  concomitant anticancer treatment, 
concomitant anticancer treatment x 
Treatment Group 
Multiple 
Imputation 
Additional 
(Interaction) 
Analysis 


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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
 
 
 
 
 
 
Change from Baseline to Week 8 in 
aPI-IBM, shown by region (regions with n 
≥ 10) 
mITT 
None 
(summary) 
NA 
Multiple 
Imputation 
Supportive 
summary for 
interaction analysis 
 
 
 
 
 
 
Change from Baseline to Week 8 in 
aPI-IBM, shown by baseline pain score 
(<= median, >median) 
mITT 
None 
(summary) 
NA 
Multiple 
Imputation 
Supportive 
summary for 
interaction analysis 
Change from Baseline to Week 8 in 
aPI-IBM, shown by type of primary cancer 
(breast, lung, etc.,) 
mITT 
None 
(summary) 
NA 
Multiple 
Imputation 
Supportive 
summary for 
interaction analysis 
Change from Baseline to Week 8 in 
aPI-IBM, shown by baseline opioid use 
(<= median, >median) 
mITT 
None 
(summary) 
NA 
Multiple 
Imputation 
Supportive 
summary for 
interaction analysis 
Change from Baseline to Week 8 in 
aPI-IBM, shown by tumor aggressiveness 
(ECOG performance status) 
mITT 
None 
(summary) 
NA 
Multiple 
Imputation 
Supportive 
summary for 
interaction analysis 
Change from Baseline to Week 8 in 
aPI-IBM, shown by concomitant 
anticancer treatment (presence/absence) 
mITT 
None 
(summary) 
NA 
Multiple 
Imputation 
Supportive 
summary for 
interaction analysis 
Change from Baseline to Week 8 in 
aPI-IBM (including subjects only 
randomized under Amendment 3) 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use 
Multiple 
Imputation 
Additional Analysis 
Change from Baseline to Days 1, 2, 3, 4, 5, 
6, 7, and to Weeks 1, 2, 4, 6, 12, 16, and 
24 in aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, , BL opioid 
use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in worst PI-IBM 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group,  stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Week 16 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use 
BOCF 
Secondary Analysis 


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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
Change from Baseline to Week 16 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use 
LOCF 
Secondary Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in weekly average PI 
non-index cancer pain sites 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in weekly worst PI 
non-index cancer pain sites 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in weekly average PI 
non-index cancer pain sites (only include 
sites where Baseline average pain is at 
least 5) 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in weekly worst PI 
non-index cancer pain sites (only include 
sites where Baseline worst pain is at 
least 5) 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
 
 
 
 
 
 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use, cancer pain site,  cancer pain site x 
Treatment Group 
Multiple 
Imputation 
Secondary Analysis 
–Interaction 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use,  BL score  x Treatment Group 
Multiple 
Imputation 
Secondary Analysis 
–Interaction 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use,  type of primary cancer, type of 
primary cancer  x Treatment Group 
Multiple 
Imputation 
Secondary Analysis 
–Interaction 
Analysis 


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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use,  BL opioid use  x Treatment Group 
Multiple 
Imputation 
Secondary Analysis 
–Interaction 
Analysis 
Change from Baseline to Week 8 in 
aPI-IBM 
mITT 
ANCOVA 
BL Score, Treatment Group, 
stratification factors, region, BL opioid 
use,  stratification factors x Treatment 
Group 
Multiple 
Imputation 
Secondary Analysis 
–Interaction 
Analysis 
 
 
 
 
 
 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in daily average PI 
non-index visceral cancer pain sites 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Weeks 1, 2, 4, 6, 
8, 12, 16, and 24 in daily worst PI 
non-index visceral cancer pain sites 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
 
 
 
 
 
 
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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
 
Change from Baseline to Weeks 2, 4, 8, 
16, and 24 in PGA-CP 
mITT 
ANCOVA 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors, region, BL 
opioid use 
Multiple 
Imputation 
Secondary Endpoint 
Analysis 
Change from Baseline to Weeks 2, 4, 8, 
16, and 24 in PGA-CP 
mITT 
CMH test  
Treatment Group [1] 
Mixed 
BOCF/LOC
F 
Sensitivity Analysis 
for PGA 
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 1, 
2, 4, 6, 8, 12, 16, and 24 in the aPI -IBM 
mITT 
Logistic 
Regression 
BL Score, Treatment Group, 
stratification factors 
Mixed 
BOCF/LOC
F 
Secondary Endpoint 
Analysis 
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 1, 
2, 4, 6, 8, 12, 16, and 24 in the aPI -IBM 
mITT 
Logistic 
Regression 
BL Score, Treatment Group, 
stratification factors 
BOCF 
Secondary Endpoint 
Analysis 
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 1, 
2, 4, 6, 8, 12, 16, and 24 in the aPI -IBM 
mITT 
Logistic 
Regression 
BL Score, Treatment Group, 
stratification factors 
LOCF 
Secondary Endpoint 
Analysis 
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 1, 
2, 4, 6, 8, 12, 16, and 24 in the worst PI –
IBM 
mITT 
Logistic 
Regression 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors 
Mixed 
BOCF/LOC
F 
Secondary Endpoint 
Analysis 
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 1, 
2, 4, 6, 8, 12, 16, and 24 in the worst PI –
IBM 
mITT 
Logistic 
Regression 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors 
BOCF 
Secondary Endpoint 
Analysis 
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 1, 
2, 4, 6, 8, 12, 16, and 24 in the worst 
PI -IBM 
mITT 
Logistic 
Regression 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors 
LOCF 
Secondary Endpoint 
Analysis 
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
mITT 
Logistic 
Regression 
BL Score, BL aPI-IBM, Treatment 
Group, stratification factors 
Mixed 
BOCF/LOC
F 
Secondary Endpoint 
Analysis 
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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
to Weeks 2, 4, 8, 16, and 24 in the 
PGA-CP   
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline to 
Weeks 8, 16 and 24 in the aPI-IBM 
mITT 
None 
(summary) 
NA 
Observed 
Secondary Endpoint 
Analysis 
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline to 
Weeks 8, 16 and 24 in the aPI-IBM 
mITT 
None 
(summary, and 
plot for week 8) 
NA 
Mixed 
BOCF/LOC
F 
Secondary Endpoint 
Analysis 
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline to 
Weeks 8, 16 and 24 in the worst PI-IBM 
mITT 
None 
(summary) 
NA 
Observed 
Secondary Endpoint 
Analysis 
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from Baseline to 
Week 8, 16 and 24 in the worst PI-IBM 
mITT 
None 
(summary, and 
plot for week 8) 
NA 
Mixed 
BOCF/LOC
F 
Secondary Endpoint 
Analysis 
Percent change from Baseline in average 
daily opioid consumption at Weeks 1, 2, 4, 
6, 8, 12, 16, and 24 (Include both ATC and 
rescue opioids)  
mITT 
ANCOVA on 
the rank scores 
BL aPI-IBM, Treatment Group, 
stratification factors, region 
LOCF 
Secondary Endpoint 
Analysis 
 
 
 
 
 
 
Total number of doses of rescue 
medication  at Weeks 1, 2, 4, 6, 8, 12, 16, 
and 24 
(The resulting analysis  will show the 
estimated rate of opioids taken as rescue 
medication for each week.) 
mITT 
Negative 
Binomial model 
(log total 
number of days 
of data 
collection 
within the 
analysis week 
as  offset 
variable) 
BL aPI-IBM, Treatment Group, 
stratification factors, region, BL opioid 
use. Use the log-total number of days of 
data collection as the subject offset 
variable. 
Observed 
Data within 
Each Week, 
LOCF for 
Weeks That 
Are Missing 
Secondary Endpoint 
Analysis 
Change from Baseline in the weekly 
Opioid-Related Symptom Distress Scale at 
Weeks 2, 4, 8, 16, and 24 
mITT 
MMRM 
BL Score, Time, Treatment Group, 
stratification factors, region, Time x 
Treatment Group 
Observed 
Data 
Secondary Endpoint 
Analysis 


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Endpoint 
Analy
sis  
Set 
Statistical 
Method  
Model/ Covariates 
Missing  
Data 
Objective 
[1] CMH test will be stratified by the levels of the combined stratification parameters (4 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, 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, 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 visit (eg, 
 
PGA-CP 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. 
Visit 
Target Study Day 
Window 
Screening  
Variable (typically up to 
37 days prior to baseline 
visit) 
[No lower limit, Day -6] 
Baseline 
1 (defined as initial day of 
study drug administration) 
[-5,1] 
Week 2 
15 
[2,22] 
Week 4 
29 
[23,43] 
Week 8 
57 
[44,85] 
Week 16 
113 
[86,141] 
Week 24 
169 
[142,197] 
 
 
For the average and worst pain intensity NRS scores, the data are collected daily via 
electronic diary up to the end of Week 8, and thereafter weekly up to Week 24. 
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The Baseline score is the mean of the  non-missing pain scores over study days -5 to -1.  If 
fewer than 5 are available between study days -5 and -1, the baseline will be the mean of the 
available scores. 
The table below describes the visit days for each week (Weeks 1-8).  All available diary data 
in each of the weekly intervals will be used to calculate the mean daily pain score for that 
study week.  


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Study 
Week 
Days 
1 
1-7 
2 
8-14 
3 
15-21 
4 
22-28 
5 
29-35 
6 
36-42 
7 
43-49 
8 
50-56 
 
However, if a subject receives the Week 8 injection dose prior to Day 57, the Week 8 score 
will be calculated using the mean of the available scores from the 7 calendar days 
immediately prior to the Week 8 injection date.  Any scores used in this calculation of Week 
8 will not also be used in an earlier week calculation, eg, if the Week 8 dose occurs on Day 
53, the available scores from Days 46-52 will be used to calculate the average score for 
Week 8, and the available scores from Days 43-45 will be used to calculate the average score 
for Week 7. 
After the Week 8 visit, pain scores are captured only once a week in the diary.  These are 
grouped in 4-week intervals using visit windows as shown below.  If a subject comes in late 
for a Week 8 visit (or weekly diary is not activated at the visit), and so has daily diary data 
collected past Day 56, these data will be averaged with any data obtained weekly for any 
given interval.  
Summary 
Week 
Includes 
Weeks 
Days 
12 
9 - 12 
57-84 
16 
13 - 16 
85-112 
20 
17 - 20 
113-140 
24 
21 - 24 
141-168 
 


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Appendix 3. STATISTICAL METHODOLOGY DETAILS  
Appendix 3.1. Further Details of Safety Data Monitoring 
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),2 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

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: 
∑
=
=
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: 
 
𝑣𝑣∗= ൬1
𝑣𝑣+
1
𝑣𝑣ො𝑜𝑜𝑜𝑜𝑜𝑜
൰
−1
, 
using 
 


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𝑣𝑣= (𝐷𝐷−1) ቆ1 +
𝐷𝐷
𝐷𝐷+ 1
𝑊𝑊ഥ𝐷𝐷
𝐵𝐵𝐷𝐷
ቇ
2
 
𝑣𝑣ො𝑜𝑜𝑜𝑜𝑜𝑜 = (1 −𝛾𝛾ො𝐷𝐷) ൬𝑣𝑣𝑐𝑐𝑐𝑐𝑐𝑐+ 1
𝑣𝑣𝑐𝑐𝑐𝑐𝑐𝑐+ 3൰𝑣𝑣𝑐𝑐𝑐𝑐𝑐𝑐 
𝛾𝛾ො𝐷𝐷= ቀ1 +
1
𝐷𝐷ቁ
𝐵𝐵𝐷𝐷
𝑇𝑇𝐷𝐷. 
 
This distribution can be used to construct the test statistics and 95% confidence intervals 
for θ. 
Appendix 3.4. ATC and Rescue Opioid Medication Endpoints 
ATC and rescue opioid medication (RM) data are collected daily using an electronic system 
up to Week 8, and during selected weeks (weekly) after Week 8 and up to Week 24.  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 a similar principle as 
described above in Appendix 2.1 for the daily and weekly pain data.  
In the case of a week based on data from fewer than 7 days due to the implementation of the 
windowing algorithm, the weekly amount and number of doses calculation will be adjusted 
to a 7-day period to account for the smaller number of days assessed. 
The number of doses of RM use (using daily and weekly data) and the total amount taken 
over the week will be calculated for the assigned week algorithm described above.  
Imputation is described in Section 5.3.  Imputation of daily data occurs for ATC opioids up 
to Week 8 where the patient is in the trial.  If the patient discontinues the study before Week 
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8, then the imputation occurs only up to the end of the week in which patient discontinued 
the study.  Afterwards, weekly data are imputed.   
An example of imputation and calculating the two endpoints using the daily diary data is 
shown below. 
Example  
In this example, a patient 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 ATC and rescue medication example data.  In this example, the subject’s Week 
2 visit was on study day 14. 


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Study Day (Week 2) 
Morphine equivalent 
of ATC Medication 
taken (mg)  
Morphine equivalent  
of ATC Medication 
taken with LOCF 
imputation (mg) 
Episodes of Rescue 
Medication taken in 
morphine equivalent 
dose  
8  
100 
100 
50 mg, 50 mg 
9  
Missing 
100 [1] 
Missing 
10  
100 
100 
0 
11  
100 
100 
50 mg 
12  
Missing 
100 [1] 
Missing 
13  
100 
100 
50 mg, 50 mg 
14  
100 
100 
50 mg, 50 mg 
[1] Using LOCF imputation for missing data 
For this subject, the two endpoints on opioid use are calculated as the following: 
• Average daily total opioid consumption (in mg of morphine equivalent doses) at 
Week 2 = 150 mg, in which 100 mg is from the average daily ATC opioid 
consumption and 50 mg is from the average daily rescue opioid consumption. 
• Average number of doses of rescue medication required per week at Week 2 =1.