Clinical trial NCT02528188
Conditions: Chronic Pain Osteoarthritis, Hip Osteoarthritis, Knee
Sponsor: Pfizer
Start date: 2015-07-21; Completion date: 2019-02-27
Enrollment: 3021 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the long-term joint safety and efficacy (pain relief) of the investigational study drug, tanezumab compared to non-steroidal anti inflammatory drugs (NSAIDs) in subjects with osteoarthritis of the hips or knees.

Detailed description:

Arms: arm 1: Subcutaneous injection of placebo for tanezumab every 8 weeks plus oral NSAID (naproxen 500 mg, celecoxib 100 mg or diclofenac 75 mg) twice daily for 56 weeks arm 2: Subcutaneous injection of tanezumab 2.5 mg every 8 weeks plus oral placebo for NSAID (naproxen, celecoxib or diclofenac ER) twice daily for 56 weeks arm 3: Subcutaneous injection of tanezumab 5 mg every 8 weeks plus oral placebo for NSAID (naproxen, celecoxib or diclofenac) twice daily for 56 weeks
Interventions: intervention 1: NSAID intervention 2: Tanezumab 2.5 mg intervention 3: Tanezumab 5 mg
Intervention descriptions: intervention 1: Orally administered NSAID (naproxen 500 mg, celecoxib 100 mg or diclofenac 75 mg) twice daily for 56 weeks intervention 2: Subcutaneous injection of tanezumab 2.5 mg every 8 weeks for 56 weeks intervention 3: Subcutaneous injection of tanezumab 5 mg every 8 weeks for 56 weeks

Protocol documents:
Prot_001.pdf: 
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CLINICAL PROTOCOL
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED, 
MULTICENTER STUDY OF THE LONG-TERM SAFETY AND EFFICACY OF 
SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN SUBJECTS WITH 
OSTEOARTHRITIS OF THE HIP OR KNEE
Compound:
PF-04383119
Compound Name:
Tanezumab
United States (US) Investigational New 
Drug (IND) Number:
BB-IND 11,680
European Clinical Trial Database 
(EudraCT) Number:
2012-003721-22
Protocol Number:
A4091058
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 and Rationale
Amendment 2
15 May 2016
Inclusion criterion #4 and associated text throughout 
the protocol has been updated to expand the number 
of pre-study, non-steroidal anti-inflammatory drug 
(NSAID) osteoarthritis pain treatment regimens that 
are considered to be qualifying. The following pre-
study NSAID treatment regimens are now considered 
to be qualifying for prospective study subjects:  
Ibuprofen 1200 – 3200 mg/day
Loxoprofen 120 – 180 mg/day
Meloxicam 5 - 15 mg/day
Nabumetone 1000 – 2000 mg/day
Aceclofenac 200 mg/day
Sulindac 200 – 400 mg/day
Ketoprofen 200 mg/day
To account for formulations of naproxen that include 
the sodium salt of naproxen, the lowest qualifying 
dose of naproxen is set at 440 mg/day.  
Exclusion criterion #21 has been updated to provide 
additional clarity regarding exclusion of subjects who 
have a history of heart block. 
Randomization criterion #9 and associated text in 
protocol Section 6.1.1 (Screening procedures) has 
been updated to provide a provision for re-selection 
of an index joint if the initially selected index joint 
does not have a qualifying Kellgren-Lawrence grade.  
Administrative updates in the Protocol Summary, 
Section 3, Section 5.8.2, Section 6.1.4 and 7.4.4 to:
•
Provide flexibility in the length of the Initial 
Pain Assessment Period (minimum of 3 days).
•
Provide clarification that the cost of standard 
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of care medication that subjects can receive 
16 weeks after the last dose of subcutaneous 
study medication will be reimbursed by the 
sponsor if allowed per local regulation.
•
Provide clarification of the intended follow-
up for subjects with severe and persistent joint 
pain.
Amendment 1
10 July 2015
Changes made in response to United States Food and 
Drug Administration Advice/Information Request 
(30 June 2015):
•
Inclusion criterion pertaining to inclusion of 
subject population with a prior history of 
failure, intolerance or unwillingness to take 
approved standard of care therapies for 
osteoarthritis pain has been added (Inclusion 
# 4).  
•
Minor revisions in Protocol Summary, and 
protocol Sections 1.2.5, 3 have been updated 
to harmonize pre-study NSAID regimen text 
with updates in exclusion criterion 4 (noted 
above).
•
Protocol Sections 6.1 and 6.1.1 have been 
updated to reflect the required level of 
evidence to establish that subjects meet the 
updated inclusion criterion pertaining to 
inclusion of a subject population with a prior 
history of failure, intolerance or unwillingness 
to take approved standard of care therapies for 
osteoarthritis pain.
•
Required washout from rescue medication 
(acetaminophen / paracetamol) use before 
clinic visits has been decreased from 48 to 
24 hours where applicable throughout the 
protocol.
The Single Reference Safety Documents cited in 
Protocol Section 1.2.5 have been updated and 
relevant text in Section 5.6 has been harmonized with 
this update.
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Definitions for completion of treatment and 
completion of study have been clarified in Protocol 
Section 3.
Text pertaining to analysis of actigraphy data in 
Section 9.4.4.2 has been revised. Specific physical 
activity intensity thresholds have been removed from 
the protocol and will be available in the statistical 
analysis plan. 
Administrative changes (instructional text pertaining 
to archiving of completed PHQ-9 questionnaires in 
subject source documents and updates for 
consistency with Pfizer Protocol Template version 16 
Feb 2015).
Original protocol
01 April 2015
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.
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PROTOCOL SUMMARY 
Background
Tanezumab is a monoclonal antibody that binds to and inhibits the actions of nerve growth 
factor (NGF).  The Nerve Growth Factor Inhibitor (NGFI) class may offer an important 
breakthrough in the treatment of chronic pain and is under clinical investigation for the 
treatment of pain associated with osteoarthritis or other chronic pain conditions. 
The completed Phase 2 and Phase 3 studies conducted to date have demonstrated that 
tanezumab is efficacious and generally safe and well tolerated for the treatment of pain due 
to osteoarthritis and chronic low back pain.  In addition, completed Phase 1/2 studies suggest 
tanezumab is also efficacious and generally safe for the treatment of neuropathic, visceral, 
and cancer pain.
In 2010, the US Food and Drug Administration’s (FDA) Division of Analgesia, Anesthetic, 
and Addiction Products (DAAAP) placed tanezumab (June/July 2010) and subsequently the 
entire NGFI class (December 2010) on partial clinical hold due to adverse events initially 
described by investigators as osteonecrosis that in some cases resulted in total joint 
replacement.  Pfizer voluntarily imposed the partial clinical hold on study conduct in all 
countries.
Extensive analyses of the reports of osteonecrosis and other total joint replacements were 
conducted.1  On March 12, 2012, the FDA Arthritis Advisory Committee reviewed these 
results as well as those prepared by the FDA.2,3  The committee endorsed continued clinical 
development of the NGFI class of compounds with additional measures to minimize the risk 
and further protect subject safety.  On August 28, 2012, the FDA lifted the partial clinical 
hold on tanezumab allowing the resumption of clinical studies for osteoarthritis and all other 
chronic pain conditions. 
Using recommendations from discussions with European agencies [United Kingdom’s 
Medicines and Healthcare products Regulatory Agency (MHRA), Germany’s Paul Ehrlich 
Institute (PEI) and Spain’s Agency on Medicinal Products and Medical Devices (AEMPS)] 
as well as the FDA Arthritis Advisory Committee and interactions with FDA, risk mitigation 
measures were developed and are incorporated in the design and objectives of the current 
study. 
The FDA placed another partial clinical hold on the tanezumab clinical development program 
as well as all anti-NGF antibody studies in 2012 due to concerns about adverse changes in 
the sympathetic nervous system of mature animals.  Only studies in patients with cancer pain 
were allowed to continue. 
In animal studies in rats and non-human primates, tanezumab treatment for up to 6 months, 
with doses producing greater systemic exposure than observed with clinical doses, was 
associated with lower sympathetic ganglion volume and lower average size of 
post-ganglionic sympathetic neurons when compared to control animals. All effects were 
completely reversible following a dosing-free recovery period. In a separate cardiovascular 
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function study in non-human primates, functional changes in the cardiovascular system 
controlled by the sympathetic nervous system were not observed. 
Although evidence of clinically important effects on the sympathetic nervous system have 
not been identified in previously completed tanezumab studies, per agreement with the FDA, 
this and other clinical studies of tanezumab will incorporate additional safety measures to 
monitor for and manage subjects who may develop evidence of clinically important 
sympathetic nervous system dysfunction.
The primary objectives of this study are: 1) to characterize the long-term joint safety risks of 
tanezumab using a composite endpoint (includes adjudication outcomes of rapidly 
progressive osteoarthritis (type-1 and type-2), subchondral insufficiency fracture (or 
SPONK), primary osteonecrosis, or pathological fracture and 2) demonstrate the analgesic 
superiority of tanezumab relative to non-steroidal anti-inflammatory drugs (NSAIDs).  
Intravenous and subcutaneous (SC) administration of tanezumab at doses of 2.5 mg, 5 mg 
and 10 mg was shown to reduce pain and improve function in a dose-related manner in prior 
Phase 3 studies of osteoarthritis.  No further study of the tanezumab 10 mg dose will be 
conducted in subjects with osteoarthritis as this dose did not provide any added efficacy 
benefit over the 5 mg dose.  However, the 5 mg dose is expected to provide added efficacy 
benefit over the 2.5 mg dose.  Tanezumab doses of 2.5 mg and 5 mg will be studied in this 
protocol. 
The 56-week duration of the study precludes the use of a placebo comparator and as such, an 
active control has been included in the study design.  To facilitate inclusion of an active 
control group that will serve as a benchmark for evaluation of the long-term safety and 
efficacy of tanezumab, subjects entering the current study must be receiving a stable dosing 
regimen of oral non-steroidal anti-inflammatory drugs (NSAID) therapy (naproxen, 
celecoxib, diclofenac, aceclofenac, loxoprofen, ibuprofen, meloxicam, nabumetone, sulindac 
or ketoprofen), be tolerating their NSAID regimen and be taking this medication regularly 
during the 30-day period prior to the Screening visit.  Subjects randomized to receive NSAID 
in the current study will receive them at protocol specified doses [naproxen 500 mg twice a 
day (BID), diclofenac extended release (ER) 75 mg BID or celecoxib 100 mg BID].  The 
doses selected for the NSAID treatments being utilized in this study correspond to maximal 
or near maximal labeled doses for the treatment of osteoarthritis. 
The study will include a number of assessments to permit further characterization of the 
pathophysiology of orthopedic events that may be observed during conduct of the study.  
These assessments are described in the main body of the protocol.
STUDY OBJECTIVES AND ENDPOINTS
Primary Objectives:
•
Characterize the long-term risk of joint safety events in subjects with osteoarthritis of 
the knee or hip who receive tanezumab 2.5 mg or tanezumab 5 mg SC versus NSAID 
treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 
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75 mg BID) over the course of 56-weeks of treatment using a composite endpoint 
(includes adjudication outcomes of rapidly progressive osteoarthritis type-1 or type-2, 
subchondral insufficiency fracture (SPONK), primary osteonecrosis, or pathological 
fracture).
•
Demonstrate superior efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus 
NSAID treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 
75 mg BID) at Week 16.
Secondary Objectives:
•
Characterize the long-term joint safety risk using a composite endpoint (includes 
adjudication outcomes of rapidly progressive osteoarthritis (type-2 only), subchondral 
insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture).
•
Characterize the long-term risk of the following individual adjudication outcomes 
occurring: rapidly progressive osteoarthritis (type-1 only), rapidly progressive 
osteoarthritis (type-2 only), rapidly progressive osteoarthritis (type-1 or type-2 
combined), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, 
and pathological fracture.
•
Characterize the long-term risk of all-cause total joint replacements (subjects who 
undergo total joint replacement plus subjects who have an adjudicated outcome of 
rapidly progressive osteoarthritis type-1 or type-2, subchondral insufficiency fracture 
(or SPONK), primary osteonecrosis, or pathological fracture whether they undergo 
total joint replacement or not) occurring. 
•
Characterize joint space width changes in subjects with Kellgren-Lawrence Grade 2 
or 3 osteoarthritis of the index knee or index hip. 
•
Demonstrate superior efficacy of tanezumab 5 mg and tanezumab 2.5 mg SC versus 
each separate NSAID treatment group (naproxen 500 mg BID, celecoxib 100 mg BID 
and diclofenac ER 75 mg BID) at Week 16.
•
Demonstrate the efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus 
NSAID (combined) treatment at all time points to Week 56.
•
Evaluate the long-term safety of tanezumab 2.5 mg and tanezumab 5 mg SC.
•
Explore relationships between adjudicated outcomes of rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fracture (or SPONK), 
primary osteonecrosis, or pathological fracture and variables that may be associated 
with these orthopedic risks.
•
Characterize changes in physical activity level.
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Primary Endpoints:
•
Incidence of a predefined composite endpoint consisting of adjudication outcomes of 
rapidly progressive osteoarthritis (type-1 or type-2), subchondral insufficiency 
fracture (or SPONK), primary osteonecrosis, or pathological fracture (primary 
composite endpoint).
The co-primary efficacy endpoints are:
•
Change from Baseline to Week 16 in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain subscale.
•
Change from Baseline to Week 16 in the WOMAC Physical Function subscale.
•
Change from Baseline to Week 16 in the Patient’s Global Assessment of 
Osteoarthritis.
The Japanese Specific co-primary efficacy endpoints are:
•
Change from Baseline to Week 16 in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain subscale.
•
Change from Baseline to Week 16 in the WOMAC Physical Function subscale.
Secondary Endpoints:
Bone and Joint Safety
•
Incidence of a predefined composite endpoint consisting of adjudication outcomes of 
rapidly progressive osteoarthritis (type-2 only), subchondral insufficiency fracture (or 
SPONK), primary osteonecrosis, or pathological fracture.
•
Incidence of individual adjudication 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 (or 
SPONK), primary osteonecrosis, and pathological fracture.
•
Incidence of all-cause total joint replacements (subjects who undergo total joint 
replacement plus subjects who have an adjudicated outcome of rapidly progressive 
osteoarthritis type-1 or type-2, subchondral insufficiency fracture (SPONK), primary 
osteonecrosis, or pathological fracture whether they undergo total joint replacement 
or not).
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Radiographic
•
Change from Baseline to Week 56 and Week 80 in Medial or Lateral Minimum Joint 
Space Width of the index knee (for subjects with Kellgren-Lawrence Grade 2 or 3 
medial or lateral osteoarthritis of the index knee).
•
Change from Baseline to Week 56 and Week 80 in Minimum Joint Space Width of 
the index hip (for subjects with Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the 
index hip).
•
Incidence of subjects with progression of osteoarthritis in the index knee according to 
Bland and Altman method, at Week 56 and Week 80 (separately) (for subjects with 
Kellgren-Lawrence Grade 2 or 3 medial or lateral osteoarthritis of the index knee).
•
Incidence of subjects with progression of osteoarthritis in the index hip according to 
Bland and Altman method, at Week 56 and Week 80 (separately) (for subjects with 
Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the index hip).
Efficacy
•
WOMAC Pain subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 40, 48, 56 
and Week 64.
•
WOMAC Physical Function subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 
40, 48, 56 and Week 64.
•
Patient’s Global Assessment of Osteoarthritis change from Baseline to Weeks 2, 4, 8, 
16 (Japan only), 24, 32, 40, 48, 56 and Week 64.
•
OMERACT-OARSI responder index at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 
Week 64.
•
Treatment Response: Reduction in the WOMAC Pain subscale of ≥30%, ≥50%, 
≥70% and ≥90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Cumulative distribution of percent change from Baseline in the WOMAC Pain 
subscale score to Week 16, 24, and 56 (endpoint for summary only).
•
Treatment Response: Reduction in the WOMAC Physical Function subscale of 
≥30%, ≥50%, ≥70% and ≥90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Cumulative distribution of percent change from Baseline in the WOMAC Physical 
Function subscale score to Week 16, 24, and 56 (endpoint for summary only).
•
Treatment Response: Improvement of ≥2 points in Patient’s Global Assessment of 
Osteoarthritis at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
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•
Average pain score in the index joint change from Baseline to Weeks 1, 2, 3, 4, 6, 8, 
10, 12, 16, 20, 24, 32, 40, 48, 56 and Week 64.
•
WOMAC Stiffness subscale change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 
48, 56 and Week 64.
•
WOMAC Average change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 
Week 64.
•
WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface, change from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
WOMAC Pain Subscale Item: Pain When Going Up or Down Stairs, change from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Work Productivity and Activity Impairment Questionnaire for Osteoarthritis 
(WPAI:OA) impairment scores change from Baseline to Weeks 16, 24, 56 and 64.
•
EuroQol 5 Dimension (EQ-5D-5L™) dimensions and overall health utility score at 
Baseline and Weeks 8, 16, 24, 40, 56 and 64.
•
Treatment Satisfaction Questionnaire Medicine v.II (TSQM v.II) satisfaction with 
effectiveness, side effects and convenience, and overall satisfaction at Weeks 16 
and 56.
•
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 
and 56.
•
Incidence and Time to discontinuation due to Lack of Efficacy.
•
Usage of rescue medication (incidence and number of days of use) during Weeks 2, 4, 
8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Usage of rescue medication (amount taken) during Weeks 2, 4, 8 and Week 16.
•
Health Care Resource Utilization at Baseline, and Weeks 64, and 80.
Activity Level Monitoring
•
Lower Extremity Activity Scale: change from Baseline to Weeks 4, 8, 16, 24, 56 and 
Week 80 (all subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of physical 
activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily physical activity counts (a 
subset of subjects).
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•
Change from Baseline to Weeks 16 and 56 in average daily minutes of moderate to 
vigorous physical activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of bouted 
(sustained) moderate to vigorous physical activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily step count (a subset of 
subjects).
General Safety
•
Adverse Events.
•
Standard safety assessments (safety laboratory testing [chemistry, hematology], 
sitting vital signs, electrocardiogram (ECG; 12-lead).
•
Orthostatic (supine/standing) blood pressure assessments.
•
Survey of Autonomic Symptom scores.
•
Neurologic exam (Neuropathy Impairment Score [NIS]).
•
Anti-tanezumab antibody assessments.
•
Physical examinations. 
Tertiary Endpoints
Pharmacokinetic and Pharmacodynamic
•
Plasma tanezumab concentrations. 
•
Serum NGF assessment.
•
Serum and urine osteoarthritis biomarker concentrations.
•
Synovial fluid NGF assessment (for a subset of subjects).
•
Synovial fluid tanezumab concentrations (for a subset of subjects).
STUDY DESIGN
This is a randomized, double-blind, active-controlled, multicenter, parallel-group 
Phase 3 study of the safety and efficacy of tanezumab when administered by SC injection for 
56 weeks compared to NSAIDs in subjects with osteoarthritis of the knee or hip.  
Approximately 3000 subjects will be randomized to one of 3 treatment groups in a 1:1:1 ratio 
(N=1000/treatment group).  Treatment groups will include:  
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1. SC placebo (to match tanezumab) once every 8 weeks (a total of 7 administrations) 
plus NSAID administered orally (PO) (naproxen 500 mg BID PO, celecoxib 100 mg 
BID PO, or diclofenac ER 75 mg BID PO) through Week 56.
2. Tanezumab 2.5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO (to match naproxen, celecoxib or diclofenac ER) through Week 56.
3. Tanezumab 5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO (to match naproxen, celecoxib or diclofenac ER) through Week 56. 
Japan specific treatment groups are:
1. SC placebo (to match tanezumab) once every 8 weeks (a total of 7 administrations) 
plus celecoxib 100 mg BID administered orally (PO) through Week 56.
2. Tanezumab 2.5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO to match celecoxib through Week 56.
3. Tanezumab 5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO to match celecoxib through Week 56. 
The study is designed with a total duration of 80 weeks and will consist of three periods:
Screening (up to a maximum of 37 days), Double-blind Treatment (56 weeks) and Safety 
Follow-up (24 weeks). 
The Screening period (beginning 37 days prior to Randomization) includes a Washout period 
(lasting 2-30 days), if required, and an Initial Pain Assessment period (the 7 days prior to 
Baseline [Day 1]; minimum of 3 days). Prior to entering the study, subjects must be 
receiving a stable dosing regimen of oral NSAID therapy consisting of one of the NSAIDs 
presented in the following table, be tolerating their NSAID regimen and be taking this 
medication regularly (defined as an average of at least 5 days per week) during the 30-day 
period prior to the Screening visit.  
Qualifying Pre-study NSAID Treatment Regimens
NSAID
Qualifying Dose Range
Naproxen 
440 mg/day* to 1000 mg/day
Celecoxib
200 mg/day (either 100 mg BID or 200 mg QD)
Diclofenac
100 mg/day to 150 mg/day
Aceclofenac
200 mg/day
Loxoprofen
120 mg/day to 180 mg/day
Ibuprofen
1200 mg/day to 3200 mg/day
Meloxicam
5 mg/day to 15 mg/day
Nabumetone
1000 mg/day to 2000 mg/day
Sulindac
200 mg/day to 400 mg/day
Ketoprofen
200 mg/day
*A minimum dose of 440 mg/day is applicable for naproxen formulations that include the 
sodium salt of naproxen otherwise the minimum qualifying dose of naproxen is 500 mg/day
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The Screening period will include collection of radiographs of the knees, hips, and shoulders
(and other major joints exhibiting signs or symptoms suggestive of osteoarthritis) and 
magnetic resonance imaging (MRIs) of hips and knees.  All radiographs will be evaluated by 
a Central Reader to determine the radiographic eligibility of subjects for the study. 
The Double-blind Treatment period ends and the Safety Follow-Up Period begins at the 
Week 56 visit. Administration of SC investigational product (placebo, tanezumab 2.5 mg or 
tanezumab 5 mg) will occur during clinic visits at Baseline, Weeks 8, 16, 24, 32, 40 and 48.  
Subjects will self administer oral investigational product (NSAID or matching placebo) BID 
from the Baseline visit to Week 56 of the study.  At Week 16 in the Double-blind Treatment 
period, the reduction in WOMAC Pain subscale score from Baseline will be calculated and 
only subjects meeting pre-defined response criteria may continue in the study.  Subjects who 
do not meet pre-defined response criteria will be discontinued from the Double-blind 
Treatment period and enter the 24-week Early Termination Follow-up period.  At Week 56, 
subjects will enter the Safety Follow-up period which lasts until Week 80.
Subjects who are discontinued from treatment prior to Week 56, either at their request or at 
the decision of the investigator, will be required to undergo 24 weeks of follow-up (referred 
to as Early Termination Follow-Up).  The 24 weeks of follow-up will be obtained through 
3 clinic visits and monthly phone calls to yield 24-weeks of post-treatment follow-up.
At Weeks 24, 56, and 80, all subjects will undergo repeat radiographs of each knee, hip and 
shoulder as well as any additional joint(s) that was imaged at Screening.  At Week 24, 
confirmation of the continuing radiographic eligibility of the subject must be received from 
the Central Reader for subjects to continue receving investigational product.  Subjects with 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis in any knee or hip joint, on the basis of the 
Central Reader’s assessment of the screening radiographs, will have follow-up MRIs of each 
hip and knee obtained at Weeks 24, 56, and 80. 
Subjects who have undergone or plan to undergo total joint replacement or other arthroplasty 
procedure during the study will be discontinued from investigational product.  In addition, 
subjects who undergo total knee, hip or shoulder joint replacement surgery during the study 
(Treatment Period or Follow-up Period) will be followed for 24 weeks after the procedure as 
part of a separate protocol, provided the subject consents.
STATISTICAL METHOD
A sample size of approximately 1000 subjects for each of the treatment groups of NSAID, 
tanezumab 2.5 mg and tanezumab 5 mg will be used in this study.  This sample size allows 
for a high probability of observing subjects with any component of the composite endpoint 
where the event rate over this study is very small.  If the event rate were 0.25%, then there 
would be a >90% probability of observing at least one subject with an event in any single 
treatment group.  In addition, the sample size allows for good precision to estimate the 
incidence rate for each treatment group in order to estimate an upper bound for the true 
incidence rate. 
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Primary Analysis
The incidence of subjects with any of the adjudication outcomes of the primary composite 
endpoint will be shown by number of subjects treated and subject years of exposure 
(treatment plus follow-up periods), for individual treatment groups and differences between 
tanezumab treatment groups and the NSAID treatment group.  The risk ratio and risk 
difference with 95% confidence intervals will be calculated for the comparisons of each 
tanezumab treatment group versus the NSAID treatment group, as well as significance tests 
for each treatment comparison.  The time to each event will be summarized, and (where there 
are sufficient numbers of subjects) Kaplan-Meier estimates of the time to event will be 
produced, together with an analysis of each tanezumab treatment group versus the NSAID 
treatment group using the log-rank test.
The primary safety and efficacy population will be the Intention-To-Treat (ITT) population, 
defined as all randomized subjects who received SC investigational product (either 
tanezumab or matching placebo).  The primary efficacy analysis will use multiple imputation 
methods for missing data at Week 16.  Details of the multiple imputation procedure are given 
below.  All treatment comparisons will use the two-sided 5% significance level.
The co-primary efficacy endpoints will be analyzed using an Analysis of Covariance 
(ANCOVA) model, with model terms for Baseline score, Baseline Diary Average Pain, 
index joint (hip or knee), Kellgren-Lawrence grade, NSAID cohort (diclofenac, celecoxib or 
naproxen) and treatment group, and study site as a random effect.  The assessment of 
significance for the tanezumab SC versus NSAID treatment contrasts of the primary efficacy 
parameters will use a step-down testing strategy within each of the co-primary efficacy 
endpoints.  This order of significance testing is defined as first testing tanezumab 5 mg 
versus NSAID, and if statistically significant (p≤0.05) to then test tanezumab 2.5 mg versus 
NSAID.  Finally, the tanezumab treatment group is declared as superior to NSAID if the 
corresponding treatment contrast is significant over all three co-primary endpoints (two 
co-primary efficacy endpoints in Japan).  This testing procedure will maintain the Type I 
error to 5% or less within each of the co-primary efficacy endpoints, and to less than 5% for 
all three co-primary efficacy endpoints (two co-primary efficacy endpoints in Japan).
The primary analysis of the co-primary endpoints will use multiple imputation for missing 
data, to account for uncertainty around the subject response.  The basis for imputing missing 
values will be dependent on the reasons for missing data.  For subjects with missing data due 
to discontinuation prior to Week 16 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 of the observed efficacy data 
at Week 16 (over all treatment groups).  For subjects with missing data for any other reason, 
imputation will be based on sampling from a normal distribution using a mean value equal to 
the subject’s last observed efficacy value and standard deviation of the observed efficacy 
data at Week 16 (over all treatment groups).  Imputed values for the Patient’s Global 
Assessment of Osteoarthritis will be rounded to integer values from 1 to 5 (For Japan, 
Patient’s Global Assessment of Osteoarthritis scores will not be imputed or used in the 
primary efficacy analysis).  Imputed values for the WOMAC Pain and Physical Function 
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subscales will be truncated at 0 and 10.  One hundred imputation samples will be used, and 
the ANCOVA model described above will be used for each imputation dataset.  The final 
results will be calculated using the combined sets of results from each imputation dataset 
analysis.4  
Additional analyses will explore the sensitivity of the effect of missing data.  The first 
analysis will use the same main effects ANCOVA model as described above, but with Last 
Observation Carried Forward (LOCF) for missing data.  The second analysis will use the 
same main effects ANCOVA model as described above, but with Baseline Observation 
Carried Forward (BOCF) for missing data.  The third analysis will use Mixed Model for
Repeated Measurements (MMRM) utilizing all observed data up to and including Week 16. 
Additional analyses of the primary efficacy endpoints include comparisons of tanezumab 
2.5 and 5 mg versus the separate NSAID treatment groups of celecoxib, naproxen and 
diclofenac.  These analyses will not use the testing strategy described above, but assessment 
of significance will be assessed across all treatment comparisons and co-primary endpoints 
individually. 
All analyses will show estimates of the treatment group response and treatment group 
differences of each tanezumab treatment group versus NSAID, with corresponding standard 
errors of the mean, and 95% confidence intervals (and p-values for treatment differences).
DATA MONITORING COMMITTEE
An independent, external Data Monitoring Committee (E-DMC) has been instituted for the 
tanezumab clinical program.  This committee will be composed of at least one 
rheumatologist, neurologist, statistician, and epidemiologist.  The E-DMC will review 
unblinded safety data including (but not limited to) adverse events and serious adverse events 
on a regular basis throughout the trial.  The E-DMC will have written operating procedures 
and a Charter, including a specific description of the scope of their responsibilities.
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Table 1.
Schedule of Activities
The Schedule of Activities tables provide an overview of the protocol visits and procedures.  
Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the subject.
SCREENING SCHEDULE OF EVENTS
Visit Identifier
Screeninga (Day -37 to Day -1)
Screening 
Stage 1 
Screening 
Stage 2
Initial Pain Assessment 
Period (IPAP)
Day -37 to Day -7
Day -7 to Day -1
Informed Consent
X
Numeric Pain Scale rating for bilateral shoulders, hips, 
knees and any other major joint that is imaged [Interactive 
Response Technology (IRT)]
X
Primary Diagnosis/selection of index joint
X
Demographics, General and Musculoskeletal Specific 
Medical History and Prior/Current medication Useb
X
General Physical Examination
X
Musculoskeletal Physical Examinationc
X
Weight/Height/BMI/Smoking Status/Female Hormonal 
Status/Alcohol Use
X
Sitting Vital Signs (BP, HR)
X
Orthostatic Blood Pressure (supine/standing)
X
Electrocardiogram (ECG 12-lead)
X
Neurologic Exam - Neuropathy Impairment Score (NIS)d
X
WOMAC Pain, Physical Function and Stiffness Subscales
(for index hip or knee)i
X
Survey of Autonomic Symptoms (SAS) questionnairei
X
Subjects Trained on use of IRT System
X
Subject Daily/Weekly Assessments (IRT)p
X
Washout of Prohibited Pain Medications
Inclusion/Exclusion Criteria
X
Female Subjects of Child-bearing Potential Instructed on 
Contraceptive Requirements for Study
X
IMAGING
Radiographs of each Hip, Knee and Shoulder
X
Collect Local Radiography Report
X
Magnetic Resonance Imaging (MRI) each hip and kneee
X
Dual-Energy X-ray Absorptiometry (DXA) per National 
Osteoporosis Foundation Guidelinese
X
ACTIVITY LEVEL MONITORING
Actigraphyf
X
LABORATORY
Hepatitis Screen (Hepatitis B & Hepatitis C); HIV test, 
Urine Toxicology screen
X
HbA1c
X
Serum FSH Testg
X
Serum Pregnancy Test
X
Hematology
X
Blood Chemistry
X
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Visit Identifier
Screeninga (Day -37 to Day -1)
Screening 
Stage 1 
Screening 
Stage 2
Initial Pain Assessment 
Period (IPAP)
Urinalysis
X
PRE-STUDY NSAID / RESCUE MEDICATION
Pre-study NSAID Dispensed/Regimen Stabilizationh
X
At least 2 weeks prior to Baseline (Day 1) 
visit
Oral Rescue Medication Dispensed
X
Abbreviations: →= ongoing/continuous event; BMI = Body Mass Index; BP = Blood Pressure; DXA = Dual Energy 
X-ray Absorptiometry; ECG = electrocardiogram; FSH = Follicle Stimulating Hormone; HbA1c = Glycosylated 
Hemoglobin; HR = Heart Rate; HIV = Human Immunodeficiency Virus; IRT = Interactive Response Technology; 
MRI = Magnetic Resonance Imaging; NIS = Neuropathy Impairment Score; NSAID = Non-Steroidal 
Anti-Inflammatory Drug; SAS = Survey of Autonomic Symptoms; WOMAC = Western Ontario and McMaster 
University Osteoarthritis Index
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DOUBLE-BLIND TREATMENT AND SAFETY FOLLOW-UP PERIOD SCHEDULE OF EVENTS
Visit Identifier
Double-Blind Treatment
Safety Follow-up
Baselinek
Week 
2
Week 
4
Week 
8k
Week 
16k
Week 
24k
Week 
32k
Week 
40k
Week 
48k
Week 56
End of 
Treatment
Week 
64
Week 
80
End of 
Study
Day 1
Day 
15
Day 
29
Day 
57
Day 
113
Day 
169
Day 
225
Day 
281
Day 
337
Day 
393
Day 449
Day 
561
Visit Window
±3 
days
±3 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
General Physical 
Examination
X
Musculoskeletal Physical 
Examinationc
X
X
X
X
X
X
X
X
X
X
X
X
Sitting Vital Signs (BP, HR)
X
X
X
X
X
X
X
X
X
X
X
X
Orthostatic Blood Pressure 
(supine/standing)
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (ECG 
12-lead)
X
X
Body Weight
X
Survey of Autonomic 
Symptoms (SAS) 
questionnairei
X
X
X
Neurologic Exam
Neuropathy Impairment 
Score (NIS)d
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion Criteria/ 
Subject Eligibility
X
Xs
Xs
Randomization
X
IMAGING
Radiographs of each Hip, 
Knee and Shoulder
X
X
X
Collect Local Radiography 
Report
X
X
X
Magnetic Resonance 
Imaging (MRI) of each hip 
and kneeq
X
X
X
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Visit Identifier
Double-Blind Treatment
Safety Follow-up
Baselinek
Week 
2
Week 
4
Week 
8k
Week 
16k
Week 
24k
Week 
32k
Week 
40k
Week 
48k
Week 56
End of 
Treatment
Week 
64
Week 
80
End of 
Study
Day 1
Day 
15
Day 
29
Day 
57
Day 
113
Day 
169
Day 
225
Day 
281
Day 
337
Day 
393
Day 449
Day 
561
Visit Window
±3 
days
±3 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
ACTIVITY LEVEL MONITORING
Lower Extremity Activity 
Scale (LEAS)
X
X
X
X
X
X
X
Sites provide accelerometers 
to subjectsf
Xf
Xf
Actigraphyf
Xf
Xf
Sites collect accelerometers 
from subjectsf
Xf
Xf
Xf
LABORATORY
Serum/Urine Pregnancy Test
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
Blood Chemistry
X
X
X
Serum 25-hydroxy vitamin D 
and parathyroid hormone
X
X
Serum and Plasma Retention 
Samples
X
X
X
X
Banked biospecimen (whole 
blood)
X
PHARMACOKINETIC, PHARMACODYNAMIC AND BIOMARKER SAMPLING
Plasma Pharmacokinetic 
Samplen
X
X
X
X
X
X
X
Serum NGF (PD) Samplen
X
X
X
X
X
Serum Anti-tanezumab 
Antibodyn
X
X
X
X
X
X
X
X
Serum and Urine 
Biomarkersn
X
X
X
Xo
Xo
Xo
Xo
Xo
Synovial Fluid Sample
Optional for subjects undergoing arthrocentesis; additional sampling may be neededt
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Visit Identifier
Double-Blind Treatment
Safety Follow-up
Baselinek
Week 
2
Week 
4
Week 
8k
Week 
16k
Week 
24k
Week 
32k
Week 
40k
Week 
48k
Week 56
End of 
Treatment
Week 
64
Week 
80
End of 
Study
Day 1
Day 
15
Day 
29
Day 
57
Day 
113
Day 
169
Day 
225
Day 
281
Day 
337
Day 
393
Day 449
Day 
561
Visit Window
±3 
days
±3 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
SUBJECT DAILY / WEEKLY ASSESSMENTS (IRT)
Numeric Pain Scale rating
Daily Entries for Index Joint and Weekly For 
Non-index Joints
Weekly Entries for Index and Non-index Joints
Rescue Medication Use
Daily Entries
Weekly Entries
Concomitant NSAID Use
Weekly Entries
STUDY TREATMENTS / RESCUE MEDICATION / STANDARD OF CARE
Subcutaneous Investigational 
Product Administered
X
X
X
X
X
X
X
Oral investigational product 
(NSAID or matching 
placebo) Dosing
X
Self administered by subjects BID
Oral investigational product
(NSAID or matching 
placebo) Dispensed and/or 
Compliance Check
X
X
X
X
X
X
X
X
X
X
Oral Rescue Medication 
Dispensed and/or 
Compliance Checkl
X
X
X
X
X
X
X
X
X
X
X
Assign Standard of Care 
Treatment as Neededm
X
SUBJECT REPORTED ASSESSMENTS (Completed at Study Visits)i
WOMAC Pain, Physical 
Function and Stiffness
Subscales (for index hip or 
knee)
X
X
X
X
X
X
X
X
X
X
X
Patient’s Global Assessment 
of Osteoarthritis
X
X
X
X
X
X
X
X
X
X
X
WPAI:OA
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
TSQM (v.II)
X
X
mPRTI
X
X
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Visit Identifier
Double-Blind Treatment
Safety Follow-up
Baselinek
Week 
2
Week 
4
Week 
8k
Week 
16k
Week 
24k
Week 
32k
Week 
40k
Week 
48k
Week 56
End of 
Treatment
Week 
64
Week 
80
End of 
Study
Day 1
Day 
15
Day 
29
Day 
57
Day 
113
Day 
169
Day 
225
Day 
281
Day 
337
Day 
393
Day 449
Day 
561
Visit Window
±3 
days
±3 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
±7 
days
Health Care Resource
Utilization Assessment
X
X
X
OTHER ASSESSMENTS / PROCEDURES
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Review Compliance With 
Subject IRT Entry and Data 
Reviewp
X
X
X
X
X
X
X
X
X
X
X
X
Female Subjects of 
Childbearing Potential 
Reminded of Contraceptive 
Requirements
X
X
X
X
X
X
X
X
X
X
Telephone Contact With 
Subjectsr
Phone contact with subject will be made at Weeks 
12, 20, 28, 36, 44, 52, 60, 68, 72 and 76
Abbreviations: →= ongoing/continuous event; BID = Twice daily; BP = Blood Pressure; ECG = electrocardiogram; HR = Heart Rate; HCRU = Health Care Resource 
Utilization; EQ-5D-5L = EuroQol 5 Dimension; IRT = Interactive Response Technology; LEAS = Lower Extremity Activity Scale; mPRTI = Patient Reported 
Treatment Impact assessment-modified; MRI = Magnetic Resonance Imaging; NGF = Nerve Growth Factor; NIS = Neuropathy Impairment Score; 
NSAID = Non-Steroidal Anti-Inflammatory Drug; PD = Pharmacodynamics; SAS = Survey of Autonomic Symptoms; TSQM (v.II) = Treatment Satisfaction 
Questionnaire Medicine version II; WOMAC = Western Ontario and McMaster University Osteoarthritis Index; WPAI:OA = Work Productivity and Activity 
Impairment Questionnaire: Osteoarthritis
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Early Termination Schedule of Eventsj
Visit Identifier
As soon as 
possible after 
determining 
subject will be 
discontinued from 
study
Early 
Termination 
Visit 1
Early 
Termination 
Telephone 
Contact 1r
Early 
Termination 
Visit 2
Early 
Termination 
Telephone 
Contact 2r
Early 
Termination 
Visit 3
~8 Weeks after 
last SC dose
~12 Weeks after 
last SC dose
~16 Weeks after 
last SC dose
~20 Weeks after 
last SC dose
~24 Weeks after 
last SC dose
Radiographs of each Hip, Knee 
and Shoulder
X
X
Collect Local Radiography Report
X
X
Magnetic Resonance Imaging 
(MRI) of each hip and kneeq
X
X
General Physical Examination
X
Musculoskeletal Physical 
Examinationc
X
X
X
Vital Signs (BP, HR)
X
X
X
Orthostatic Blood Pressure 
(supine/standing)
X
X
X
Body Weight 
X
Electrocardiogram (ECG 12-lead)
X
X
Survey of Autonomic Symptoms 
(SAS) questionnairei
X
X
Neurologic Exam Neuropathy 
Impairment Score (NIS)d
X
X
X
Lower Extremity Activity Scale
(LEAS)
X
X
X
Subject Weekly Assessments 
(IRT)
Review Compliance With Subject 
IRT Entry and Data Reviewp
X
X
X
X
X
Adverse Event Assessment
X
X
X
X
X
Female Subjects of Childbearing 
Potential Reminded of 
Contraceptive Requirements
X
X
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Visit Identifier
As soon as 
possible after 
determining 
subject will be 
discontinued from 
study
Early 
Termination 
Visit 1
Early 
Termination 
Telephone 
Contact 1r
Early 
Termination 
Visit 2
Early 
Termination 
Telephone 
Contact 2r
Early 
Termination 
Visit 3
~8 Weeks after 
last SC dose
~12 Weeks after 
last SC dose
~16 Weeks after 
last SC dose
~20 Weeks after 
last SC dose
~24 Weeks after 
last SC dose
SUBJECT REPORTED ASSESSMENTS (Completed at Study Visits)i
WOMAC Pain, Physical Function 
and Stiffness Subscales
X
X
Patient’s Global Assessment of 
Osteoarthritis
X
X
WPAI:OA
X
X
EQ-5D-5L
X
X
TSQM (v.II)
X
mPRTI
X
Health Care Resource Utilization
X
X
RESCUE MEDICATION / STANDARD OF CARE
Concomitant Medication Review
X
X
X
X
X
Oral Rescue Medication 
Dispensedl
X
X
Oral Rescue Medication Return 
and Compliance Check
X
X
Assign Standard of Care 
Treatment as Neededm
X
LABORATORY
Serum Pregnancy Test
X
X
Hematology
X
Blood Chemistry
X
Serum and Plasma Retention 
Samples
X
X
Serum Anti-tanezumab Antibodyn
X
X
X
Plasma Pharmacokinetic samplen
X
X
Serum NGF (PD) samplen
X
X
Serum and Urine Biomarkersn
Xo
Xo
Xo
Synovial Fluid Sample 
Optional for subjects undergoing arthrocentesis; additional sampling may be neededt
Serum 25-hydroxy vitamin D and 
parathyroid hormone
X
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Visit Identifier
As soon as 
possible after 
determining 
subject will be 
discontinued from 
study
Early 
Termination 
Visit 1
Early 
Termination 
Telephone 
Contact 1r
Early 
Termination 
Visit 2
Early 
Termination 
Telephone 
Contact 2r
Early 
Termination 
Visit 3
~8 Weeks after 
last SC dose
~12 Weeks after 
last SC dose
~16 Weeks after 
last SC dose
~20 Weeks after 
last SC dose
~24 Weeks after 
last SC dose
Abbreviations: →= ongoing/continuous event; BP = Blood Pressure; ECG = electrocardiogram; HR = Heart Rate; HCRU = Health Care Resource Utilization; EC = ethics 
committee; EQ-5D-5L = EuroQol 5 Dimension; IRT = Interactive Response Technology; LEAS = Lower Extremity Activity Scale; mPRTI = Patient Reported Treatment 
Impact assessment-modified; MRI = Magnetic Resonance Imaging; NGF = Nerve Growth Factor; NIS = Neuropathy Impairment Score; NSAID = Non-Steroidal 
Anti-Inflammatory Drug; PD = Pharmacodynamics; SAS = Survey of Autonomic Symptoms; TSQM (v.II) = Treatment Satisfaction Questionnaire Medicine version II; 
WPAI:OA = Work Productivity and Activity Impairment Questionnaire: Osteoarthritis
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a.
The Screening period begins up to a maximum of 37 days prior to randomization and lasts a minimum of 
14 or 21 days, allowing completion of the 2 or 3 week period of pre-randomization NSAID regimen 
stabilization (refer to Section 6.1.1 for additional detail regarding NSAID regimen stabilization).  Prior to 
entering the IPAP, subjects must washout from prohibited pain medications for at least 5 half-lives or 
48 hrs (which ever is greater).  During the IPAP, diary entries (joint pain and rescue medication use) must 
be provided for a minimum of 3 days in the 7 days immediately preceding randomization. 
b.
At Screening, a comprehensive musculoskeletal medical history is obtained and will include current and 
past history of osteoarthritis, osteoporosis, osteopenia, other musculoskeletal syndromes, orthopedic
surgeries (including arthroscopic procedures) ligament tear or rupture, gout and fracture.  All treatments 
used to treat osteoarthritis and osteoarthritis pain.
c.
A musculoskeletal directed physical examination will be performed at each study visit; findings will be 
recorded on a case report form and findings considered clinically significant will be reported as adverse 
events.  This physical examination is described in Section 7.3.2). 
d.
A neurological examination (NIS) will be performed by the Investigator (or designated physician) at each 
study visit and assessed for clinically significant changes from Baseline.  Requirements for neurological 
consultation at which a full neurological examination is to be performed by a neurologist are detailed in 
Section 7.3.13.
e.
Magnetic Resonance Images and Dual Energy X-ray Absorptiometry scans (if applicable, refer to Section 
Section 7.3.11 and Section 7.3.12) should only be completed after the subject has been determined to be 
eligible from a radiographic perspective as per the Central Reader.
f.
Actigraphy will only be performed at selected sites.  Actigraphy performed during the Screening period 
should only be completed after the subject has been determined to be eligible from a radiographic 
perspective as per the Central Reader.  Actigraphy will also be performed at approximately Week 16 
(between Weeks 14 and 16) and Week 56 (between Weeks 54 and 56), refer to Section 7.3.9. 
g.
FSH testing in female subjects as described in Section 7.3.3.4.
h.
Pre-study NSAIDs will be dispensed in the Screening period and subjects will be required to maintain at 
least 70% (5 of 7 days per week) compliance during the final two or three weeks of the Screening period 
immediately prior to Baseline (Day 1) (refer to Section 6.1.1 for additional detail regarding NSAID 
regimen stabilization). 
i.
The WOMAC subscales, Patient’s Global Assessment of Osteoarthritis, WPAI:OA, EQ-5D-5L and TSQM 
(v.II), mPRTI, Health Care Resource Utilization and Survey of Autonomic Symptoms questionnaires will 
be administered at site visits using IRT. 
j.
Subjects discontinuing the study at their request or at the decision of the Investigator prior to Week 56 
should be withdrawn from treatment and begin the 24-week Early Termination Follow-Up period described 
in Section 6.4.  Subjects who undergo total joint replacement will be followed for 24 weeks after the 
procedure as described in Section 6.4.2.
k.
All study activities at dosing visits (Baseline [Day 1] and Weeks 8, 16, 24, 32, 40 and 48), including 
sample collection, are performed prior to dosing, unless otherwise noted.
l.
Rescue medication should be discontinued at least 24 hours prior to any on site study visit up to and 
including Week 64 (including during the Early Termination Follow-Up period).  Subjects should return 
rescue medication bottles at each study visit for assessment of compliance. 
m. If needed, following completion of the visit at which final efficacy assessments are collected (Week 64 
and/or 16 weeks after the last dose of investigational product administered), standard of care treatment (as 
described in Section 5.8.2) may be initiated, and usage recorded on the appropriate concomitant medication 
CRF. 
n.
Samples for Anti-tanezumab Antibody, PK, NGF and biomarkers should be obtained pre-dose (if 
applicable to the visit).  Biomarker samples should be collected at approximately the same time of the day 
at all scheduled time points and following a fasting period of at least 8 hours. 
o.
Serum and urine biomarker sample collections at Weeks 32, 48, 56, 64 and 80 (or at early termination) will 
occur only for subjects that have activity level monitoring via accelerometry (N ~360). 
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p.
Subject Daily/Weekly Assessments (IRT) – Review of joint pain scores, rescue medication use and
concomitant NSAID use entries (refer to Section 7.1).  Compliance with IRT assessments is to be reviewed 
at each study visit, including Phone visits. 
q.
Post-baseline MRIs will only be performed for subjects with Kellgren-Lawrence Grade 3 or 4 osteoarthritis 
in any knee or hip joint, on the basis of the Central Reader’s assessment of the Screening X-rays (refer to 
Section Section 7.3.11).
r.
To assess compliance with oral investigational product, concomitant medication use, conduct IRT entry 
review and compliance check, update adverse events, assess completion of actigraphy (Weeks 12 and 52 if 
applicable), verify follow-up radiographs and MRIs (if applicable) are scheduled (Weeks 20, 52 and 76), 
provide contraceptive requirement reminder as appropriate.
s.
At the Week 16 visit, subjects must have a 30% or greater reduction in WOMAC Pain subscale relative to 
Baseline in the index joint and a 15% or greater reduction in WOMAC Pain subscale from Baseline at 
either Week 2, 4 or 8 in order to continue investigational product.  At Week 24, the continuing eligibility 
check will be based upon Central Reader review of radiographs (each hip, knee and shoulder) collected for 
the Week 24 visit.
t.
Synovial fluid sample collection is not a scheduled or required protocol procedure.  Synovial fluid samples 
will only be collected for subjects who at the recommendation of the investigator, have arthrocentesis 
performed.  Subjects will be asked to provide informed consent for analysis of the synovial fluid sample 
and potentially collection (if not already being collected at a scheduled timepoint) and analysis of 
additional blood samples for analysis of tanezumab pharmacokinetics, NGF and biomarkers (refer to 
Sections 7.4.7, 7.5.1, 7.5.2, 7.5.3, 7.6.3. Sample processing instructions are provided in the Laboratory 
Manual.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................34
LIST OF FIGURES .................................................................................................................35
APPENDICES .........................................................................................................................35
1. INTRODUCTION ...............................................................................................................36
1.1. Mechanism of Action/Indication.............................................................................36
1.2. Background and Rationale ......................................................................................36
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain...........................36
1.2.2. Description of Investigational Product.......................................................36
1.2.3. Overview of Clinical Studies......................................................................36
1.2.3.1. Overview of Efficacy in Osteoarthritis Clinical Studies...........38
1.2.3.2. Overview of Safety in Clinical Studies.....................................39
1.2.3.3. Subcutaneous Administration of Tanezumab in Clinical 
Studies ...............................................................................................42
1.2.3.4. Joint Safety................................................................................43
1.2.4. Dose Selection Rationale............................................................................44
1.2.5. Subject Population Selection Rationale......................................................45
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................47
2.1. Objectives................................................................................................................47
2.2. Endpoints.................................................................................................................48
2.2.1. Primary Endpoints ......................................................................................48
2.2.2. Secondary Endpoints ..................................................................................49
2.2.2.1. Bone and Joint Safety................................................................49
2.2.2.2. Radiographic .............................................................................49
2.2.2.3. Efficacy .....................................................................................50
2.2.2.4. Activity Level Monitoring ........................................................51
2.2.2.5. General Safety...........................................................................52
2.2.3. Tertiary Endpoints ......................................................................................52
2.2.3.1. Pharmacokinetic and Pharmacodynamic ..................................52
3. STUDY DESIGN.................................................................................................................52
4. SUBJECT SELECTION......................................................................................................59
4.1. Inclusion Criteria.....................................................................................................59
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4.2. Exclusion Criteria....................................................................................................61
4.3. Randomization Criteria ...........................................................................................65
4.4. Life Style Guidelines...............................................................................................66
4.5. Sponsor Qualified Medical Personnel.....................................................................67
5. STUDY TREATMENTS.....................................................................................................67
5.1. Allocation to Treatment ..........................................................................................68
5.2. Breaking the Blind ..................................................................................................68
5.3. Subject Compliance.................................................................................................69
5.4. Drug Supplies..........................................................................................................69
5.4.1. Dosage Form(s) and Packaging..................................................................69
5.4.1.1. Tanezumab ................................................................................69
5.4.1.2. Placebo for Tanezumab.............................................................69
5.4.1.3. Non-steroidal Anti-inflammatory Drugs (NSAID)...................69
5.4.2. Preparation and Dispensing........................................................................70
5.5. Administration.........................................................................................................71
5.5.1. SC Investigational Product Administration................................................71
5.5.2. Oral Investigational Product Administration..............................................71
5.6. Investigational Product Storage ..............................................................................71
5.7. Investigational Product Accountability...................................................................72
5.7.1. Destruction of Investigational Product Supplies ........................................72
5.8. Concomitant Treatment(s).......................................................................................72
5.8.1. Prohibited Medications...............................................................................72
5.8.2. Permitted Medications................................................................................74
5.9. Rescue Therapy.......................................................................................................74
6. STUDY PROCEDURES .....................................................................................................76
6.1. Screening Period .....................................................................................................76
6.1.1. Screening Period Stage 1 (Initial Screening Visit).....................................77
6.1.2. Screening Period Stage 2............................................................................80
6.1.3. Washout Period...........................................................................................80
6.1.4. Initial Pain Assessment Period (IPAP).......................................................81
6.2. Double-Blind Treatment Period..............................................................................81
6.2.1. Baseline (Day 1) Clinic Visit......................................................................81
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6.2.1.1. Assessment of Randomization Criteria and 
Randomization...................................................................................81
6.2.1.2. Randomization ..........................................................................82
6.2.1.3. Pre-dosing (Day 1) ....................................................................83
6.2.1.4. Dosing (Day 1)..........................................................................83
6.2.1.5. Post-dosing (Day 1)...................................................................84
6.2.2. Week 2 Clinic Visit ....................................................................................84
6.2.3. Week 4 Clinic Visit ....................................................................................85
6.2.4. Week 8 Clinic Visit ....................................................................................86
6.2.4.1. Pre-dosing..................................................................................86
6.2.4.2. Subcutaneous Dosing ................................................................87
6.2.4.3. Post-dosing................................................................................87
6.2.5. Week 12 Telephone Contact.......................................................................87
6.2.6. Week 16 Clinic Visit (Primary Efficacy Time Point) ................................88
6.2.6.1. Pre-dosing..................................................................................88
6.2.6.2. Subcutaneous Dosing ................................................................89
6.2.6.3. Post-dosing................................................................................90
6.2.7. Week 20 Telephone Contact.......................................................................90
6.2.8. Week 24 Clinic Visit ..................................................................................91
6.2.8.1. Pre-dosing..................................................................................91
6.2.8.2. Subcutaneous Dosing ................................................................92
6.2.8.3. Post-dosing................................................................................92
6.2.9. Week 28 Telephone Contact.......................................................................92
6.2.10. Week 32 Clinic Visit ................................................................................93
6.2.10.1. Pre-dosing................................................................................93
6.2.10.2. Subcutaneous Dosing ..............................................................94
6.2.10.3. Post-dosing..............................................................................94
6.2.11. Week 36 Telephone Contact.....................................................................94
6.2.12. Week 40 Clinic Visit ................................................................................94
6.2.12.1. Pre-dosing................................................................................94
6.2.12.2. Subcutaneous Dosing ..............................................................95
6.2.12.3. Post-dosing..............................................................................95
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6.2.13. Week 44 Telephone Contact.....................................................................96
6.2.14. Week 48 Clinic Visit ................................................................................96
6.2.14.1. Pre-dosing................................................................................96
6.2.14.2. Subcutaneous Dosing ..............................................................97
6.2.14.3. Post-dosing..............................................................................97
6.2.15. Week 52 Telephone Contact.....................................................................98
6.2.16. Week 56 Clinic Visit (End of Double-Blind Treatment)..........................98
6.3. Safety Follow-up Period........................................................................................100
6.3.1. Week 60 Telephone Contact.....................................................................100
6.3.2. Week 64 Clinic Visit ................................................................................101
6.3.3. Week 68 Telephone Contact.....................................................................102
6.3.4. Week 72 Telephone Contact.....................................................................102
6.3.5. Week 76 Telephone Contact.....................................................................102
6.3.6. Week 80 Clinic Visit (End of Study)........................................................103
6.4. Subject Withdrawal/Early Termination ................................................................104
6.4.1. Early Termination Follow-up Period........................................................106
6.4.1.1. Early Termination Follow-up Visit 1 (8 weeks after last 
dose of SC investigational product treatment) ................................106
6.4.1.2. Early Termination Follow-up Phone Contact (12 weeks 
after last dose of SC investigational product)..................................107
6.4.1.3. Early Termination Follow-up Visit 2 (16 weeks after last 
dose of SC investigational product) ................................................108
6.4.1.4. Early Termination Follow-up Phone Contact (20 Weeks 
after last dose of SC investigational product)..................................109
6.4.1.5. Early Termination Follow-up Visit 3 (24 weeks after last 
dose of SC investigational product) ................................................109
6.4.2. Procedures for Subjects Undergoing Joint Replacement..........................111
6.4.2.1. Total Joint Replacement Follow-up Protocol..........................111
7. ASSESSMENTS................................................................................................................112
7.1. Subject Diary Assessments ...................................................................................112
7.1.1. Daily/Weekly Pain Assessments ..............................................................112
7.1.2. Rescue Medication and Amount...............................................................113
7.1.3. Concomitant NSAID Use .........................................................................113
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7.2. Study Visit Efficacy Assessments.........................................................................114
7.2.1. Western Ontario and McMaster Universities Osteoarthritis Index ..........114
7.2.1.1. WOMAC Pain Subscale..........................................................114
7.2.1.2. WOMAC Physical Function Subscale ....................................114
7.2.1.3. WOMAC Stiffness Subscale...................................................114
7.2.2. Patient’s Global Assessment of Osteoarthritis .........................................115
7.2.3. Work Productivity and Activity Impairment Questionnaire -
Osteoarthritis – Knee or Hip v2.0 (WPAI:OA)..............................................115
7.2.4. EuroQol 5 Dimension (EQ-5D-5L)..........................................................116
7.2.5. Treatment Satisfaction Questionnaire for Medication v.II (TSQM) ........116
7.2.6. Patient Reported Treatment Impact Assessment-modified (mPRTI).......116
7.2.7. Assessment of Health Care Resource Utilization.....................................116
7.3. Safety Assessments ...............................................................................................117
7.3.1. General Physical Examination..................................................................117
7.3.2. Musculoskeletal History and Physical Examination ................................117
7.3.3. Laboratory Safety Assessments................................................................117
7.3.3.1. Blood Tests..............................................................................118
7.3.3.2. Urinalysis and Urine Toxicology Screen ................................119
7.3.3.3. Pregnancy Tests.......................................................................119
7.3.3.4. Serum FSH Testing .................................................................119
7.3.4. Assessment of Pain in Major Joints at Screening with Numeric Pain 
Scale Rating (NRS)........................................................................................120
7.3.5. Vital Signs ................................................................................................120
7.3.5.1. Orthostatic Blood Pressure Measurement...............................120
7.3.6. 12-Lead Electrocardiogram ......................................................................121
7.3.7. Survey of Autonomic Symptoms (SAS)...................................................122
7.3.8. Lower Extremity Activity Scale (LEAS) .................................................122
7.3.9. Activity Level Monitoring (Actigraphy) ..................................................122
7.3.10. Radiographic Assessments .....................................................................123
7.3.10.1. Radiation Exposure ...............................................................124
7.3.11. Magnetic Resonance Imaging (MRI) .....................................................125
7.3.12. Dual Energy X-ray Absorptiometry (DXA) Scan ..................................125
7.3.13. Neurologic Examination.........................................................................126
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7.3.14. Anti-Tanezumab Antibody Testing ........................................................127
7.4. Triggered Requirements and Subject-Level Stopping Rules ................................127
7.4.1. Dysesthesia/Allodynia ..............................................................................127
7.4.2. Hypersensitivity or Injection Site Reactions ............................................127
7.4.3. Orthostatic Hypotension and Sympathetic Function Adverse Events......128
7.4.4. Evaluation and Follow-up for Increased, Severe Persistent Joint Pain ....131
7.4.5. Central Reader and Subject-Level Stopping Criteria for Joint Safety 
Events.............................................................................................................132
7.4.6. Procedures for Subjects Undergoing Joint Replacement..........................132
7.4.7. Procedures for Subjects Undergoing Arthrocentesis................................132
7.5. Pharmacokinetic (PK) and Pharmacodynamic (PD).............................................133
7.5.1. Plasma for Analysis of Tanezumab ..........................................................133
7.5.2. Nerve Growth Factor (NGF) for Pharmacodynamic Analyses ................133
7.5.3. Synovial Fluid for Analysis of Tanezumab and NGF ..............................134
7.6. Biomarkers ............................................................................................................134
7.6.1. Serum Biomarkers ....................................................................................134
7.6.2. Urine Biomarkers......................................................................................135
7.6.3. Synovial Fluid Biomarkers.......................................................................136
7.7. Banked Biospecimens ...........................................................................................136
7.7.1. Markers of Drug Response.......................................................................136
7.7.2. Additional Research..................................................................................137
8. ADVERSE EVENT REPORTING....................................................................................138
8.1. Adverse Events......................................................................................................138
8.2. Reporting Period ...................................................................................................138
8.3. Definition of an Adverse Event.............................................................................138
8.4. Medication Errors..................................................................................................139
8.5. Abnormal Test Findings........................................................................................140
8.6. Serious Adverse Events.........................................................................................140
8.6.1. Protocol-Specified Serious Adverse Events.............................................141
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................141
8.7. Hospitalization ......................................................................................................142
8.8. Severity Assessment..............................................................................................144
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8.9. Causality Assessment............................................................................................144
8.10. Exposure During Pregnancy................................................................................144
8.10.1. Additional Postnatal Development Follow-up .......................................146
8.11. Occupational Exposure .......................................................................................146
8.12. Withdrawal Due to Adverse Events (See Also Section 6.4 Subject 
Withdrawal).............................................................................................................146
8.13. Eliciting Adverse Event Information ..................................................................146
8.14. Reporting Requirements......................................................................................146
8.14.1. Serious Adverse Event Reporting Requirements ...................................146
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................147
8.14.3. Medical Device Reporting Requirements...............................................147
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ..............147
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................147
9.1. Sample Size Determination...................................................................................148
9.2. Primary Analysis...................................................................................................149
9.2.1. Analysis of Primary Endpoints.................................................................149
9.2.2. Analysis of Secondary Endpoints.............................................................151
9.3. Safety Analysis......................................................................................................153
9.3.1. Anti-Tanezumab Antibodies.....................................................................154
9.4. Analysis of Other Endpoints .................................................................................155
9.4.1. Pharmacokinetic Data...............................................................................155
9.4.2. Pharmacodynamic (NGF) Data ................................................................155
9.4.3. Biomarker Data.........................................................................................155
9.4.4. Physical Activity Level Data....................................................................155
9.4.4.1. Lower Extremity Activity Scale (LEAS)................................155
9.4.4.2. Actigraphy...............................................................................156
9.5. External Adjudication Committee.........................................................................156
9.6. Data Monitoring Committee .................................................................................157
9.6.1. Protocol-Level Rules for Dosing Suspension/Safety Assessment............158
9.6.1.1. Serious Adverse Events...........................................................158
9.6.1.2. Events Consistent with Hy’s Law ...........................................159
9.6.2. Joint Safety Events ...................................................................................159
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10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................160
11. DATA HANDLING AND RECORD KEEPING ...........................................................161
11.1. Case Report Forms/Electronic Data Record .......................................................161
11.2. Record Retention.................................................................................................161
12. ETHICS............................................................................................................................162
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................162
12.2. Ethical Conduct of the Study ..............................................................................162
12.3. Subject Information and Consent........................................................................162
12.4. Subject Recruitment ............................................................................................163
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................163
13. DEFINITION OF END OF TRIAL.................................................................................163
13.1. End of Trial in a Member State...........................................................................163
13.2. End of Trial in all other Participating Countries.................................................164
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................164
15. PUBLICATION OF STUDY RESULTS........................................................................164
15.1. Communication of Results by Pfizer ..................................................................164
15.2. Publications by Investigators ..............................................................................165
16. REFERENCES ................................................................................................................167
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................16
Table 2.
Adverse Drug Reactions in All Subjects Receiving Tanezumab .........................40
Table 3.
Number Needed to Harm (NNH) Estimates for a Composite Joint Safety 
Endpoint1 in Phase 3 Osteoarthritis Studies2........................................................46
Table 4.
Number Needed to Treat (NNT) with Tanezumab versus NSAID in the 
Treatment of Osteoarthritis...................................................................................47
Table 5.
Stratified Randomization Scheme ........................................................................54
Table 6.
Qualifying Pre-study NSAID Treatment Regimens.............................................54
Table 7.
Qualifying Pre-study NSAID Treatment Regimens.............................................60
Table 8.
Study Treatments..................................................................................................68
Table 9.
Orthostatic Blood Pressure Changes and Subject Management.........................121
Table 10.
Estimated Event Incidence Rate Precision .........................................................148
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LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................53
Figure 2.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events.............130
APPENDICES
Appendix 1. American American College of Rheumatology (ACR) Classification 
Criteria for Osteoarthritis....................................................................................176
Appendix 2. American Society of Anesthesiologists (ASA) Physical Status 
Classification ......................................................................................................177
Appendix 3. Half-Lives of Prohibited Prior and Concomitant Medications .........................178
Appendix 4. Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC)..........................................................................................................182
Appendix 5. Patient’s Global Assessment of Osteoarthritis..................................................188
Appendix 6. Work Productivity and Activity Impairment Questionnaire: Osteoarthritis 
of the Knee or Hip V2.0 (WPAI:OA).................................................................189
Appendix 7. EuroQol 5 Dimension (EQ-5D-5L) ..................................................................191
Appendix 8. Neuropathy Impairment Score (NIS) Sample...................................................193
Appendix 9. Patient Health Questionnaire (PHQ-9)..............................................................195
Appendix 10. Osteoporosis Risk Factors...............................................................................196
Appendix 11. American College of Radiology Safety Screening Form and Magnetic 
Resonance Hazard Checklist ..............................................................................197
Appendix 12. Lower Extremity Activity Scale......................................................................199
Appendix 13. Treatment Satisfaction Questionnaire Medicine v.II ......................................200
Appendix 14. Adjudication Categories..................................................................................203
Appendix 15. Survey of Autonomic Symptoms (SAS)60 ......................................................204
Appendix 16. Patient Reported Treatment Impact assessment-modified (mPRTI) ..............205
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Tanezumab (PF-04383119, formerly RN624) is an anti-nerve growth factor monoclonal 
antibody under development for the relief of signs and symptoms of osteoarthritis (OA).
1.2. Background and Rationale
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain
During mammalian development, nerve growth factor (NGF) is required for the survival and 
growth of several populations of neurons.  In adults, the effect of NGF signaling shifts from 
the regulation of neuronal survival to the regulation of neuronal phenotype and function.  The 
role of NGF in the adult mammal appears to principally be as a modulator of nociceptive 
neuronal activity.  Thus, NGF plays an important role in modulation of the pain response.5,6  
Many studies employing a variety of antibodies to NGF or tropomyosin receptor kinase A 
(trkA)-IgG fusion protein have demonstrated that blocking NGF bioactivity normalizes pain 
sensitivity, particularly in states of allodynia and hypersensitivity, following a variety of 
insults such as Freund’s adjuvant, carrageenan, or surgical incision.6,7
Both interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) have been shown to induce 
synthesis of NGF.  Inhibition of NGF in turn blocks the hyperalgesia experienced after 
administration of these cytokines.8,9  Together these observations suggest that NGF may play 
a role in pain secondary to inflammation or injury.
1.2.2. Description of Investigational Product
Tanezumab is a humanized immunoglobulin G Type 2 (IgG2) monoclonal antibody, derived 
from a murine precursor by grafting the murine complementarity determining regions onto a 
human antibody framework, followed by extensive site-directed mutagenesis using 
proprietary technology to improve binding affinity and specificity.  A mutation was 
performed in the Fc portion of the antibody to decrease its ability to activate complement or 
to support antibody dependent cell-mediated cytotoxicity.10,11
Tanezumab is highly potent in sequestering NGF and preventing interaction with the trkA or 
p75 receptors.  Tanezumab and/or the murine precursor have been shown to be an effective 
analgesic in nonclinical animal models of pathological pain including arthritis, cancer pain, 
and post-surgical pain models.12
1.2.3. Overview of Clinical Studies
A total of 32 clinical studies involving over 11,000 patients have been conducted with 
tanezumab as of September 2014.  Approximately 9,810 healthy volunteers or patients have 
been treated with tanezumab in non-cancer pain clinical studies.  In patients treated with 
tanezumab monotherapy or tanezumab + NSAID in completed non-cancer pain studies, 
treatment experience with tanezumab approximates 5900 patient-years of treatment exposure.
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A total of 17 clinical studies overall, (4 Phase 2 studies and 13 Phase 3 studies
[10 controlled]), were initiated to provide evidence of efficacy and safety of tanezumab with 
intravenous (IV) or subcutaneous (SC) administration for the relief of the signs and 
symptoms of osteoarthritis alone or in combination with NSAIDs.  Both IV and SC routes of 
administration with tanezumab at fixed dose levels of 2.5 mg, 5 mg, and 10 mg every 
8 weeks were evaluated in Phase 3 clinical studies in patients with osteoarthritis.
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 pain 
conditions and 2 Phase 2 studies in metastatic bone pain have been conducted.  In these 
studies, tanezumab was administered by IV or SC administration every 8 weeks at fixed 
doses ranging from 1 mg to 20 mg or equivalent body-weight adjusted doses up to 100 mg.
In 2010, the US Food and Drug Administration’s (FDA) Division of Analgesia, Anesthetic, 
and Addiction Products (DAAAP) placed tanezumab (June/July 2010) and subsequently the 
entire nerve growth factor inhibitor (NGFI) class (December 2010) on partial clinical hold 
due to adverse events initially described by investigators as osteonecrosis that in some cases 
resulted in total joint replacement.  Pfizer voluntarily imposed the partial clinical hold on 
study conduct in all countries.  The conduct of Phase 2/3 studies in osteoarthritis or other 
chronic pain conditions was impacted to varying extents by the partial clinical hold placed on 
the tanezumab clinical development program in June/July 2010.
Extensive analyses of the reports of osteonecrosis and other total joint replacements were 
conducted.1  On March 12, 2012, the FDA Arthritis Advisory Committee reviewed these 
results as well as those prepared by the FDA.2,3  The committee endorsed continued clinical 
development of the NGFI class of compounds with additional measures to minimize the risk 
and further protect subject safety.  On August 28, 2012, the FDA lifted the partial clinical 
hold on tanezumab allowing the resumption of clinical studies for osteoarthritis and all other 
chronic pain conditions. 
The FDA placed another partial clinical hold on the tanezumab clinical development program 
as well as all anti-NGF antibody studies in December 2012 due to concerns about adverse 
changes in the sympathetic nervous system of mature animals. Only studies in patients with 
cancer pain were allowed to continue. During 2013-2014, Pfizer conducted a comprehensive 
series of nonclinical studies to investigate the nonclinical effects on the sympathetic nervous 
system which led to the partial clinical hold (described in Section 5.3 of the tanezumab 
Investigators’ Brochure). 
In animal studies in rats and non-human primates (described in Section 5.3 of the tanezumab 
Investigators’ Brochure), tanezumab treatment for up to 6 months, with doses producing 
greater systemic exposure than observed with clinical doses, was associated with lower 
sympathetic ganglion volume and lower average size of post-ganglionic sympathetic neurons 
when compared to control animals.  All effects were completely reversible following a 
dosing-free recovery period.  In a separate cardiovascular function study in non-human 
primates (described in Section 5.1 of the tanezumab Investigators’ Brochure), functional
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changes in the cardiovascular system controlled by the sympathetic nervous system were not 
observed. 
Although evidence of clinically important effects on the sympathetic nervous system have 
not been identified in previously completed tanezumab studies, per agreement with the FDA, 
this and other clinical studies of tanezumab will incorporate additional safety measures to 
monitor for and manage subjects who may develop evidence of clinically important 
sympathetic nervous system dysfunction.
1.2.3.1. Overview of Efficacy in Osteoarthritis Clinical Studies
Across the 3 co-primary measures of efficacy in four completed Phase 3 studies of 
tanezumab monotherapy (IV administration), doses of 2.5 mg, 5 mg, and 10 mg provided 
significant improvement over placebo treatment.  All of the tanezumab doses tested were 
consistently efficacious.  In Studies A409101113 and A4091014,14 the degree of mean 
improvement across the three efficacy domains was similar and generally dose ordered with 
tanezumab 10 mg providing the greatest mean response in each of the studies 3 co-primary 
endpoint comparisons to placebo treatment although only small differences in the magnitude 
of response were evident among the three doses of tanezumab.  In Studies A409101515 and 
A4091018,16 tanezumab 5 mg provided modestly greater mean improvement over tanezumab 
10 mg across most of the co-primary endpoints. 
In each of these four studies, the mean Baseline WOMAC17 Pain subscale scores exceeded 
7 on a scale of 0 to 10 indicating a subject population with severe pain on average prior to 
study entry.  The mean reduction in pain with tanezumab treatment was typically 3 points or 
greater yielding an improvement in pain on average from severe to nearly mild in severity.  
This reduction in pain was associated with equivalent improvements in function and global 
well being.
The clinical significance of the reduction in pain with tanezumab treatment was assessed by 
the evaluation of subject responder rates using a categorical assessment of the WOMAC Pain 
subscale results, the OMERACT-OARSI18 (Outcomes Measures in Arthritis Clinical Trials 
Osteoarthritis Research Society International) Responder Index and a 2-grade or larger 
categorical improvement in the Patient’s Global Assessment of Osteoarthritis.  All responder 
analyses were determined with Baseline Observation carried Forward (BOCF) imputation 
unless otherwise noted. 
In Studies A4091011 and A4091014, statistically significant response rates compared to 
placebo treatment were demonstrated at Week 16 with all tanezumab doses for the 
percentage of subjects with reductions in pain ≥30%, ≥50%, ≥70%, and ≥90% on the 
WOMAC Pain subscale in both studies with one exception (A4091011 ≥70% reduction with 
tanezumab 2.5 mg vs placebo p-value was 0.053).
A prospectively defined analysis of subjects participating in Studies A4091011, A4091014, 
A4091015, or A4091018 was carried out to evaluate the efficacy of tanezumab with severe 
symptomatic osteoarthritis.  Subjects defined with severe pain were those with a Baseline 
WOMAC Pain score ≥7 and a WOMAC Physical Function score of ≥7 and a score of “poor” 
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or “very poor” in the Patient’s Global Assessment of Osteoarthritis.  Of the 2979 subjects 
enrolled across the 4 studies, 742 (25.1%) met these criteria for severe disease.  Tanezumab 
5 mg and 10 mg provided significant and clinically meaningful benefit in this severe subject 
cohort when compared to placebo treatment.
A key objective of Studies A4091015 and A4091018 was to compare the efficacy of 
tanezumab 5 mg and 10 mg versus naproxen 500 mg bid for the symptomatic treatment of 
osteoarthritis.  To control the type 1 error rate for multiple comparisons, fixed sequence (step 
down) testing and the Hochberg procedure were predefined to begin with the highest dose 
(tanezumab 10 mg) followed by tanezumab 5 mg.  As a result, despite replicate statistically 
significant differences with tanezumab 5 mg versus naproxen across 3 co-primary endpoints, 
a total of 6 comparisons, it is only possible to conclude statistically that tanezumab was 
superior to naproxen with respect to WOMAC Physical Function in both studies and the 
Patient’s Global Assessment of Osteoarthritis in one study.
In Study A4091030,19 a key objective was to demonstrate that tanezumab 5 mg and 
tanezumab 10 mg administered by IV infusion were superior, or at a minimum non-inferior, 
to oxycodone controlled-release (CR) 10-40 mg administered every 12 hours in the treatment 
of osteoarthritis.  This objective was achieved.  All four comparisons were statistically 
significant at Week 8; non-inferiority of tanezumab 10 mg versus oxycodone CR, superiority 
of tanezumab 10 mg versus oxycodone CR (p=0.018), non-inferiority of tanezumab 5 mg 
versus oxycodone CR, and superiority of tanezumab 5 mg versus oxycodone CR (p<0.001).  
In this study, oxycodone CR failed to separate from placebo treatment across all response 
measures at Week 8.  Treatment with tanezumab 10 mg did not provide additional efficacy 
benefit above that observed with tanezumab 5 mg treatment.
In the largest safety and efficacy study, Study A4091025,20 the addition of tanezumab 5 mg 
or 10 mg (administered by IV infusion) to oral NSAID treatment (ie, celecoxib 100 mg BID 
or naproxen 500 mg BID) did not provide substantial efficacy benefit over tanezumab 
5 mg or 10 mg monotherapy, respectively.  Only two statistically significant treatment 
differences were observed among these co-primary endpoint comparisons.
1.2.3.2. Overview of Safety in Clinical Studies
Based on data from all subject populations who have received tanezumab in completed 
clinical studies to date, the adverse drug reactions listed in Table 2 are considered to be 
expected in subjects who are treated with tanezumab. 
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Table 2.
Adverse Drug Reactions in All Subjects Receiving Tanezumab
System Organ Class
Adverse Drug Reactions
Frequency2
Nervous system disorders
Burning sensation
Carpal tunnel syndrome
Hyperesthesia
Hypoesthesia
Paresthesia
Common
Allodynia
Neuropathy peripheral
Uncommon
Musculoskeletal and connective tissue disorders
Rapidly Progressive 
Osteoarthritis
(in patients with 
underlying 
osteoarthritis1)
Uncommon
Arthralgia
Joint swelling
Myalgia
Pain in extremity
Common
General disorders and administration site 
conditions
Oedema peripheral
Common
1 Rapidly Progressive Osteoarthritis may occur in subjects with underlying osteoarthritis.  The frequency is 
estimated from adjudicated events of rapidly progressive osteoarthritis in historic clinical studies of 
tanezumab, which did not include specific risk minimization measures for this adverse reaction.
2 Common (≥1% and <10%); Uncommon (≥0.1% and <1%).
A total of 7491 subjects were treated in 9 controlled Phase 3 osteoarthritis studies.  The 
majority of these subjects were treated in studies using IV administration of tanezumab; 
however, approximately 900 subjects were treated in 2 studies in subjects with osteoarthritis 
using SC administration.  The adverse event profile of SC administration of tanezumab is 
comparable to the IV route based on the results of study A4091027 which compared SC 
versus IV administration in subjects with osteoarthritis.  The incidence of adverse events, 
withdrawals due to adverse events, and serious adverse events in subjects treated with 
tanezumab monotherapy (5-10 mg) was similar to subjects receiving active comparator 
treatment and increased over placebo-treated subjects.  In the tanezumab 2.5 mg 
monotherapy treatment group, the incidence of adverse events was similar to active 
comparator while the incidence of withdrawals due to adverse events, and serious adverse 
events was similar to that of the placebo treatment group.  Across the tanezumab 
monotherapy doses, the rates of adverse events, withdrawals due to adverse events, and 
serious adverse events, were similar with tanezumab 5 mg and 10 mg, and elevated in 
comparison to tanezumab 2.5 mg.  Tanezumab/NSAID combination therapy was associated 
with higher overall adverse event rates.  The relationship of incidence to the dose of 
tanezumab administered was similar to that seen with tanezumab monotherapy.
Based on data from the Phase 3 osteoarthritis studies and results of an independent 
adjudication of investigator-reported adverse events of osteonecrosis and total joint 
replacements, the risk of rapidly progressive osteoarthritis with tanezumab treatment was
greater than with placebo or active comparator treatment. 
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Among the most frequently reported adverse events in the controlled Phase 3 osteoarthritis 
studies, the incidence of peripheral edema, upper respiratory tract infection, fall, arthralgia, 
back pain, joint swelling, pain in extremity, hypoesthesia, and paresthesia tended to be higher 
in subjects receiving tanezumab monotherapy than subjects receiving either placebo or active 
comparator treatment.  The incidence of peripheral edema, arthralgia, joint swelling, pain in 
extremity, and paresthesia increased with increasing doses of tanezumab monotherapy.  The 
adverse events with increased incidence observed with active comparator over tanezumab 
monotherapy included the following: constipation, nausea, urinary tract infection, 
nasopharyngitis, osteoarthritis, and hypertension.
The most common adverse events reported in the non-controlled, long-term Phase 3 
osteoarthritis studies were similar to those seen in the controlled Phase 3 osteoarthritis 
studies with the exception of the inclusion of musculoskeletal pain and exclusion of 
hypertension and nasopharyngitis and all gastrointestinal-related adverse events.  
Dose-related increases in the incidence of peripheral edema, joint swelling, osteoarthritis and 
paresthesia were observed.
1.2.3.2.1. Sympathetic Nervous System
In completed Phase 3 osteoarthritis studies, the incidence and discontinuation rates due to 
adverse events consistent with decreased sympathetic function associated with tanezumab 
monotherapy (combined doses of 2.5 to 10 mg) were less than or equal to rates with placebo 
or active comparator.  No evidence of dose related elevations in the frequency of adverse 
events suggestive of decreased sympathetic nervous system function were observed at doses 
of 2.5 to 10 mg in subjects with osteoarthritis.  Tanezumab 20 mg in chronic low back pain 
had marginally higher event rates compared to placebo and active comparator treatment 
groups. 
Based on completed osteoarthritis studies where orthostatic blood pressure, heart rate deep 
breathing, or autonomic symptoms captured with the Neuropathy Symptom Change (NSC) 
questionnaire were specifically assessed, the data are not suggestive of an adverse effect of 
tanezumab on autonomic function. 
Although evidence of clinically important effects on the sympathetic nervous system have 
not been identified in previously completed tanezumab studies, per agreement with the FDA, 
this and other clinical studies of tanezumab will incorporate additional safety measures to 
monitor for and manage subjects who may develop evidence of clinically important 
sympathetic nervous system dysfunction.
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1.2.3.3. Subcutaneous Administration of Tanezumab in Clinical Studies
The formulation of tanezumab that has been administered by SC injection is identical to what 
has been administered by IV infusion and is administered as a 1 mL SC injection in the thigh 
or abdomen.  The safety and efficacy of tanezumab when administered by SC injection has 
been evaluated in OA subjects primarily in two studies, A409102721 and A409104322, and in 
subjects with chronic low back pain in one study (A409103923), all of which were impacted 
by the FDA-imposed clinical hold. A total of 1905 subjects were treated in these studies. 
The observed efficacy and safety profile of tanezumab administered SC was similar to IV 
administration.
Study A409102721 was designed as a randomized, placebo-controlled study to demonstrate 
the efficacy and safety of tanezumab 2.5 mg, 5 mg, or 10 mg SC administered at 8-week 
intervals and the therapeutic equivalence of tanezumab 10 mg SC and tanezumab 10 mg IV 
administered at 8-week intervals in subjects with osteoarthritis of the knee.  Due to the 
clinical hold, enrollment was stopped prematurely and, therefore, was insufficient to yield 
adequate power to fulfill the primary objectives.  The overall incidence of adverse events was 
comparable to that observed in previous tanezumab IV osteoarthritis studies, and with the 
exception of injection-site reactions, the adverse event profile was comparable to that of 
previous tanezumab IV studies in subjects with osteoarthritis.  The higher incidence of 
injection-site reaction compared to other studies was likely due to the implementation of 
directed injection-site assessment – a procedure that was not a component of earlier 
tanezumab studies, which had included only IV administration of tanezumab.  The majority 
of reported adverse events of injection-site reaction were mild, and none were severe.  Across 
treatment groups, the incidence of serious adverse events and discontinuation due to adverse 
events was low. 
Study A409104322 was a randomized, double-blind, parallel-group, multicenter long-term 
safety study of tanezumab when administered by SC injection in subjects with OA of the 
knee or hip.  Approximately 600 subjects were to be entered into the study.  All subjects 
were randomized to receive SC administration of tanezumab 2.5, 5, or 10 mg at 8-week 
intervals (7 doses total) for approximately 1 year (56 weeks).  A total of 231, 222, and 
226 subjects were assigned to tanezumab 2.5, 5, and 10 mg treatment groups, respectively; 
all of these subjects were treated with investigational product except for 1 subject in the 
tanezumab 2.5 mg treatment group who was randomized but not treated.  No subjects 
completed the study as a result of the clinical hold. The overall incidence of adverse events 
(all causality) was dose responsive and was highest in the tanezumab 10 mg (80.1%) 
treatment group which was followed by successively lower incidences in the tanezumab 
5 mg (76.1%) and 2.5 mg (68.7%) treatment groups.  Overall and based upon a tendency 
toward greater incidences of adverse events, serious adverse events, all-cause total joint 
replacement, abnormalities in neurological examinations, and neurological consultation 
findings thought to be consistent with new or worsened peripheral neuropathy, the 
tanezumab 10 mg treatment group appeared to be less well tolerated relative to the 
tanezumab 2.5 and 5 mg dose levels.
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1.2.3.4. Joint Safety
Following the imposition of the clinical hold, a comprehensive investigation and analyses 
related to joint-safety were conducted, based on tanezumab monotherapy exposure in over 
6400 subjects and tanezumab/NSAID combination therapy in 3400 subjects.  There were 
over 5000 subjects who received tanezumab treatment alone or in combination with NSAIDs 
for 6 months or longer.  The program was sufficient to define and characterize the adverse 
event of concern – rapidly progressive osteoarthritis – and evaluate the risk of rapidly 
progressive osteoarthritis in the context of the overall benefit-risk profile of tanezumab 
compared to standard of care.  The results and conclusions regarding tanezumab and the 
other anti-NGF therapies are provided in detail elsewhere.1
After careful investigation, no evidence was found to substantiate that tanezumab is 
associated with an increased risk of osteonecrosis, a disease process quite distinct from 
osteoarthritis.  A risk of rapidly progressive osteoarthritis was identified.  The risk of rapidly 
progressive osteoarthritis with tanezumab monotherapy was well below that observed with 
tanezumab/NSAID combination therapy but greater than with placebo or active comparator 
treatment.  A majority of subjects identified with rapidly progressive osteoarthritis had 
advanced osteoarthritis of the affected joint prior to treatment.  The event rate of all-cause 
joint replacements in subjects with osteoarthritis was comparable among placebo, active 
comparator, and tanezumab monotherapy treatment groups.
Risk mitigation measures have been developed as an outgrowth of the joint-related safety 
analyses to reduce the risk of rapidly progressive osteoarthritis.  Using recommendations 
from discussions with European agencies [United Kingdom’s Medicines and Healthcare 
products Regulatory Agency (MHRA), Germany’s Paul Ehrlich Institute (PEI) and Spain’s 
Agency on Medicinal Products and Medical Devices (AEMPS)] as well as the FDA Arthritis 
Advisory Committee and interactions with FDA, risk mitigation measures were developed. 
These risk mitigation measures have been included in this study and are outlined as follows:
Risk Minimization: (1) exclude chronic concomitant NSAID use, (2) exclude tanezumab 
doses that have been explored and do not demonstrate benefit over lower doses in the 
condition under study, (3) exclude subjects with evidence of rapidly progressive 
osteoarthritis or risk factors for such from participating in clinical studies, (4) discontinue 
treatment with investigational product in subjects who fail to achieve adequate pain relief and 
(5) exclude subjects who are not suitable candidates for total joint replacement from study 
participation.
Risk Identification and Management: (1) evaluation and follow-up for severe persistent 
joint pain, (2) extended post-treatment follow-up, (3) a program-level Central Radiograph 
Reader and subject-level stopping criteria, (4) an Adjudication Committee, and (5) a Data 
Monitoring Committee and protocol-level stopping rules.
Risk Characterization: (1) Comprehensive evaluation of osteoarthritis medical history prior 
to study entry, (2) scheduled radiographic assessments during the studies, (3) Magnetic 
Resonance Imaging (MRI) scans, (4) Dual-energy X-ray Absorptiometry (DXA) scans 
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(5) activity monitoring, (6) surgical and post-operative total joint replacement outcomes, and 
(7) biomarker determinations.
1.2.3.4.1. Rapidly Progressive Osteoarthritis
Rapidly progressive osteoarthritis of the hip was first described by Forestier in 1957 and 
subsequently described in a number of studies as atrophic osteoarthritis, rapidly destructive 
osteoarthritis, rapidly destructive arthropathy, rapidly progressive hip disease, or rapidly 
destructive coxarthrosis.24-36  Rapidly progressive hip osteoarthritis is characterized by 
subjects who typically present with hip pain, often severe, with radiographs that show rapid 
joint space narrowing as a result of chrondrolysis from a prior radiograph and, subsequently, 
an osteolytic phase with severe progressive atrophic bone destruction involving the femoral 
head and the acetabulum.  There can be marked flattening of the femoral head and loss of 
subchondral bone in the weight-bearing area and in some cases the femoral head appears 
sheared off.  Osteophytes are typically conspicuously small or absent.  Bone sclerosis is often 
present at sites of impaction of the femoral head and the acetabulum, subchondral detritus is 
invariably present and bone fragmentation and debris are commonly observed that can lead 
to synovitis.  Lequesne proposed that subjects with 2 mm/year or greater of joint space 
narrowing or loss of more than 50% of the joint space within 1 year should be considered to 
have rapidly progressive osteoarthritis.26  Due to a lack of longitudinal studies, it is not clear 
what proportion of subjects with rapid loss of joint space (chondrolysis) will progress to have 
bone destruction.  Rapid progression of osteoarthritis has also been described in the shoulder 
and the knee.37,38
The incidence of rapidly progressive osteoarthritis in the overall osteoarthritis population is 
not well defined.  For rapid progression of hip osteoarthritis, the prevalence ranges from 
approximately 2% to 18% based on clinical case series analyses.27,28,30,31,32,39
The pathophysiology of rapidly progressive osteoarthritis is not understood.  Various 
mechanisms have been proposed including; ischemia, venous stasis, local nutritional 
deficiencies, synovitis, mechanical overloading, NSAID or corticosteroid use, intra-articular 
deposition of hydroxyapatite or pyrophosphate crystals and subchondral insufficiency 
fractures.29,32,36,40,41
One objective of the current study is to explore relationships between a variety of biomarkers 
(biochemical, physical activity level and radiographic) and joint safety events with an aim of 
further characterizing the pathophysiology of orthopedic events that may be observed in the 
study. 
1.2.4. Dose Selection Rationale
Intravenous and SC administration of tanezumab at doses of 2.5 mg, 5 mg and 10 mg was 
shown to reduce pain and improve function in a dose-related manner in Phase 3 studies of 
osteoarthritis.  As one of the risk mitigation features identified through analysis of orthopedic 
safety and efficacy data, no further study of the tanezumab 10 mg dose will be conducted in 
subjects with osteoarthritis as this dose did not provide sufficient additional efficacy benefit 
over the 5 mg dose. Unlike the 10 mg dose which did not provide added efficacy benefit 
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over the 5 mg dose, the 5-mg dose is expected to provide added efficacy benefit over the 
2.5-mg dose.  Based upon prior studies, this additional efficacy benefit is likely to be most 
evident in subjects considered to have severe symptomatic osteoarthritis as defined above in 
Section 1.2.3.1. 
The current study will investigate the safety and efficacy of fixed-dose levels of tanezumab 
2.5 mg and 5 mg administered up to 7 times at 8-week intervals relative to an active 
comparator treatment group (NSAID).  Subjects randomized to the active comparator 
treatment group will receive the NSAID they were receiving prior to study entry (naproxen, 
diclofenac ER or celecoxib).  Subjects randomized to receive NSAID in the current study 
will receive them at protocol specified doses (naproxen 500 mg BID, diclofenac ER 
75 mg BID or celecoxib 100 mg BID).  These doses represent maximal or near maximal 
labeled doses used for the treatment of osteoarthritis. 
Inclusion of the active comparator treatment group will allow the safety of tanezumab to be 
benchmarked against three common NSAIDs that are used in the treatment of pain associated 
with osteoarthritis.  In particular, the long duration of this study necessitated the use of an 
active comparator rather than placebo.  As no single NSAID is widely used across all 
geographic regions, inclusion of three different NSAIDs in a large study such as this will 
facilitate subject enrollment across geographic regions. 
1.2.5. Subject Population Selection Rationale
The primary objectives of this study are: 1) to characterize the long term joint safety risks of 
tanezumab using a composite endpoint to include adjudication outcomes of rapidly 
progressive osteoarthritis (type-1 or type-2), subchondral insufficiency fracture (or SPONK), 
primary osteonecrosis, or pathological fracture and 2) demonstrate the analgesic superiority 
of tanezumab relative to NSAID.  The long duration of the current study precludes the use of 
a placebo control group and necessitates the use of an active control group that provides 
subjects with some degree of efficacy.  To facilitate inclusion of an active control treatment 
group that will serve as a benchmark for evaluation of the long-term safety and efficacy of 
tanezumab, subjects entering the current study must have moderate to severe pain while 
receiving their current stable dosing regimen of oral NSAID therapy (naproxen, celecoxib,
diclofenac, aceclofenac, ibuprofen, loxoprofen, meloxicam, nabumetone, sulindac or 
ketoprofen), be tolerating their NSAID regimen and be taking this medication regularly 
during the 30-day period prior to the Screening Visit. 
To frame the risk of subjects experiencing joint safety events in this and other studies of 
tanezumab in subjects with osteoarthritis, Number Needed to Harm (NNH) estimates were 
calculated.  The NNH estimates represent the number of subjects that would need to be in 
each treatment group, such that there would be one additional joint safety event in the 
tanezumab group compared to the active comparator group.  The NNH estimates were based 
upon the incidence of joint safety events that formed a composite endpoint consisting of 
all-cause total joint replacement, adjudicated osteonecrosis, adjudicated rapidly progressive 
osteoarthritis and adjudicated subchondral insufficiency fracture.  To show the potential 
impact of risk mitigation measures on event rates, NNH estimates were calculated using 
observed data and data considered to be representative of joint safety event rates that might 
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be seen after implementation of risk mitigation measures outlined in Section 1.2.3.4.  The 
NNH estimates are presented in Table 3 and suggest that with implementation of risk 
mitigation measures, the level of risk subjects may experience in this study is low and 
potentially lower (for the tanezumab 2.5 mg treatment group) than what a subject may 
experience during treatment with an active comparator. 
Table 3.
Number Needed to Harm (NNH) Estimates for a Composite Joint Safety 
Endpoint1 in Phase 3 Osteoarthritis Studies2
Observed Results
Results with Risk Mitigation Measures 
Applied
Tanezumab 
Overall
Tanezumab 
Monotherapy 
Tanezumab + 
NSAID 
Tanezumab Monotherapy
Doses
2.5 mg – 10 mg
2.5 mg – 10 mg
2.5 mg – 10 mg
2.5 mg – 5 mg
2.5 mg
5 mg
N
6701
4273
3028
1578
396
1182
n (%)
76 (1.1)
23 (0.5)
53 (1.8)
4 (0.3)
0 (0)
4 (0.3)
NNH
102
263
63
**
**
2506
N = Number of subjects; n (%) = number (%) of subjects with a joint safety event; NNH = Number of 
subjects treated with tanezumab instead of active comparator to observe 1 additional joint safety event
**= Indicates that a negative number is needed to harm translating to a lower risk with tanezumab than with 
active comparator
1 Includes all-cause total-joint replacement, adjudicated osteonecrosis or rapidly progressive osteoarthritis 
and subchondral insufficiency fracture
2 A4091011, A4091014, A4091015, A4091016, A4091017, A4091018, A4091025, A4091026, A4091027, 
A4091030, and A4091043
To quantitate the benefit (pain relief) of treatment with tanezumab relative to active 
comparator, Number Needed to Treat (NNT) estimates were calculated using data from 
controlled Phase 3 osteoarthritis studies.  The NNT represents the number of subjects that 
would need to be treated in each treatment group, such that there would be one additional 
responder in the tanezumab group compared to the active comparator group.  Responders 
were defined as subjects who had a decrease from Baseline WOMAC pain score of ≥50%, 
≥70% or ≥90%.  There were no Phase 3 osteoarthritis studies that included a tanezumab 
2.5 mg monotherapy and an active comparator treatment group which precluded the ability to 
calculate an NNT for 2.5 mg monotherpy versus active comparator.  The NNT values are 
presented in Table 4.
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Table 4.
Number Needed to Treat (NNT) with Tanezumab versus NSAID in the 
Treatment of Osteoarthritis
Number of subjects treated with 
tanezumab instead of active 
comparator1 to observe 1 additional 
responder
Tanezumab Monotherapy2
Tanezumab + NSAID3
2.5 mg
5 mg
N=852
10 mg
N=858
2.5 mg
N=157
5 mg
N=686
10 mg
N=687
WOMAC Pain ≥50% Response
__
10
10
27
8
6
WOMAC Pain ≥70% Response
__
9
11
29
11
7
WOMAC Pain ≥90% Response
__
20
22
26
21
14
1 Active Comparator = naproxen 500 mg BID, celecoxib 100 mg BID, diclofenac ER 75 mg BID.
2 Efficacy determined by BOCF imputation at Week 16 landmark analysis for studies 1015, 1018, & 
1025 combined. 
3 Efficacy determined by BOCF imputation at Week 16 landmark analysis for study 1017 alone (2.5 mg), 
or Studies 1017 & 1025 combined (5 mg and 10 mg).
Considering the risk mitigation measures that have been included in this study and the impact 
they may have on minimizing risk relative to the expected benefit as expressed in NNH and 
NNT estimates, respectively, the benefit vs. risk relationship for subjects in this study is 
expected to be positive (ie, favoring a benefit). 
Complete information for this compound may be found in the Single Reference Safety 
Document, which for this study is the Investigator’s Brochure.  The Single Reference Safety 
Document (SRSD) for the comparator agents are the Company Core Data Sheet for 
celecoxib, the US Package Insert for naproxen (Amneal) and the Summary of Product 
Characteristics (UK) for diclofenac ER (Novartis).
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objectives
•
Characterize the long-term risk of joint safety events in subjects with osteoarthritis of 
the knee or hip who receive tanezumab 2.5 mg or tanezumab 5 mg SC versus NSAID 
treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 
75 mg BID) over the course of 56-weeks of treatment using a composite endpoint 
(includes adjudication outcomes of rapidly progressive osteoarthritis type-1 or type-2, 
subchondral insufficiency fracture (SPONK), primary osteonecrosis, or pathological 
fracture).
•
Demonstrate superior efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus 
NSAID treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 
75 mg BID) at Week 16.
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Secondary Objectives
•
Characterize the long-term joint safety risk using a composite endpoint (includes 
adjudication outcomes of rapidly progressive osteoarthritis (type-2 only), subchondral 
insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture).
•
Characterize the long-term risk of the following individual adjudication outcomes 
occurring: rapidly progressive osteoarthritis (type-1 only), rapidly progressive 
osteoarthritis (type-2 only), rapidly progressive osteoarthritis (type-1 or type-2 
combined), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, 
and pathological fracture.
•
Characterize the long-term risk of all-cause total joint replacements (subjects who 
undergo total joint replacement plus subjects who have an adjudicated outcome of 
rapidly progressive osteoarthritis type-1 or type-2, subchondral insufficiency fracture 
(or SPONK), primary osteonecrosis, or pathological fracture whether they undergo 
total joint replacement or not) occurring.
•
Characterize joint space width changes in subjects with Kellgren-Lawrence Grade 2 
or 3 osteoarthritis of the index knee or index hip. 
•
Demonstrate superior efficacy of tanezumab 5 mg and tanezumab 2.5 mg SC versus 
each separate NSAID treatment group (naproxen 500 mg BID, celecoxib 100 mg BID 
and diclofenac ER 75 mg BID) at Week 16.
•
Demonstrate the efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus 
NSAID (combined) treatment at all time points to Week 56.
•
Evaluate the long-term safety of tanezumab 2.5 mg and tanezumab 5 mg SC.
•
Explore relationships between adjudicated outcomes of rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fracture (or SPONK), 
primary osteonecrosis, or pathological fracture and variables that may be associated 
with these orthopedic risks.
•
Characterize changes in physical activity level.
2.2. Endpoints
2.2.1. Primary Endpoints
•
Incidence of a predefined composite endpoint consisting of adjudication outcomes of 
rapidly progressive osteoarthritis (type-1 or type-2), subchondral insufficiency 
fracture (or SPONK), primary osteonecrosis, or pathological fracture (primary 
composite endpoint).
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The co-primary efficacy endpoints are:
•
Change from Baseline to Week 16 in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain subscale.
•
Change from Baseline to Week 16 in the WOMAC Physical Function subscale.
•
Change from Baseline to Week 16 in the Patient’s Global Assessment of 
Osteoarthritis.
The Japanese Specific co-primary efficacy endpoints are:
•
Change from Baseline to Week 16 in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain subscale.
•
Change from Baseline to Week 16 in the WOMAC Physical Function subscale.
2.2.2. Secondary Endpoints
2.2.2.1. Bone and Joint Safety
•
Incidence of a predefined composite endpoint consisting of adjudication outcomes of 
rapidly progressive osteoarthritis (type-2 only), subchondral insufficiency fracture (or 
SPONK), primary osteonecrosis, or pathological fracture.
•
Incidence of individual adjudication 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 (or 
SPONK), primary osteonecrosis, and pathological fracture.
•
Incidence of all-cause total joint replacements (subjects who undergo total joint 
replacement plus subjects who have an adjudicated outcome of rapidly progressive 
osteoarthritis type-1 or type-2, subchondral insufficiency fracture (SPONK), primary 
osteonecrosis, or pathological fracture whether they undergo total joint replacement 
or not).
2.2.2.2. Radiographic
•
Change from Baseline to Week 56 and Week 80 in Medial or Lateral Minimum Joint 
Space Width of the index knee (for subjects with Kellgren-Lawrence Grade 2 or 3 
medial or lateral osteoarthritis of the index knee).
•
Change from Baseline to Week 56 and Week 80 in Minimum Joint Space Width of 
the index hip (for subjects with Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the 
index hip).
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•
Incidence of subjects with progression of osteoarthritis in the index knee according to 
Bland and Altman method, at Week 56 and Week 80 (separately) (for subjects with 
Kellgren-Lawrence Grade 2 or 3 medial or lateral osteoarthritis of the index knee).
•
Incidence of subjects with progression of osteoarthritis in the index hip according to 
Bland and Altman method, at Week 56 and Week 80 (separately) (for subjects with 
Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the index hip).
2.2.2.3. Efficacy
•
WOMAC Pain subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 40, 48, 56 
and Week 64.
•
WOMAC Physical Function subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 
40, 48, 56 and Week 64.
•
Patient’s Global Assessment of Osteoarthritis change from Baseline to Weeks 2, 4, 8, 
16 (Japan only), 24, 32, 40, 48, 56 and Week 64.
•
OMERACT-OARSI responder index at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 
Week 64.
•
Treatment Response: Reduction in the WOMAC Pain subscale of ≥30%, ≥50%, 
≥70% and ≥90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Cumulative distribution of percent change from Baseline in the WOMAC Pain 
subscale score to Week 16, 24, and 56 (endpoint for summary only).
•
Treatment Response: Reduction in the WOMAC Physical Function subscale of 
≥30%, ≥50%, ≥70% and ≥90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Cumulative distribution of percent change from Baseline in the WOMAC Physical 
Function subscale score to Week 16, 24, and 56 (endpoint for summary only).
•
Treatment Response: Improvement of ≥2 points in Patient’s Global Assessment of 
Osteoarthritis at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Average pain score in the index joint change from Baseline to Weeks 1, 2, 3, 4, 6, 8, 
10, 12, 16, 20, 24, 32, 40, 48, 56 and Week 64.
•
WOMAC Stiffness subscale change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 
48, 56 and Week 64.
•
WOMAC Average change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 
Week 64.
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•
WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface, change from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64. 
•
WOMAC Pain Subscale Item: Pain When Going Up or Down Stairs, change from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Work Productivity and Activity Impairment Questionnaire for Osteoarthritis 
(WPAI:OA) impairment scores change from Baseline to Weeks 16, 24, 56 and 64.
•
EuroQol 5 Dimension (EQ-5D-5L™) dimensions and overall health utility score at 
Baseline and Weeks 8, 16, 24, 40, 56 and 64.
•
Treatment Satisfaction Questionnaire Medicine v.II (TSQM v.II) satisfaction with 
effectiveness, side effects and convenience, and overall satisfaction at Weeks 16 
and 56.
•
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 
and 56.
•
Incidence and Time to discontinuation due to Lack of Efficacy.
•
Usage of rescue medication (incidence and number of days of use) during Weeks 2, 4, 
8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Usage of rescue medication (amount taken) during Weeks 2, 4, 8 and Week 16.
•
Health Care Resource Utilization at Baseline and Weeks 64, and 80.
2.2.2.4. Activity Level Monitoring
•
Lower Extremity Activity Scale: change from Baseline to Weeks 4, 8, 16, 24, 56 and 
Week 80 (all subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of physical 
activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily physical activity counts (a 
subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of moderate to 
vigorous physical activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of bouted 
(sustained) moderate to vigorous physical activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily step count (a subset of 
subjects).
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2.2.2.5. General Safety
•
Adverse Events.
•
Standard safety assessments (safety laboratory testing [chemistry, hematology], 
sitting vital signs, electrocardiogram (ECG; 12-lead).
•
Orthostatic (supine/standing) blood pressure assessments.
•
Survey of Autonomic Symptom scores.
•
Neurologic exam (Neuropathy Impairment Score [NIS]).
•
Anti-tanezumab antibody assessments.
•
Physical examinations. 
2.2.3. Tertiary Endpoints
2.2.3.1. Pharmacokinetic and Pharmacodynamic
•
Plasma tanezumab concentrations.
•
Serum NGF assessment.
•
Serum and urine osteoarthritis biomarker concentrations.
•
Synovial fluid NGF assessment (for a subset of subjects).
•
Synovial fluid tanezumab concentrations (for a subset of subjects).
3. STUDY DESIGN
This is a randomized, double-blind, active-controlled, multicenter, parallel-group 
Phase 3 study of the safety and efficacy of tanezumab when administered by SC injection for 
56 weeks compared to NSAIDs in subjects with osteoarthritis of the knee or hip.  
Approximately 3000 subjects will be randomized to one of 3 treatment groups in a 1:1:1 ratio 
(N=1000/treatment group).  Treatment groups will include:  
1. SC placebo (to match tanezumab) once every 8 weeks (a total of 7 administrations) 
plus NSAID administered orally (PO) (naproxen 500 mg BID PO, celecoxib 100 mg 
BID PO, or diclofenac ER 75 mg BID PO) through Week 56.
2. Tanezumab 2.5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO (to match naproxen, celecoxib or diclofenac ER) through Week 56.
3. Tanezumab 5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO (to match naproxen, celecoxib or diclofenac ER) through Week 56. 
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Japan specific treatment groups are:
1. SC placebo (to match tanezumab) once every 8 weeks (a total of 7 administrations) 
plus celecoxib 100 mg BID administered orally (PO) through Week 56.
2. Tanezumab 2.5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO to match celecoxib through Week 56.
3. Tanezumab 5 mg SC once every 8 weeks (a total of 7 administrations) plus placebo 
BID PO to match celecoxib through Week 56. 
Figure 1.
Study Schematic
Double-Blind Treatment Period
PO NSAID1,2 + SC Placebo (to match tanezumab) 
SC Tanezumab 5 mg + PO Placebo (to match naproxen, celecoxib or diclofenac)2
SC Tanezumab 2.5 mg + PO Placebo (to match naproxen, celecoxib or diclofenac)2
Week
Day
0
1
8
57
16
24
32
40
48
56
113
169
225
281
337
393
Subcutaneous Administration of Tanezumab
561
80
*
End of Study
Safety Follow-up Period
*Phone Contact with Patient
64
449
-37
-7
Baseline Pain 
Days -7 to -1
Randomization 
1st Dose of 
Study 
Medication
Screening
*
*
4
2
29
15
12
85
*
*
*
*
*
*
1 NSAID = naproxen 500 mg BID, celecoxib 100 mg BID or diclofenac ER 75 mg BID
*
2 In Japan, PO study treatment will consist of celecoxib 100 mg BID or matching placebo
The Screening period also 
includes stabilization of the 
NSAID treatment regimen 
Randomization will be stratified by index joint, most severe Kellgren-Lawrence grade of any 
knee or hip joint and NSAID treatment administered during the Screening period (in Japan, 
all subjects will receive celecoxib during Screening).  This will result in a 18-group (6-group 
in Japan) stratified randomization scheme as shown in Table 5.
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Table 5.
Stratified Randomization Scheme
Randomization 
Strata
NSAID Treatment Taken 
During Screening
Index joint
Most Severe 
Kellgren-Lawrence 
Grade
1
Naproxen
Hip
2
2
Naproxen
Hip
3
3
Naproxen
Hip
4
4
Naproxen
Knee
2
5
Naproxen
Knee
3
6
Naproxen
Knee
4
7
Celecoxib
Hip
2
8
Celecoxib
Hip
3
9
Celecoxib
Hip
4
10
Celecoxib
Knee
2
11
Celecoxib
Knee
3
12
Celecoxib
Knee
4
13
Diclofenac
Hip
2
14
Diclofenac
Hip
3
15
Diclofenac
Hip
4
16
Diclofenac
Knee
2
17
Diclofenac
Knee
3
18
Diclofenac
Knee
4
A minimum of 660 subjects (approximately 220/treatment group) taking each NSAID 
(naproxen, celecoxib or diclofenac) during Screening will be randomized into the study.
The study is designed with a total (post-randomization) duration of 80 weeks and will consist 
of three periods: Screening (up to a maximum of 37 days), Double-blind Treatment 
(56 weeks) and Safety Follow-up (24 weeks).  The Screening period (beginning up to 
37 days prior to Randomization) includes a Washout Period (lasting 2-30 days), if required, 
and an Initial Pain Assessment Period (the 7 days prior to Baseline [Day 1]; minimum of 
3 days). 
Prior to entering the study, subjects must be receiving a stable dosing regimen of oral NSAID 
therapy consisting of one of the NSAIDs presented in the following table, be tolerating their 
NSAID regimen and be taking this medication regularly (defined as an average of at least 
5 days per week) during the 30-day period prior to the Screening visit. 
Table 6.
Qualifying Pre-study NSAID Treatment Regimens
NSAID
Qualifying Dose Range
Naproxen 
440 mg/day* to 1000 mg/day
Celecoxib
200 mg/day (either 100 mg BID or 200 mg QD)
Diclofenac
100 mg/day to 150 mg/day
Aceclofenac
200 mg/day
Loxoprofen
120 mg/day to 180 mg/day
Ibuprofen
1200 mg/day to 3200 mg/day
Meloxicam
5 mg/day to 15 mg/day
Nabumetone
1000 mg/day to 2000 mg/day
Sulindac
200 mg/day to 400 mg/day
Ketoprofen
200 mg/day
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*A minimum dose of 440 mg/day is applicable for naproxen formulations that include the sodium salt of 
naproxen otherwise the minimum qualifying dose of naproxen is 500 mg/day
The Screening period will include the discontinuation and washout of all prohibited pain 
medications for at least 5 times the elimination half-life as well as the time needed to obtain 
confirmation of subject radiographic eligibility for the study from the Central Reader.  The 
Screening period is a minimum of 2 or 3 weeks (14 to 21 days) to ensure subjects are on a 
stable regimen of study provided NSAID for at least 2 or 3 weeks prior to randomization.  
The length of the NSAID regimen stabilization period will depend on the NSAID subjects 
are receiving in the 30 days prior to screening.  The NSAID regimen stabilization period will 
be a minimum of 2 weeks if the pre-study NSAID is celecoxib, naproxen or diclofenac or a 
minimum of 3 weeks if the pre-study NSAID is aceclofenac, loxoprofen, ibuprofen, 
meloxicam, nabumetone, sulindac, or ketoprofen.  The minimum washout period is 2 days 
(48 hrs) for all prohibited pain medications that have an elimination half-life of less than 
10 hours.  The washout of prohibited pain medication may occur in parallel with the 2 or 
3-week NSAID regimen stabilization.  During the Washout Period, subjects will be provided 
with rescue medication (acetaminophen/paracetamol) that may be taken, if necessary, up to 
the maximum daily dose of 3000 mg per day.  Use of rescue medication must be 
discontinued at least 24 hours prior to the Baseline (Randomization) Visit.
At the Screening visit, all subjects who were receiving celecoxib, diclofenac or naproxen 
prior to Screening will be provided with this same NSAID for use during the remainder of 
the Screening period and will be stabilized on an NSAID dosing regimen of celecoxib 
100 mg BID, naproxen 500 mg BID, or diclofenac ER 75 mg BID for at least the final 
2 weeks of the Screening period directly prior to the Baseline (Randomization/Day 1) visit.  
All subjects who were receiving aceclofenac, loxoprofen, ibuprofen, meloxicam, 
nabumetone, sulindac or ketoprofen prior to Screening will be assigned to celecoxib, 
naproxen or diclofenac.  The specific NSAID that subjects will be assigned to (celecoxib, 
naproxen or diclofenac) will be the choice of the investigator.  Subjects will use this NSAID
for the remainder of the Screening period and will be stabilized on a dosing regimen of 
celecoxib 100 mg BID, naproxen 500 mg BID, or diclofenac ER 75 mg BID for at least the 
final 3 weeks of the Screening period directly prior to the Baseline (Randomization/Day 1) 
visit.  
During NSAID regimen stabilization, all subjects will be expected to maintain a minimum 
compliance of 70% (average of 5 of 7 days per week).  Begining at Screening, subjects 
should use study-supplied oral investigational product (NSAID during Screening and NSAID 
or matching placebo post-randomization) through Week 56. 
The Screening period will include collection of radiographs of each knee, hip, and shoulder.  
All X-rays will be evaluated by a Central Reader to determine the radiographic eligibility of 
subjects for the study.  Other major joints exhibiting signs or symptoms suggestive of 
osteoarthritis should also be imaged.  A major joint is defined as a mobile synovial joint in 
the limbs such as shoulders, elbows, wrists, hips, knees, ankles and excluding the joints of 
the toes and hands.  Screening X-rays should be obtained as early as possible in the 
Screening period to facilitate completion of all required screening procedures within the 
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37-day Screening period.  During Screening, subjects will also provide a pain score (scored 
with an 11-point numerical rating scale [NRS]) via Interactive Response Technology (IRT)
for bilateral shoulders, hips and knees and any other major joint for which a radiograph is 
obtained (refer to Section 7.3.4). 
Subjects who have been determined to be eligible from a radiographic (as determined by the 
Central Reader) and general screening procedure perspective (laboratory, ECGs, history etc.) 
will have MRIs of each hip and knee obtained prior to the Baseline (Day 1) visit.  In addition, 
DXA scans will be obtained in subjects meeting National Osteoporosis Foundation 
recommendations for bone mineral density testing (refer to Section 7.3.12 and Appendix 10).  
These procedures will likely occur in parallel with washout of prohibited pain medications 
and the 2-week period of pre-randomization NSAID regimen stabilization and must be 
completed prior to the Baseline (Day 1) visit.
Subjects at selected sites (to recruit approximately 360 subjects) will also have physical 
activity monitored via actigraphy over the course of 7 consecutive days during the Screening 
period.  The activity monitoring will take place once subjects have been determined to be 
eligible from a radiographic (as determined by the Central Reader) and general screening 
procedure perspective (laboratory, ECGs, history etc.).  Activity monitoring via actigraphy 
will be completed prior to the Baseline (Day 1) visit and will likely occur in parallel with 
washout of prohibited pain medications, the 2-week period of pre-randomization, NSAID
regimen stabilization and collection of MRIs and DXA scans (if applicable). 
Eligible subjects who have completed washout of prohibited pain medications and all other 
screening (Stage 1) assessments may begin the Initial Pain Assessment Period (IPAP).  
During the IPAP, the daily average pain score in the index joint (scored with an 11-point 
numerical rating scale [NRS]) and rescue medication use by subjects will be collected via 
IRT.  Pain in major non-index joints will also be assessed once during the IPAP.  The IPAP 
will begin approximately 7 days prior to the Baseline (Day 1) randomization visit.  During 
the IPAP, subjects must complete at least 3 daily diary entries (joint pain and rescue 
medication use).  Accelerometry (if applicable), MRI and DXA (if applicable) may be 
performed in parallel with the IPAP. 
Those subjects who qualify at the Baseline (Day 1) visit will be randomized to 1 of 
3 treatment groups. 
Tanezumab 2.5 mg, 5 mg, or placebo for tanezumab will be administered as a SC injection 
and subjects will be observed for adverse events including signs and symptoms of 
hypersensitivity in the clinic for a minimum of 1 hour after each administration of 
investigational product.  Subjects will take their first oral dose of NSAID (naproxen 
500 mg BID, celecoxib 100 mg BID, or diclofenac ER 75 mg BID) or matching placebo of 
the Double-blind Treatment period in the evening on Day 1 (ie, a morning dose of oral 
double-blind, investigational product will not be taken).  Additional administrations of SC 
investigational product will occur every 8 weeks following the Baseline (Day 1) 
administration through Week 48.  Oral investigational product (NSAID or matching placebo) 
will be self-administered by subjects BID through Week 56 of the study.  Efficacy, activity 
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level and safety assessments will be conducted during clinic visits between Weeks 2 and 64.  
In addition, subjects will be contacted by telephone every 8 weeks between Weeks 12 and 60 
and every 4 weeks between Weeks 64 and 80 (ie, Weeks 68, 72 and 76). 
At the Week 16 visit, subjects must have a 30% or greater reduction in WOMAC Pain 
subscale relative to Baseline in the index joint and a 15% or greater reduction in WOMAC 
Pain subscale from Baseline at either Week 2, 4 or 8 in order to continue investigational 
product.  Subjects who do not meet these response criteria will be discontinued from the 
Treatment Period and enter the 24-week Early Termination Follow-up period. 
At Weeks 24, 56, and 80, all subjects will undergo repeat radiographs of each knee, hip and 
shoulder as well as any additional joint(s) that was imaged at Screening.  At Week 24, 
confirmation of the continuing radiographic eligibility of subjects must be received from the 
Central Reader prior to administration of the Week 24 SC investigational product.  Subjects 
with Kellgren-Lawrence Grade 3 or 4 osteoarthritis in any knee or hip joint, on the basis of 
the Central Reader’s assessment of the screening X-rays, will have follow-up MRIs of each 
hip and knee obtained at Weeks 24, 56, and 80. 
With the completion of the Double-blind Treatment period at the Week 56 visit, subjects will 
begin the 24-week Safety Follow-up period and will be asked to return to the clinic for 
2 additional study visits.  At Week 64 (16 weeks after the last dose of investigational 
product) efficacy assessments, adverse event and concomitant medication information will be 
collected and standard of care medication may be initiated.  At the end of the 24-week Safety 
Follow-up period, subjects will return for a final study visit at Week 80 (End of Study).  At 
the Week 80 visit, all End of Study procedures are to be completed.  Between Weeks 64 and 
80 in the Safety Follow-up period, subjects will be contacted by clinical research site staff at 
approximately monthly intervals to collect adverse event, concomitant drug and concomitant 
non-drug data.
Continuing on from the Initial Pain Assessment Period, subjects will provide a daily 
assessment of their index joint pain through Week 16 via IRT.  Between Weeks 16 and 
80 (End of Study), subjects will provide pain scores in the index joint weekly via IRT using a 
24-hour recall period.  Subjects will also provide a weekly assessment of their non-index 
joint (major joints, refer to Section 7.1.1) pain via IRT using a 24-hour recall period from the 
Initial Pain Assessment Period to Week 80.  The use of rescue medication 
(acetaminophen/paracetamol) will be collected daily via IRT beginning in the IPAP to the 
Week 16 visit and then weekly until Week 80.  On a weekly basis between Baseline and 
Week 80, subjects will record the number of days of concomitant NSAID (outside of oral 
investigational product) use via IRT. 
Subjects who complete the Week 56 visit will be considered to have completed the 
Double-blind Treatment period and will enter the 24-week Safety Follow-up period.  
Subjects who have completed the Double-blind Treatment period and have entered the 
24-week Safety Follow-up period and complete the Week 80 visit will be considered to have 
completed the study.  Subjects who discontinue study treatment prior to completing the 
Week 56 visit will not be considered to have completed the Double-blind Treatment period. 
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Subjects who do not complete the Double-blind Treatment period but who enter and 
complete the 24-week Early-termination follow-up period will be considered to have 
completed the study while those subjects who do not complete the 24-week 
Early-termination follow-up period, will not be considered to have completed the study.
Subjects who are discontinued from treatment prior to Week 56, either at their request or at 
the decision of the investigator, will be required to undergo 24 weeks of follow-up (referred 
to as Early Termination Follow-Up).  The 24 weeks of follow-up will be obtained through 
3 clinic visits and monthly phone calls to yield 24-weeks of post-treatment follow-up.  In 
addition, subjects will be asked to continue to enter pain scores for index joints (and 
non-index joints when applicable) via IRT, weekly, through the end of the 24-week 
follow-up period.  Subjects who have entered the Early Termination Follow-up period will 
also be asked to record weekly rescue medication and concomitant NSAID use via IRT. 
Radiographs of each shoulder, knee and hip (and any other major joint imaged at Screening 
or identified as at risk [refer to Section 7.4.4] 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.  Subjects that were 
determined to have Kellgren-Lawrence Grade 3 or 4 osteoarthritis in any knee or hip joint at 
Screening should also have an MRI of each knee and hip performed.  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 investigational product (as described in 
Section 6.4.1.1).  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 investigational product (which corresponds to more than 5 times the elimination 
half-life of tanezumab) to collect safety and efficacy data (as described in Section 6.4.1.3).  
Once the clinic visit 16-weeks after the last administration of SC investigational product has 
been completed and final efficacy assessments have been collected, standard of care 
treatment will be offered to subjects for the remaining 8 weeks of the required Safety 
Follow-up period.  Standard of care treatment may be initiated as needed and should be 
recorded on the concomitant medication Case Report Form (CRF).  The third and final clinic 
visit should be scheduled to take place approximately 24-weeks after the subject received the 
last dose of SC investigational product.  That visit (as described in Section 6.4.1.5), will 
include repeat radiographs of each shoulder, knee and hip (and any other major joint imaged 
at Screening or identified as at risk during the study) providing at least 30 days have elapsed 
since the last radiographs were obtained.  Subjects that were determined to have 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis in any knee or hip joint at Screening should 
also have an MRI of each knee and hip performed.  Every effort should be made to have the 
subject agree to complete the entire 24-week Early Termination Safety Follow-up described 
above.
In the event a subject refuses to enter the Early Termination Safety Follow-up, or chooses to 
discontinue during the regularly planned Safety Follow-up period (after Week 56 and 
through Week 80), a complete early termination visit should be performed.  This early 
termination visit should include all procedures scheduled for the Week 64 and Week 80 
visits, unless the Week 64 visit has already been completed; in that case, only Week 80 
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procedures will be required.  In addition, if the Week 56 visit was not completed prior to 
termination, a general physical examination, body weight, WPAI:OA, EQ-5D-5L, 
TSQM v.II, and mPRTI will also be obtained.  Females of childbearing potential will be 
advised to continue their contraception regimen during a period of 112 days (16 weeks) after 
the last dose of SC investigational product.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether 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:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.
2. Male or female of any race, ≥18 years of age. 
3. A diagnosis of osteoarthritis of the index hip or knee based on American College of 
Rheumatology criteria with X-ray confirmation (a Kellgren-Lawrence42 X-ray Grade 
of ≥2 as diagnosed by the Central Reader; Appendix 1). 
4. Subjects must meet the following criteria pertaining to their osteoarthritis treatment 
regimen:
•
Documented history indicating that acetaminophen therapy has not provided 
sufficient pain relief;
•
Currently receiving a stable dose regimen of oral NSAID therapy consisting of
one of the NSAIDs presented in the following table, be tolerating this NSAID and 
be taking this medication regularly (defined as an average of at least 5 days per 
week) during the 30 day period prior to the Screening visit.):
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Table 7.
Qualifying Pre-study NSAID Treatment Regimens
NSAID
Qualifying Dose Range
Naproxen 
440 mg/day* to 1000 mg/day
Celecoxib
200 mg/day (either 100 mg BID or 200 mg QD)
Diclofenac
100 mg/day to 150 mg/day
Aceclofenac
200 mg/day
Loxoprofen
120 mg/day to 180 mg/day
Ibuprofen
1200 mg/day to 3200 mg/day
Meloxicam
5 mg/day to 15 mg/day
Nabumetone
1000 mg/day to 2000 mg/day
Sulindac
200 mg/day to 400 mg/day
Ketoprofen
200 mg/day
*A minimum dose of 440 mg/day is applicable for naproxen formulations that 
include the sodium salt of naproxen otherwise the minimum qualifying dose of 
naproxen is 500 mg/day
•
Maintain a stabilized dose regimen of either naproxen 500 mg BID, celecoxib 
100 mg BID or diclofenac ER 75 mg BID (provided at Screening) with a 
minimum compliance of 70% (ie, 5 of 7 days per week) for the final 2 or 3 weeks 
of the Screening period directly prior to the Baseline (Day 1) visit.
AND at least 1 of the following criteria:
•
Documented history indicating that tramadol treatment has not provided adequate 
pain relief or subject is unable to take tramadol due to contraindication or inability 
to tolerate;
•
Documented history indicating that opioid treatment has not provided adequate 
pain relief or subject is unwilling to take opioids, or unable to take opioids due to 
contraindication or inability to tolerate.
5. WOMAC Pain subscale NRS ≥5 in the index knee or index hip at Screening.
6. Be willing to discontinue all non-study pain medications for osteoarthritis and not use 
prohibited pain medications throughout the duration of the study except as permitted 
per protocol.
7. Female subjects of childbearing potential and at risk for pregnancy must agree to use 
2 highly effective methods of contraception throughout the study and for 112 days 
(16 weeks) after the last dose of assigned subcutaneous investigational product. 
NOTE:  In Japan, female subjects must not be of childbearing potential to be eligible 
for this study.
8. Female subjects who are not of childbearing potential (i.e, must meet at least one of 
the following criteria):
•
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
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•
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.
9. Subjects who are willing and able to comply with lifestyle guidelines, scheduled 
visits, treatment plan, laboratory tests, and other study procedures through the End of 
Study visit. 
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.
2. Body Mass Index (BMI) of >39 kg/m2.  For subjects requiring DXA scan (refer to 
Section 7.3.12) body weight ≥300 lbs is exclusionary.
3. History of other disease that may involve the index joint including inflammatory joint 
disease such as rheumatoid arthritis, seronegative spondyloarthropathy 
(eg, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease related 
arthropathy), crystalline disease (eg, gout or pseudogout), endocrinopathies, 
metabolic joint diseases, lupus erythematosus, joint infections, Paget’s disease, or 
tumors. 
4. Radiographic evidence of any of the following conditions in any screening radiograph 
as determined by the central radiology reviewer and as defined in the tanezumab 
program imaging atlas: excessive malalignment of the knee, severe 
chondrocalcinosis; other arthropathies (eg, rheumatoid arthritis), systemic metabolic 
bone disease (eg, pseudogout, Paget’s disease, metastatic calcifications), large cystic 
lesions, primary or metastatic tumor lesions, stress or traumatic fracture. 
5. Radiographic evidence of any of the following conditions as determined by the 
central radiology reviewer and as defined in the tanezumab program imaging atlas at 
Screening: 1) rapidly progressive osteoarthritis, 2) atrophic or hypotrophic 
osteoarthritis, 3) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of 
the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture.
6. A history of osteonecrosis or osteoporotic fracture (ie, a subject with a history of 
osteoporosis and a minimally traumatic or atraumatic fracture).
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7. History of significant trauma or surgery to a knee, hip or shoulder within the previous 
year.
8. Planned surgical procedure during the duration of the study.
9. Largely or wholly incapacitated, (eg, subject bedridden or confined to a wheelchair, 
permitting little or no selfcare).
10. Fibromyalgia, regional pain caused by lumbar or cervical compression with 
radiculopathy or other moderate to severe pain that may confound assessments or 
self-evaluation of the pain associated with osteoarthritis. Subjects with a present 
(current) history of sciatica are not eligible for participation.  Subjects with a past 
history of sciatica who have been asymptomatic for at least one year and who have no 
evidence of radiculopathy or sciatic neuropathy on thorough neurologic examination 
are eligible participation.
11. A past history of carpal tunnel syndrome (CTS) with signs or symptoms of CTS in 
the one year prior to Screening.
12. Considered unfit for surgery, defined as Grade >3 on the American Society of 
Anesthesiologists (ASA) physical classification system for surgery (refer to 
Appendix 2), or subjects who would not be willing to undergo joint replacement 
surgery if required.
13. Contraindications to magnetic resonance imaging (refer to Appendix 11, and 
Reference 59).
14. History of intolerance or hypersensitivity to the relevant oral NSAID (naproxen, 
celecoxib or diclofenac) the subject could be randomized to receive or any of its 
excipients or existence of a medical condition or use of concomitant medication for 
which the use of this NSAID is contraindicated (refer to product labeling).
15. History of intolerance or hypersensitivity to acetaminophen (paracetamol) or any of 
its excipients or existence of a medical condition or use of concomitant medication 
for which the use of acetaminophen is contraindicated (refer to product labeling).
16. Use of prohibited medications without the appropriate washout period (if applicable) 
prior to Screening or Initial Pain Assessment Period (refer to Section 5.8.1). 
17. Oral or intramuscular corticosteroids within 30 days prior to the IPAP.
18. Intra-articular corticosteroid injection in the index joint within 12 weeks, or to any 
other joint within 30 days prior to the IPAP.
19. Intra-articular hyaluronic acid injection in the index joint within 30 days (or within 
18 weeks for long-acting formulations such as Synvisc) prior to the IPAP.
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20. History of cancer within 5 years prior to Screening, except for cutaneous basal cell or 
squamous cell cancer resolved by excision.
21. Signs and symptoms of clinically significant cardiac disease including but not limited 
to:
•
Ischemic cardiac disease (eg, unstable angina, myocardial infarction) in the 
6 months prior to Screening;
•
Surgery or stent placement for coronary artery disease in the 6 months prior to 
Screening;
•
New York Heart Association (NYHA) Class III or IV congestive heart failure or 
known left ventricular dysfunction with ejection fraction ≤35%, cardiomyopathy, 
myocarditis in the 6 months prior to Screening;
•
Resting tachycardia (heart rate ≥120) or resting bradycardia (heart rate ≤45) on 
ECG at Screening;
•
QTcF interval >500 msec in the absence of confounding factors like bundle 
branch block or paced rhythm at Screening;
•
Any other cardiovascular illness that in the opinion of the Investigator would 
render a subject unsuitable to participate in the study;
•
Subjects with a history of heart block requiring ongoing treatment or that is 
associated with symptoms.
22. Diagnosis of a transient ischemic attack in the 6 months prior to Screening, diagnosis 
of stroke with residual deficits (eg, aphasia, substantial motor or sensory deficits), 
that would preclude completion of required study activities.
23. History, diagnosis, or signs and symptoms of clinically significant neurological 
disease, including but not limited to:
•
Alzheimer’s disease or other types of dementia;
•
Clinically significant head trauma within the past year;
•
Peripheral or autonomic neuropathy;
•
Multiple sclerosis;
•
Epilepsy or seizure disorder with history of seizure within the last 2 years;
•
Myopathy.
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24. History, diagnosis, signs or symptoms of any clinically significant psychiatric 
disorder, including but not limited to:
•
Psychotic disorders;
•
Somatoform disorders;
•
Bipolar disorders;
•
Hospital admission for depression or suicide attempt within 5 years of Screening, 
or active severe major depression at Screening (determined from medical history: 
if needed, severity of depression may be assessed using the Patient Health 
Questionnaire [PHQ-9].43  A score of ≥15 on questions 1-9 of the PHQ-9 
corresponds to severe depression.  Refer to Appendix 9);
•
Any other psychiatric illness that in the opinion of the Investigator would render a 
subject unsuitable to participate in the study.
25. History of known alcohol, analgesic or drug abuse within 2 years of Screening.
26. Previous exposure to exogenous NGF or to an anti-NGF antibody.
27. History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal 
antibody or IgG-fusion protein.
28. Resting, sitting blood pressure (BP) ≥160 mm Hg in systolic pressure or ≥100 mm Hg 
in diastolic pressure at Screening.  If a subject is found to have untreated significant 
hypertension at Screening and antihypertensive treatment is initiated, assessment for 
study eligibility should be deferred until BP and antihypertensive medication have 
been stable for at least one month.  For subjects with previously diagnosed 
hypertension, antihypertensive medications must be stable for at least 1 month prior 
to Screening.
29. Subjects who have evidence of orthostatic hypotension based upon replicate 
orthostatic blood pressure measurements (refer to Section 7.3.5.1).  If orthostatic 
blood pressure change is not able to be determined (eg, unable to establish a stable 
supine systolic and diastolic blood pressure) then subject is not eligible for the study. 
30. Subjects with a total impact score of >7 on the Survey of Autonomic Symptoms 
(SAS), See Appendix 15.
31. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3.0 times the 
upper limit of normal, or creatinine exceeding 1.7 mg/dL (150 μmol/L) in men or 
1.5 mg/dL (133 μmol/L) in women, or hemoglobin A1c ≥10% at Screening.  Repeat 
confirmatory tests may be performed.
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32. Presence of drugs of abuse (including prescription medications without a valid 
prescription), or illegal drugs in the urine toxicology screen obtained at Screening.
33. Positive Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) tests at 
Screening indicative of current infection.
34. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
30 days (or 90 days for biologics) before Screening.
35. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential who are unwilling or unable to use two (2) highly effective 
methods of contraception as outlined in this protocol for the duration of the study and 
for 112 days (16 weeks) after last dose of investigational product.
36. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.
4.3. Randomization Criteria
In addition to meeting all inclusion and exclusion criteria requirements listed above, there are 
requirements for the following to be met before randomization can be called into the IRT 
system at the Baseline visit:
1. Subject must have completed appropriate washout of analgesics.
2. Subject must have made at least 3 pain diary entries in the 7 days prior to the Baseline 
(Day 1) visit.
3. Subject must have maintained a stabilized dose regimen of either naproxen 
500 mg BID, celecoxib 100 mg BID or diclofenac ER 75 mg BID (depending on the 
subject’s pre-study NSAID) with a minimum compliance of 70% (ie, 5 of 7 days per 
week) for at least the final 2 or 3 weeks of the Screening period directly prior to the 
Baseline (Day 1) visit.
NOTE:  In Japan, all subjects will maintain a stabilized dose regimen of celecoxib as 
defined above.
4. Subject must have abstained from taking rescue medication 
(acetaminophen/paracetamol) within the 24 hours that precede dosing. 
5. WOMAC Pain and Physical Function subscales NRS ≥5 in the index knee or index 
hip at Baseline.
6. Patient’s Global Assessment of Osteoarthritis must be “fair”, “poor,” or “very poor” 
at Baseline.
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7. Review of the ECG and laboratory results and confirmation that there are no 
clinically significant or exclusionary findings.
8. Subject must have had required Baseline X-rays, MRI and DXA (if appropriate) 
scan(s) obtained.
9. The index joint should be the most painful joint with a qualifying WOMAC Pain 
score and Kellgren-Lawrence Grade as confirmed by the Central Reader.
10. In Japan, confirm female subjects are not of childbearing potential. 
4.4. Life Style 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 investigational 
product and followed as described in Section 6.4.2.
Refer to Sections 5.8.1, 5.8.2 and Appendix 3 for guidance on permitted and prohibited 
medications.
All female subjects who, are of child-bearing potential and are sexually active and at risk for 
pregnancy, must agree to use two (2) methods of highly effective contraception consistently 
and correctly for the duration of the active treatment period and for 112 days (16 weeks) after 
the last dose of SC investigational product.  The investigator or his/or her designee, in 
consultation with the subject, will confirm the subject has selected the most appropriate 
forms of contraception for the individual subject from the permitted list of contraception 
methods (see below) and instruct the subject in its consistent and correct use.  Subjects need 
to affirm that they meet the criteria for correct use of at least two of the selected methods of 
contraception.  The investigator or his/her designee will discuss with the subject the need to 
use highly effective contraception consistently and correctly according to the Schedule of 
Activities and document such conversation in the subject’s chart.  In addition, the 
investigator or his/or her designee will instruct the subject to call immediately if the selected 
contraception methods are discontinued or if pregnancy is known or suspected in the subject
or the subject’s partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected, implanted, or transdermal hormonal 
methods of contraception is allowed provided the subject plans to remain on the same 
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treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact center number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigational site and the study team are not available.  It is therefore intended to augment, 
but not replace the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study.  
The contact number is not intended for use by the subject directly, and if a subject calls that 
number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
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5.1. Allocation to Treatment
Subjects will be randomized at Baseline to one of the following treatment groups, all subjects 
will receive SC and PO treatment during the Double-blind Treatment period of the study: 
Table 8.
Study Treatments
Treatment 
Group
Subcutaneous Investigational Product 
(SC)
Oral Investigational Product (PO)*
1
Placebo for tanezumab once every 8 weeks 
x 7 doses
Naproxen 500 mg BID, celecoxib 100 mg 
BID, or diclofenac ER 75 mg BID through 
Week 56
2
Tanezumab 2.5 mg once every 8 weeks x 7 
doses
Placebo for BID naproxen, BID diclofenac ER 
or BID celecoxib through Week 56
3
Tanezumab 5 mg once every 8 weeks x 
7 doses
Placebo for BID naproxen, BID diclofenac ER 
or BID celecoxib through Week 56
*In Japan, the oral investigational product will consist of celecoxib 100 mg BID or matching placebo for 
celecoxib BID
Subjects will be randomly assigned in a 1:1:1 ratio to the above treatment regimens 
according to a computer generated randomization schedule.  As detailed in Section 3, 
randomization will be stratified by index joint, most severe Kellgren-Lawrence grade (of any 
knee or hip joint) and NSAID treatment at study entry.  Randomization will be coordinated 
centrally through Interactive Response Technology (IRT).  The system will provide subject 
identification numbers at Screening, which will subsequently be linked to the treatment 
assignments at Randomization.  The randomization code will be securely maintained by a 
person(s) who is independent of the trial conduct and produces the randomization code.  It is 
the responsibility of the Principal Investigator to ensure that the subject is eligible for 
participation in the study before requesting Randomization.  The study site will obtain the 
subject’s randomization number and dispensable unit identification numbers (ie, the drug 
supply to be administered or supplied to subjects at relevant study visits) from the IRT.  
Further details will be provided in the Pharmacist Manual.
5.2. Breaking the Blind
This is a randomized, double-blind, active-controlled, parallel group study.  The subjects, 
Investigators, Study Coordinators, clinical site staff, Clinical Research Associate (CRA), and 
staff directly involved with the study at Pfizer and its designees will be blinded to subject 
assignment.
Blinding should 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 CRF.
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5.3. Subject Compliance
Tanezumab and NSAID (celecoxib 100 mg, naproxen 500 mg, diclofenac 75 mg ER) or 
corresponding placebo (SC or PO) dosing will be recorded on the appropriate CRF.  Because 
tanezumab or corresponding placebo will be administered by site staff, subject compliance 
with SC treatment is not anticipated to be an issue. 
For oral NSAID treatments (celecoxib, naproxen, diclofenac ER or corresponding placebo) 
and rescue medication (acetaminophen / paracetamol), compliance will be reviewed and 
reconciled at each study visit.  For oral investigational product (NSAID or matching 
placebo), investigators should encourage subjects to maintain 100% compliance.  If a 
subject’s overall compliance with oral investigational product falls to <70% in an 8 week 
dosing interval, the investigator will counsel the subject on the importance of good 
compliance and document efforts to improve the subject’s compliance.  The use of non-study 
NSAIDs is prohibited during the study except as described in Section 5.8. 
Protocol rules governing the use of rescue medication are described in Section 5.8.2. 
5.4. Drug Supplies
5.4.1. Dosage Form(s) and Packaging
Tanezumab, placebo for tanezumab, NSAID (celecoxib, naproxen and diclofenac ER) and 
placebo for NSAID will be supplied by the Sponsor or designee.
5.4.1.1. Tanezumab
Tanezumab 2.5 mg is presented as a sterile solution for subcutaneous administration, in a 
glass pre-filled syringe (PFS).  Each PFS contains a sufficient amount of tanezumab to 
provide the intended dose of drug at a concentration of 2.5 mg/mL. 
Tanezumab 5 mg is presented as a sterile solution for subcutaneous administration, in a glass 
pre-filled syringe (PFS).  Each PFS contains a sufficient amount of tanezumab to provide the 
intended dose of drug at a concentration of 5 mg/mL.
Each prefilled syringe is packed in an individual carton.  Each prefilled syringe has a unique 
container number.
5.4.1.2. Placebo for Tanezumab
Placebo for tanezumab is presented as a sterile solution for subcutaneous administration, in a 
matching glass pre-filled syringe (PFS). Each pre-filled syringe is packaged in an individual 
carton.  Each prefilled syringe has a unique container number.
5.4.1.3. Non-steroidal Anti-inflammatory Drugs (NSAID)
5.4.1.3.1. Celecoxib 100 mg
Celecoxib will be provided as oral capsules containing 100 mg of active celecoxib. 
Celecoxib 100 mg will be packaged in high-density polyethylene (HDPE) bottles with child 
resistant closures.  The bottles used for the screening period contain 80 capsules (open-label 
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supply) and the bottles used for the treatment period contain 70 capsules (double-blind 
supply).
5.4.1.3.2. Placebo to match celecoxib 100 mg
Placebo for celecoxib will be provided as oral capsules matching those used for celecoxib 
100 mg capsules.  Placebo to match celecoxib 100 mg will be packaged in HDPE bottles 
with child resistant closures containing 70 capsules (double-blind supply).
5.4.1.3.3. Naproxen 500 mg
Naproxen will be provided as oral tablets containing 500 mg of active naproxen. Naproxen 
500 mg will be packaged in HDPE bottles with child resistant closures.  The bottles used for 
the screening period contain 80 tablets (open-label supply) and the bottles used for the 
treatment period contain 70 tablets (double-blind supply).
5.4.1.3.4. Placebo to match naproxen 500 mg
Placebo for naproxen will be provided as oral tablets matching those used for naproxen 
500 mg tablets.  Placebo to match naproxen 500 mg will be packaged in HDPE bottles with 
child resistant closures containing 70 tablets (double-blind supply).
5.4.1.3.5. Diclofenac 75 mg ER
Diclofenac will be provided as oral extended release capsules containing 75 mg of active 
diclofenac sodium.  Diclofenac 75 mg ER will be packaged in HDPE bottles with child 
resistant closures.  The bottles used for the screening period contain 80 capsules (open-label 
supply) and the bottles used for the treatment period contain 70 capsules (double-blind 
supply).
If required due to availability of drug product, a product supplied as diclofenac SR 75 mg 
may be used in place of diclofenac ER 75 mg. 
5.4.1.3.6. Placebo to match diclofenac 75 mg ER
Placebo to match diclofenac will be provided as oral capsules matching those used for 
diclofenac 75 mg ER active.  Placebo to match diclofenac 75 mg ER will be packaged in 
HDPE bottles with child resistant closures containing 70 capsules (double-blind supply).
5.4.1.3.7. Acetaminophen/Paracetamol (rescue medication)
Acetaminophen/paracetamol will be issued by the study sites in its approved marketed 
product dress, (carton, bottle, documents).  Any approved commercial product of 
acetaminophen/paracetamol tablet/caplet/capsule is permitted.
5.4.2. Preparation and Dispensing
See the DAI for instructions on how to prepare tanezumab 2.5 mg SC, 5 mg SC and placebo 
SC for administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
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physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.
5.5. Administration
5.5.1. SC Investigational Product Administration
Tanezumab or matching placebo will be administered via SC injection by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, practitioner, or pharmacist) as allowed by local, state, and institutional guidance 
and at facilities which can handle allergic reactions.  All subjects will receive 1 mL of 
investigational product administered as a SC injection.  Subcutaneous injections are to be 
administered in the abdomen or anterior aspect of the thigh.  Selection of the SC injection 
site for each injection will be at the discretion of the investigator taking into account subject 
preferences when possible.  The SC injection should not be administered in areas where the 
skin is burned, reddened, inflamed, swollen, or scarred. 
5.5.2. Oral Investigational Product Administration
During the Screening period of the study, subjects will be provided with the NSAID they 
were taking prior to study entry and will maintain a stabilized dose regimen of either 
naproxen 500 mg BID, celecoxib 100 mg BID or diclofenac ER 75 mg BID (depending on 
the subject’s pre-study NSAID) for at least the final 2 weeks of the Screening period directly 
prior to the Baseline (Randomization/Day 1) visit.  Subjects should be advised to take their 
morning dose of the Screening Period NSAID before arriving for the Randomization/Day 1 
clinic visit. 
Celecoxib 100 mg, naproxen 500 mg and diclofenac 75 mg ER or corresponding placebo will 
be self-administered by subjects orally twice a day (morning and evening) during the 
double-blind treatment period of the study.  Subjects will swallow the oral investigational 
product whole, and will not manipulate or chew the medication prior to swallowing.  On 
Study Day 1, a morning dose of oral investigational product (NSAID or corresponding 
placebo) will not be administered to or taken by subjects.  The first dose of oral 
investigational product will be self administered by subjects on the evening of Day 1.  On the 
days of all other clinic visits (Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56), subjects should be 
advised to take their morning dose of NSAID or corresponding placebo at home prior to the 
clinic visit. 
5.6. Investigational Product Storage
The Investigator or an approved representative (eg, Pharmacist) will ensure that all 
investigational products, including any comparative agents and/or marketed products are
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  See the Pharmacy Manual for storage conditions of the product. 
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Storage conditions stated in the single reference safety document (SRSD) (ie, investigator’s 
brochure [IB]; core data sheets [CDS]; US Package Insert or UK Summary of Product 
Characteristics), will be superseded by the storage conditions stated in the investigational 
product labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.
The site should actively pursue options for returning the product to the storage conditions as 
described in the labelling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the sponsor approves the use of the investigational 
product after the temperature excursion.  Use of the investigational product prior to sponsor 
approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site.
5.7. Investigational Product Accountability
The Investigator’s site 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. Prohibited Medications
Use of analgesics (including marijuana) except acetaminophen/paracetamol is prohibited 
through Week 64 of the study beginning 48 hours prior to the start of the IPAP (the seven 
days prior to Randomization/Baseline (Day 1) or at the period of time prior to the start of the
IPAP that is at least 5 times the half-life of the particular analgesic used, whichever is 
greater.  Refer to Appendix 3: Half-Lives of Prohibited Prior and Concomitant Medications, 
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for a detailed washout schedule for prohibited medications.  This list is not all-inclusive, the 
assigned study monitor or study clinician should be consulted for assistance if needed, in 
determining whether or not specific medications are permitted.  Sites must consult product 
labeling and conduct a taper according to the product instructions if a taper is required. 
As specified in Section 5.8.2, occasional use of medication to relieve pain is permitted in 
certain situations.  Use of NSAIDs and COX-2 selective inhibitors (outside of oral 
investigational product), both prescription or over-the-counter (OTC) is prohibited through 
the Week 64 visit. 
Using IRT, subjects will record the number of days of concomitant NSAID use weekly from 
Baseline (Day 1) through the Week 80 visit.  Additional information regarding NSAID use 
such as medication names and dosage will be collected by the site on a CRF.  Subjects who 
report concomitant use of prescription or OTC NSAIDs during the study will be managed as 
per the following guidelines: 
•
Subjects who report concomitant use of NSAID should be interviewed by study site 
personnel to determine 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 osteoarthritis pain relief or who 
indicate that they cannot or will not be able to comply with concomitant medication 
restrictions will be withdrawn from investigational product 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, for conditions other than OA) in a SC dosing interval 
(defined as the period of 8 weeks between 2 SC doses) and who after counseling 
report further concomitant NSAID use should be withdrawn from investigational 
product and entered in the Early Termination Follow-Up period (refer to Section 6.4). 
Subjects will be instructed that many over-the-counter medications contain NSAIDs and to 
be aware of this during their selection of OTC 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 
the IPAP will be allowed to continue their regimen.  Subjects should be advised that 
St. John’s Wort and other inducers of the cytochrome (CYP3A4/5) enzyme system 
(eg, carbamazepine and rifampin) may interfere with the efficacy of hormonal contraceptive 
products. 
Biologics (for example: TNF-α inhibitors such as adalimumab, etanercept, infliximab) other 
than investigational product, and live attenuated vaccines must not have been taken within 
3 months prior to the IPAP and are prohibited during the study.  Flumist® Influenza Virus 
Vaccine Live, Intranasal or other inhaled influenza vaccines (in regions where these vaccines 
are approved) are the only exception of a live attenuated vaccine that will be permitted 
during the study. 
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5.8.2. Permitted Medications
Daily low dose aspirin (≤325 mg or per local prescribing practice) therapy for cardiovascular 
prophylaxis is permitted without restriction.
Medications for other (non-osteoarthritis, non-pain) conditions are permitted provided the 
subject has received a stable dose for at least 30 days before the IPAP (30 days prior to 
Screening for antihypertensive medications) and the dose is not expected to change during 
the study.  Note however that dose adjustments (includes starting a new therapy) during the 
study can be made if required, and recorded on the concomitant medication CRF.
Occasional use of pain medications for pain is permitted in situations such as outpatient 
diagnostic procedures (eg, colonoscopy, dental procedures) or limited accidental injury 
(eg, ankle sprains, minor fractures, minor burns/sunburns).  Subjects should be counseled to 
avoid scheduling prospective procedures such that pain medications would be needed within 
48 hours of a study visit.  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. 
For subjects who have discontinued investigational product, the investigator may prescribe 
standard of care treatment for subjects to take while completing the 24-week Safety 
Follow-up period once the last efficacy assessments have been obtained at the visit occurring 
16 weeks after the last dose of SC investigational product.  In this study, standard of care 
treatment refers to analgesics approved by FDA (for US subjects) or another applicable 
Health Authority (for non-US subjects) to relieve the pain of osteoarthritis.  These 
medications include opioids, topical analgesics, NSAIDs, capsaicin products, injectable 
corticosteroids and viscosupplementation (eg, hyaluronan) and are prescribed at the 
discretion of the Investigator.  Pre-specified analgesics are not considered investigational 
product but will be reimbursed by Pfizer, if allowed per local regulation while the subject is 
participating in the 24-week Safety Follow-up period after at least 16 weeks have elapsed 
since their last dose of SC treatment was administered.  Their use will be recorded on the 
concomitant medication CRF. 
5.9. Rescue Therapy
Acetaminophen/paracetamol will be issued to the subject by the study sites in its approved 
marketed product dress, (carton, bottle, documents) for use as rescue medication. 
During the Washout period and the Initial Pain Assessment Period, subjects may take rescue 
medication (acetaminophen/paracetamol) as needed for osteoarthritis or other types of pain 
or illness up to a maximum daily dose of 3000 mg/day.  Rescue medication must be 
discontinued at least 24 hours prior to the Baseline (Day 1) visit. 
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In the event of inadequate pain relief for osteoarthritis during the Double-blind Treatment 
period (between the Baseline [Day 1] visit and Week 16), subjects may take up to a 
maximum permitted daily dose of 3000 mg but only up to 3 days per week. 
From the Baseline (Day 1) visit through Week 16 visit, subjects taking rescue medication 
greater than 3 days per week (any level of acetaminophen/paracetamol used specifically for 
osteoarthritis pain) must be interviewed by study site personnel to determine if this is due to 
lack of efficacy or other reasons, and the discussion should be noted in the subject’s source 
documents.  Subjects who have taken rescue medication more frequently than specified in the 
protocol during the treatment period due to lack of efficacy and indicate that they cannot or 
will not follow the rescue medication protocol requirements because of insufficient 
osteoarthritis pain relief should be withdrawn from investigational product due to lack of 
efficacy and entered in the Early Termination Follow-up period (refer to Section 6.4).  
Subjects who indicate that they anticipate being able to take rescue medication no more than 
3 days per week going forward will be allowed to continue in the treatment period.  
However, if these subjects continue to take rescue medication more than 3 days per week, 
they should be withdrawn from investigational product and entered into the Early 
Termination Follow-up period (refer to Section 6.4). 
Between the Week 16 and Week 64 visits, subjects may take acetaminophen / paracetamol
rescue medication daily, up to the maximum permitted dose of 3000 mg per day.  After the 
Week 64 visit, subjects may be started on standard of care treatments for osteoarthritis pain.  
Subjects may continue to use acetaminophen as needed up to the maximal permitted dose of 
acetaminophen per day as permitted by local or national labeling.
During the Early Termination Follow-up period (described in Section 6.4); up to 16 weeks 
after the last dose of SC investigational product, subjects may take 
acetaminophen/paracetamol rescue medication up to the maximum permitted dose of 
3000 mg/day.  After Early Termination Visit 2 (approximately 16 weeks after the last dose of 
SC investigational product) subjects may be started on standard of care treatments for 
osteoarthritis pain. Subjects may continue to use acetaminophen/paracetamol as needed up 
to the maximal permitted dose of acetaminophen/paracetamol per day per local or national 
labeling.
All rescue medication must be discontinued at least 24 hours prior to any scheduled study 
visit at which efficacy data is collected (ie, up to the Week 64 visit that occurs 16 weeks after 
the last dose of SC investigational product).
Subjects should bring back rescue medication bottles at each study visit for assessment of 
compliance.
Subjects will be instructed that many over-the-counter medications contain 
acetaminophen/paracetamol, and to guard against overuse.  Subjects will be instructed to 
record their acetaminophen / paracetamol rescue medication usage daily via IRT through 
Week 16.  After Week 16 and through the Week 80 visit, usage of 
acetaminophen/paracetamol rescue medication will be recorded once weekly via the IRT.  
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The dose and reason for acetaminophen/paracetamol use in instances other than as rescue 
medication (eg, toothache, headache, fever) must be recorded on the appropriate concomitant 
medication CRF.
6. STUDY PROCEDURES 
If possible, each subject’s clinic visit should be conducted at approximately the same time of 
day throughout their participation in the study.  As a general rule, scales/instruments should 
be completed by the subject first, upon arrival at the clinic; vital signs should be assessed 
prior to blood draws.
Study visit windows are ±3 days for Weeks 2 and 4, and ±7 days for Weeks 8, 16, 24, 32, 40, 
48, 56, 64 and 80.  The study visit windows for the telephone visits at Weeks 12, 20, 28, 36, 
44, 52, 60, 68, 72, 76 and during the Early Termination Follow-up are ±7 days.  Study visits 
should be scheduled with reference to the original baseline visit date as much as possible.  
Subject scheduling issues should be brought to the attention of the assigned study monitor or 
study clinican for resolution.  Dosing visits should occur no earlier than 7 weeks from the 
previous injection.  The Week 24 X-rays may be obtained up to 30 days before the Week 24 
visit, but must be completed and read by the Central Reader before the Week 24 dose of 
SC investigational product is administered.  The visit window for the Week 56 X-rays is 
±30 days from the nominal time point of the visit.  The window for the Week 80 X-rays is 
±30 days of the nominal time of the visit but should be obtained as close as possible to the 
Week 80 visit, and preferably no more than 14 days after the Week 80 visit.
Subjects will be reminded to abstain from taking rescue medication 24 hours prior any study 
visit at which efficacy data is collected.
6.1. Screening Period
The Screening period will consist of a maximum of 37 days prior to Randomization and will 
last a minimum of 2 or 3 weeks (14 or 21 days).  The 2 or 3-week minimum Screening period 
is needed to complete the pre-randomization, NSAID regimen stabilization.  The length of 
the NSAID regimen stabilization period will depend on the NSAID subjects are receiving in 
the 30 days prior to screening.  The NSAID regimen stabilization period will be a minimum 
of 2 weeks if the pre-study NSAID is celecoxib, naproxen or diclofenac or a minimum of 
3 weeks if the pre-study NSAID is aceclofenac, loxoprofen, ibuprofen, meloxicam, 
nabumetone, sulindac, or ketoprofen. Prior to entering the Initial Pain Assessment Period 
(IPAP), subjects taking prohibited medications must complete the required washout from 
these medications for at least 5 half-lives or 48 hours (whichever is greater).  Screening 
procedures should be staged to minimize burden to the subject and to minimize conduct of 
procedures that may not be required if a subject is found to be ineligible.  To assist in this 
staging, screening procedures have been sorted into Screening Stage 1 and Screening 
Stage 2. 
Written informed consent will be obtained from each subject prior to any trial assessments.  
Each subject will be assessed as to his/her suitability per inclusion/exclusion criteria review. 
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Subject demographics and the date of OA diagnosis for every affected joint will be obtained.  
A comprehensive medical history and concomitant medication review will be performed for 
each subject; in addition, a comprehensive evaluation of musculoskeletal history and 
musculoskeletal physical exam will be performed (refer to Section 7.3.2).  The index joint 
(hip or knee) will be selected at the Screening Stage 1 visit.  If bilateral knee and/or hip pain 
is present, the investigator will select the more painful joint as the study (index) joint.  X-ray 
confirmation of eligibility (Kellgren-Lawrence grade ≥2 for selected index joint and absence 
of exclusionary conditions) will be obtained from the imaging Central Reader based on the 
radiographs of each knee, hip and shoulder (and any other major joints imaged at Screening) 
prior to the Screening Stage 2 visit.  Anticipate that it may take up to 2 weeks to obtain X-ray 
confirmation from the Central Reader. 
Evidence of subjects receiving a stable dose regimen of oral NSAID therapy at doses and for 
the duration/frequency specified in protocol inclusion criterion along with a history of 
insufficient pain relief from, inability to tolerate or contraindication to taking 
acetaminophen/paracetamol and tramadol or opioid treatments will be clearly documented on 
the appropriate CRF page.  The required level of evidence to establish that subjects meet this 
inclusion criterion will be based upon the investigator’s judgment.  Investigators should rely 
upon available medical records that he or she may already have access to, prescription 
medication records (eg, retail pharmacy records), records or information provided by 
referring physicians and/or subject historical recall if the investigator is satisfied with the 
level of detail subjects are able to provide on past medication use.  Investigators should 
clearly document in source records the information used to establish whether a subject does 
or does not meet this inclusion criterion.  As a guide, investigators should document 
medication names, medication doses, reasons for use, dates of use and reason for 
discontinuation.  If one or more of the above medications could not be used due to 
contraindication or if the subject refuses to take the medication due to fear of known side 
effects, this should also be clearly documented with supporting detail.  NOTE: In Japan, 
Investigators will also need to document the outcome of a trial of acetaminophen.  
6.1.1. Screening Period Stage 1 (Initial Screening Visit)
•
Informed consent.
•
Demographics and general medical history.
•
Assessment of depression by medical history (Use of PHQ-9 is optional and 
suggested as a tool to assess seriousness of depression if needed.  If the PHQ-9 is 
utilized, the completed questionnaire should be archived in the subject’s source 
documents.).
•
Numeric Pain Scale rating (IRT) for major joints (bilateral shoulders, hips and knees) 
and any painful joint imaged at Screening.
•
Primary diagnosis and selection of index hip or knee.
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NOTE: If the subject experiences pain in more than one joint, then the most painful 
joint should be selected as the index joint.  Radiographic eligibility of the selected 
index joint will need to be confirmed by the Central Reader. In the event the index 
joint selected at screening does not have a qualifying Kellgren-Lawrence Grade, the 
sponsor study team may be contacted to discuss the potential for reselection of the 
index joint and to rescreen the subject providing the subject is not disqualified from 
study participation for any other reason.
•
WOMAC (all subscales via IRT) for index hip or knee. 
NOTE: Subjects should be thoroughly instructed on completion of WOMAC scales, 
no coaching or other interpretative assistance should be given to subjects during 
completion of these questionnaires.
•
Comprehensive musculoskeletal/joint related medical history (includes past history of 
osteoarthritis, osteoporosis, osteopenia, joint pain, injury, trauma, joint surgeries 
(including arthroscopic procedures), ligament tear or rupture, fractures, gout, joint 
injuries or other conditions. 
•
Medication history (record prior 12 month use of medications for osteoarthritis, prior 
30 day use for all other medications). 
•
Weight and Height with BMI calculation, Smoking Status, Alcohol Use/Dependency, 
Female Hormonal Status (if known or pending laboratory results).
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement. 
•
General physical examination.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score.
•
Survey of Autonomic Symptoms (SAS).
•
ECG (12-lead).
•
X-rays of each knee, hip and shoulder (and any other painful, major joint if 
appropriate) and collect local radiology report.
•
Clinical laboratory tests (blood chemistry, hematology, and urinalysis, serum 
Hepatitis B, C, and HIV screen, urine toxicology screen, HbA1c), serum pregnancy 
testing/FSH testing if needed.
NOTE: Clinically significant abnormal laboratory tests (except urine toxicology 
screen) or tests not meeting inclusion/exclusion criteria may be repeated for 
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verification prior to Baseline.  Refer to Section 7.3.3 for specific instructions related 
to laboratory screening tests.
•
Inclusion/exclusion review (pending results of laboratory tests, ECG and X-rays).  If 
a subject qualifies other than pending results they may begin the washout of 
prohibited pain medications (refer to Section 5.8.1).  Subjects who are found to be 
ineligible subsequent to the receipt of disqualifying laboratory, ECG or X-ray results 
may be asked to return requested study related materials and will exit the Screening 
period (Screen Failure).
•
Female subjects of child-bearing potential will be instructed on the contraception 
requirements for this study; the investigator or designee will confirm that female 
subjects of child-bearing potential have selected 2 highly effective forms of 
contraception from the list of acceptable methods and instruct the subject in their 
consistent and correct use.  The conversation will be documented in the subject chart. 
•
Dispense Screening period rescue medication; subjects will be instructed on the 
permissible amounts of rescue medication during the washout period, during the 
IPAP and during the treatment period, as well as the need to refrain from rescue 
medication use at least 24 hours prior to a study visit (refer to Section 5.8.2).
•
Subjects in Japan who have not had a trial of acetaminophen (as monotherapy or in 
combination with tramadol) for their osteoarthritis, will undergo at least 1-week trial 
of an approved daily dose of acetaminophen after obtaining informed consent because 
subjects are required to have documentation that acetaminophen has not provided 
sufficient pain relief. The 1-week trial of acetaminophen should be completed at least 
two weeks prior to the Baseline/Day 1 visit.  If they obtain sufficient response to 
acetaminophen, as judged by the subject and Investigator, they will then be 
withdrawn from the study.  Those who do not have a sufficient response to 
acetaminophen will continue with the screening process.  Subjects who have not 
achieved an adequate response to an approved dose of Tramacet® (1-2 tablets four 
times a day (QID): total daily tramadol 150 mg – 300 mg and acetaminophen 1300 
mg – 2600 mg) can be considered to meet the acetaminophen and tramadol inclusion 
criterion.  
•
Dispense Screening period oral NSAID.
NOTE: Begining at Screening, subjects should use study-supplied oral 
investigational product (NSAID during Screening and NSAID or matching placebo 
post-randomization) through Week 56. 
Subjects who were receiving celecoxib, diclofenac or naproxen prior to Screening 
will receive this same oral NSAID but may need to change dosing regimen to a BID 
dosing regimen for the duration of the study.  Subjects must maintain the BID dosing 
regimen of celecoxib 100 mg, naproxen 500 mg, or diclofenac ER 75 mg for at least 
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the final 2 weeks of the Screening period directly prior to the Baseline 
(Randomization/Day 1) Visit.
Subjects who were receiving aceclofenac, loxoprofen, ibuprofen, meloxicam, 
nabumetone, sulindac or ketoprofen prior to Screening will be assigned to celecoxib, 
naproxen or diclofenac.  The specific NSAID that subjects will be assigned to 
(celecoxib, naproxen or diclofenac) will be the choice of the investigator.  Subjects 
will use this NSAID for the remainder of the Screening period and will be stabilized 
on a dosing regimen of celecoxib 100 mg BID, naproxen 500 mg BID, or diclofenac 
ER 75 mg BID for at least the final 3 weeks of the Screening period directly prior to 
the Baseline (Randomization/Day 1) visit.
During NSAID regimen stabilization, all subjects will be expected to maintain a 
minimum compliance of 70% (average of 5 of 7 days per week).
6.1.2. Screening Period Stage 2
Subjects who satisfy inclusion/exclusion criteria (to this point) and for whom radiographic 
eligibility has been confirmed, will undergo the following additional screening procedures:
•
MRIs of each hip and knee (all subjects). 
•
DXA scans of the hip and lumbar spine.
NOTE: DXA scans will only be performed for subjects meeting National 
Osteoporosis Foundation recommendations for bone mineral density testing (refer to 
Section 7.3.12).
•
Subjects at selected sites will be provided with activity level monitors 
(accelerometers) and instructions on completion of 7 consecutive days of activity 
monitoring (refer to Section 7.3.9).
•
Subjects will be instructed in the use of the IRT system to record daily/weekly pain 
ratings, rescue medication use, with specific instructions as when to test the system 
and when to begin entering data.
•
Subjects will maintain the BID dosing regimen of celecoxib 100 mg, naproxen 
500 mg, or diclofenac ER 75 mg for at least the final 2 or 3 weeks (average of 5 of 
7 days per week; ie, minimum 70% compliance) of the Screening period directly prior 
to the Baseline (Day 1) visit. 
6.1.3. Washout Period
The beginning of the Washout Period will preferably be scheduled based on the planned start 
of the Initial Pain Assessment Period so as to minimize the time spent without analgesic 
medications prior to Randomization.  The Washout Period will include the discontinuation 
and washout of all prohibited medications for at least 5 half-lives or 48 hours (whichever is 
greater) prior to the Initial Pain Assessment Period (the 7 days prior to randomization) and 
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will be a minimum of 2 days (Refer to Appendix 3).  Subjects experiencing pain during the 
Washout Period may take acetaminophen as needed up to 3000 mg per day, but must 
discontinue rescue medication for at least 24 hours prior to the Baseline (Randomization) 
Visit.
If necessary, the Screening/Washout Period may be adjusted due to individual subject 
circumstances (eg, stabilization of a concomitant medication), contact study management for 
guidance.  However, the total duration of the Screening period is not to exceed 37 days.
6.1.4. Initial Pain Assessment Period (IPAP)
The IPAP will begin approximately 7 days (minimum of 3 days) prior to the Baseline 
(Day 1) randomization visit, and subjects must complete at least 3 diary entries during the 
IPAP period, but all diary entries will be used to determine the baseline value for the average 
pain score in the index joint. 
•
During this time, subjects will record daily pain scores for their index joint (knee or 
hip) and rescue medication use via the IRT (refer to Sections 7.1.1 and 7.1.2).  
Assessment of the non-index joint pain will be performed once during the IPAP.
NOTE: Study sites will monitor the IRT reports for compliance with diary recordings 
and rescue medication use and reschedule those subjects who fail to provide 3 diary 
days or fail to refrain from rescue medication use 24 hours prior to Baseline.
6.2. Double-Blind Treatment Period
The Double-blind Treatment period begins with the Baseline (Day 1) visit and concludes 
with completion of the Week 56 visit procedures.  The Double-blind Treatment period is 
56 weeks in duration and consists of 10 clinic visits (Day 1 and Weeks 2, 4, 8, 16, 24, 32, 40, 
48 and 56) and 6 telephone contacts (Weeks 12, 20, 28, 36, 44, 52) between site staff and 
study subjects. 
6.2.1. Baseline (Day 1) Clinic Visit
6.2.1.1. Assessment of Randomization Criteria and Randomization
Subjects must continue to satisfy Inclusion/Exclusion Criteria [general criteria and those 
specific to the Baseline (Day 1) visit – refer to Section 4.3] to be eligible for Randomization.  
Full eligibility, including (but not limited to) confirmation of appropriate washout of 
concomitant medication, compliance with NSAID treatment regimen stabilization, abstinence 
from acetaminophen in the previous 24 hours, completion of at least 3 diary entries in the 
past 7 days, required WOMAC Pain and Physical Function subscale and Patient’s Global 
Assessment of Osteoarthritis scores, required MRI and DXA scans (if appropriate) have been 
obtained and that no adverse events occurred since signing informed consent that would 
render the subject ineligible for randomization, should be assessed before carrying out 
randomization in the IRT system.
Subjects will undergo the following assessments prior to randomization:
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•
Sites performing activity level monitoring (actigraphy) will collect activity level
monitors from subjects.
•
Inclusion/exclusion review (including results of ECG, laboratory and X-rays obtained 
at the Screening visits).
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis. 
NOTE: Subjects should be thoroughly instructed on completion of Patient’s Global 
Assessment of Osteoarthritis questionnaires, no coaching or other interpretative 
assistance should be given to subjects during completion of these questionnaires.
•
Musculoskeletal physical examination.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Review of concomitant medication.
•
Rescue medication (acetaminophen/paracetamol) review.
•
Baseline NSAID compliance review.
•
Instruction/review of subject compliance with daily/weekly assessments and 
operation of the IRT.
•
Confirm with females of child-bearing potential that they understand and are willing 
to follow the contraceptive requirements.
•
Adverse events that occurred after signing the Informed Consent Document 
(pretreatment adverse events).
•
Urine pregnancy test for females of childbearing potential (must be negative).
6.2.1.2. Randomization
Subjects satisfying eligibility requirements will be randomized via an IRT system.  The 
randomization number assigned to the subject will be provided by the system.  Subjects 
satisfying eligibility requirements will undergo the following assessments prior to the first 
dose of investigational product. 
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6.2.1.3. Pre-dosing (Day 1)
Randomized subjects will undergo the following assessments prior to the first dose of 
investigational product.  Some of these may be performed prior to randomization for 
convenience:
•
WPAI:OA.
•
EQ-5D-5L.
•
Assessment of Health Care Resource Utilization.
•
Lower Extremity Activity Scale (LEAS).
•
Neurologic exam/Neuropathy Impairment Score.
•
Clinical laboratory tests (blood chemistry and hematology).
•
Serum samples for 25-hydroxy vitamin D and parathyroid hormone.
•
Serum and plasma retention samples.
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
Blood samples for PK and PD (NGF) analyses (refer to Section 7.5).
•
Blood and urine samples for biomarkers (fasting if possible, urine sample should be 
from 2nd void of the day or after; refer to Section 7.6).
•
Blood sample for banked biospecimens (see Section 7.7.1 Markers of Drug Response 
and Additional Research, Section 7.7.2).
•
Dispense rescue medication.
•
Dispense oral investigational product (NSAID or matching placebo).
•
Females of child-bearing potential to be reminded of contraceptive requirements.
6.2.1.4. Dosing (Day 1)
•
Subjects will receive a single SC injection of blinded investigational product
according to the treatment assigned by the IRT system (refer to Section 5).
The administration of investigational product must be performed by trained medical staff and 
where facilities to handle allergic reactions are available (eg, diphenhydramine hydrochloride 
for injection, epinephrine 1:1000 for management of acute or severe reactions such as 
anaphylaxis).  Should a subject experience symptoms typical of an allergic reaction
(eg, shortness of breath, anaphylaxis, urticaria, angioedema), then investigational product
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administration should be discontinued immediately and permanently.  Subjects will receive 
appropriate treatment such as corticosteroids, antihistamine, or acetaminophen at the 
discretion of the Investigator.  No other dosage modifications are allowed.
•
A morning dose of oral investigational product (NSAID or matching placebo) will not
be administered on Study Day 1.  The evening dose of oral investigational product on 
Study Day 1 and all subsequent dosing of oral investigational product will be 
performed by subjects at home.
6.2.1.5. Post-dosing (Day 1)
Subjects will be observed in the clinic for at least 1 hour after dosing.  The following 
procedures will be completed at approximately 1-hour post-dose:
•
Review and record adverse events.
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.2. Week 2 Clinic Visit
The following procedures will be performed:
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
Vital signs after sitting for at least 5 minutes, (blood pressure and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required, refer to Section 7.3.13).
•
Concomitant medication review/update.
•
Adverse event review.
•
Subject daily/weekly IRT entry compliance and data review (daily index joint pain 
score, weekly non-index joint pain assessment and as applicable, daily rescue 
medication and weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
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•
Review daily and weekly (as applicable) joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid, plasma 
and serum samples for analysis (refer to Sections 7.5.1, 7.5.2, and 7.5.3).
6.2.3. Week 4 Clinic Visit
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
Vital signs after sitting for at least 5 minutes, (blood pressure and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Lower Extremity Activity Scale (LEAS).
•
Concomitant medication review/update. 
•
Adverse event review.
•
Subject daily/weekly IRT entry compliance (daily index joint pain score, weekly 
non-index joint pain assessment and as applicable, daily rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review daily and weekly (as applicable) joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance review.
•
Females of child-bearing potential to be reminded of contraceptive requirements;
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•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid, plasma 
and serum samples (refer to Sections 7.5.1, 7.5.2 and 7.5.3).
6.2.4. Week 8 Clinic Visit
6.2.4.1. Pre-dosing
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
EQ-5D-5L.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Lower Extremity Activity Scale (LEAS).
•
Concomitant medication review/update. 
•
Adverse event review.
•
Subject daily/weekly IRT entry compliance (daily index joint pain score, weekly 
non-index joint pain assessment and as applicable, daily rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review daily and weekly (as applicable) joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance 
review/dispense.
•
Blood samples for PK and PD (NGF) analyses (refer to Section 7.5).
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
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•
Blood and urine samples for biomarkers (fasting if possible, urine sample should be 
from 2nd void of the day or after; refer to Section 7.6).
•
Urine pregnancy test for females of childbearing potential (must be negative prior to 
dosing).
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect a synovial fluid sample 
(refer to Section 7.5.3).
6.2.4.2. Subcutaneous Dosing 
Subjects will receive a single injection of blinded, SC investigational product according to 
the treatment assigned by the IRT system (refer to Section 5). 
6.2.4.3. Post-dosing
Subjects will be observed in clinic for at least 1 hour after dosing.  The following procedures 
will be completed at approximately 1-hour post-dose: 
•
Review and record adverse events.
•
Sites that are performing actigraphy will provide subjects who completed Baseline 
activity monitoring (actigraphy) with instructions and an actigraphy device to be used 
over the course of 14 consecutive days between Week 14 and the Week 16 Visit 
(refer to Section 7.3.9).
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.5. Week 12 Telephone Contact
•
Review/update of concomitant medication and subject daily/weekly IRT entries 
compliance (daily index joint pain score, weekly non-index joint pain assessment and 
as applicable, daily rescue medication and weekly NSAID use entries).
•
Compliance with oral investigational product (NSAID or matching placebo).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review daily and weekly (as applicable) joint pain scores.
•
Rescue medication (acetaminophen / paracetamol) compliance review.
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•
Adverse events review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
Sites that are performing actigraphy should remind their subjects to conduct 
14 consecutive days of actigraphy between Week 14 and the Week 16 visit. 
6.2.6. Week 16 Clinic Visit (Primary Efficacy Time Point)
6.2.6.1. Pre-dosing
•
Review subject eligibility.
NOTE: At the Week 16 visit, subjects must have a 30% or greater reduction in 
WOMAC Pain subscale relative to Baseline in the index joint and a 15% or greater 
reduction in WOMAC Pain subscale from Baseline at either Week 2, 4 or 8 in order 
to continue investigational product.  As a risk mitigation measure, subjects who do 
not meet this efficacy response criteria will be discontinued from the Double-blind 
Treatment period and enter the 24-week Early Termination Follow-up period (refer to 
Section 6.4).  The efficacy response calculation will be performed by the IRT system. 
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
WPAI:OA.
•
EQ-5D-5L.
•
TSQM (v.II).
•
mPRTI.
•
Lower Extremity Activity Scale (LEAS).
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Serum and plasma retention samples.
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•
Clinical laboratory tests (blood chemistry and hematology).
•
Blood sample for PK analysis (refer to Section 7.5).
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
Blood and urine samples for biomarkers (fasting if possible, urine sample should be 
from 2nd void of the day or after; refer to Section 7.6).
•
Urine pregnancy test for females of childbearing potential (must be negative prior to 
dosing).
•
Sites performing activity level monitoring (actigraphy) will collect activity level 
monitors from subjects.
•
Concomitant medication review/update. 
•
Subject daily/weekly IRT entry compliance (daily index joint pain score, weekly 
non-index joint pain assessment and as applicable, daily rescue medication and 
weekly NSAID use entries).
•
Instruct subjects that after the Week 16 visit the index joint pain score, non-index 
joint pain assessment, rescue medication and NSAID use will all be assessed once 
weekly using IRT (See Section 7.1).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review daily and weekly (as applicable) joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance 
review/dispense.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid and 
serum samples (refer to Sections 7.5.2, 7.5.3).
6.2.6.2. Subcutaneous Dosing
Eligible subjects will receive a single injection of blinded SC investigational product
according to the treatment assigned by the IRT system (refer to Section 5). 
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6.2.6.3. Post-dosing
Subjects will be observed in clinic for at least 1 hour after dosing.  The following procedures 
will be completed at approximately 1-hour post-dose:
•
Review and record adverse events.
•
Schedule subjects for follow-up radiographic assessments (X-rays) of each shoulder, 
hip and knee and any other major joint for which a radiograph was obtained at the 
Screening visit or any at risk joint identified during the study period (refer to 
Section 7.3.10). 
•
Subjects meeting criteria (subjects who had Kellgren-Lawrence grade 3 or 4 
osteoarthritis of any knee or hip at Screening/Baseline, refer to Section 7.3.11) should 
be scheduled for follow-up MRIs of each hip and knee. 
NOTE: Follow-up radiographs and MRIs (if applicable) should be scheduled to 
occur at least 2 weeks and no more than 4 weeks (30 days) prior to the Week 24 clinic 
visit. 
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.7. Week 20 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment 
and as applicable, weekly rescue medication and weekly NSAID use entries).
•
Compliance with oral investigational product (NSAID or matching placebo).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen / paracetamol) compliance review.
•
Adverse events review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
Verify that follow-up radiographs and MRIs (if applicable) required for Week 24 visit 
have been scheduled and will be completed (refer to Sections 7.3.10 and 7.3.11).
NOTE: Follow-up radiographs and MRIs (if applicable) should be completed at least 
2 weeks prior to the Week 24 clinic visit.  Local radiology reports should be obtained.
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6.2.8. Week 24 Clinic Visit
6.2.8.1. Pre-dosing
•
Review subject radiographic eligibility as determined by Central Reader and collect 
local radiology report.
NOTE: Subjects who do not continue to meet radiographic eligibility as determined 
by the Central Reader should be discontinued from the Double-blind Treatment 
period and entered into the 24-week Early Termination Follow-up period as described 
in Section 6.4.
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
WPAI:OA.
•
EQ-5D-5L.
•
Lower Extremity Activity Scale (LEAS).
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Survey of Autonomic Symptoms (SAS).
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Concomitant medication review/update. 
•
Subject weekly IRT entries compliance review (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
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•
Oral investigational product (NSAID or matching placebo) compliance 
review/dispense.
•
Urine pregnancy test for females of childbearing potential (must be negative prior to 
dosing).
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid, plasma 
and serum samples (refer to Sections 7.5.1, 7.5.2 and 7.5.3).
6.2.8.2. Subcutaneous Dosing
Eligible subjects will receive a single injection of blinded SC investigational product
according to the treatment assigned by the IRT system (refer to Section 5). 
6.2.8.3. Post-dosing
Subjects will be observed in clinic for at least 1 hour after dosing.  The following procedures 
will be completed at approximately 1-hour post-dose:  
•
Review and record adverse events.
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.9. Week 28 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment 
and as applicable, weekly rescue medication and weekly NSAID use entries).
•
Compliance with oral investigational product (NSAID or matching placebo).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review.
•
Adverse events review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
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6.2.10. Week 32 Clinic Visit
6.2.10.1. Pre-dosing
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Concomitant medication review/update. 
•
Subject weekly IRT entry compliance review (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance 
review/dispense.
•
Blood samples for PK analyses (refer to Section 7.5).
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
Urine pregnancy test for females of childbearing potential (must be negative prior to 
dosing).
•
Females of child-bearing potential to be reminded of contraceptive requirements.
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•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid and 
serum samples (refer to Sections 7.5.2, 7.5.3).
6.2.10.2. Subcutaneous Dosing
Eligible subjects will receive a single injection of blinded, SC investigational product
according to the treatment assigned by the IRT system (refer to Section 5). 
6.2.10.3. Post-dosing
Subjects will be observed in clinic for at least 1 hour after dosing.  The following procedures 
will be completed at approximately 1-hour post-dose:
•
Review and record adverse events.
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.11. Week 36 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment 
and as applicable, weekly rescue medication and weekly NSAID use entries).
•
Compliance with oral investigational product (NSAID or matching placebo).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review.
•
Adverse events review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
6.2.12. Week 40 Clinic Visit
6.2.12.1. Pre-dosing
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
EQ-5D-5L.
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•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Concomitant medication review/update. 
•
Patient weekly IRT entries compliance review (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance 
review/dispense.
•
Urine pregnancy test for females of childbearing potential (must be negative prior to 
dosing).
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid, plasma 
and serum samples (refer to Sections 7.5.1, 7.5.2 and 7.5.3).
6.2.12.2. Subcutaneous Dosing
Eligible subjects will receive a single injection of blinded, SC investigational product
according to the treatment assigned by the IRT system (refer to Section 5). 
6.2.12.3. Post-dosing
Subjects will be observed in clinic for at least 1 hour after dosing. The following procedures 
will be completed at approximately 1-hour post-dose:
•
Review and record adverse events.
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Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic.
6.2.13. Week 44 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment 
and as applicable, weekly rescue medication and weekly NSAID use entries).
•
Compliance with oral investigational product (NSAID or matching placebo).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review.
•
Adverse events review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
6.2.14. Week 48 Clinic Visit
6.2.14.1. Pre-dosing
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Concomitant medication review/update. 
•
Subject weekly IRT entries compliance review (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
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•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance 
review/dispense.
•
Blood samples for PK and PD (NGF) analyses (refer to Section 7.5).
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
Urine pregnancy test for females of childbearing potential (must be negative prior to 
dosing).
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect a synovial fluid sample 
(refer to Section 7.5.3).
6.2.14.2. Subcutaneous Dosing
Eligible subjects will receive a single injection of blinded, SC investigational product
according to the treatment assigned by the IRT system (refer to Section 5). 
6.2.14.3. Post-dosing
Subjects will be observed in clinic for at least 1 hour after dosing.  The following procedures 
will be completed at approximately 1-hour post-dose: 
•
Review and record adverse events.
•
Sites that are performing actigraphy will provide subjects who completed Baseline 
activity monitoring (actigraphy) with instructions and an actigraphy device to be used 
over the course of 14 consecutive days between Week 54 and the Week 56 Visit 
(refer to Section 7.3.9).
Each subject should be reminded to seek medical care and/or contact the Investigator if the 
subject experiences symptoms of an acute or severe hypersensitivity reaction (eg, shortness 
of breath, anaphylaxis, urticaria, angioedema) after leaving the clinic. 
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6.2.15. Week 52 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment 
and as applicable, weekly rescue medication and weekly NSAID use entries).
•
Compliance with oral investigational product (NSAID or matching placebo).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review.
•
Adverse events review.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
Schedule subject for follow-up radiographic assessments (X-rays) of each shoulder, 
hip and knee and any other major joint for which a radiograph was obtained at the 
Screening visit or any at risk joint identified during the study period (refer to 
Section 7.3.10). 
•
Sites that are performing actigraphy should remind their subjects to conduct 
14 consecutive days of actigraphy between Week 54 and the Week 56 visit. 
•
Subjects meeting criteria (subjects who had Kellgren-Lawrence Grade 3 or 4 
osteoarthritis of any knee or hip at Screening/Baseline, refer to Section 7.3.11) should 
be scheduled for magnetic resonance imaging of the each hip and knee. 
NOTE: Follow-up radiographs and MRIs should be completed within 30 days 
(ie, between Weeks 52 and 60) of the Week 56 visit.  Local radiology reports should 
be obtained.
6.2.16. Week 56 Clinic Visit (End of Double-Blind Treatment)
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
WPAI:OA.
•
EQ-5D-5L.
•
TSQM (v.II).
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•
mPRTI.
•
Lower Extremity Activity Scale (LEAS).
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Serum and plasma retention samples.
•
ECG (12-lead).
•
Body weight.
•
Musculoskeletal physical examination.
•
Survey of Autonomic Symptoms (SAS).
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Sites performing activity level monitoring (actigraphy) will collect activity level 
monitors from subjects.
•
General physical examination.
•
Concomitant medication review/update. 
•
Subject weekly IRT entries compliance review (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
•
Oral investigational product (NSAID or matching placebo) compliance review.
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
Blood samples for PK and PD (NGF) analyses (refer to Section 7.5).
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•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
Serum pregnancy test for females of childbearing potential.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
•
If not already completed, schedule subject for follow-up radiographic assessments 
(X-rays) of each shoulder, hip and knee and any other major joint for which a 
radiograph was obtained at the Screening visit or any at risk joint identified during the 
study period (refer to Section 7.3.10).
•
If not already completed, subjects meeting criteria (subjects who had 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis of any knee or hip at 
Screening/Baseline, refer to Section 7.3.11) should be scheduled for magnetic 
resonance imaging of each hip and knee.
NOTE: Follow-up radiographs and MRIs should be completed within 30 days of the 
Week 56 visit (ie, no later than the Week 60 telephone contact).  Local radiology 
reports should be obtained.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect a synovial fluid sample 
(refer to Section 7.5.3).
6.3. Safety Follow-up Period
The Safety Follow-up period begins once the Week 56 procedures have been completed and 
concludes with completion of the Week 80 visit procedures.  The Safety Follow-up period is 
24 weeks in duration and consists of 2 clinic visits (Weeks 64 and 80) and 4 telephone 
contacts (Weeks 60, 68, 72 and 76) between site staff and enrolled subjects. 
6.3.1. Week 60 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment 
and as applicable, weekly rescue medication and weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID (outside of oral investigational 
product) use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen / paracetamol) compliance review.
•
Adverse events review.
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•
Confirm that follow-up radiographs and MRIs if required (refer to Section 7.3.10,
7.3.11) have been completed, local radiology reports should be obtained.
•
Females of child-bearing potential to be reminded of contraceptive requirements.
6.3.2. Week 64 Clinic Visit
•
Adverse event review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
WPAI:OA.
•
EQ-5D-5L.
•
Health Care Resource Utilization.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Clinical laboratory tests (blood chemistry, hematology, serum 25-hydroxy vitamin D 
and parathyroid hormone).
•
Serum and plasma retention samples.
•
Serum pregnancy test for females of childbearing potential.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Concomitant medication review/update. 
•
Subject weekly IRT entries compliance review (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen/paracetamol) compliance review/dispense. 
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•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
Blood samples for PK and PD (NGF) analyses (refer to Section 7.5).
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
Initiate standard of care treatment for osteoarthritis pain at the discretion of the 
investigator.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect a synovial fluid sample 
(refer to Section 7.5.3).
6.3.3. Week 68 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment as 
applicable, weekly rescue medication and weekly NSAID use entries).
•
Adverse Events review.
6.3.4. Week 72 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment as 
applicable, weekly rescue medication and weekly NSAID use entries).
•
Adverse Events review.
6.3.5. Week 76 Telephone Contact
•
Review/update of concomitant medication and subject weekly IRT entries 
compliance (weekly index joint pain score, weekly non-index joint pain assessment as 
applicable, weekly rescue medication and weekly NSAID use entries).
•
Adverse Events review.
•
Schedule subject for follow-up radiographic assessments (X-rays) of each shoulder, 
hip and knee and any other major joint for which a radiograph was obtained at the 
Screening visit or any at risk joint identified during the study period (refer to 
Section 7.3.10).
•
Subjects meeting criteria (subjects who had Kellgren-Lawrence Grade 3 or 4 
osteoarthritis of any knee or hip at Screening/Baseline, refer to Section 7.3.11) should 
be scheduled for magnetic resonance imaging of each hip and knee.
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NOTE:  Follow-up radiographs and MRIs should be completed up to 30 days before 
and preferably, no more than 14 days after the Week 80 visit and local radiology 
reports should be obtained.
6.3.6. Week 80 Clinic Visit (End of Study)
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
ECG (12-lead).
•
Musculoskeletal physical examination.
•
Survey of Autonomic Symptoms (SAS).
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Lower Extremity Activity Scale (LEAS).
•
Health Care Resource Utilization.
•
Concomitant medication review/update. 
•
Review weekly index joint pain scores and weekly non-index joint pain assessment as 
applicable, weekly rescue medication and weekly NSAID use entries.
•
Adverse event review.
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 
Section 7.3.14).
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
If not already completed, schedule subject for follow-up radiographic assessments 
(X-rays) of each shoulder, hip and knee and any other major joint for which a 
radiograph was obtained at the Screening visit or any at risk joint identified during the 
study period (refer to Section 7.3.10).
•
If not already completed, subjects meeting criteria (subjects who had 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis of any knee or hip at 
Screening/Baseline, refer to Section 7.3.11) should be scheduled for magnetic 
resonance imaging of each hip and knee.
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NOTE:  Follow-up radiographs and MRI scans should be completed up to 30 days 
before and preferably, no more than 14 days after the Week 80 visit and local 
radiology reports should be obtained. 
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid, plasma 
and serum samples (refer to Sections 7.5.1, 7.5.2 and 7.5.3).
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.  A subject thought to be lost to follow-up, must be contacted through a minimum of 
3 documented phone call attempts and, if phone calls are unsuccessful, a certified letter sent 
to the subject.  In any circumstance, every effort should be made to document the subject’s 
outcome, if possible.  The Investigator should inquire about the reason for withdrawal, 
request the return of all unused investigational product, 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.  Females of child-bearing potential should be reminded to 
continue contraceptive measures at least 112 days (16 weeks) after the last dose of SC 
investigational product.
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.
Subjects discontinuing from treatment (prior to Week 56), whether at their request or at the 
decision of the investigator, will be required to undergo 24 weeks of post-treatment 
follow-up (as described in Section 6.4.1).  The 24 weeks of follow-up will be obtained 
through 3 clinic visits and monthly phone calls to yield 24 weeks of follow-up, as described 
in Section 6.4.1.  Subjects will be asked to continue to enter pain scores for index and 
non-index joints (as applicable) via IRT, weekly, through the end of the 24 week safety 
follow-up period.  On a weekly basis during the 24 week safety follow-up period, subjects 
will also be asked to continue to record rescue medication and NSAID use.
Radiographs of each knee, shoulder and hip (and any other major 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.  Subjects meeting criteria (subjects who had 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis of any knee or hip at Screening/Baseline, refer 
to Section 7.3.11) should also be scheduled for magnetic resonance imaging of each hip and 
knee.  The remainder of efficacy and safety assessments should be done at the scheduled first 
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visit which is to occur approximately 8 weeks after the last dose of SC investigational 
product (refer to Section 6.4.1.1). 
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 
investigational product (which corresponds to more than 5 times the elimination half-life of 
tanezumab) to collect safety and efficacy data (refer to Section 6.4.1.3).  Once the clinic visit 
16 weeks after the last administration of SC investigational product has been completed and 
final efficacy assessments have been collected, standard of care treatment may be offered to 
subjects for 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 investigational product (refer to Section 6.4.1.5).  That visit 
includes repeat X-rays of the hips, knees and shoulders as well as any additional joint that 
was imaged at Screening or any joint identified as at risk during the study, providing at least 
30 days have elapsed since the last radiographs were obtained.  Subjects meeting criteria 
(subjects who had Kellgren-Lawrence Grade 3 or 4 osteoarthritis of any knee or hip at 
Screening/Baseline, refer to Section 7.3.11) should also be scheduled for magnetic resonance 
imaging of each hip and knee.  Follow-up radiographs and MRIs should be completed up to 
30 days before and preferably, no more than 14 days after the Early Termination Follow-up 
Visit 3 (24 weeks after last dose of SC investigational product).  Telephone contact will be 
made with subjects at approximately 12 and 20 weeks following the last SC dose of 
investigational product.  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.
In the event a subject refuses the Early Termination safety follow-up, or chooses to 
discontinue during the safety follow-up (after Week 56 and through Week 80), a complete 
early termination visit should be performed.  This early termination visit should include all 
procedures scheduled for the Week 64 and Week 80 visits unless the Week 64 visit has 
already been completed, in which case only Week 80 procedures will be required.  In 
addition, if the Week 56 visit was not completed prior to termination, a general physical 
examination, body weight, WPAI:OA, EQ-5D-5L, TSQM v.II and mPRTI will also be 
obtained.  Subjects will be advised to continue their contraception regimen during a period of 
112 days (16 weeks) after the last dose of investigational product. 
Subjects entered in the Early Termination Follow-up period will be able to take 
acetaminophen/paracetamol rescue medication daily up to the Early Termination Follow-up 
period Visit 2 (which occurs 16 weeks after the last dose of SC investigational product), but 
will be advised not to exceed the maximal daily dose of 3000 mg.  Subjects will be requested 
not to take acetaminophen/paracetamol (or any other analgesic) in the 24 hours that precede 
clinic visits at which efficacy assessments are collected (Early Termination Follow-up period 
Visits 1 and 2, which occur 8 and 16 weeks after the last dose of SC investigational product, 
respectively).  After the second Early Termination Follow-up visit occurring 
approximately16 weeks after the last SC dose of investigational product, subjects may be 
started on standard of care treatments for osteoarthritis pain.  Subjects may continue to use 
acetaminophen/paracetamol as needed per local or national labeling.
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6.4.1. Early Termination Follow-up Period
As soon as possible following a decision to withdraw a subject from the study is made the 
following procedures should be completed:
•
Provided at least 30 days have passed since the last set of X-rays were collected, 
schedule subjects for follow-up radiographic assessments (X-rays) of each shoulder, 
hip and knee and any other major joint for which a radiograph was obtained at the 
Screening visit or any at risk joint identified during the study period (refer to 
Section 7.3.10), local radiology reports should be obtained.
•
Subjects meeting criteria (subjects who had Kellgren-Lawrence Grade 3 or 4 
osteoarthritis of any knee or hip at Screening/Baseline, refer to Section 7.3.11) should 
be scheduled for magnetic resonance imaging of each hip and knee. 
6.4.1.1. Early Termination Follow-up Visit 1 (8 weeks after last dose of SC 
investigational product treatment)
•
Adverse events review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
WPAI:OA.
•
EQ-5D-5L.
•
TSQM (v.II).
•
mPRTI.
•
Lower Extremity Activity Scale (LEAS).
•
Survey of Autonomic Symptoms (SAS).
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
ECG (12-lead).
•
Body weight.
•
General physical examination.
•
Musculoskeletal physical examination.
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•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Review/update of concomitant medication.
•
Assess compliance with weekly IRT entries (weekly index joint pain score, weekly 
non-index joint pain assessment and as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen / paracetamol) compliance review/dispense. 
•
Serum pregnancy test for females of childbearing potential.
•
Serum and plasma retention samples.
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
Blood samples for PK and PD (NGF) analyses (refer to Section 7.5).
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
Reminder to females of child-bearing potential to continue with contraceptive 
requirements.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect a synovial fluid sample 
(refer to Section 7.5.3).
6.4.1.2. Early Termination Follow-up Phone Contact (12 weeks after last dose of SC 
investigational product)
•
Adverse events review.
•
Review/update of concomitant medication.
•
Review subject compliance with weekly IRT entries (weekly index joint pain score, 
weekly non-index joint pain assessment and as applicable, weekly rescue medication 
and weekly NSAID use entries).
•
Rescue medication (acetaminophen / paracetamol) compliance review.
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•
Reminder to females of child-bearing potential to continue with contraceptive 
requirements.
6.4.1.3. Early Termination Follow-up Visit 2 (16 weeks after last dose of SC 
investigational product)
•
Adverse events review.
•
WOMAC (all subscales).
•
Patient’s Global Assessment of Osteoarthritis.
•
WPAI:OA.
•
EQ-5D-5L.
•
Lower Extremity Activity Scale (LEAS).
•
Health Care Resource Utilization.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Clinical laboratory tests (blood chemistry, hematology, serum 25-hydroxy vitamin D 
and parathyroid hormone).
•
Blood sample for anti-tanezumab antibody assessment.
•
Blood samples for PK and PD (NGF) analyses. 
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
Serum and plasma retention samples.
•
Serum pregnancy test for females of childbearing potential.
•
Review/Update of concomitant medication.
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•
Assessment of compliance with weekly IRT entries (weekly index joint pain score, 
weekly non-index joint pain assessment and as applicable, weekly rescue medication 
and weekly NSAID use entries).
•
Monitor for violations of concomitant NSAID use.
•
Review weekly joint pain scores.
•
Rescue medication (acetaminophen / paracetamol) compliance review/dispense. 
•
Initiate of standard of care treatment for osteoarthirits pain at the discretion of the 
investigator. 
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect a synovial fluid sample 
(refer to Section 7.5.3).
6.4.1.4. Early Termination Follow-up Phone Contact (20 Weeks after last dose of SC 
investigational product)
•
Adverse events review.
•
Review/update of concomitant medication.
•
Review subject compliance with weekly IRT entries (weekly index joint pain score, 
weekly non-index joint pain assessment as applicable, weekly rescue medication and 
weekly NSAID use entries).
•
Schedule subject for follow-up radiographic assessments (X-rays) of each shoulder, 
hip and knee and any other major joint for which a radiograph was obtained at the 
Screening visit or any at risk joint identified during the study period (refer to 
Section 7.3.10), local radiology reports should be obtained.
•
Subjects meeting criteria (subjects who had Kellgren-Lawrence Grade 3 or 4 
osteoarthritis of any knee or hip at Screening/Baseline, refer to Section 7.3.11) should 
be scheduled for magnetic resonance imaging of each hip and knee. 
NOTE:  Follow-up radiographs and MRIs should be completed up to 30 days before 
and preferably, no more than 14 days after the Early Termination Follow-up Visit 3 
(24 weeks after last dose of SC investigational product).
6.4.1.5. Early Termination Follow-up Visit 3 (24 weeks after last dose of SC 
investigational product)
•
Adverse events review.
•
Lower Extremity Activity Scale (LEAS).
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•
Survey of Autonomic Symptoms (SAS).
•
Health Care Resource Utilization.
•
Vital signs after sitting for at least 5 minutes, (blood pressure, and heart rate).
•
Orthostatic blood pressure (supine/standing) measurement.
•
ECG (12-lead).
•
Musculoskeletal physical examination.
•
Neurologic exam/Neuropathy Impairment Score (referral for neurological consult if 
required).
•
Review/update of concomitant medication.
•
Review weekly index joint pain scores and weekly non-index joint pain assessment as 
applicable, weekly rescue medication and weekly NSAID use entries.
•
Blood sample for anti-tanezumab antibody assessment (refer to Section 7.3.14).
•
For subjects that performed activity level monitoring via accelerometry, blood and 
urine samples for biomarkers (fasting if possible, urine sample should be from 2nd
void of the day or after; refer to Section 7.6).
•
If not already completed, schedule subject for follow-up radiographic assessments 
(X-rays) of each shoulder, hip and knee and any other major joint for which a 
radiograph was obtained at the Screening visit or any at risk joint identified during the 
study period (refer to Section 7.3.10).
•
If not already completed, subjects meeting criteria (subjects who had 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis of any knee or hip at 
Screening/Baseline, refer to Section 7.3.11) should be scheduled for magnetic 
resonance imaging of each hip and knee.
NOTE:  Follow-up radiographs and MRIs should be completed up to 30 days before 
and preferably, no more than 14 days after the Early Termination Follow-up Visit 3 
(24 weeks after last dose of SC investigational product) and local radiology reports 
should be obtained.
•
If arthrocentesis will be performed for a subject (refer to Section 7.4.7) and the 
subject has provided the applicable informed consent, collect synovial fluid, plasma 
and serum samples (refer to Sections 7.5.1, 7.5.2 and 7.5.3).
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6.4.2. Procedures for Subjects Undergoing Joint Replacement
Subjects who have undergone or plan to undergo total joint replacement or other arthroplasty 
procedure during the study will be discontinued from investigational product. 
Subjects who undergo total knee, hip or shoulder joint replacement surgery during the study 
(Double-blind Treatment Period or Follow-up Period) will be followed for 24 weeks after the 
procedure as part of a separate protocol (Study A4091064), provided the subject consents.
Transition procedures into Study A4091064 are determined by the timing of total joint 
replacement surgery:  
•
Subjects who have undergone or plan an immediate total knee, hip or shoulder joint 
replacement will be discontinued from the Double-Blind Treatment period and enter 
into the total joint replacement follow-up protocol (Study A4091064).  At the 
discontinuation visit, all procedures scheduled for the Week 56 and Week 64 visits 
should be completed unless the Subject has already completed the Week 56 and 
Week 64 visits, in which case only Week 80 procedures will be required.  In addition, 
if the Week 56 visit was not completed prior to termination, a general physical 
examination, body weight, WPAI:OA, EQ-5D-5L, TSQM v.II and mPRTI will also 
be obtained.  Applicable Study A4091064 Baseline Visit activities should be 
completed on the same day as the Study A4091058 End of Treatment Visit. 
•
Subjects who plan to undergo total knee, hip or shoulder joint replacement during the 
study will be discontinued from the Double-blind Treatment Period and entered into 
Early Termination Follow-up (See Section 6.4) until their joint replacement 
procedure.  For these subjects, a complete early termination visit should be conducted 
prior to the total joint replacement (See Section 6.4) and entrance into Study 
A4091064.  Study A4091064 Baseline Visit activities should be completed on the 
same day as the Study A4091058 early termination visit.  Subjects who have not 
undergone or scheduled total joint replacement surgery within the investigational 
product or safety follow-up period of this study will not be eligible for Study 
A4091064. 
Subjects who undergo other types of joint replacement surgery or arthroplasty during the 
study should be discontinued from investigational product and complete the protocol 
specified Safety Follow-up Period, but not be entered into Study A4091064 for follow-up. 
6.4.2.1. Total Joint Replacement Follow-up Protocol
As part of the total joint replacement follow-up protocol, all source documents from the 
surgical procedure (including any prior orthopedic consultations and pre-operative 
assessments), immediate post-operative recovery, and follow-up therapy will be collected.  In 
addition, the surgeon will be asked to complete an assessment of procedural difficulty.  
Imaging studies of the affected joint (such as X-rays and MRI scans) will be collected.  
Instructions regarding pathology specimens will be provided.
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7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Subject Diary Assessments
7.1.1. Daily/Weekly Pain Assessments
If possible diary assessments of pain in the index joint and assessment of the major 
non-index joints will be completed by the subject at approximately the same time each day 
(or each week).  Average pain will be assessed with an 11-point Numeric Rating Scale (NRS) 
ranging from zero (no pain) to 10 (worst possible pain) captured through IRT.  The subjects 
should describe their pain in the index joint (and non-index joint when applicable) during the 
past 24 hours by choosing the appropriate number from 0 to 10.  If possible, subjects should 
conduct the self-assessment in the evening prior to midnight.
Index Joint Pain Assessment
Average pain in the index joint will be assessed by the subject daily from the beginning of 
the IPAP to the Week 16 Visit, followed by weekly beginning after the Week 16 visit 
through Week 80 (and weekly during the Early Termination Follow-Up Period). 
•
Example question when the identified index joint is the right knee:
Select the number that best describes your average pain in your index joint, the right knee in 
the past 24 hours:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
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•
Example question when the index joint is the right hip:
Select the number that best describes your average pain in your index joint, the right hip in 
the past 24 hours:
0             1          2          3          4          5          6          7          8          9          10
No
   Worst Possible
Pain
   Pain
Non-index Joint Pain Assessment
On a weekly basis beginning at the Initial Pain Assessment Period and through Week 80 of 
the study (and weekly during the Early Termination Follow-Up Period), subjects will also be 
asked if he/she experienced new onset or increased pain in any major non-index joint.  A 
major joint is defined as a mobile synovial joint in the limbs such as shoulders, elbows, 
wrists, hips, knees, ankles and excluding the joints of the toes and hands.  If a subject 
responds that he/she has experienced new onset or increased pain in a non-index joint or 
other major joint (post-baseline), the subject will be asked to rate his/her pain in that joint on 
the same 11-point numeric rating scale shown above and will be asked to rate his/her pain in 
that joint for the remainder of the study.
7.1.2. Rescue Medication and Amount
Rescue medication use will be collected daily via IRT from the beginning of the IPAP to the 
Week 16 Visit.  The dosage strength of the acetaminophen tablets/caplets/capsules will be 
captured.  The subject should note the number of tablets/caplets/capsules of rescue 
medication taken during the last 24 hours. 
Following the Week 16 visit up to the Week 80 visit and during the Early Termination 
Follow-Up Period for subjects who enter this phase of the study, the use of acetaminophen / 
paracetamol as rescue medication will be collected once weekly using IRT.  The subject will 
record the number of days rescue medication was used and maximum number of tablets, 
capsules or caplets of rescue medication taken on any day in the past week.
7.1.3. Concomitant NSAID Use
Use of over-the-counter or prescription NSAID use will be collected weekly via IRT from 
the Baseline (Day 1) visit until the Week 80 visit.  During the Early Termination Follow-Up 
Period for subjects who enter this phase of the study, the use of over-the-counter or 
prescription NSAID will be collected once weekly using IRT.  Subjects will record the 
number of days of NSAID use in the past week using IRT.  At telephone or clinic visits, sites 
will interview the subject regarding their NSAID use and record additional information, such 
as the medication name, dosage 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 guidance provided in Section 5.8.1. 
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7.2. Study Visit Efficacy Assessments
7.2.1. Western Ontario and McMaster Universities Osteoarthritis Index
A copy of the WOMAC44 Osteoarthritis NRS Index is provided in Appendix 4.  The 
WOMAC subscales will be recorded via IRT at relevant study visits.
7.2.1.1. WOMAC Pain Subscale
The WOMAC Pain subscale questionnaire is to be completed by subjects at Screening, 
Baseline (Day 1), prior to SC dosing and Weeks 2, 4, prior to SC dosing on Weeks 8, 16 
(Primary Efficacy Endpoint), 24, 32, 40 and 48 and on Weeks 56 and 64 or at Early 
Termination (as described in Section 6.4). 
At Screening and for the remainder of a subject’s participation in the study, a WOMAC pain 
subscale questionnaire will only be completed for the index knee or hip. 
The WOMAC Pain subscale is comprised of 5 questions regarding the amount of pain 
experienced due to osteoarthritis in the index joint (selected study knee or hip) in the past 
48 hours.  The WOMAC Pain subscale is calculated as the mean of the scores from the five 
individual questions, which may not be a whole (integer) number.  The WOMAC Pain 
subscale NRS scores for each question, and the WOMAC Pain subscale score, range from 
0 to 10, with higher scores indicating higher pain.
7.2.1.2. WOMAC Physical Function Subscale
Subjects will complete the WOMAC Physical Function subscale questionnaire at Screening, 
Baseline (Day 1) prior to SC dosing and Weeks 2, 4, prior to SC dosing on Weeks 8, 16 
(Primary Efficacy Endpoint), 24, 32, 40 and 48 and on Weeks 56 and 64 or at Early 
Termination (as described in Section 6.4).
At Screening and for the remainder of a subject’s participation in the study, a WOMAC 
Physical Function subscale questionnaire will only be completed for the index knee or hip.
The WOMAC Physical Function subscale is comprised of 17 questions regarding the degree 
of difficulty experienced due to arthritis in the index joint (selected knee or hip) in the past 
48 hours.  The WOMAC Physical Function subscale is calculated as the mean of the scores 
from the seventeen individual questions, which may not be a whole (integer) number.  The 
WOMAC Physical Function subscale NRS scores for each question, and the WOMAC 
Physical Function subscale score, range from 0 to 10 with higher scores indicating worse 
function.  This refers to the subject's ability to move around and perform usual activities of 
daily living.
7.2.1.3. WOMAC Stiffness Subscale
Subjects will complete the WOMAC Stiffness subscale questionnaire at Screening, Baseline 
(Day 1) prior to SC dosing and Weeks 2, 4, prior to SC dosing on Weeks 8, 16 (Primary 
Efficacy Endpoint), 24, 32, 40 and 48 and on Weeks 56 and 64 or at Early Termination (as 
described in Section 6.4).
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At Screening and for the remainder of a subject’s participation in the study, a WOMAC 
Stiffness subscale questionnaire will only be completed for the index knee or hip.
The WOMAC Stiffness subscale is comprised of 2 questions regarding the amount of 
stiffness experienced in the index joint in the past 48 hours.  The WOMAC Stiffness subscale 
is calculated as the mean of the scores from the two individual questions, which may not be a 
whole (integer) number.  The WOMAC Stiffness subscale NRS scores for each question, and 
the WOMAC Stiffness subscale score, range from 0 to 10 with higher scores indicating more 
stiffness.  Stiffness is defined as a sensation of decreased ease with which the subject moves 
the index knee or hip.
7.2.2. Patient’s Global Assessment of Osteoarthritis
Subjects will complete the Patient’s Global Assessment of Osteoarthritis questionnaire 
(Appendix 5) at Baseline (Day 1) prior to SC dosing and Weeks 2, 4 and prior to SC dosing 
on Weeks 8, 16 (Primary Efficacy Endpoint), 24, 32, 40 and 48 and on Weeks 56 and 64 or 
at Early Termination (as described in Section 6.4).  Subjects will record their responses using 
IRT.
At the Baseline (Day 1) visit and for the remainder of a subject’s participation in the study, a 
Patient’s Global Assessment of Osteoarthritis questionnaire will only be completed for the 
index knee or hip.
Subjects who have a knee as index joint will answer the following question: “Considering all 
the ways your osteoarthritis in your knee affects you, how are you doing today?”  
Subjects who have a hip as index joint will answer the following question: “Considering all 
the ways your osteoarthritis in your hip affects you, how are you doing today?”  
Subjects will rate their condition using the following scale:
Grade
Description
1 – Very Good
Asymptomatic and no limitation of normal activities
2 – Good 
Mild symptoms and no limitation of normal activities
3 – Fair 
Moderate symptoms and limitation of some normal activities
4 – Poor 
Severe symptoms and inability to carry out most normal activities
5 – Very Poor
Very severe symptoms which are intolerable and inability to carry out all 
normal activities
7.2.3. Work Productivity and Activity Impairment Questionnaire - Osteoarthritis –
Knee or Hip v2.0 (WPAI:OA)
Subjects will complete the WPAI:OA prior to SC dosing at Baseline (Day 1) and at 
Weeks 16, 24, 56 and 64 (or at early Termination, as described in Section 6.4).  Subjects will 
record their responses using IRT.
The WPAI-OA Knee or Hip is a 6-item validated questionnaire that assesses the impact of 
osteoarthritis on absenteeism, presenteeism, work productivity, and activity impairment.45  
Each subscale score is expressed as an impairment percentage (0-100) where higher numbers 
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indicate greater impairment and less productivity.  The WPAI-OA is self-administered by the 
subject and takes less than 5 minutes to complete (Appendix 6).
7.2.4. EuroQol 5 Dimension (EQ-5D-5L)
The EQ-5D-5L™will be completed prior to SC dosing at Baseline (Day 1) and prior to SC 
dosing at Weeks 8, 16, 24, 40, 56 and 64 (or at Early Termination as described in 
Section 6.4).  Subjects will record their responses using IRT.
The EQ-5D-5L™is a subject completed questionnaire designed to assess the subject’s 
current health and translate that score into an index value or utility score.  Health status is 
described in terms of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression.  There are two components to the EQ-5D-5L™: a Health State Profile 
and a visual analog scale (VAS) item.  The 5 item health state profile will be assessed to 
calculate a single index value (see Appendix 7).  This instrument provides a mechanism for 
conducting cost-effectiveness and cost-utility analyses.46
7.2.5. Treatment Satisfaction Questionnaire for Medication v.II (TSQM)
Subjects will complete the Treatment Satisfaction Questionnaire for Medication v.II 
(Appendix 13) at Weeks 16 and 56 (or at early termination, as described in Section 6.4). 
Subjects will record their responses using IRT.
The Treatment Satisfaction Questionnaire for Medication (TSQM v.II) is an 11-item 
validated scale that quantifies the subject’s level of satisfaction with study medication, 
effectiveness and side effects/tolerability.  Most items are scored on a 7-point Likert scale 
ranging from ‘Extremely Satisfied’ to ‘Extremely Dissatisfied’.  The domains of 
Effectiveness, Side Effects, Convenience and Global Satisfaction are scored from 0-100 with 
a higher score indicating greater satisfaction.  The TSQM v.II is self-administered by the 
subject and takes less than 5 minutes to complete.47
7.2.6. Patient Reported Treatment Impact Assessment-modified (mPRTI)
The mPRTI is a self-administered questionnaire containing three items to assess patient 
satisfaction, previous treatment, preference and willingness to continue using the study 
medication.  Higher scores indicate greater satisfaction, preference or willingness to use the 
study medication; see Appendix 16.  Subjects will record their responses using IRT.
The questionnaire will be completed by the subject at Weeks 16 and 56 and at Early 
Termination (refer to Section 6.4).
7.2.7. Assessment of Health Care Resource Utilization
The utilization of health care resources (eg, doctor office visits, hospitalizations, surgeries or 
procedures, etc.) during the 3 months prior to Baseline will be assessed by questionnaire at 
Baseline (Day 1).  In addition, Health Care Resource Utilization will be collected at study 
visits at Weeks 64 and 80 (or at early termination, as described in Section 6.4).  Subjects will 
record their responses using IRT. 
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7.3. Safety Assessments
Each subject will provide a general medical history as well as a detailed 
musculoskeletal/joint specific medical history.  The information will be recorded on the 
appropriate CRF(s) at Screening.  Information on prior medications (within 30 days of the 
Screening Visit for non-analgesic medications, 12 months for pain and other medications for 
the treatment and relief of symptoms of osteoarthritis), non-pharmacologic therapies, 
supplements and concomitant medication use will be collected at Screening and concomitant 
medication at each scheduled study visit.  Information regarding tobacco and alcohol use and 
dependency will also be collected at Screening.
7.3.1. General Physical Examination
Each subject will undergo a general physical examination at Screening and Week 56, or at 
Early Termination (as described in Section 6.4). 
7.3.2. Musculoskeletal History and Physical Examination
Each subject will also undergo a musculoskeletal physical examination at Screening, 
Baseline (Day 1), and at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 (or at Early 
Termination, as described in Section 6.4). 
At Screening, the investigator should collect a thorough musculoskeletal history.  The 
investigator should inquire about current and past history of osteoarthritis, ligament tear or 
rupture, joint surgeries (including arthroscopic procedures), fractures, gout, osteoporosis,
osteopenia, joint injuries or other conditions.
At each visit, the investigator will conduct a thorough musculoskeletal physical examination
of all major joints.  The musculoskeletal physical examination should evaluate the joints for 
swelling, redness, tenderness, deformity, osteophytes or nodes, crepitus and pain on motion 
and will be documented on the CRF.  The investigator should also collect subject-reported 
information on any current joint symptoms including pain, stiffness, and swelling.  Any 
clinically significant change in symptoms or the examination should be reported as an 
adverse event. 
7.3.3. 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:
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Chemistry
Hematology
Other
Urinalysis
Screening, Baseline (Day 1), 
Weeks 16 and 64 (or Early 
Termination Visit 2):
Sodium, 
potassium, 
chloride, 
bicarbonate, 
glucose (non fasting), 
Blood Urea Nitrogen (BUN),
creatinine, 
calcium, 
phosphorus, 
magnesium, 
total and direct bilirubin, 
total protein, 
albumin, 
cholesterol, 
triglycerides, 
gamma glutamyltransferase 
(GGT), 
alanine aminotransferase 
(ALT), 
aspartate aminotransferase 
(AST),
lactic dehydrogenase (LDH), 
alkaline phosphatase, 
creatine phosphokinase 
(CPK), 
and uric acid
Screening, Baseline 
(Day 1), Weeks 16 
and 64 (or Early 
Termination
Visit 2):
Complete blood 
count with 
differential
Screening only:
HbA1c
Hepatitis screen (eg, 
HBsAg, Anti-HCV), 
HIV test (HIV Ab screen)
Urine toxicology screen (eg, 
for opiates, barbiturates, 
amphetamines, cocaine, 
propoxyphene, methadone, 
phencyclidine, and 
methaqualone).
Serum FSH if applicable
Screening, Weeks 56 and 64 
(or Early Termination Visits 
1 and 2):
Serum Pregnancy Test
Baseline, Weeks 8, 16, 24, 
32, 40 and 48 (Prior to 
dosing at Dosing Visits):
Urine Pregnancy Test
Baseline, Weeks 16, 56 and 
64 (or Early Termination
Visits 1 and 2):
Serum and plasma retention 
samples
Baseline, Week 64 (or Early 
Termination Visit 2)
Serum 25-OH Vit D, serum 
parathyroid hormone (PTH)
Screening only:
pH, 
protein, 
glucose, 
ketones, 
blood, 
bilirubin, 
nitrite, 
specific gravity 
and leukocytes. 
Microscopic 
analysis performed 
if abnormalities 
are present on the 
above 
components.
Does not include PK, PD (NGF), Anti-tanezumab Antibodies, biomarker or synovial fluid (refer to 
sections below for collection details)
7.3.3.1. Blood Tests
Blood tests for clinical laboratory testing (chemistry, hematology) will be performed at 
Screening, Baseline (Day 1) and Weeks 16 and 64 (or at Early Termination, as described in 
Section 6.4).  An unscheduled visit(s) may be necessary for follow-up of abnormal test 
results. 
Serum and plasma retention samples will be collected at Baseline (Day 1), Weeks 16, 56 and 
64 or at Early Termination (as described in Section 6.4).
See Section 7.3.3.3 for sample collected for serum pregnancy test and Section 7.3.3.4 for 
sample collected for FSH testing.
Blood samples collected for PK, PD (NGF), biomarkers and anti-tanezumab antibody 
measurements are described in Sections 7.5.1, 7.5.2, 7.6 and 7.3.14.
Synovial fluid samples collected for PK, PD (NGF) are described in Section 7.5.3.
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7.3.3.2. Urinalysis and Urine Toxicology Screen
Urinalysis and urine toxicology screen will be performed at Screening only.
Urine samples collected for biomarker analyses are described in Section 7.6.2.
7.3.3.3. Pregnancy Tests
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed during the Screening period, reviewed and confirmed as 
negative.  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 double-blind treatment period (or when potential pregnancy is otherwise 
suspected), and repeated at Visits at Weeks 56 and 64 or at Early Termination as described in 
Section 6.4 to confirm the subject has not become pregnant during the study.  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.  These tests will 
be performed prior to dosing with SC investigational product at Baseline (Day 1), and 
Weeks 8, 16, 24, 32, 40 and 48.  Qualitative point-of-service urine pregnancy tests will be 
conducted with the test kit approved by the sponsor 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). 
Refer to Sections 8.10 and 8.10.1 for guidance pertaining to exposure during pregnancy and 
post-natal follow-up.
7.3.3.4. Serum FSH Testing
Female subjects of non-childbearing potential 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 must undergo serum FSH testing to determine 
post-menopausal status.  A serum FSH level within the laboratory’s reference range for 
post-menopausal females is required.  Female subjects who have been amenorrheic less than 
1 year will be considered of child-bearing potential.  Female subjects of childbearing 
potential do not require serum FSH testing.
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7.3.4. Assessment of Pain in Major Joints at Screening with Numeric Pain Scale Rating 
(NRS)
Average pain in the major joints (bilateral shoulders, hips and knees) or any other painful, 
major joint that will be imaged at Screening, will be assessed by the subject at the Screening 
Visit with an 11-point Numeric Rating Scale (NRS) ranging from zero (no pain) to 10 (worst 
possible pain) and captured using IRT.
7.3.5. Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) will be collected and 
recorded throughout the study at Screening, prior to SC dosing at Baseline (Day 1) and on 
Weeks 2, 4, 8, 16, 24, 32, 40 and 48, and at Weeks 56, 64 and 80 (or at Early Termination, as 
described in Section 6.4).  Vital signs will be collected after the subject has been in a sitting 
position for at least five minutes at each noted visit. 
7.3.5.1. Orthostatic Blood Pressure Measurement
In addition to sitting vital sign measurements, orthostatic blood pressure measurements will 
be obtained using a standard manual sphygmomanometer at Screening, Baseline/Day 1 and 
at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 (or at Early Termination, as described in 
Section 6.4).  At each of these clinic visits, blood pressure will be assessed in supine and 
standing positions.  Orthostatic blood pressure measurements will be obtained after collection 
of the sitting vital signs and before any required phlebotomy (and prior to dosing at dosing 
visits).  To minimize chances of orthostatic hypotension related to volume depletion, subjects 
should be reminded to report for clinic visits well hydrated.  In this regard, investigators 
could consider recommending to subjects that they consume 8-16 ounces (240-480 mL) of 
water prior to reporting to the clinic for study visits.  All orthostatic blood pressure 
measurements will be recorded in the IRT system.
Supine blood pressure measurement will be obtained after subjects have been in the supine 
position for a minimum of 10 minutes.  To ensure that a stable supine blood pressure 
measurement is obtained, at least two systolic and diastolic measurements will be performed.  
If the replicate systolic and diastolic measurements differ by no more than 10 mmHg and 
5 mmHg, respectively, the supine blood pressure will be considered to be stable.  The mean 
of the two stable replicate measures will be considered to represent the baseline supine blood 
pressure (mean systolic and mean diastolic blood pressure) for that visit.  Once the supine 
blood pressure is considered to be stable, subjects will be asked to assume the standing 
position.  After subjects have been in the standing position for 1 minute and 3 minutes, 
systolic and diastolic blood pressure will be measured and recorded for both time points.  If 
the measurements do not meet the criteria for orthostatic (postural) hypotension, no further 
measurements are needed.  If either the 1 minute or 3 minute standing BP measurements 
show decreases meeting the criteria shown in Table 9, the sequence of supine and standing 
measurements should be repeated up to 2 more times.  Refer to Table 9 for the criteria 
defining orthostatic hypotension and actions that should be taken when orthostatic 
hypotension criteria are met. 
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Table 9.
Orthostatic Blood Pressure Changes and Subject Management
Mean Supine 
Systolic Blood 
Pressure
Decrease in Blood 
Pressure Defining 
Orthostatic (postural) 
Hypotension
Actions (for both criteria)
≤150 mmHg
≥20 mmHg systolic or
≥10 mmHg diastolic
- Repeat the sequence of measurements (supine 
and standing) up to 2 times.  If either the 1 
minute or 3 minute standing BP meets the 
orthostatic (postural) hypotension criteria, then 
that sequence is considered positive.  If 2 of 2 or 
2 of 3 sequences are positive, then orthostatic 
hypotension is considered confirmed and an 
adverse event of orthostatic hypotension will be 
reported. 
- Refer to Section 7.4.3 for subject management 
and dosing guidance.
OR
>150 mmHg
≥30 mmHg systolic or
≥15 mmHg diastolic
Refer to Section 7.4.3 for guidance on determining which subjects with confirmed orthostatic 
hypotension will require consultation with a neurologist or cardiologist.
7.3.6. 12-Lead Electrocardiogram
A 12-lead ECG will be performed at Screening for determination of ECG-related eligibility. 
Additional 12-Lead ECGs will be performed at Weeks 56 and 80 (or at Early Termination, as 
described in Section 6.4).  Post-Screening ECGs may be collected if needed (for cause), at 
the discretion of the investigator. 
A 12–lead ECG should be recorded after subjects have been resting at least 5 minutes in the 
supine position in a quiet environment.  Digital ECG tracings will be performed using 
equipment from and analyzed by a central ECG laboratory.  All standard intervals (PR, QRS, 
QT, QTcF, QTcB, RR intervals and HR) will be collected.  The QTc interval reading 
produced by machine will be listed in the data listings.  The QT interval will be manually 
measured by the central laboratory.  The cardiologist at the central ECG laboratory reading 
the ECGs will be blinded regarding investigational product assignment.  In the event a 
clinically significant ECG abnormality is seen at a visit on an ECG obtained for cause 
(post-treatment), the investigator should consider evaluation of the subject by a cardiologist.
Investigators will also be alerted of subjects with evidence of the following as a potential 
indicator of sympathetic nervous system dysfunction:
•
Significant bradycardia (heart rate of ≤45 beats per minute (BPM) on an ECG, 
exclusionary at Screening).
•
Heart rate decrease from Screening of ≥25% with resulting heart rate <60 BPM.
Investigators should report adverse events of bradycardia for subjects who meet the ECG 
criteria listed above.  Refer to Section 7.4.3 for additional details pertaining to subject 
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evaluation and further dosing with investigational product in subjects with sympathetic 
function adverse events. 
7.3.7. Survey of Autonomic Symptoms (SAS)
The Survey of Autonomic Symptoms (SAS) is a validated, easily administered instrument to 
measure autonomic symptoms that has been proposed to be valuable in assessing neuropathic 
autonomic symptoms in clinical trials (refer to Appendix 15). 
Subjects will complete the SAS at Screening, prior to SC dosing at Week 24, and at 
Weeks 56 and 80 (or at Early Termination, as described in Section 6.4).  Subjects will enter 
responses in IRT. 
7.3.8. Lower Extremity Activity Scale (LEAS)
Subjective assessments of subject activity will be assessed in all subjects participating in the 
study using the Lower Extremity Activity Scale (LEAS).48  The LEAS is a single item, self 
administered scale that was developed and validated to assess actual activity level in subjects 
having total knee arthroplasty (refer to Appendix 12).
The LEAS scale was designed to reflect four major levels of lower-extremity activity 
(1) housebound (essentially unable to walk or a minimal ability to walk), (2) more ordinary 
walking about the house, (3) walking about the community, and (4) walking about the 
community as well as substantial work or exercise.  The instrument relies upon 12 questions 
with three of these questions having three levels of response that permit finer gradation at the 
high end of physical activity.  The resulting, 18-level scale allows subjects to select a single 
description that most represents his or her self-perceived activity level.  The final score is 
simply the number of the descriptor selected by the subject as being most representative of 
his or her activity level.  The minimum possible score is 1 (entirely bedbound) and the 
maximum possible score is 18 (currently competitive athlete).
Subjects will complete the LEAS prior to SC dosing at Baseline (Day 1) and on Weeks 8, 16 
and 24, and at Weeks 4, 56 and 80 (or at Early Termination, as described in Section 6.4).  
Subjects will enter responses in IRT or a subject worksheet. 
7.3.9. Activity Level Monitoring (Actigraphy)
Subject activity level will be assessed using actigraphy in subjects at selected sites (to recruit 
a maximum of 360 subjects) in three separate monitoring periods.  The monitoring periods 
will occur during the Screening period (Stage 2) and at approximately Weeks 16 and 56.  
During the Screening period, actigraphy over 7 consecutive days may take place anytime 
during the 2-week, pre-randomization NSAID regimen stabilization and prohibited drug 
washout periods and in parallel with the IPAP.  Accelerometry to be completed prior to the 
Week 16 and Week 56 visits will take place over two separate, 14 consecutive day 
monitoring periods between Week 14 and the Week 16 visit and between Week 54 and the 
Week 56 visit, respectively. 
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Prior to each monitoring period, subjects will be instructed how to wear the accelerometer 
and to put the accelerometer on upon arising in the morning, and to wear the accelerometer 
continuously (except for water activities) until going to bed at night for 7 or 14 consecutive 
days (depending on the monitoring period) while going about their usual daily activities.  
Subjects will also be encouraged to maintain a log (electronic or written) to record when the 
accelerometer was put on in the morning and removed at night (or if removed for any other 
purpose). 
7.3.10. Radiographic Assessments
Scheduled radiographics of each shoulder, hip and knee will be obtained at Screening and at 
the Week 24, 56 and 80 (or at Early Termination, as described in Section 6.4) visits. 
Radiographic assessments of other major joints exhibiting signs or symptoms suggestive of 
osteoarthritis should also be imaged.  A major joint is defined as a mobile synovial joint in 
the limbs such as shoulders, elbows, wrists, hips, knees, ankles and excluding the joints of 
the toes and hands.  Any joint imaged at Screening or other at-risk joints identified during the 
study period should also be imaged at Week 24, 56 and 80 (or at Early Termination, as 
described in Section 6.4) visits. 
NOTE: It is recommended that the radiographs required at Screening be obtained as soon as 
possible after the Screening visit (Stage 1) to permit central radiology review of the images 
for determination of subject radiographic eligibility to proceed to Screening Stage 2 
procedures and for initial dosing in the study.  Subjects will not be permitted to start dosing 
in the study until the Screening radiographs are reviewed by the Central Reader and 
eligibility is established.  Radiographs required for the Week 24 visit may be conducted up to 
30 days before the visit, but it is recommended that the Week 24 radiographs be obtained at 
least two weeks prior to the Week 24 visit to permit Central Reader review of the images and 
to establish eligibility for continuation in the study.  Radiographs required for the Week 56 
visit may be conducted within 30 days of the visit (ie, before or after the visit).  Radiographs 
for the Week 80 visit may be conducted up to 30 days before and preferably, no more than 
14 days after the visit.
For subjects who are discontinued prior to the Week 56 visit, follow-up radiographs of each 
shoulder, hip and knee (and any other major joint imaged at Screening or other at risk joints 
identified during the study period) should be performed as soon as possible (refer to 
Section 6.4) after the decision to withdraw from the study has been made, provided at least 
30 days have passed since the last set of X-rays were collected.  A final set of follow-up 
radiographs of each knee, hip and shoulder (and any other major joint imaged at Screening or 
other at risk joints identified during the study period) should be obtained 24 weeks (Early 
Termination Visit 3, Section 6.4.1.5) after the last dose of SC investigational product was 
administered. 
If a local radiology reading was performed for X-rays obtained in the study, the local 
radiology report should be obtained and provided to Pfizer or its designee (eg, the radiology 
Central Reader). 
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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 reproducibility and accuracy of joint space width measurement in the knees, a 
semi-automated software and positioning frame will be utilized.  The Core Imaging 
Laboratory will be responsible for working with the sites to ensure quality, standardization 
and reproducibility of the radiographic images/assessments made at the Screening and 
follow-up time-points.  Additional details regarding the required X-rays will be provided in a 
site imaging manual.
Central radiology readers (Central Readers) will be board certified radiologists or have the 
international equivalent as musculoskeletal radiologists.  The Central Readers will be 
governed by an imaging atlas and an imaging Charter which includes a specific description 
of the scope of their responsibilities.  Central Readers will review radiology images at 
Screening for assessment of eligibility (including determination of Kellgren-Lawrence 
Grade) and identification of exclusionary joint conditions such as rapidly progressive 
osteoarthritis, atrophic or hypotrophic osteoarthritis, subchondral insufficiency fractures 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis and pathological 
fractures.  After randomization, Central Readers will review radiology images for diagnosis 
of joint conditions that would warrant further evaluation by the Adjudication Committee such 
as possible or probable rapidly progressive osteoarthritis, subchondral insufficiency fractures 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis or pathological 
fracture and 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. 
7.3.10.1. 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 
“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)
Knee51
0.024 mSv
Hip49,50
1.9 mSv
Shoulder49
0.04 mSv
TOTAL
1.964 mSv
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Subject annual exposure per body part imaged is shown in the table above.  The annual total 
effective dose per subject in this study is expected to be approximately 2.0 mSv.  This can be 
compared to the annual effective dose from natural background radiation of approximately 
3.0 mSv.52  In some cases, it is expected that a repeat image of a joint may be necessary due 
to the quality of the X-ray images.  Subjects requiring a DXA scan will receive an additional 
radiation dose of approximately 0.025 mSv.52  
7.3.11. Magnetic Resonance Imaging (MRI)
All subjects who advance to the Stage 2 Screening visit (refer to Section 6.1.2) will have 
MRI of each hip and knee.  For subjects who are determined by the Central Reader to have 
Kellgren-Lawrence Grade 3 or 4 osteoarthritis in any knee or hip in the Screening 
radiographs, follow-up MRIs of each hip and knee will be performed at Weeks 24, 56 and 80 
(or at early Termination, as described in Section 6.4). 
In addition to obtaining MRIs at scheduled time points specified above, investigators and the 
Central Reader may request an MRI to further evaluate subjects who present with severe and 
persistent joint pain or to confirm or further evaluate image findings recorded in a locally 
read radiology report.  The Central Reader will review MRI images that were obtained to 
further evaluate subjects who present with severe and persistent joint pain or to confirm or 
further evaluate suspect image findings for diagnosis of joint conditions that would warrant 
further evaluation by the Adjudication Committee such as possible or probable rapidly 
progressive osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of 
the knee [SPONK]), primary osteonecrosis or pathological fracture. 
Additional details regarding the required MRIs will be provided in a site imaging manual. 
7.3.12. Dual Energy X-ray Absorptiometry (DXA) Scan
Dual Energy X-ray Absorptiometry scans of the hip and lumbar spine, will be performed for 
subjects meeting National Osteoporosis Foundation recommendations for bone mineral 
density testing who advance to the Stage 2 Screening Visit (refer to Section 6.1.2).  Typically 
the left hip will be scanned, in the event that the left hip cannot be scanned (eg, prosthetic hip 
in place) the right hip will be scanned. 
National Osteoporosis Foundation recommendations for bone mineral density testing:  
1. All females ≥65 yrs of age. 
2. Post-menopausal females and men (50-69 yrs) with risk factors (refer to 
Appendix 10). 
3. Men ≥70 yrs.
4. In post-menopausal women and men age 50 and older who have had an adult age 
fracture (major skeletal sites excluding fractures of the fingers, toes, facial bones and 
skull).
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In addition, to the above:
1. All subjects with a medical history of osteoporosis or receiving bisphosphonates at 
the screening visit will be required to have DXA scans during Stage 2 of the 
screening process.
Additional details regarding the required DXA scans will be provided in a site imaging 
manual. 
7.3.13. Neurologic Examination
Neurologic examinations will be performed by a designated physician and assessed for 
clinically significant changes from Baseline.  The examinations will be performed at 
Screening, Baseline, and Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 (or at Early 
Termination, as described in Section 6.4) and the Neuropathy Impairment Score (NIS) will 
be completed at these time points based on this neurological exam (refer to Appendix 8).  
Neurologic examination will assess strength of groups of muscles of the head and neck, 
upper limbs and lower limbs, deep tendon reflexes and sensation (tactile, vibration, joint 
position sense and pin prick) of index fingers and great toes in order to complete the NIS.  
The NIS is a standardized instrument which has been tested in both healthy subjects and 
patients with neuropathy and which has been used to evaluate subjects for signs of peripheral 
neuropathy in clinical trials.53  Investigators and other designated physicians performing the 
neurologic evaluations are required to attend a training session for neurological exam in 
order to apply consistency across sites.  The neurological exams must be performed in a 
controlled and consistent manner and by the same examiner when possible.
A neurologic evaluation should be performed by a consulting neurologist if any of the 
following occurs: 
•
If an adverse event suggestive of new or worsening peripheral neuropathy or an 
adverse event of abnormal peripheral sensation (eg, allodynia, burning sensation, 
carpal tunnel syndrome, dysesthesia, hyperesthesia, hyperpathia, hypoesthesia, 
neuralgia, neuritis, neuropathy peripheral, pallanesthesia, paresthesia, peripheral 
sensory neuropathy, sciatica, sensory disturbance, sensory loss, tarsal tunnel 
syndrome) reported as: 1) a serious adverse event or 2) an adverse event which has 
resulted in the subject being withdrawn from the study, or 3) an adverse event 
ongoing at the end of the subject’s participation in the study, or 4) an adverse event of 
severe intensity. 
•
A new or worsened clinically significant abnormality on the neurologic exam should 
be reported as an adverse event and may result in a neurologic evaluation/consult 
further to the guidance above. 
•
A neurological adverse event which is non-neuropathic (eg, stroke, seizure) but which 
the investigator considers medically important should also result in a neurological 
consultation.
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In these cases, a neurologic evaluation should be obtained as soon as possible after these 
signs and symptoms are known.  The results of the neurological consultation will be recorded 
on the appropriate CRF and adverse event (if applicable) forms.  Adverse events will be 
reported where applicable as described in Section 8.
7.3.14. Anti-Tanezumab Antibody Testing
Blood samples for the assessment of anti-tanezumab antibodies will be collected at Baseline 
(Day 1; pre-dose), Week 8 (pre-dose), Week 16 (pre-dose), Week 32 (pre-dose), Week 48
(pre-dose) and at Weeks 56, 64 and 80 (or at Early Termination, as described in Section 6.4). 
If subjects terminate prior to Week 56, blood samples for the assessment of anti-tanezumab 
antibodies will be collected at approximately 8, 16 and 24 weeks after the last dose if SC 
investigational product was administered (or at Early Termination, as described in 
Section 6.4).
Instructions regarding sample processing (eg, sample volumes, tube types, storage 
temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
Standard Operating Procedures.
Samples may be used for further evaluation of the bioanalytical method.  These data will be 
used for internal exploratory purposes and will not be included in the clinical report.
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the trial.
7.4. Triggered Requirements and Subject-Level Stopping Rules
The following rules will apply to individual subjects at the time of the second and subsequent
injections of SC investigational product.
7.4.1. Dysesthesia/Allodynia
Transient, resolved dysesthesia/allodynia: Administer SC investigational product as planned 
as long as the condition has resolved before the next scheduled dose of SC investigational 
product. 
Unresolved dysesthesia/allodynia: Withhold the SC investigational product for a maximum 
of 14 days beyond the planned dosing day to allow for resolution of the adverse event.  If the 
dysesthesia/allodynia has not resolved within the 14-day period after the scheduled dosing 
date, the subject will not receive any additional doses of investigational product and will 
enter the Early Termination Follow-up period (refer to Section 6.4). 
7.4.2. Hypersensitivity or Injection Site Reactions
If a severe hypersensitivity reaction or severe injection reaction occurs following any 
administration of SC investigational product, the investigational product should be 
discontinued immediately and no further administrations of SC investigational product will 
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be allowed.  Subjects experiencing these types of reactions will enter the Early Termination 
Follow-up period (refer to Section 6.4).
Severe hypersensitivity reactions are defined as those causing anaphylaxis.  Severe injection 
site reactions are defined as those in which ulceration or severe necrosis occurs. 
7.4.3. Orthostatic Hypotension and Sympathetic Function Adverse Events
Blood pressure changes meeting the pre-specified criteria for orthostatic hypotension and 
confirmed as described in Section 7.3.5.1 will be designated as confirmed orthostatic 
hypotension episode and should be reported as an adverse event whether or not the subject 
had accompanying symptoms.
Confirmed episodes of orthostatic hypotension: If a confirmed episode of orthostatic 
hypotension occurs (as defined in Section 7.3.5.1) it should be reported as an adverse event 
and the subject should be further evaluated as described below to determine if a neurology or 
cardiology consultation should be obtained and/or whether further treatment with 
investigational product should occur.  Figure 2 provides a flow diagram for the process 
described below.
1. If no apparent medical cause (eg, dehydration, illness, medications) is identified at the 
time the orthostatic hypotension criterion is met and the subject is symptomatic, the 
subject should be further evaluated for the presence of sympathetic autonomic 
neuropathy by a cardiologist or neurologist as soon as possible.  See “Sympathetic 
function adverse events” below for decisions regarding subject management and 
continued dosing with investigational product.
2. If an apparent medical cause is identified at the time the orthostatic hypotension 
criterion is met or if the subject is asymptomatic, the subject should have a repeat 
assessment of orthostatic hypotension performed at least 1 week later but not more 
than 4 weeks later.  During this time the investigator should attempt to address the 
underlying medical cause of the orthostatic hypotension.  If confirmed orthostatic 
hypotension (as defined in Section 7.3.5.1) is present at the follow-up visit, the 
subject should be further evaluated for the presence of sympathetic autonomic 
neuropathy by a cardiologist or neurologist as soon as possible.  See “Sympathetic 
function adverse events” below for decisions regarding subject management and 
repeat dosing. 
Sympathetic function adverse events:  Subjects reporting adverse events (any seriousness or 
severity) with preferred terms of bradycardia (see Section 7.3.6 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 
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assessment as to the specialist best able to evaluate the subject.  Pfizer will provide a 
guidance document which outlines appropriate recommendations regarding tests to consider 
for subject work-up.
These subjects should not be dosed with SC investigational product until the absence of 
sympathetic autonomic neuropathy has been confirmed.  Subjects who are not deemed to 
have a sympathetic autonomic neuropathy based on this evaluation can continue the study 
provided no more than 12 weeks have elapsed since the last dose of SC treatment (Boxes H 
and K of flow diagram, Figure 2).  However, if the subject is still symptomatic with 
bradycardia, syncope, orthostatic hypotension, anhidrosis or hypohidrosis up to 12 weeks 
after the last dose of SC treatment, s/he should not receive additional investigational product, 
even if a sympathetic autonomic neuropathy has not been confirmed (Boxes J and L of flow 
diagram, Figure 2), and will enter the Early Termination Follow up period (refer to 
Section 6.4).  Subjects found to have a sympathetic autonomic neuropathy (Boxes I and L of 
flow diagram, Figure 2) should not receive additional investigational product and will enter 
the Early Termination Follow up period (refer to Section 6.4).
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Figure 2.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events
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7.4.4. Evaluation and Follow-up for Increased, Severe Persistent Joint Pain
Average daily pain in the index joint (hip or knee) will be assessed with an 11-point numeric 
rating scale (0 to 10) and collected via IRT beginning in the IPAP through Week 16 of the 
study followed by weekly assessments between Weeks 16 and 80.  In addition, on a weekly 
basis beginning at the Initial Pain Assessment Period and through Week 80 of the study, the 
subject will also be asked if he/she experienced new onset or increased pain in a major 
non-index joint (refer to Section 7.1.1).  If a subject responds that he/she has experienced 
new onset or increased pain in a non-index joint or other major joint (post-baseline), the 
subject will be asked to rate his/her pain in that joint on the same 11-point numeric rating 
scale, using a 24-hour recall (refer to Section 7.1.1) and will be asked to rate his/her pain in 
that joint for the remainder of the study. 
Joint pain scores recorded electronically will be monitored by site staff to identify subjects 
who have a pattern of severe pain over several days or a rapid increase in pain.  Subjects who 
record increased pain scores of severe intensity (eg, a score of 7-10 out of 10 on a numerical 
rating scale) in a knee, hip, shoulder or other major joint which is persistent for at least 
2 weeks despite treatment with analgesic medication should be evaluated 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 WOMAC Pain Scores, electronically 
recorded pain scores, and relevant spontaneously reported adverse events will be 
implemented.  In addition, adverse events of joint pain, joint swelling, joint injury/accidents, 
fractures or worsening of osteoarthritis symptoms in index or non-index joints will be 
evaluated by the site personnel.  An assessment of the subjects’ general health and major 
joints for any changes in their osteoarthritis status will be carried out. 
Musculoskeletal physical exam findings, review of reported musculoskeletal adverse events, 
and in-clinic efficacy assessments will be recorded on specific case report forms for each 
study visit. 
Subjects meeting the criteria for increased severe or persistent pain or with other clinically 
significant findings based on the assessment of the Investigator are considered to have a 
joint(s) at risk and must have radiographs (X-rays) of the joint(s) obtained and sent to the 
Central Reader for assessment.  MRI scans will not be required but may be obtained if 
warranted for diagnostic purposes.  If warranted, the subject will be referred to an orthopedic 
surgeon for evaluation.
Radiographic (and any MRI) images collected as part of follow-up procedures for reports of 
increased severe or persistent pain or clinically significant findings of the investigator will be 
assessed by the Central Reader for possible or probable events of rapidly progressive 
osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee 
[SPONK]), primary osteonecrosis, or pathological fracture (refer to Section 7.4.5 and 
Section 9.5). 
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7.4.5. Central Reader and Subject-Level Stopping Criteria for Joint Safety Events
Subjects identified through the measures described above (in Section 7.4.4) who are 
determined by the Central Reader to have a possible or probable joint safety event (rapidly 
progressive osteoarthritis (type-1 or type-2), subchondral insufficiency fractures 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis, or pathological 
fracture), will be withdrawn from treatment and enter the Early Termination Follow-up
period (refer to Section 6.4). 
The Central Reader will review the radiology images on an ongoing basis and provide 
assessments to the investigator and Pfizer.  For subjects who are identified with a possible or 
probable joint safety event described above and for subjects undergoing total joint 
replacement for any reason, all images and other source documentation will be provided to 
the blinded tanezumab Adjudication Committee for review and adjudication of the event.  
The Adjudication Committee’s assessment of the event will represent the final classification 
of the event (refer to Appendix 14). 
Subjects with adverse event reports of rapidly progressive osteoarthritis (type-1 or type-2), 
subchondral insufficiency fractures (spontaneous osteonecrosis of the knee [SPONK]), 
primary osteonecrosis, or pathological fracture, will be withdrawn from treatment and enter 
the Early Termination Follow-up period (refer to Section 6.4). 
In addition to Subject-Level Stopping Criteria for Joint Safety Events, this study will also 
employ Protocol-Level Stopping Criteria. Protocol-Level Stopping Criteria for Joint Safety 
Events are described in Section 9.6.2.
7.4.6. Procedures for Subjects Undergoing Joint Replacement
Subjects who have undergone or plan to undergo total joint replacement or other arthroplasty 
procedure during the study will be discontinued from investigational product.  Follow-up 
procedures for these subjects are described in Section 6.4.2.  In addition, subjects who 
undergo total knee, hip or shoulder joint replacement surgery during the study (Treatment 
Period or Follow-up Period) will be followed for 24 weeks after the procedure as part of a 
separate protocol, provided the subject consents (refer to Section 6.4.2.1).
7.4.7. Procedures for Subjects Undergoing Arthrocentesis
If an investigator determines that arthrocentesis is necessary for a subject participating in the 
study, investigators are requested to submit a synovial fluid sample for exploratory analysis 
of synovial NGF, tanezumab and potentially biomarker concentrations. 
Subjects will be asked to provide informed consent for the investigator to submit and have 
the synovial fluid sample analyzed and to collect and analyze additional blood samples 
unless the arthrocentesis is performed at a visit in which PK/PD blood samples are already 
being obtained.  These blood samples will be used for analysis of plasma tanezumab, serum 
NGF and potentially biomarker concentrations. 
Refer to Sections 7.5.1, 7.5.2, 7.5.3 and 7.6.3.
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7.5. Pharmacokinetic (PK) and Pharmacodynamic (PD)
7.5.1. Plasma for Analysis of Tanezumab
Blood samples for the assessment of the pharmacokinetics of tanezumab will be collected at 
Baseline (Day 1; pre-dose), Week 8 (pre-dose), Week 16 (pre-dose), Week 32 (pre-dose), 
Week 48 (pre-dose) and at Weeks 56 and 64 (or at Early Termination, as described in 
Section 6.4). If subjects terminate prior to Week 56, PK will be determined at approximately 
8 and 16 weeks after the last SC dose was administered (or at Early Termination, as 
described in Section 6.4).
If a subject has arthrocentesis performed (refer to Section 7.4.7) at a visit (scheduled or 
unscheduled) other than those identified above and the subject has provided informed 
consent for sample collection and analysis, a blood sample should be obtained for the 
assessment of the pharmacokinetics of tanezumab.  If this occurs at a visit in which a SC 
dose of investigational product is to be administered, the blood sample should be obtained 
pre-dose.
Instructions regarding sample collection and processing (eg, sample volumes, tube types, 
storage temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
PK samples may be used for further evaluation of the bioanalytical method.  These data will 
be used for internal exploratory purposes and will not be included in the clinical report.
The shipment address will be provided to the investigator site prior to initiation of the trial.
7.5.2. Nerve Growth Factor (NGF) for Pharmacodynamic Analyses
Blood samples will be collected for the assessment of NGF.  Nerve Growth Factor can exist 
in different forms including but not limited to NGF bound to drug or not bound to drug, NGF 
bound to soluble p75, and proNGF.  Blood volume collected may limit the number of NGF 
assessments to 3 to 4 NGF endpoints including a measure of total NGF (sum of all NGF 
forms). The NGF forms that will be analyzed will depend on the availability of suitable 
analytical methods. Blood samples for assessment of NGF will be collected at Baseline 
(Day 1; pre-dose), Week 8 (pre-dose), Week 48 (pre-dose) and at Weeks 56 and 64 (or at 
Early Termination, as described in Section 6.4).  If subjects terminate prior to Week 56, NGF 
will be determined at approximately 8 and 16 weeks after the last dose of SC investigational
product was administered (or at Early Termination as described in Section 6.4).
If a subject has arthrocentesis performed (refer to Section 7.4.7) at a visit (scheduled or 
unscheduled) other than those identified above and the subject has provided informed 
consent for sample collection and analysis, a blood sample should be obtained for the 
assessment of NGF.  If this occurs at a visit in which a SC dose of investigational product is 
to be administered, the blood sample should be obtained pre-dose.
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Instructions regarding sample collection and processing (eg, sample volumes, tube types, 
storage temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
NGF samples may be used for further evaluation of the bioanalytical methods used for 
measuring NGF.  These data will be used for internal exploratory purposes and will not be 
included in the clinical report.
The shipment address will be provided to the investigator site prior to initiation of the study. 
7.5.3. Synovial Fluid for Analysis of Tanezumab and NGF 
Providing the applicable informed consent has been obtained, synovial fluid samples for the 
assessment of tanezumab and NGF (See Sections 7.5.1, 7.5.2) assessments may be collected 
whenever an investigator performs arthrocentesis for a subject.  As arthrocentesis will be 
performed at the discretion of the investigator, it is not a scheduled or required protocol 
procedure and may occur at a scheduled or unscheduled visit. 
The total volume of synovial fluid that was collected as part of the procedure will be 
processed to accomodate the analysis of tanezumab, NGF and potentially biomarkers (refer 
to Section 7.6.3). 
Instructions regarding sample collection and processing (eg, sample volumes, tube types, 
storage temperatures) will be provided in the laboratory manual.
Samples will be analyzed using validated analytical methods in compliance with Pfizer 
standard operating procedures. 
Tanezumab and NGF samples may be used for further evaluation of the bioanalytical 
method.  This could include measurement of endogenous proteins that can bind to NGF.  
These data will be used for internal exploratory purposes and will not be included in the 
clinical report.
The shipment address will be provided to the investigator site prior to initiation of the study.
7.6. Biomarkers
7.6.1. Serum Biomarkers
Blood samples for the assessment of biomarkers that can be modulated by osteoarthritis will 
be collected at Baseline (Day 1; pre-dose), Week 8 (pre-dose), and Week 16 (pre-dose) for 
all subjects. 
For subjects that will have activity level monitoring via accelerometry (N ~360), additional 
biomarker samples will be collected at Week 32 (pre-dose), Week 48 (pre-dose), and at 
Weeks 56, 64, 80 (or at Early Termination, as described in Section 6.4).  If subjects terminate 
prior to Week 56, biomarker samples will be collected at approximately 8, 16 and 24 weeks 
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after the last dose of SC investigational product was administered (or at Early Termination, 
as described in Section 6.4). 
If possible, the samples should be obtained following a fasting period of at least 8 hours and 
at approximately the same time at each study visit to control for variation in the biomarkers
related to prandial status and diurnal cycle.  The fasting status will be recorded in the eCRF.
Currently the measurement of 12 biomarkers is planned: 
 
 
 
 
 
 
  This selection of biomarkers could change due to 
blood volume limitations and/or assay performance issues.  Osteoarthritis biomarkers that are 
different from the ones listed could be added or substituted if considered informative to 
further understand the osteoarthritis condition. 
Instructions regarding sample collection and processing (eg, sample volumes, tube types, 
storage temperatures) will be provided in the laboratory manual. 
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
Biomarker samples may be used for further evaluation of biomarkers other than the ones 
listed that could improve the understanding of the safety and efficacy profile of tanezumab.  
These data will be used for internal exploratory purposes and will not be included in the 
clinical report.
The shipment address will be provided to the investigator site prior to initiation of the study.
7.6.2. Urine Biomarkers
For the assessment of the cartilage biomarker 
 
urine samples will be collected at Baseline (Day 1; pre-dose), Week 8 (pre-dose), Week 16
(pre-dose) in all subjects.
For subjects that will have activity level monitoring via accelerometry (N ~360), additional 
biomarker samples will be collected at Week 32 (pre-dose), Week 48 (pre-dose) and at 
Weeks 56, 64, 80 (or at Early Termination, as described in Section 6.4).  If subjects terminate 
prior to Week 56, the biomarker samples will be collected at approximately 8, 16 and 
24 weeks after the last dose of SC investigational product was administered (or at Early 
Termination, as described in Section 6.4). 
Urine samples should be collected from the second void of the day or later.  If possible, the 
samples should be obtained following a fasting period of at least 8 hours and at 
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approximately the same time at each study visit to control for variation in the biomarkers 
related to prandial status and diurnal cycle.  The fasting status will be recorded in the eCRF.
Instructions regarding sample collection and processing (eg, sample volumes, tube types, 
storage temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
Biomarker samples may be used for further evaluation of biomarkers other than the ones 
listed that could improve the understanding of the safety and efficacy profile of tanezumab.  
These data will be used for internal exploratory purposes and will not be included in the 
clinical report.
The shipment address will be provided to the investigator site prior to initiation of the study.
7.6.3. Synovial Fluid Biomarkers
For subjects who had arthrocentesis performed during the study and who provided consent 
for analysis of synovial fluid samples, additional exploratory analyses of biomarker 
concentrations in synovial fluid may be undertaken.  If deemed appropriate following review 
of the available safety, synovial fluid and serum concentration (NGF and tanezumab) data, 
exploratory analyses would be initiated if assay methodology and residual sample volume 
permit.
7.7. Banked Biospecimens
7.7.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the DNA (deoxyribonucleic acid), 
RNA (ribonucleic acid), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. 
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited as such by local regulations or ethics committee decision. 
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by badge-swipe.  Data will be stored on password-protected computer 
systems.  The key between the code and the subject’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
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have access to the key nor any personally identifying information.  Biospecimens will only 
be used for the purposes described here and in the informed consent document/subject
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also post-marketing 
research.  Subjects can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses.  It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants.  Subjects are notified in the informed consent document/subject
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator.  Results will not be 
provided to family members or other physicians; nor will they be recorded in the subject’s 
medical record.  There is no intention to contact subjects after completion of the clinical 
study.
A 4 mL blood biospecimen Prep D1 (K2 EDTA whole blood collection optimized for DNA 
analysis) will be collected at the Baseline (Day 1) visit to be retained for potential 
pharmacogenomic/biomarker analyses related to drug response, unless prohibited by local 
regulations or ethics committee decision.  For example, putative safety biomarkers, drug 
metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to 
the mechanism of drug action may be examined.
The Banked Biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual. 
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/patient information sheet that 
they will not be compensated in this event.
7.7.2. Additional Research
Unless prohibited by local regulations, or ethics committee decision, subjects will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:
•
Investigations of the disease under study in the clinical trial, and related conditions.
•
Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
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Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Markers of Drug Response Section will be used.  Subjects may 
still participate in the clinical trial if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a
Serious Adverse Event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through the end of the safety Follow-up period or through 
and including 112 calendar days after the subject’s last administration of the subcutaneous 
investigational medication if the subject refuses the protocol defined Follow-up period. 
Serious adverse events occurring to a subject after the active reporting period has ended 
should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, 
all SAEs that the investigator believes have at least a reasonable possibility of being related 
to investigational product are to be reported to the Sponsor.
Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of investigational product through the subject’s last visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
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•
Abnormal test findings;
•
Clinically significant symptoms and signs;
•
Changes in physical examination findings;
•
Hypersensitivity;
•
Progression/worsening of underlying disease;
•
Drug abuse;
•
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:
•
Drug overdose;
•
Drug withdrawal;
•
Drug misuse; 
•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy (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 CRF, which is a specific version of the AE page, and on the serious adverse event 
(SAE) form when appropriate.  In the event of medication dosing error, the sponsor should 
be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:
•
Medication errors involving subject exposure to the investigational product;
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•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an adverse event, as determined by 
the investigator, the medication error is captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF 
page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
•
Test result is associated with accompanying symptoms, and/or
•
Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or
•
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or
•
Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A Serious Adverse Event is any untoward medical occurrence at any dose that:
•
Results in death;
•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
•
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.
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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 Complaint Reporting Requirements).  An incident is any malfunction 
(ie, the failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 
directly or indirectly, might lead to or might have led to the death of a subject, or user, or of 
other persons, or to a serious deterioration in their state of health. 
A serious injury that can cause a serious deterioration in state of health can include:
•
a life-threatening illness, even if temporary in nature;
•
a permanent impairment of a body function or permanent damage to a body structure; 
•
a condition necessitating medical or surgical intervention to prevent the above 2 
bulleted items;
Examples: clinically relevant increase in the duration of a surgical procedure, a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;
•
any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;
•
fetal distress, fetal death, or any congenital abnormality or birth defects.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the 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:
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•
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 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:
•
For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values ≥2 times the baseline values and ≥3 X ULN, or 
≥8 X ULN (whichever is smaller).
Concurrent with
•
For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X 
ULN or if the value reaches ≥3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen/paracetamol, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted.  All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for liver function test (LFT)
abnormalities identified at the time should be considered potential Hy’s law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
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.
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Hospitalization does not include the following:
•
Rehabilitation facilities;
•
Hospice facilities;
•
Respite care (eg, caregiver relief);
•
Skilled nursing facilities;
•
Nursing homes;
•
Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 
•
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality);
•
Social admission (eg, subject has no place to sleep);
•
Administrative admission (eg, for yearly physical examination);
•
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);
•
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);
•
Hospitalization for observation without a medical AE;
•
Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
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8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (refer to Section 8.14 Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
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).
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2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on 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 pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 
•
Spontaneous abortion includes miscarriage and missed abortion.
•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product 
Additional information regarding the 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.
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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 report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a 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 Section 6.4 Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  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 timeframe 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. 
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In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Medical Device Reporting Requirements
All medical device complaints regardless of whether the medical device complaint is 
associated with an AE will be collected on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might have led to death or serious deterioration 
in health. 
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.
Refer to the Pharmacy Manual for procedures for forwarding medical device complaints not 
associated with an SAE to Pfizer.
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  
This document may modify the plans outlined in the protocol; however, any major 
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modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
A sample size of approximately 1000 subjects for each of the treatment groups of NSAID, 
tanezumab 2.5 mg and tanezumab 5 mg will be used in this study.  This sample size allows 
for a high probability of observing subjects with any component of the composite endpoint 
where the event rate over this study is very small.  If the event rate were 0.25%, then there 
would be a >90% probability of observing at least one subject with an event in any single 
treatment group.
In addition, the sample size allows for good precision to estimate the incidence rate for each 
treatment group in order to estimate an upper bound for the true incidence rate.  The table 
below gives the width of the 95% confidence intervals for the individual treatment groups 
with this sample size.
Table 10.
Estimated Event Incidence Rate Precision
Observed Rate of Rapidly 
Progressive Osteoarthritis Type 2
95% Confidence Interval for 
Individual Treatment Groups 
(N=1000)
0%
[0, 0.37%]
0.1%
[0.00, 0.56%]
0.2%
[0.02, 0.72%]
0.3%
[0.06, 0.87%]
0.4%
[0.11, 1.02%]
0.5%
[0.16, 1.16%]
1.0%
[0.48, 1.83%]
For the assessment of the incidence of subjects with a total joint replacement, a sample size 
of approximately 1000 subjects per group would be sufficient to demonstrate a significant 
difference (p≤0.05) between any two treatment groups, for a difference of 2% with an 
observed control group rate for total joint replacement of 2%.  Similarly, for the assessment 
of the incidence of subjects with an adjudication outcome of rapidly progressive 
osteoarthritis type 2, a sample size of approximately 1000 subjects per group would be 
sufficient to demonstrate a significant difference (p≤0.10) between any two treatment groups, 
for a difference of 1% with an observed control group rate for rapidly progressive 
osteoarthritis of 0%.
For the efficacy assessments, a sample size of approximately 1000 subjects per group gives 
76% power for the treatment comparisons of both tanezumab 5 mg versus NSAID and 
tanezumab 2.5 mg versus NSAID all three co-primary efficacy endpoints, for assumed 
treatment differences of -0.73/-0.45 (tanezumab 5 mg/2.5 mg versus NSAID), -0.80/-0.53 
and -0.21/-0.11 for WOMAC Pain subscale, WOMAC Physical Function subscale and the 
Patient’s Global Assessment of Osteoarthritis, respectively.  The within-group standard 
deviations were 2.73, 2.58 and 0.92 for WOMAC Pain subscale, WOMAC Physical Function 
subscale and Patient’s Global Assessment of Osteoarthritis, respectively.  The correlation of 
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the change from Baseline to Week 16 value for WOMAC Pain subscale versus WOMAC 
Physical Function subscale was 0.93.  The correlations between Patient’s Global Assessment 
of Osteoarthritis and WOMAC Pain and Physical Function subscales were approximately 
0.68. 
For the Japanese specific efficacy assessments, a sample size of 1000 subjects per group 
gives 95% power for the treatment comparisons of both tanezumab 5 mg versus NSAID and 
tanezumab 2.5 mg versus NSAID two co-primary efficacy endpoints, for assumed treatment 
differences of -0.73/-0.45 (tanezumab 5 mg/2.5 mg versus NSAID) and -0.80/-0.53 for 
WOMAC Pain subscale and WOMAC Physical Function subscale, respectively.  The 
within-group standard deviations were 2.73 and 2.58 for WOMAC Pain subscale and 
WOMAC Physical Function subscale of Osteoarthritis, respectively.  The correlation of the 
change from Baseline to Week 16 value for WOMAC Pain subscale versus WOMAC Physical 
Function subscale was 0.93.
A sample size of approximately 220 subjects per treatment group is required within each of 
the three NSAID cohorts (celecoxib, naproxen and diclofenac).  This sample size would give 
an 80% power to detect statistical significance at the 5% significance level, for the 
comparison of tanezumab 5 mg versus individual NSAID groups in the WOMAC Pain 
subscale, assuming a treatment difference of -0.73 and a within-group standard deviation 
of 2.73.
Formal sample size calculation was not peformed for the actigraphy data collection, as 
published actigraphy data in a clinical trial with matched population was not available.  
However, data from Farr (2008), where the mean minutes of moderate to vigorous physical 
activity in an OA population is approximately 24 minutes per day, with a standard deviation 
of 20.  Assuming a standard deviation for the change from Baseline of 14 (using a Baseline 
to post-Baseline correlation of 0.75 to represent strong association in activity over 
2 timepoints), then a sample size of 120 subjects per treatment group would give 79 and 
91% power for treatment differences of 5 and 6 minutes respectively (approximately 20 and 
25% of the Baseline mean shown in this paper).61  
9.2. Primary Analysis
9.2.1. Analysis of Primary Endpoints
The incidence of subjects with any of the adjudication outcomes of rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fracture (or SPONK), primary 
osteonecrosis, or pathological fracture (primary composite endpoint) will be shown by 
number of subjects treated and subject years of exposure (treatment plus follow-up periods), 
for individual treatment groups and differences between tanezumab treatment groups and the 
NSAID treatment group.  The risk ratio and risk difference with 95% confidence intervals 
will be calculated for the comparisons of each tanezumab treatment group versus the NSAID 
treatment group, as well as significance tests for each treatment comparison.  The time to 
each event will be summarized, and (where there are sufficient numbers of subjects) 
Kaplan-Meier estimates of the time to event will be produced, together with an analysis of 
each tanezumab treatment group versus the NSAID treatment group using the log-rank test.
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The primary safety and efficacy population will be the ITT population, defined as all 
randomized subjects who received SC investigational product (either tanezumab or matching 
placebo).  The primary efficacy analysis will use multiple imputation methods for missing 
data at Week 16.  Details of the multiple imputation procedure are given below.  All 
treatment comparisons will use the two-sided 5% significance level.
The co-primary efficacy endpoints will be analyzed using an ANCOVA model, with model 
terms for Baseline score, Baseline Diary Average Pain, index joint (hip or knee), 
Kellgren-Lawrence grade, NSAID cohort (diclofenac, celecoxib or naproxen) and treatment 
group, and study site as a random effect.  The assessment of significance for the tanezumab 
SC versus NSAID treatment contrasts of the primary efficacy parameters will use a 
step-down testing strategy within each of the co-primary efficacy endpoints.  This order of 
significance testing is defined as first testing tanezumab 5 mg versus NSAID, and if 
statistically significant (p≤0.05) to then test tanezumab 2.5 mg versus NSAID.  Finally, the 
tanezumab dose group is declared as superior to NSAID if the corresponding treatment 
contrast is significant over all three co-primary endpoints (two co-primary efficacy endpoints 
in Japan).  This testing procedure will maintain the Type I error to 5% or less within each of 
the co-primary efficacy endpoints, and to less than 5% for all three co-primary efficacy 
endpoints (two co-primary efficacy endpoints in Japan).
The primary analysis of the co-primary endpoints will use multiple imputation for missing 
data, to account for uncertainty around the subject response.  The basis for imputing missing 
values will be dependent on the reasons for missing data.  For subjects with missing data due 
to discontinuation prior to Week 16 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 of the observed efficacy data 
at Week 16 (over all treatment groups).  For subjects with missing data for any other reason, 
imputation will be based on sampling from a normal distribution using a mean value equal to 
the subject’s last observed efficacy value and standard deviation of the observed efficacy 
data at Week 16 (over all treatment groups).  Imputed values for the Patient’s Global 
Assessment of Osteoarthritis will be rounded to integer values from 1 to 5 (For Japan, 
Patient’s Global Assessment of Osteoarthritis scores will not be imputed or used in the 
primary efficacy analysis).  Imputed values for WOMAC Pain and Physical Function 
subscales will be truncated at 0 and 10.  One hundred imputation samples will be used, and 
the ANCOVA model described above will be used for each imputation dataset.  The final 
results will be calculated using the combined sets of results from each imputation dataset 
analysis.4  
Additional analyses will explore the sensitivity of the effect of missing data. The first 
analysis will use the same main effects ANCOVA model as described above, but with Last 
Observation Carried Forward (LOCF) for missing data.  The second analysis will use the 
same main effects ANCOVA model as described above, but with Baseline Observation 
Carried Forward (BOCF) for missing data.  The third analysis will use Mixed Model for 
Repeated Measurements (MMRM) utilizing all observed data up to and including Week 16. 
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Additional analyses of the primary efficacy endpoints include comparisons of tanezumab 
2.5 and 5 mg versus the separate NSAID treatment groups of celecoxib, naproxen and 
diclofenac.  These analyses will not use the testing strategy described above, but assessment 
of significance will be made across all treatment comparisons and co-primary endpoints 
individually. 
All analyses will show estimates of the treatment group response and treatment group 
differences of each tanezumab treatment group versus NSAID, with corresponding standard 
errors of the mean, and 95% confidence intervals (and p-values for treatment differences).
9.2.2. Analysis of Secondary Endpoints
The incidence of subjects with any of the adjudication outcomes of rapidly progressive 
osteoarthritis (type-2), subchondral insufficiency fracture (or SPONK), primary 
osteonecrosis, or pathological fracture will be analyzed as described above for the primary 
endpoint.  In addition the same analysis will be performed for the individual events of 
all-cause total joint replacements, and adjudicated outcomes of rapidly progressive 
osteoarthritis (type-1, type-2 and both types 1 and 2 combined), subchondral insufficiency 
fracture (or SPONK), primary osteonecrosis and pathological fracture. 
Secondary efficacy endpoints will examine the change from Baseline to additional timepoints 
in the WOMAC Pain and Physical Function subscales, and the Patient’s Global Assessment 
of Osteoarthritis, using the multiple imputation for missing data procedure and analysis 
described above.  Other secondary endpoints include the WOMAC Stiffness subscale, 
WOMAC Average score and WOMAC Pain subscale items (Pain When Walking on a Flat 
Surface, and Pain When Going Up or Down Stairs), conducted for the change from Baseline 
to Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56.  Analysis of Average Pain in the index joint will 
be conducted for the change from Baseline to Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 
40, 48 and 56.  The analysis of these endpoints will use the same ANCOVA analysis as 
described above for the co-primary endpoints, with multiple imputation for missing data.
The OMERACT-OARSI responder index, and subject response endpoints of improvement in 
the WOMAC Pain ≥30, 50, 70 and 90%, WOMAC Physical Function ≥30, 50, 70 and 90%,
and improvement in the Patient’s Global Assessment of Osteoarthritis ≥2 will be analyzed 
for change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56 using logistic regression 
for binary data, with model terms for Baseline WOMAC Pain subscale score, Baseline 
WOMAC Physical Function or Baseline Patient’s Global Assessment score, Baseline Diary 
Average Pain, index joint, Kellgren-Lawrence grade, NSAID group and treatment group.  
The cumulative distribution of percent change to Weeks 16, 24 and 56 in the WOMAC Pain 
subscale score and WOMAC Physical Function subscale score will be summarized for the 
response categories of reductions of >0%, ≥10 to 90% (in steps of 10%) and 100% (no 
reported pain or difficulties at timepoint of interest).  Imputation for missing data will use 
both LOCF and BOCF, where imputation with BOCF will lead to the subject being assessed 
as a nonresponder for the response endpoint at a particular timepoint.  In addition, in order to 
closely match the primary imputation analysis, a mixed BOCF/LOCF imputation for 
response endpoints will be used.  In this analysis BOCF imputation (ie, a subject would be a 
nonresponder) would be used for missing data due to discontinuation for reasons of lack of 
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efficacy, adverse event or death up to the timepoint of interest, and LOCF imputation would 
be used for missing data for any other reason.
The change from Baseline in the Patient’s Global Assessment of Osteoarthritis to Weeks 2, 4, 
8, 16, 24, 32, 40, 48 and 56 will also be analyzed using the Cochran-Mantel-Haenszel test
(stratified by the combinations of the three stratification factors).  Changes by each level of 
improvement will be summarized.  For this analysis imputation for missing data will used 
mixed BOCF/LOCF, as well as BOCF and LOCF separately. 
The incidence and number of days per week of rescue medication use will be analyzed for 
Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56, and the amount of rescue medication use per week 
will be analyzed for Weeks 2, 4, 8 and 16.  The incidence of use of rescue medication will be 
analyzed using logistic regression for binary data, with model terms for Baseline WOMAC 
Pain subscale score, Baseline Diary Average Pain, index joint, Kellgren-Lawrence grade, 
NSAID group and treatment group.  The number of days and amount of rescue medication 
(mg dosage of acetaminophen) will be analyzed using the Negative Binomial model, with 
model terms of Baseline WOMAC Pain subscale score, Baseline Diary Average Pain, index 
joint, Kellgren-Lawrence grade, NSAID cohort, and treatment group.  Estimated levels of 
rescue medication use will be shown for each treatment group, and the ratio (with 95% CI) 
for comparisons versus NSAID will be shown.  Imputation for missing rescue medication 
data will use LOCF only.  The incidence and number of days of rescue medication use will 
be summarized up to Week 64, and the amount of rescue medication taken in a week 
summarized up to Week 16. 
The incidence of and time to withdrawal due to lack of efficacy will also be analyzed for 
discontinuation up to Week 56 (end of treatment period).  The time to discontinuation will be
analyzed using the log-rank test, with Kaplan-Meier estimates of the time to discontinuation 
shown for selected percentiles, dependent on the level of discontinuation.  The expectation is 
that these would be the 1st, 2nd, 5th, 10th and 25th percentiles.  Other percentiles may be shown 
if the level of discontinuation due to lack of efficacy as calculated using Kaplan-Meier 
procedure is sufficiently large.  The analysis of the incidence of discontinuation due to lack 
of efficacy will be made using logistic regression for binary data, with model terms for 
baseline WOMAC Pain subscale score, Baseline Diary Average Pain, index joint, 
Kellgren-Lawrence grade, NSAID group and treatment group.
A table showing number and percentage of subjects will summarize the response for each 
dimension (item) of the EQ-5D-5L at Baseline and Weeks 8, 16, 24, 40, 56 and 64.  These 
summary tables will be shown by treatment group.  In addition, for each treatment and each 
time point assessed, descriptive statistics (mean, standard deviation, median, number of 
subjects) will characterize the five-item health status profile on the EQ-5D-5L in terms of the 
health utility score and the EQ-VAS.
Summaries of the change from Baseline to Weeks 16, 24, 56 and 64 in the WPAI:OA 
impairment scores will be shown by treatment group.
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All data from TSQM and mPRTI will be summarized by visit.  The domains of the TSQM 
(satisfaction with effectiveness, side effects and convenience and overall satisfaction) and 
two items of the mPRTI (patient willingness to use drug again; patient preference of drug 
versus prior treatment) will be analyzed using the Cochran-Mantel-Haenszel test (stratified 
by the combination of the three stratification factors) at both Weeks 16 and 56.  For any 
analysis using the Cochran-Mantel-Haenszel test, if there are too few subjects in any 
stratification combination group then an unstratified test will be performed.  The HCRU data 
will be reported as outlined in the Statistical Analysis Plan.
All endpoints up to Week 64 will be summarized (where available), and endpoints up to 
Week 56 will be analyzed.  Any efficacy data collected at the Week 64 visit will be excluded 
from summary and analyses of efficacy with the following exception: Any efficacy data 
collected at the Week 64 visit for subjects that have discontinued the study early, and the 
observations are within 10 weeks after the last dose (8 weeks plus a window of 2 weeks) can 
be included in the efficacy summaries and analyses for the appropriate efficacy window in 
which the data falls.
9.3. Safety Analysis
Adverse events, concomitant medications, laboratory safety tests, physical and neurological 
examinations, vital signs, electrocardiogram (ECG), the anti-tanezumab antibody test will be 
collected for each subject during the study according to the Schedule of Assessments.  
Standard safety reporting tables will summarize and list the safety data. 
Separate adverse event summaries by treatment group for adverse events of decreased 
sympathetic function will be conducted.  More specifically, adverse events with the 
following preferred terms will be considered to represent adverse events of decreased 
sympathetic function:  Blood pressure orthostatic decreased, bradycardia, dizziness postural, 
heart rate decreased, orthostatic hypotension, presyncope, sinus bradycardia, syncope, 
anhidrosis, hypohidrosis, abdominal discomfort, diarrhea, early satiety, fecal incontinence, 
nausea, vomiting, ejaculation delay, ejaculation disorder, ejaculation failure, hypertonic 
bladder, micturition urgency, nocturia, urinary frequency, urinary hesitation, urinary 
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 9.6).
Selected adverse events of interest and common adverse events will be summarized using 
Risk Differences (with 95% confidence intervals) between each tanezumab group and 
NSAID.  In addition, significance testing will be performed for adverse events of interest 
between each tanezumab group and NSAID.  There will be no multiplicity adjustment for 
these significance tests. 
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Incidence of orthostatic hypotension using postural changes in blood pressure, in addition to 
mean changes in postural blood pressure will be summarized.
The Survey of Autonomic Symptoms (SAS) scores will be summarized by treatment group 
for the total number of symptoms reported and total impact score.  The summary will be 
shown by visit, and for the change from Baseline. 
The Neuropathy Impairment Score (NIS) is the sum of scores over all 37 items from both the 
Left and Right side.  The change from baseline to each post-baseline visit in the NIS (using 
LOCF for missing data), and to worst (largest) change from Baseline (over all post-Baseline 
visits) will be summarized, and analyzed using Cochran-Mantel-Haenszel test (stratified by 
the combinations of three stratification factors).  The NIS data, the neurological consultation 
data and the conclusion from neurological examination data will be reported.  The 
neurological consultation data will be summarized for all subjects, and for subjects with 
adverse events of abnormal peripheral sensation, which are described in the adverse event 
section above.  The “conclusion from the neurological examination” data will be summarized 
for each timepoint, and then a summary of the final assessment over all neurological 
examinations for each subject.
The change from Baseline to Weeks 56 and 80 in the Minimum Joint Space Width (JSW) for 
subjects with Kellgren-Lawrence grades of 2 or 3 in the index joint will be analyzed for 
subjects with measurements in the knee and hip separately.  The percentage of subjects with 
narrowing over a certain measurement will be shown, over the range of values from 0 
(ie, >0 mm, or any narrowing) to ≥2 mm, in addition to summary statistics of the mean (with 
standard error) and median narrowing.  Significant progression of osteoarthritis will be 
defined using the Bland-Altman method,54 as proposed by OARSI-OMERACT.55  
Progression will be defined as 1.96 times the within-subject standard deviation of the change 
in JSW.  The incidence of subjects with JSW narrowing greater than or equal to these values 
will be shown (with Kellgren-Lawrence grades of 2 or 3 in the index joint), and incidence 
analyzed using logistic regression for binary data, taking into account study site and baseline 
JSW as covariates.  This summary and analysis will be performed separately for subjects 
with osteoarthritis of the hip and knee.  These analyses will use the Week 56 End of 
Treatment/Early Termination data and then Week 80 End of Study/Early Termination 
regardless of the study day of assessment and/or where subjects have discontinued early from 
the study.  In the event of missing data, baseline data will not be carried forward for 
Radiographic data.  An additional analysis will be performed for assessments at one year and 
one and a half years (equivalent to observed data analysis for subjects who reach these 
timepoints).
9.3.1. Anti-Tanezumab Antibodies 
The following assessments of anti-tanezumab antibody formation will include:
•
For each tanezumab dose arm, a listing of anti-drug antibody test results sorted by 
subject, dose and nominal time post-dose.  The listing of results will also include the 
actual times post dose.
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•
For each tanezumab dose arm, the proportion of subjects who develop anti-tanezumab 
will be summarized.
•
Individual subjects with positive anti-tanezumab antibody results will be evaluated 
for potential impact on the individual’s pharmacokinetic, efficacy and safety profile.
9.4. Analysis of Other Endpoints
9.4.1. Pharmacokinetic Data
Tanezumab concentrations will be measured to support the development of a SC population 
PK model that allows for the prediction of the tanezumab concentration over time in 
individuals.  In addition tanezumab concentrations will be measured to inform the 
immunogenicity profile of tanezumab.
Reporting of PK data will include the following:
•
A listing of plasma tanezumab concentrations sorted by subject, dose and nominal 
time post dose.  The listing of concentrations will also include the actual times post 
dose.
•
A descriptive summary of the plasma tanezumab concentrations based on nominal 
time post dose for each dose.
•
A listing of available synovial fluid tanezumab concentrations sorted by subject, dose 
and nominal time post dose.  The listing of concentrations will also include the actual 
times post dose.
•
A descriptive summary of the available synovial fluid tanezumab concentrations 
based on nominal time post dose for each dose.
9.4.2. Pharmacodynamic (NGF) Data
Nerve Growth Factor data analyses will be conducted according to the NGF analysis plan.
9.4.3. Biomarker Data
Biomarker data analysis will be conducted according to the tanezumab biomarker analysis 
plan.
9.4.4. Physical Activity Level Data
9.4.4.1. Lower Extremity Activity Scale (LEAS)
The Lower Extremity Activity Scale score will be a integer value from 1 (bed bound) to 
18 (competitive athlete).  The number and percentage of subjects whose activity score is 
improved (increased), worsened (decreased) or have no change will be shown by treatment 
group for Weeks 4, 8, 16, 24, 56 and 80 (using LOCF for any missing data).  The change 
from baseline to each post-baseline visit (using LOCF for missing data), and for the worst 
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change from Baseline (over all post-Baseline visits) will be summarized, and analyzed using 
Cochran-Mantel-Haenszel test.
9.4.4.2. Actigraphy
Monitoring of physical activity level via actigraphy will be conducted in approximately 
360 subjects.
A valid day of monitoring will be defined as 10 or more wear hours in a 24-hour period as 
verified from accelerometer output.  During Screening, a complete monitoring period will be 
defined as containing at least 1 valid weekend day of data and a minimum of 4 valid days of 
monitoring.  During activity level monitoring between Week 14 and the Week 16 visit and 
between Week 54 and the Week 56 visit, a complete monitoring period will be defined as 
containing at least 2 valid weekend days of data and a minimum of 8 valid days of 
monitoring.
An average daily activity count will be calculated for each subject.  These data will then be 
sorted into three intensity thresholds: light, moderate and vigorous physical activity levels. 
The intensity count thresholds for each of these activity levels are described in the statistical 
analysis plan.  The data will be further summarized as total daily time (minutes) for each 
intensity level.  From these data the following parameters will be calculated:
1. Average daily physical activity counts.
2. Average daily minutes of physical activity.
3. Average daily minutes of moderate to vigorous physical activity (MVPA).
4. Average daily minutes of bouted MVPA.  A “bout” is defined as 10 or more 
consecutive minutes above the moderate physical activity level threshold, with 
allowance for interruptions of 1 or 2 minutes below the threshold. 
5. Average daily step count.
The change from Baseline to Week 16 and 56 will be calculated for these parameters.  
Summaries and analyses of these endpoints will use observed data for change from Baseline 
to Weeks 16 and 56, and imputation using last observation carried forward for Week 56. 
These parameters will be analyzed using the Negative Binomial model, with model terms of 
Baseline activity score, index joint, Kellgren-Lawrence grade, NSAID cohort, and treatment 
group. Estimated levels of each activity parameter will be shown for each treatment group, 
and the ratio (with 95% CI) for comparisons versus NSAID will be shown.
9.5. External Adjudication Committee
A blinded Adjudication Committee consisting of external experts in orthopedic surgery, 
rheumatology, orthopedic pathology, or radiology with expertise in subjects with end stage 
osteoarthritis and osteonecrosis will be convened.  The Adjudication Committee will have 
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written operating procedures and a Charter, including a specific description of the scope of 
their responsibilities.  In general, the Adjudication Committee will be asked to review all 
possible or probable joint-related safety events identified by the Central Reader (refer to 
Section 7.4.5), total joint replacement, as well as investigator reported adverse events of
osteonecrosis, rapidly progressive osteoarthritis, subchondral insufficiency fracture 
(spontaneous osteonecrosis of the knee [SPONK]) or pathologic fracture.  Adverse events 
related to joint safety that the investigator or sponsor considers medically important may also 
be reviewed by the Adjudication Committee.  These will include, but will not be limited to 
events identified for adjudication by the Central Reader (refer to Section 7.3.10).
Prior to the Adjudication Committee’s review of a given event, the Committee will be 
provided with blinded, available source documentation of progress reports from the 
investigator, orthopedic consult reports, operative reports, radiology reports, pathology 
reports, X-ray images, MRI images, and pathology specimens for review.  Copies of all 
relevant clinical information including the items listed above should be provided to Pfizer or 
its designee for review by the external Adjudication Committee.  Copies of the information 
should include the study number, site number and subject number, but it should not include 
the subject’s name or initials.
The E-DMC will be provided with a blinded summary of the Adjudication Committee’s 
review of events after each review meeting. 
9.6. Data Monitoring Committee 
An independent, E-DMC has been instituted for the tanezumab clinical program.  This 
committee will be composed of at least one rheumatologist, neurologist, statistician, and 
epidemiologist.  The E-DMC will review unblinded safety data including (but not limited to) 
adverse events and serious adverse events on a regular basis throughout the trial.  Adverse 
events of syncope, bradycardia, orthostatic hypotension, anhidrosis or hypohidrosis along 
with other adverse events that are possibly related to the sympathetic nervous system will be 
monitored by the E-DMC during review of unblinded safety data.  The E-DMC will have 
written operating procedures and a Charter, including a specific description of the scope of 
their responsibilities.
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the Charter.  If the blinded Adjudication Committee identifies adjudicated 
events of rapidly progressive osteoarthritis type 2, subchondral insufficiency fracture 
(spontaneous osteonecrosis of the knee [SPONK]), primary osteonecrosis or pathological
fracture, occurring at a rate that could trigger the protocol-based stopping criteria, an urgent, 
ad hoc assessment of the events will be made by the E-DMC. 
Any recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision.  Pfizer will forward such decisions which may include 
summaries of aggregate analyses of endpoint events and of safety data that are not endpoints, 
to regulatory authorities, as appropriate. 
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Pfizer Standard Operating Procedures regarding periodic safety reviews by the study team 
and the Tanezumab Risk Management Committee will be followed.  This committee will be 
composed of members inside and outside the immediate study team who will review blinded 
safety data from individual studies as well as data pooled across the studies on an ongoing 
basis.  A safety review plan will be in place governing the frequency and extent of safety 
review. 
9.6.1. Protocol-Level Rules for Dosing Suspension/Safety Assessment
9.6.1.1. Serious Adverse Events
Tanezumab safety will be reviewed at two levels; blinded data reviews by Pfizer and 
unblinded reviews by the 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 
control group subjects, the protocol-based rule for dosing suspension will be triggered.
The pre-specified serious adverse events are: 
•
Sudden cardiac death or cardiac death.
•
Acute renal failure.
•
Anaphylactic shock or severe anaphylactic reaction.
•
Neuropathic joint or neuropathic arthropathy (ie, Charcot joint).
•
Peripheral neuropathy confirmed with objective findings such as treatment-emergent 
abnormalities on neurologic examination, nerve conduction abnormalities or biopsy 
findings consistent with peripheral neuropathy.
•
One of the events related to sympathetic dysfunction (orthostatic hypotension, 
bradycardia, syncope, anhidrosis, or hypohidrosis).
If a protocol-based rule for dosing suspension is triggered, it will result in suspension of 
further dosing of subjects in the study until a decision is reached regarding whether it is safe 
to resume dosing in some or all treatment groups or whether the study should be terminated 
completely.  This decision will be made by the Sponsor in consultation with the tanezumab 
E-DMC.  
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If the protocol-based stopping rule is triggered, the E-DMC will consider the implications of 
this action on a program-level basis and formulate a recommendation whether it is safe to 
continue dosing (for some or all treatment groups) in other ongoing tanezumab clinical 
studies.  Decisions regarding stopping treatment in other ongoing tanezumab clinical studies 
will be made by the Sponsor in consultation with the E-DMC.
Factors that may be considered in making this decision in relation to serious adverse events 
or adjudicated clinically significant adverse events include:
•
Consideration of relationship of investigational product to the adverse event.
•
Consideration of whether similar adverse events are occurring in other tanezumab 
studies with similar subject populations.
•
Dosage of tanezumab (2.5 mg or 5 mg) and distribution of adverse events across 
tanezumab dose arms.
•
Possible differences in the baseline demographics between treatment groups.
•
Use of concomitant medications.
•
Possible differences in baseline medical history and/or co-morbidities.
•
Duration of therapy (0-6 months, 6-12 months).
9.6.1.2. Events Consistent with Hy’s Law
If two events are reported which are consistent with Hy’s Law in tanezumab-treated subjects, 
irrespective of dose across all ongoing osteoarthritis and chronic low back pain studies, 
dosing will be temporarily suspended in all studies until the relationship to study drug is 
established for the given events which were consistent with Hy’s Law. If two events 
consistent with Hy’s Law are considered to be related to treatment with tanezumab or the 
cause cannot be determined, all dosing in the tanezumab osteoarthritis and chronic low back 
pain program may be stopped.  The E-DMC will determine whether the dosing suspension 
should be triggered.  Subsequently the E-DMC will formulate a recommendation whether all 
studies should be permanently terminated.  Decisions regarding permanently stopping 
treatment and terminating studies will be made by the Sponsor in consultation with the DMC.
9.6.2. Joint Safety Events
If the blinded Adjudication Committee identifies adjudicated events of rapidly progressive 
osteoarthritis type 2, subchondral insufficiency fractures (or spontaneous osteonecrosis of the 
knee [SPONK]), primary osteonecrosis, or pathological fracture occurring at a combined rate 
that could trigger the protocol-based stopping criteria, an urgent, ad hoc assessment of the 
events will be made by the Data Monitoring Committee. 
The protocol (or treatment group) stopping rule has three components; the difference in the 
number of subjects with an adjudicated joint safety event, the exposure-adjusted risk 
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difference (RD) and the exposure adjusted risk ratio (RR) between each tanezumab treatment 
group and the active comparator group.  The exposure-adjusted RD will be calculated as the 
difference in the ratios of the number of subjects with an adjudicated joint safety event 
divided by exposure (patient-years) between each tanezumab group and the comparator 
group.  The exposure-adjusted RR will be similarly calculated using the ratio of exposure 
adjusted event rates (number of subjects with an adjudicated joint safety event divided by 
exposure) for each tanezumab group relative to the comparator group.  The exposure will be 
calculated as the combined treatment and follow-up periods.
If the RD 
 
 and the RR is 
and the difference in the number of subjects with adjudicated events joint safety events 
for any tanezumab treatment group versus the comparator treatment group, the 
protocol-based stopping rule will be triggered.  If the protocol-based stopping rule is 
triggered, the E-DMC will formulate a recommendation whether it is safe to continue dosing 
in some or all treatment groups or whether the study should be terminated completely.  This 
decision will be made by Pfizer in consultation with the E-DMC.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
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 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to the International Conference on Harmonisation 
(ICH) guidelines, local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
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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 in any other disclosures, except 
where required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, address, birth date and other identifiable data will be replaced by a numerical code 
based on a numbering system provided by Pfizer in order to de-identify study subjects.  The 
study site will maintain a confidential list of subjects who participated in the study, linking 
each subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer 
will maintain high standards of confidentiality and protection of subjects’ personal data 
consistent with applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
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The investigator must ensure that each study subject, or his/her legally acceptable
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then, 
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his or her own consent, the source documents 
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative before any 
study-specific activity is performed.  The investigator will retain the original of each subject's 
signed consent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
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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, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of tanezumab at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 1 week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome,
whether the clinical 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 
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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 multi center study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this Section.
For all publications relating to the Study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the (Clincial Study Agreement) CSA
between Pfizer and the institution.  In this section entitled Publications by Investigators, the 
defined terms shall have the meanings given to them in the CSA.
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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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29.
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influencing neuropathic endpoints: The Rochester Diabetic Neuropathy Study of 
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57.
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Abbreviations
This is a list of abbreviations that may or may not be used in the protocol.  
Abbreviation
Term
Ab
antibody
ACR
American College of Rheumatology
ADA
anti-drug antibody
AE
adverse event
AEMPS
Agency on Medicinal Products and Medical Devices
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASA
American Society of Anesthesiologists
AST
aspartate aminotransferase
BID
twice a day
BMI
body mass index
BOCF
baseline observation carried forward
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
CPK
creatine phosphokinase
CRF
case report form
CR
controlled release
CRA
Clinical Research Associate
 
CSA
clinical study agreement
CT
computed tomography
CTA
clinical trial application
CTS
carpal tunnel syndrome
CYP
cytochrome enzyme system
DAAP
United States Food and Drug Administration Division of 
Analgesia, Anesthetic, and Addiction Products
DAI
Dosage andAdministration Instructions
DNA
deoxyribonucleic acid
DXA
dual energy x-ray absorptiometry
EC
Ethics Committee
ECG
electrocardiogram
E-DMC
External Data Monitoring Committee
EDTA
edetic acid (ethylenediaminetetraacetic acid)
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CCI
CCI
CCI
CCI
CCI
CCI
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EIU
exposure in-utero
EQ-5D-5L
EuroQol 5 Dimension
ER
extended release
ESR
erythrocyte sedimentation rate
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator Brochure
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiation Protection
IND
Investigational New Drug application
INR
International Normalized Ratio
IgG
immunoglobulin G
IgG2
immunoglobulin G Type 2
IPAP
Initial Pain Assessment Period
IRB
institutional review board
IL
interleukin
IL-1β
Interleukin-1 beta
IRT
interactive response technology
ITT
intent to treat
IUD
intrauterine device
IV
intravenous 
JSW
joint space width
LDH
lactate dehydrogenase
LEAS
Lower Extremity Activity Scale
LFT
liver function test
LOCF
Last Observation Carried Forward
LSLV
last subject last visit 
LSMean
least squared mean
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MHRA
Medicines and Healthcare prodcuts Regulatory Agency
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CCI
CCI
CCI
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MMRM
mixed model for repeated measures
mPRTI
Patient Reported Treatment Impact assessment-modified
MMR
measles, mumps and rubella
MR
magnetic resonance
MRI
magnetic resonance imaging
mSv
millisievert
MVPA
moderate to vigorous physical activity
N/A
not applicable
NCI
National Cancer Institute
NGF
nerve growth factor
NGFI
nerve growth factor inhibitor
NIS
Neuropathy Impairment Score
NNH
number needed to harm
NNT
number needed to treat
NRS
numeric rating scale
NSAID
non-steroidal anti-inflammatory drug
NSC
Neuropathy Symptom Change
NYHA
New York Heart Association
OA
osteoarthritis
OMERACT-OARSI
Outcome Measures in Rheumatology – Osteoarthritis Research 
Society Initiative
OTC
over-the-counter
PCD
primary completion date
PD
pharmacodynamic
PEI
Paul Ehrlich Institute
PGA
Patient Global Assessment
PHQ-9
Patient Health Questionnaire 
PK
pharmacokinetic
PO
oral administration (per os)
PT
prothrombin time
PTH
parathyroid hormone
QD
once daily
QT
in electrocardiography, the time corresponding to the beginning 
of depolarization to repolarization of the ventricles
QTc
in electrocardiography, the time corresponding to the beginning 
of depolarization to repolarization of the ventricles, corrected for 
heart rate
QTcB
QT corrected for heart rate using Bazett’s formula
QTcF
QT corrected for heart rate using Fridericia’s formula
RD
risk difference
RNA
ribonucleic acid
RPOA
rapidly-progressive osteoarthritis
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CC
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RR
risk ratio
SAE
serious adverse event
SAS
Survey of Autonomic Symptoms
SC
subcutaneous
SOA
schedule of activities
SPONK
spontaneous osteonecrosis of the knee
SRSD
single reference safety document
TNF-α
tumor necrosis factor alpha
trkA
tropomyosin receptor kinase A
TSQM v.II
Treatment Satisfaction Questionnaire Medicine version II
ULN
upper limit of normal
US
United States
VAS
visual analog scale
WOMAC
Western Ontario and McMaster University Osteoarthritis Index
WPAI:OA
Work Productivity and Activity Impairment Questionnaire: 
Osteoarthritis 
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Appendix 1. American American College of Rheumatology (ACR) Classification 
Criteria for Osteoarthritis
1986 Osteoarthritis Knee Criteria54
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 Criteria56
Combined clinical (history, physical examination, laboratory) and radiographic criteria for 
osteoarthritis of the hip, traditional format.
1. Hip pain.
2. AND at least 2 of the 3 following features:
•
Erythrocyte sedimentation rate (ESR) less than 20 mm/hour.
•
Radiographic femoral or acetabular osteophytes.
•
Radiographic joint space narrowing (superior, axial, and/or medial).
Because the presence of osteophytes on X-ray is a protocol requirement (defined by a 
Kellgren-Lawrence X-ray Grade of ≥2 in inclusion criteria #3), protocol defined requirement 
for diagnosis of osteoarthritis of the hip will be the presence of hip pain, presence of 
osteophytes on X-ray and either an ESR<20 mm/hour OR joint space narrowing on X-ray.
ESR testing may be conducted at the local laboratory.
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Appendix 2. American Society of Anesthesiologists (ASA) Physical Status Classification
ASA Physical Status Classification
The ASA physical status classification system is used for assessing the fitness of patients 
before surgery.  In 1963 the American Society of Anesthesiologists (ASA) adopted the 
five-category physical status classification system;57 a sixth category was later added 
(http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Class
ification-System). 
1. A normal healthy patient.
2. A patient with mild systemic disease.
3. A patient with severe systemic disease.
4. A patient with severe systemic disease that is a constant threat to life.
5. A moribund patient who is not expected to survive without the operation.
6. A declared brain-dead patients whose organs are being removed for donor purposes.
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Appendix 3. Half-Lives of Prohibited Prior and Concomitant Medications
Half-Lives of NSAIDs and Other Analgesics
Use of analgesics (including marijuana) except acetaminophen / paracetamol is prohibited 
through Week 64 of the study beginning 48 hours prior to the start of the IPAP (the seven 
days prior to Randomization/Baseline (Day 1) or at the period of time prior to the start of the 
IPAP that is at least 5 times the half-life of the particular analgesic used, whichever is 
greater.  Note that a stable regimen of aspirin taken for cardiac prophylaxis at a dose of 
≤325 mg/day is permitted throughout the study.
These lists are not all-inclusive.  The Physician’s Desk Reference provides half-life 
information.
HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
Analgesic
Half-life (hours)
Minimum Washout Period
Aspirin >325 mg/day
0.25
2 days
Azapropazone
15.0
4 days
Bromfenac
1.3-3.1
2 days
Capsaicin (cream, 
ointments, patches)
2.0
2 days
Carprofen
12.0
3 days
Celecoxib
11.0
3 days
Codeine
3.5
2 days
Diclofenac gels
1.9
2 days
Diclofenac
1.1
2 days
Diclofenac/misoprostol
2.4-9.0
2 days
Diflunisal
13.0
3 days
Dipyrone
2.0-5.0
2 days
Etodolac
6.0
2 days
Fenbufen
11.0
3 days
Fentanyl
Contact study clinician
Fenoprofen
2.5
2 days
Flufenamic acid
1.4
2 days
Flurbiprofen
3.8
2 days
Hydrocodone
4.5
2 days
Hydromorphone
3.0
2 days
Ibuprofen
2.1
2 days
Indomethacin
4.6
2 days
Ketoprofen
1.8
2 days
Ketorolac
4.0-9.0
2 days
Lidocaine patch or EMLA
(lidocaine/prilocaine)
2.0 
2 days
Meclofenamate
2.0-4.0
2 days
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HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
Mefenamic acid
2.0
2 days
Meloxicam
16.0 to 20.0
5 days
Meperidine
3.7
2 days
Mexiletine
6.0-17.0 
4 days
Morphine
2.0
2 days
Nabumetone
26.0
6 days
Naproxen
14.0
3 days
Oxaprofen
40.0-50.0
11 days
Oxaprozin
58.0
13 days
Oxycodone
3.2
2 days
Oxycodone CR
8.0
2 days
Oxymorphone
7.3-9.4
2 days
Phenylbutazone
68.0
15 days
Piroxicam
57.0
12 days
Pirprofen
3.8
2 days
Propoxyphene
12.0
3 days
Salicylates
2.0-15.0
4 days
Sulindac
14
3 days
Suprofen
2.5
2 days
Tapentadol
4
2 days
Tenoxicam
60.0
13 days
Tiaprofenic acid
3.0
2 days
Tolmetin
1.0
2 days
Tramadol
5.9
2 days
Corticosteroids The following use of oral or intramuscular corticosteroids is prohibited 
through Week 64 of the study and: 1) within 30 days prior to the Initial Pain Assessment 
Period (the seven days prior to Randomization/Baseline) or, 2) at the period of time prior to 
the start of the Initial Pain Assessment Period that is at least 5 times the half-life of the 
particular corticosteroid used, whichever is greater or, 3) the anticipated need to start such 
during the study.  Intra-articular injection of corticosteroids within 12 weeks to the index 
joint or to any other joint within 30 days prior to the Initial Pain Assessment Period is 
PROHIBITED.  Topical, inhaled and intranasal corticosteroids are PERMITTED.
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Corticosteroids
Generic
Brand
betamethasone
Celestone, Soluspan
Cortisone
dexamethasone
Decadron, Dexacort, Turbinaire
fludrocortisone
Florinet
hydrocortisone
A-hydroCort, Cortef, Hydrocortone, Solu-Cortef
methylprednisolone
Medrol, Solu-Medrol
Prednisolone
Orapred, Prelone
Prednisone
Cortan, Deltasone, Medicorten
Hyaluronic Acid
Intra-articular hyaluronic acid injection to the index knee is prohibited within 30 days (or 
within 18 weeks for long-acting formulations such as Synvisc) of the Initial Pain Assessment 
Period and throughout the study.
Biologicals
Use of biologicals is prohibited within 3 months of the Initial Pain Assessment Period and 
during the study. 
The following lists are provided for your reference but may not be all-inclusive.  Refer to the 
Physician’s Desk Reference for exclusion determination of a particular agent.
TNFα Inhibitors
Generic
Brand
Adalimumab
Humira
Etanercept
Enbrel
Infliximab
Remicade
Use of live attenuated vaccines (with the exception of Flumist® Influenza Virus Vaccine 
Live, Intranasal or other inhaled live attenuated influenza vaccines and Pneumovax) is 
prohibited within 3 months of Initial Pain Assessment Period and during the study. 
The following lists are provided for your reference but may not be all-inclusive.  Refer to the 
Physician’s Desk Reference for exclusion determination of a particular agent.
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Live Attenuated Vaccines
Generic
Brand
BCG (for tuberculosis)
Not available in the US
Herpes zoster vaccine
Zostavax
Influenza, intranasal
FluMist
Measles
Attenuvax
Measles, Mumps, and Rubella (MMR)
MMR
Mumps
Mumpsvax
Oral poliovirus vaccine, oral
OPV (no longer available in the US)
Rotavirus, oral
RotaTeq
Rubella
Meruvax II
Smallpox
Dryvax (Not commercially available in the US)
Typhoid, oral
Vivotif Berna
Varicella zoster
Varivax
Yellow fever
YF-VAX
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Appendix 4. Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC)
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Appendix 5. Patient’s Global Assessment of Osteoarthritis
Patient’s Global Assessment of Osteoarthritis – Knee
Subjects will answer the following question when the knee is selected as index joint:
Considering all the ways your osteoarthritis in your knee affects you, how are you doing 
today?
Subjects will rate their condition using the following scale: 
Grade
Description
1 – Very Good
Asymptomatic and no limitation of normal activities
2 – Good 
Mild symptoms and no limitation of normal activities
3 – Fair 
Moderate symptoms and limitation of some normal activities
4 – Poor 
Severe symptoms and inability to carry out most normal activities
5 – Very Poor
Very severe symptoms which are intolerable and inability to carry out all 
normal activities
Patient’s Global Assessment of Osteoarthritis – Hip
Subjects will answer the following question when the hip is selected as index joint:
Considering all the ways your osteoarthritis in your hip affects you, how are you doing 
today?
Subjects will rate their condition using the following scale: 
Grade
Description
1 – Very Good
Asymptomatic and no limitation of normal activities
2 – Good 
Mild symptoms and no limitation of normal activities
3 – Fair 
Moderate symptoms and limitation of some normal activities
4 – Poor 
Severe symptoms and inability to carry out most normal activities
5 – Very Poor
Very severe symptoms which are intolerable and inability to carry out all 
normal activities
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Appendix 6. Work Productivity and Activity Impairment Questionnaire: Osteoarthritis 
of the Knee or Hip V2.0 (WPAI:OA)
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Appendix 7. EuroQol 5 Dimension (EQ-5D-5L)
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Appendix 8. Neuropathy Impairment Score (NIS) Sample
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Appendix 9. Patient Health Questionnaire (PHQ-9)
Administration of the PHQ-9 is not mandatory but may be used by the investigator to assess 
the severity of depression.  The severity score is the sum of questions 1-9 only.  A score of 
15 or higher on questions 1 through 9 indicates severe depression.  If used the PHQ-9 should 
be stored in the subject file.  The results of this instrument will not be entered into a database, 
nor will it be analyzed.
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Appendix 10. Osteoporosis Risk Factors58
Osteoporosis Risk Factors
Lifestyle Factors
Low calcium intake
Vitamin D insufficiency
Excess vitamin A
High caffeine intake
High salt intake
Aluminum (antacid use)
Alcohol (≥3 drinks / day)
Inadequate physical activity
Immobilization
Smoking (active or passive)
Falling
Thinness
Genetic Factors
Cystic fibrosis
Homocystinuria
Osteogenesis imperfect 
Ehlers-Danlos
Hypophosphatasia
Parental history of hip fracture
Gaucher’s disease
Idiopathic hypercalciuria
Porphyria
Glycogen storage disease
Marfan syndrome
Riley-Day syndrome
Hemochromatosis
Menkes steely hair syndrome
Hypogonadal States
Androgen insensitivity
Hyperprolactinemia
Turner’s & Klinefelter’s syndromes
Anorexia nervosa bulimia
Panhypopituitarianism
Athletic amenorhea
Premature ovarian failure
Endocrine Disorders
Adrenal insufficiency 
Diabetes mellitus
Thyrotoxicosis
Cushing’s syndrome
Hyperparathyroidism
Gastrointestinal Disorders
Celiac disease
Inflammatory bowel disease
Primary biliary cirrhosis
Gastric bypass
Malabsorption
GI surgery
Pancreatic disease
Hematologic Disorders
Hemophilia
Multiple myeloma
Systemic mastocytosis
Leukemia and lymphomas
Sickle cell disease
Thalassemia 
Rheumatic and Autoimmune Diseases
Ankylosing spondylitis
Lupus
Rheumatoid arthritis
Miscellaneous Conditions and Diseases
Alcoholism
Emphysema
Muscular dystrophy
Amyloidosis
End stage renal disease
Parenteral nutrition
Chronic metabolic acidosis
Epilepsy
Post-transplant bone disease
Congestive heart failure
Idiopathic scoliosis
Prior fracture as an adult
Depression
Multiple sclerosis
Sarcoidosis
Medications
Anticoagulants (heparin)
Cancer chemotherapeutic 
drugs
Gonadotrophin releasing hormone 
agonists
Anticonvulsants
Cyclosporine A and 
tacrolimus
Lithium
Aromatase inhibitors
Depo-medroxyprogesterone
Barbiturates
Glucocorticoids (≥5 mg/day of prednisone or equivalent for ≥3 months)
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Appendix 11. American College of Radiology Safety Screening Form and Magnetic 
Resonance Hazard Checklist59
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Appendix 12. Lower Extremity Activity Scale48
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Appendix 13. Treatment Satisfaction Questionnaire Medicine v.II
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Appendix 14. Adjudication Categories
Adjudication 
Category
Adjudicated Condition
1
Primary Osteonecrosis
2
Worsening Osteoarthritis
2a
Rapidly Progressive Osteoarthritis (type-1 or type-2)
2b
Normal progression of osteoarthritis
2c
Not enough information to distinguish between rapidly progressive osteoarthritis and 
normal progression of osteoarthritis
3
Subchondral insufficiency fracture
4
Pathologic fracture
5
Other (with diagnosis specified)
6
Not enough information to specify a diagnosis 
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Appendix 15. Survey of Autonomic Symptoms (SAS)60
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


Before enrolling in this clinical trial, what is the current or most recent treatment you were receiving for your 
osteoarthritis pain?
% + " $('%.	
(1) Injectable prescription medicines
(2) Prescription medicines taken by mouth 
(3) Surgery
(4) Prescription medicines and surgery
(5) No treatment
Overall, do you prefer the drug that you received in this study to the treatment you received before this clinical 
trial?
% + " $('%.	
(1) Yes, I definitely prefer the drug that I am receiving now
(2) I have a slight preference for the drug that I am receiving now
(3) I have no preference either way
(4) I have a slight preference for my previous treatment
(5) No, I definitely prefer my previous treatment





In the future, would you be willing to use the same drug that you have received in this study for your 
osteoarthritis pain?
(1) Yes, I would definitely want to use the same drug again
(2) I might want to use the same drug again
(3) I am not sure
(4) I might not want to use the same drug again
(5) No, I definitely would not want to use the same drug again
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SAP_000.pdf: 
Protocol A4091058 (PF-04383119) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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Protocol A4091058
A Phase 3 Randomized, Double-Blind, Active-Controlled, Multicenter Study of the 
Long-Term Safety and Efficacy of Subcutaneous Administration of Tanezumab in 
Subjects with Osteoarthritis of the Hip or Knee
Statistical Analysis Plan 
(SAP)
Version:
3.0
Author:
(Statistics, GPD)
Date:
01 March 2019
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PPD
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................8
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................9
4. APPROPRIATE HYPOTHESES AND DECISION RULES.............................................10
4.1. Statistical Hypotheses .............................................................................................10
4.2. Statistical Decision Rules........................................................................................10
5. ANALYSIS SETS ...............................................................................................................12
5.1. Full Analysis Set .....................................................................................................12
5.2. Per Protocol Analysis Set........................................................................................12
5.3. Safety Analysis Set..................................................................................................13
5.4. Other Analysis Sets .................................................................................................13
5.5. Treatment Misallocations........................................................................................13
5.6. Protocol Deviations.................................................................................................13
5.6.1. Major Deviations Assessed Prior to Randomization..................................14
5.6.2. Major Deviations Assessed Post-Randomization.......................................14
6. ENDPOINTS AND COVARIATES ...................................................................................14
6.1. Efficacy Endpoint(s) ...............................................................................................15
6.2. Safety Endpoints .....................................................................................................16
6.3. Other Endpoints.......................................................................................................20
6.3.1. PK Endpoints..............................................................................................20
6.3.2. PD Endpoints..............................................................................................20
6.3.3. Outcomes Research Endpoints ...................................................................20
6.3.4. Activity Level Monitoring Endpoints.........................................................21
6.4. Covariates................................................................................................................22
6.5. Subgroup Analyses..................................................................................................23
7. HANDLING OF MISSING VALUES ................................................................................23
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................27
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8.1. Statistical Methods ..................................................................................................28
8.1.1. Analyses for Continuous Data....................................................................28
8.1.2. Analyses for Categorical Data....................................................................29
8.1.3. Analyses for Binary Endpoints...................................................................30
8.2. Statistical Analyses .................................................................................................31
8.2.1. Primary Analysis (Efficacy) .......................................................................31
8.2.2. Secondary Analyses (Efficacy)...................................................................32
8.2.3. Safety Analyses ..........................................................................................37
8.2.3.1. Safety Endpoints (including Primary Joint Safety 
Endpoint)...........................................................................................37
8.2.3.2. Other Safety Assessments .........................................................39
8.2.4. Other Analyses............................................................................................42
8.2.4.1. Pharmacokinetics ......................................................................42
8.2.4.2. Pharmacodynamics (NGF)........................................................43
8.2.4.3. Osteoarthritis Biomarkers .........................................................43
8.2.5. Summary of Efficacy Analyses ..................................................................44
9. REFERENCES ....................................................................................................................57
10. APPENDICES ...................................................................................................................58
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................................5
LIST OF FIGURES
Figure 1.
Graphical Multiple Testing Procedure for Strong Control of Type I Error..........11
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................58
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................58
Appendix 1.2. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations............................................................................................62
Appendix 1.3. Definition of Analysis Populations/Sets ..........................................................62
Appendix 1.4. Further Definition of Endpoints.......................................................................62
Appendix 2. WPAI:OA Endpoints ..........................................................................................64
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Appendix 3. STATISTICAL METHODOLOGY DETAILS..................................................70
Appendix 3.1. Further Details of Interim Analyses.................................................................70
Appendix 3.2. Further Details of the Statistical Methods........................................................70
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
12 Feb 2014
Original 
01 Apr 2015
N/A
N/A
2
28 Mar 2016
1
10 Jul 2015
Regulatory 
input, 
clarification of 
prior version
•
Clarifications on various analysis 
populations or subsets for efficacy, 
safety, etc;
•
Analysis windows for visit-based 
assessments and for pain diary weekly 
means;
•
Updates and clarifications on various 
endpoints for analysis purpose including 
PK, PD and OA biomarkers; 
•
Specifications on the safety and efficacy 
analysis and summary periods; 
•
Revising the Tier 3 AE definition from 
1% to 5%;
•
Miscellaneous updates or changes to 
align with the amended protocol.
3
01 Mar 2019
2
15 May 2016
Blinded data 
review,
Clarification of 
prior version,
Program 
decisions
•
Various formatting and editorial 
clarifications (throughout);
•
Updating of definitions and analyses for 
consistency with protocol and program 
(throughout);
•
Clarification of treatment period and 
safety follow-up period as main periods 
for safety summaries (throughout);
•
Specification of gatekeeping testing 
strategy for co-primary and key 
secondary endpoints (Section 4.2);
•
Clarification of analysis set definitions 
(Section 5);
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•
Clarification of baseline definition 
(Section 6);
•
Updated adverse event terms (Section 
6.2);
•
Specification of seeds for efficacy 
datasets (Section 7);
•
Clarification of on-/off-treatment data 
and windowing (Section 8);
•
Addition of sensitivity analysis 
excluding sites with potential 
compliance issues (Section 8.2.1);
•
Clarification of joint space width 
analysis (Section 8.2.3.1).
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicized.
2.1. Study Design
The study design is summarized in the diagram below.
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Subjects will be randomized to one of three treatment groups (placebo SC + NSAID, 
tanezumab 2.5 mg SC + oral placebo, or tanezumab 5 mg SC + oral placebo).  NSAID 
dosing will be BID, and SC dosing will be every 8 weeks at Baseline and Weeks 8, 16, 24, 
32, 40 and 48 (a maximum of 7 doses of SC tanezumab or placebo).
The end of treatment period is at Week 56, with the safety follow-up period up to Week 80.  
The primary time point for efficacy is Week 16.  The period of interest for most safety results 
is the treatment period.  Selected safety results will also be provided 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.
The randomization is stratified by Index Joint (Knee or Hip), the NSAID treatment that the 
subject was taking prior to the study start (naproxen, celecoxib or diclofenac), and the highest 
Kellgren-Lawrence grade (Grade 2, 3 or 4) for the subject for any knee or hip joint, which 
may not necessarily relate to the index joint.
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2.2. Study Objectives
Primary Objectives
•
Characterize the long-term risk of joint safety events in subjects with osteoarthritis of 
the knee or hip who receive tanezumab 2.5 mg or tanezumab 5 mg SC versus NSAID 
treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 
75 mg BID) over the course of 56-weeks of treatment using a composite endpoint 
(includes adjudication outcomes of rapidly progressive osteoarthritis type-1 or 
type-2, subchondral insufficiency fracture, primary osteonecrosis, or pathological 
fracture).
•
Demonstrate superior efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus 
NSAID treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 
75 mg BID) at Week 16.
Secondary Objectives
•
Characterize the long-term joint safety risk using a composite endpoint (includes 
adjudication outcomes of rapidly progressive osteoarthritis (type-2 only), 
subchondral insufficiency fracture, primary osteonecrosis, or pathological fracture).
•
Characterize the long-term risk of the following individual adjudication outcomes 
occurring: 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.
•
Characterize the long-term risk of all-cause total joint replacements (subjects who 
undergo total joint replacement plus subjects who have an adjudicated outcome of 
rapidly progressive osteoarthritis type-1 or type-2, subchondral insufficiency 
fracture, primary osteonecrosis, or pathological fracture whether they undergo total 
joint replacement or not) occurring. 
•
Characterize joint space width changes in subjects with Kellgren-Lawrence Grade 2 
or 3 osteoarthritis of the index knee or index hip. 
•
Demonstrate superior efficacy of tanezumab 5 mg and tanezumab 2.5 mg SC versus 
each separate NSAID treatment group (naproxen 500 mg BID, celecoxib 100 mg BID 
and diclofenac ER 75 mg BID) at Week 16.
•
Demonstrate the efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus NSAID 
(combined) treatment at all time points to Week 56.
•
Evaluate the long-term safety of tanezumab 2.5 mg and tanezumab 5 mg SC.
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•
Explore relationships between adjudicated outcomes of rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fracture, primary 
osteonecrosis, or pathological fracture and variables that may be associated with 
these orthopedic risks.
•
Characterize changes in physical activity level.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
There is no interim analysis for efficacy data planned for this study. The final analysis will 
be performed after the database is released. 
Safety data will be subject to regular and ongoing reporting and review throughout the study.  
The details of these interim analyses will be documented in a separate Statistical Analysis 
Plan.  Review of the safety data will be by the tanezumab external Data Monitoring 
Committee (E-DMC).
A blinded Adjudication Committee will be convened and asked to review all possible or 
probable joint-related safety events identified by the Central Reader (rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fractures, primary osteonecrosis, 
or pathological fracture), total joint replacement as well as investigator reported adverse 
events of osteonecrosis, rapidly progressive osteoarthritis, subchondral insufficiency fracture 
or pathologic fracture.  Adverse events related to joint safety that the investigator or sponsor 
considers medically important may also be reviewed by the Adjudication Committee.  A 
stopping rule relating to a set of adjudicated outcomes has been defined, and is described 
below.
If the blinded Adjudication Committee identifies adjudicated events of rapidly progressive 
osteoarthritis type 2, subchondral insufficiency fractures, primary osteonecrosis, or 
pathological fracture occurring at a combined rate that could trigger the protocol-based 
stopping criteria, an urgent, ad hoc assessment of the events will be made by the Data 
Monitoring Committee.
The protocol (or treatment group) stopping rule has three components; the difference in the 
number of subjects with an adjudicated joint safety event, the exposure-adjusted risk 
difference (RD) and the exposure adjusted risk ratio (RR) between each tanezumab treatment 
group and the active comparator group. The exposure-adjusted RD will be calculated as the
difference in the ratios of the number of subjects with an adjudicated joint safety event 
divided by exposure (patient-years) between each tanezumab group and the comparator 
group. The exposure-adjusted RR will be similarly calculated using the ratio of exposure 
adjusted event rates (number of subjects with an adjudicated joint safety event divided by 
exposure) for each tanezumab group relative to the comparator group. The exposure will be 
calculated as the combined treatment and follow-up periods.
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If the protocol-based stopping rule is triggered, the E-DMC will formulate a 
recommendation whether it is safe to continue dosing in some or all treatment groups or 
whether the study should be terminated completely. This decision will be made by Pfizer in 
consultation with the E-DMC.
A separate set of dosing suspension rules for specified Serious Adverse Events and events 
consistent with Hy’s Law are described in Section 9.6.1 of the protocol.
4. APPROPRIATE HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The treatment comparisons being made in this study are tanezumab 2.5 mg and 5 mg versus 
NSAID (for combined, and individual NSAIDs). The co-primary efficacy endpoints are
changes from baseline to Week 16 in the WOMAC pain subscale and physical function 
subscale and in the Patient’s Global Assessment of Osteoarthritis, respectively. For these 
treatment comparisons, the null and alternative hypotheses are shown below (note 
μTREATMENT relates to the mean change from Baseline for the specified treatment group).  All 
tests will be 2-sided.
Null Hypotheses
H0: 
0
NSAID
2.5mg
  
TANEZUMAB
=
−μ
μ
H0: 
0
NSAID
5mg
  
TANEZUMAB
=
−μ
μ
Alternative Hypotheses
H1: 
0
NSAID
2.5mg
  
TANEZUMAB
≠
−μ
μ
H1: 
0
NSAID
5mg
  
TANEZUMAB
≠
−μ
μ
The hypotheses for other types of analyses (eg, for the binary response endpoints) would be 
similar to those shown above.
4.2. Statistical Decision Rules
The Type I error rate (α-level) used in the assessment of pair-wise treatment comparisons for 
the primary efficacy endpoints is 5%.  The testing strategy of the co-primary and key 
secondary efficacy endpoints is described below.
In addition to the three co-primary endpoints, the percentage of subjects with ≥50% reduction 
from baseline in WOMAC Pain at Week 16 is identified as a key secondary endpoint.  The 
testing of these co-primary endpoints and key secondary endpoint will follow the graphical 
approach of gate keeping strategy proposed by Bretz et al (2011), as depicted in the 
following figure.  This will be implemented to control the family-wise type I error rate of 
5% (two-sided), and this graphical approach is a closed testing procedure; hence, it strongly 
controls the family-wise error rate (Alosh et al. 2014).5
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Figure 1.
Graphical Multiple Testing Procedure for Strong Control of Type I Error
The co-primary outcome of tanezumab (TAN) 5 mg versus NSAID will first be tested at a 
two-sided α=0.05 (ie, WOMAC Pain subscale, WOMAC Physical Function subscale, and 
PGA at 16 weeks for TAN 5 mg vs NSAID must all be significant at two-sided α=0.05 for 
the co-primary to be significant). If the null hypothesis is not rejected, no further testing is 
conducted as the α for that test is considered “spent” and cannot be passed to other 
endpoints. The testing process continues as long as at least one null hypothesis can be 
rejected at its assigned α-level. Each time a null hypothesis is rejected, the graph is updated 
to reflect the reallocation of α assigned to that hypothesis, which is considered “recycled” 
(Alosh et al. 2014). This iterative process of updating the graph and reallocating α is 
repeated until all hypotheses have been tested or when no remaining hypotheses can be 
rejected at their corresponding α level.
In the Figure 1, the three co-primary endpoints are represented by a single graphical node per 
dose. As described above, a particular tanezumab dose group is declared as superior to 
placebo on the primary analysis if the corresponding treatment contrast is significant over all 
three co-primary endpoints. This is equivalent to a sequential gatekeeping approach where 
each of the three co-primary endpoints are tested in order of WOMAC Pain, WOMAC 
Physical Function, and PGA. If all three are significant, the alpha is reallocated to the next 
endpoint(s). For clarity of the graph (and to highlight that all three endpoints must be
significant for that dose), the co-primaries are grouped by dose rather than displaying all six 
tests individually. This testing procedure will maintain the Type I error to 5% or less for 
each dose’s co-primary efficacy endpoint overall, and to less than 5% for each dose’s three 
co-primary efficacy endpoints individually. 
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For Japan, the procedures outlined above are followed for the two co-primary endpoints, 
WOMAC Pain and WOMAC Physical Function.
The primary analysis will be that with the multiple imputation approach (see below for 
details), and thus the overall type I error is controlled for each of the two doses (2.5 mg and 
5 mg) since all three (two) co-primary endpoints need to be significant for a single dose. The 
overall type I error of the study is also controlled given the step-down testing strategy for 
each of the endpoints. Control of the family wise type I error rate accounting for multiplicity 
of contrasts will only apply to the three (two) co-primary endpoints (model with the primary 
imputation analysis) and the key secondary endpoint.
Regardless of the outcome of the primary analyses and the key secondary endpoint, other 
secondary endpoints will be tested.  No adjustment for multiple comparisons will be made 
for the secondary and safety endpoints.  The α-level for each hypothesis test for the 
secondary and exploratory analyses will be 5%.  There is no testing strategy for the primary 
safety endpoint.
5. 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.
5.1. Full Analysis Set
The intent to treat (ITT) analysis set is the primary analysis set for efficacy and safety 
analyses.  It consists of all randomized subjects who received at least one dose of SC study 
medication (either tanezumab or placebo SC).  This analysis set is used in the presentations
of all efficacy data, and all data listings, and is labeled as the ‘ITT Analysis Set’ or ‘ITT 
Population’. 
This analysis set is expected to be the same as the safety analysis set.  If a subject is treated 
without having been randomized, then the analysis sets will be different, and safety analyses 
will use this different safety analysis set (see Section 5.3).  If the sets are the same, safety 
analyses may still refer to it as the ‘Safety Population’.
5.2. Per Protocol Analysis Set 
The per-protocol (PP) analysis set is the secondary efficacy analysis set.  It is defined as all 
subjects in the ITT analysis set who are not major protocol deviators (which would 
potentially affect efficacy).  The criteria for major protocol deviators are described below in 
Section 5.6.  The identification of specific subjects included and excluded (and reason for 
exclusion) for this analysis set will be done prior to unblinding.  Protocol deviations for the 
PP analysis set will be obtained from the collected list of potentially important protocol 
deviations, and this list will comprise deviations identified from review of programmed 
listings and study monitoring.  This analysis set is used in a specific sensitivity analysis of 
the co-primary efficacy endpoints, and is labeled as the ‘Per Protocol Population’.
1
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5.3. Safety Analysis Set
The safety analysis set is defined as all subjects treated with tanezumab or placebo SC. And 
it will be labeled as the ‘Safety Analysis Set’ or ‘Safety Population’ in the corresponding 
data analysis and summary presentations. 
5.4. Other Analysis Sets
Accelerometry Analysis Set: This is defined as all subjects treated with tanezumab or 
placebo SC who have any baseline or post-baseline accelerometry data. Only a subset of the 
enrolled subjects will have accelerometry data collected.
Joint Safety Event Biomarker Analysis Set: This analysis set will be described separately 
from this analysis plan.
NGF Subgroup Analysis Set: This analysis set includes selected subjects in each treatment 
group for whom serum NGF results are available.
Synovial Fluid Analysis Set: Subjects who have arthrocentesis performed and for whom 
synovial fluid data is available. 
5.5. Treatment Misallocations 
If a subject was:
•
Randomized but not treated with SC treatment, 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 reviewed on a 
case-by-case basis by the study team and a decision on potential changes related to 
the subject and on how to analyze the data for safety analyses will be made in a 
timely manner and prior to database unblinding.
5.6. Protocol Deviations
The PP analysis set is the secondary efficacy analysis set.  It is defined as all subjects in the 
ITT analysis set who are not major protocol deviators (which would potentially affect 
efficacy).  The criteria for defining a major protocol deviator are described below in 
Section 5.6.1 and Section 5.6.2.  The identification of specific subjects included and excluded 
(and reason for exclusion) for this analysis set will be made and documented prior to 
unblinding.  Any other major deviation which is not pre-specified below, but results in a 
subject being excluded from the PP analysis set, will be specified in the protocol deviations 
document which is completed prior to unblinding.
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The following protocol deviations are defined as ‘major’ and would exclude a subject from 
the PP analysis set (see Section 5.2).  These deviation criteria can be split into those assessed 
prior to randomization relating to the protocol inclusion and exclusion criteria, and those 
assessed post randomization. 
5.6.1. Major Deviations Assessed Prior to Randomization
•
Inclusion criteria: #3-5.
•
Exclusion criteria: #3, 4 (if any of the following conditions are in the index joint: 
severe chondrocalcinosis, other arthropathies [eg, rheumatoid arthritis], systemic 
metabolic bone disease [eg, pseudogout, Paget’s disease, metastatic calcifications], 
primary or metastatic tumor lesions, stress or traumatic fracture),10, 16, 17, 18 (if 
index joint was involved), 19.
•
Randomization criteria: #1, 3-6.  Note, subjects with missing Baseline data for any of 
the co-primary endpoints would not meet the randomization/inclusion criteria for 
Baseline co-primary endpoints and so would be defined as a deviation according to 
these criteria.
5.6.2. Major Deviations Assessed Post-Randomization
•
Mismatch in specification of index joint in the CRF vs. electronic tablet for WOMAC 
data collection.
•
Rescue medication taken within 24 hours prior to the Week 16 visit.
•
Prohibited medications that could affect pain and function assessments (protocol 
section 5.8.1) taken (i) within 48 hours prior to Week 16 visit for non-NSAID 
medications (or any use if long-acting, eg, Synvisc), or (ii) within 48 hours prior to 
Week 16 visit or within the wash-out period specified by Appendix 3 of the protocol, 
for NSAID medications.
•
Subjects who were <50% compliant with oral study medication between the baseline 
and the Week 16 visit.
In addition, unforeseen major protocol deviations may be added to this list. However the 
final definition of this criteria and the per-protocol population will be made prior to 
unblinding of this study.
6. ENDPOINTS AND COVARIATES
Baseline is generally defined as the last observation prior to first receipt of study drug, within 
the baseline window as defined in Appendix 1.1.
For analysis of diary pain intensity scores for the index joint, baseline is defined as the mean 
average daily Pain NRS score using the last 3 values during the final 7 days of the Initial Pain 
Assessment Period prior to Randomization/Day 1.
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6.1. Efficacy Endpoint(s)
The co-primary efficacy endpoints are listed below.
•
Change from Baseline to Week 16 in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain subscale.
•
Change from Baseline to Week 16 in the WOMAC Physical Function subscale.
•
Change from Baseline to Week 16 in the Patient’s Global Assessment of 
Osteoarthritis (Note, this is not a primary endpoint for Japan).
The secondary efficacy endpoints are listed below.
•
WOMAC Pain subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 40, 48, 56 and 
Week 64.
•
WOMAC Physical Function subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 
40, 48, 56 and Week 64.
•
Patient’s Global Assessment of Osteoarthritis change from Baseline to Weeks 2, 4, 8, 
16 (Japan only), 24, 32, 40, 48, 56 and Week 64.
•
OMERACT-OARSI responder index at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 
Week 64.
•
Treatment Response: Reduction in the WOMAC Pain subscale of ≥30%, ≥50%, ≥70% 
and ≥90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Cumulative distribution of percent change from Baseline in the WOMAC Pain 
subscale score to Week 16, 24, and 56 (endpoint for summary only).
•
Treatment Response: Reduction in the WOMAC Physical Function subscale of 
≥30%, ≥50%, ≥70% and ≥90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Cumulative distribution of percent change from Baseline in the WOMAC Physical 
Function subscale score to Week 16, 24, and 56 (endpoint for summary only).
•
Treatment Response: Improvement of ≥2 points in Patient’s Global Assessment of 
Osteoarthritis at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Average pain score in the index joint change from Baseline to Weeks 1, 2, 3, 4, 6, 8, 
10, 12, 16, 20, 24, 32, 40, 48, 56 and Week 64.
•
WOMAC Stiffness subscale change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 
56 and Week 64.
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•
WOMAC Average change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 
Week 64.
•
WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface, change from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
WOMAC Pain Subscale Item: Pain When Going Up or Down Stairs, change from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Work Productivity and Activity Impairment Questionnaire for Osteoarthritis 
(WPAI:OA) impairment scores change from Baseline to Weeks 16, 24, 56 and 64.
•
EuroQol 5 Dimension (EQ-5D-5L™) dimensions and overall health utility score at 
Baseline and Weeks 8, 16, 24, 40, 56 and 64.
•
Treatment Satisfaction Questionnaire Medicine v.II (TSQM v.II) satisfaction with 
effectiveness, side effects and convenience, and overall satisfaction at Weeks 16 
and 56.
•
Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 
and 56.
•
Incidence and Time to discontinuation due to Lack of Efficacy.
•
Usage of rescue medication (incidence and number of days of use) during Weeks 2, 4, 
8, 16, 24, 32, 40, 48, 56 and Week 64.
•
Usage of rescue medication (amount taken) during Weeks 2, 4, 8 and Week 16.
•
Health Care Resource Utilization at Baseline and Weeks 64, and 80.
Note, in this document where reference is made to three co-primary efficacy endpoints this 
relates to all countries except Japan, where there are only two co-primary efficacy endpoints
(WOMAC Pain and Physical Function subscale scores).
6.2. Safety Endpoints
The primary joint safety endpoint is listed below:
•
Incidence of a predefined composite endpoint consisting of adjudication outcomes of 
rapidly progressive osteoarthritis (type-1 or type-2), subchondral insufficiency 
fracture, primary osteonecrosis, or pathological fracture (primary composite 
endpoint).
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The secondary bone and joint safety endpoints are listed below:
•
Incidence of a predefined composite endpoint consisting of adjudication outcomes of 
rapidly progressive osteoarthritis (type-2 only), subchondral insufficiency fracture, 
primary osteonecrosis, or pathological fracture.
•
Incidence of individual adjudication 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.
•
Incidence of all-cause total joint replacements (subjects who undergo total joint 
replacement plus subjects who have an adjudicated outcome of rapidly progressive 
osteoarthritis type-1 or type-2, subchondral insufficiency fracture, primary 
osteonecrosis, or pathological fracture whether they undergo total joint replacement 
or not).
Reporting of total joint replacement events including surgery and recovery will be 
described in a separate Statistical Analysis Plan for Study 1064, and reported in the 
1064 study report.  Corresponding data from Studies 1056, 1057 and 1058 will be 
reported under study 1064, as well as patients who enter study 1064 from studies 1059, 
1061, and 1063 due to those studies closing out.
The Radiographic Endpoints are listed below:
•
Change from Baseline to Week 56 and Week 80 in Medial or Lateral Minimum Joint 
Space Width of the index knee (for subjects with Kellgren-Lawrence Grade 2 or 
3 medial or lateral osteoarthritis of the index knee).
•
Change from Baseline to Week 56 and Week 80 in Minimum Joint Space Width of the 
index hip (for subjects with Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the 
index hip).
•
Incidence of subjects with progression of osteoarthritis in the index knee according to 
Bland and Altman method, at Week 56 and Week 80 (separately) (for subjects with 
Kellgren-Lawrence Grade 2 or 3 medial or lateral osteoarthritis of the index knee).
•
Incidence of subjects with progression of osteoarthritis in the index hip according to 
Bland and Altman method, at Week 56 and Week 80 (separately) (for subjects with 
Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the index hip).
The Bland-Altman method for defining progression of Joint Space Width (JSW), is to 
calculate the t-statistic (based on the number of subjects in the sample for the 
0.975 percentile of the t-distribution) multiplied by the standard deviation of the change from 
Baseline to Week 56 and to Week 80 (two separate values, giving two different definitions of 
progression for each joint).  These values represent the limit of the 95% confidence interval 
(CI) for a change of 0 over these time points.  Note, 95% CI for the observed mean change is 
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not used because this would be affected by any treatment effect seen in the trial, that this 
endpoint is aiming to explore, and would be potentially biased.  The lower bounds of the 
95% CI for change from Baseline to Week 56 and to Week 80 would represent the 
definitions of progression of Osteoarthritis (OA) for Hip and Knee OA separately.  The 
incidence of subjects with a reduction in JSW will then be compared according to the 
appropriate definition (Week 56 or Week 80; Hip or Knee).  The calculation of the 
progression of OA definition and analysis of incidence will be performed separately for 
Weeks 56 and 80 and subjects with OA of the Hip and Knee, for the subset of subjects with 
Kellgren-Lawrence grade 2 or 3 and with just grade 3 (knee). 
The adverse events of Abnormal Peripheral Sensation (APS) are defined in the table below.  
Allodynia
Neuralgia
Axonal neuropathy
Neuritis
Burning sensation
Neuropathy peripheral
Decreased Vibratory Sense
Paraesthesia
Demyelinating polyneuropathy
Paraesthesia oral
Dysaesthesia
Peripheral sensorimotor neuropathy
Formication
Peripheral sensory neuropathy
Hyperaesthesia
Polyneuropathy
Hyperpathia
Polyneuropathy chronic
Hypoaesthesia
Sensory disturbance
Hypoaesthesia oral
Sensory loss
Intercostal neuralgia
Thermohypoaesthesia
Sciatica
Carpal tunnel syndrome
Tarsal tunnel syndrome
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Adverse Events of the Sympathetic Nervous System are defined in the table below.
Abdominal discomfort
Micturition urgency
Anhidrosis
Nausea
Blood pressure orthostatic decreased
Nocturia
Bradycardia
Orthostatic hypotension
Diarrhoea
Presyncope
Dizziness postural
Respiratory distress
Early satiety
Respiratory failure
Ejaculation delayed
Sinus bradycardia
Ejaculation disorder
Syncope
Ejaculation failure
Pollakiuria
Anal incontinence
Urinary hesitation
Heart rate decreased
Urinary incontinence
Hypertonic bladder
Vomiting
Hypohidrosis
A smaller set of the above Adverse Events will also be summarized.  These are defined 
below.
Anhidrosis
Orthostatic hypotension
Bradycardia
Syncope
Hypohidrosis
The lists given above may be updated depending on any additional adverse events observed 
in any tanezumab study.  There are a number of summaries based on these groupings of 
adverse events.
The Neuropathy Impairment Score (NIS) is the sum of scores over all 37 items from both the 
left and right side.  Items 1-24 are scored on a 0-4 scale (0, 1, 2, 3, 3.25, 3.5, 3.75, 4) and 
items 25-37 are scored on a 0-2 scale (0, 1, 2).  The possible range of the NIS is 0-244.
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 8.2.3.
All summaries of adverse events will be shown for adverse events that begin or worsen from 
the first SC dose (treatment-emergent) up to the end of the treatment period.  In addition a 
selection of adverse event tables will be produced for the safety follow-up period and for the 
whole period up to the end of the study, including the treatment period and safety follow-up 
period.
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:
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•
For subjects with Baseline supine systolic Blood Pressure ≤150 mmHg: 
•
Reduction in sBP (standing minus supine) ≥20, OR
•
Reduction in dBP (standing minus supine) ≥10
•
For subjects with Baseline supine systolic Blood Pressure >150 mmHg: 
•
Reduction in sBP (standing minus supine) ≥30, OR
•
Reduction in dBP (standing minus supine) ≥15.
An additional summary will be provided of outcomes of 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.
The Survey of Autonomic Symptoms (SAS) is a 12 item (11 for females) questionnaire.  
From this the total number of symptoms (0-12 for males and 0-11 for females) will be 
calculated.  Where a subject has a symptom then the impact of that symptom is then rated 
from 1 (‘not at all’) to 5 (‘a lot’).  The total impact score is calculated using this 1-5 scale, 
with 0 assigned where the subject does not have the particular symptom.  The range for the 
total impact score is 0-60 for males and 0-55 for females.
Additional safety endpoints include anti-drug antibody (ADA) assessments.
6.3. Other Endpoints
6.3.1. PK Endpoints 
•
Plasma tanezumab concentrations.
•
Synovial fluid tanezumab concentrations (for a subset of subjects).
6.3.2. PD Endpoints 
The following assessments will be made:
•
Serum NGF assessment.
•
Serum and urine osteoarthritis biomarker concentrations.
•
Synovial fluid NGF assessment (for a subset of subjects).
6.3.3. Outcomes Research Endpoints 
The Baseline and Weeks 8, 16, 24, 40, 56 and 64 responses in the five dimensions (mobility; 
self-care; usual activities; pain/discomfort; anxiety/depression) and overall health utility 
score from the EuroQol 5 Dimensions (EQ-5D-5L), and the EQ-VAS will be summarized.  
The overall health utility score is calculated using the EuroQol value sets, and is described in 
Appendix 1.4.
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The change from baseline to Weeks 16, 24, 56 and 64 in the impairment scores of the Work 
Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) will be 
summarized.  These are listed below:
•
Percent work time missed due to Osteoarthritis.
•
Percent impairment while working due to Osteoarthritis.
•
Percent overall work impairment due to Osteoarthritis.
•
Percent activity impairment due to Osteoarthritis.
The calculation of these endpoints is described in Appendix 1.4.
The 11 questions of the TSQM are used to calculate the 4 endpoints of Effectiveness, Side 
Effects, Convenience and Global Satisfaction, each scored on a 0-100 scale with 100 being 
the best level of satisfaction.  The calculation of these 4 parameters are described in 
Appendix 1.4.
6.3.4. Activity Level Monitoring Endpoints 
The Lower Extremity Activity Scale (LEAS) is an 18-point integer scale reflecting the 
subjects physical function status, ranging from 1 (bed bound) to 18 (competitive athlete).
The accelerometry endpoints of average daily minutes of physical activity, average daily 
physical activity counts, minutes of moderate to vigorous physical activity (MVPA), minutes 
of bouted MVPA, and average daily step count will be calculated from the raw data.
The Activity Level Monitoring endpoints are listed below:
•
Lower Extremity Activity Scale: change from Baseline to Weeks 4, 8, 16, 24, 56 and 
Week 80 (all subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of physical 
activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily physical activity counts (a 
subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of moderate to 
vigorous physical activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily minutes of bouted 
(sustained) moderate to vigorous physical activity (a subset of subjects).
•
Change from Baseline to Weeks 16 and 56 in average daily step count (a subset of 
subjects).
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A valid day of monitoring will be defined as 10 or more wear hours in a 24-hour period as 
verified from accelerometer output. During Screening, a complete monitoring period will be 
defined as containing at least 1 valid weekend day of data and a minimum of 4 valid days of 
monitoring. During activity level monitoring between Week 14 and the Week 16 visit and 
between Week 54 and the Week 56 visit, a complete monitoring period will be defined as 
containing at least 2 valid weekend days of data and a minimum of 8 valid days of 
monitoring.
For the purposes of the MVPA endpoints, the three intensity levels of activity are defined as 
light (100 – <1,500 counts), moderate (1,500 – <6,500 counts), and vigorous
(≥6,500 counts).  The data will be further summarized as total daily time (minutes) for each 
intensity level.  
A “bout” of moderate to vigorous activity is defined as 10 or more consecutive minutes 
above the moderate physical activity level threshold, with allowance for interruptions of 1 or 
2 minutes below the threshold.
The daily data for each endpoint will be calculated as indicated above.  These daily scores 
will be used to calculate the score for Baseline, and Weeks 16 and 56 relative to the 
appropriate visit (ie, 7 days within the screening period for Baseline and 14 days prior to the 
Weeks 16 and 56 visits).  All valid data will be used even if it exceeds the intended 7/14 days 
specified in the protocol.
6.4. Covariates
For all models analyzing the continuous primary and secondary efficacy endpoints (except 
rescue medication) the corresponding Baseline value will be used as a covariate, in addition 
to Baseline diary average pain.  Study site will be fitted as a random effect in the ANCOVA
models.  The randomization stratification variables of index joint (hip or knee), NSAID 
cohort (celecoxib, naproxen and diclofenac), and highest Kellgren-Lawrence grade of any
Hip/Knee joints (grade 2, 3 or 4) will be included as fixed effects.  
A listing of subjects with mis-matches between the stratification variables entered at 
randomization and the case report form data (including central lab data for 
Kellgren-Lawrence grade) will be provided.  In analysis models, the strata entered at 
randomization will be used, but for descriptive summarization of the population and 
identification of subgroups, the strata as indicated on the case report form data will be used.
For the models analyzing the amount and number of days of rescue medication use the model 
will include terms for Baseline WOMAC Pain, Baseline diary average pain and stratification 
factors.
The analysis of the incidence of treatment discontinuation due to lack of efficacy will include 
model terms for baseline WOMAC Pain subscale score, Baseline Diary Average Pain, index 
joint, Kellgren-Lawrence grade, NSAID group and treatment group.  
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For treatment response endpoints relating to WOMAC Pain and PGA, the Baseline WOMAC 
Pain and PGA values will be used respectively as covariates in the analysis model, in 
addition to the stratification parameters of index joint, highest Kellgren-Lawrence grade of 
any hip or knee joint, NSAID group and Baseline diary average pain.  For the OMERACT 
response value, the Baseline WOMAC Pain subscale score will be used to represent the 
Baseline score covariate, in addition to the covariates named above (Baseline diary average 
pain, and the three stratification factors).
Additional analyses of the three co-primary endpoints will examine the treatment interactions 
with Study site and Country.  Note, separate analyses will be performed for the individual 
NSAID groups.  
The Baseline diary average pain is used in the analysis of most endpoints. However if a 
patient has a missing value for this covariate then to avoid exclusion of the patient for the 
endpoint then a Baseline value will be imputed as the patient’s WOMAC Pain subscale 
score. This imputed value will not be used in the analysis of the Average Pain from the 
diary, but as a covariate for other endpoints.
6.5. Subgroup Analyses
Separate tables will be produced for subjects in the ITT analysis set in Japanese sites.  These 
tables will be defined prior to the unblinding of the study.
The accelerometry data is collected in the subset of subjects (the accelerometry analysis set), 
so analysis of these subjects will occur in this subset.
Analysis of tanezumab versus individual NSAID groups will occur in the individual NSAID 
cohort subsets.
7. HANDLING OF MISSING VALUES
The three co-primary efficacy endpoints are the changes from Baseline to Week 16 in the
WOMAC Pain subscale, the WOMAC Physical Function subscale, and the Patient Global
Assessment of Osteoarthritis.  For Japan, the two co-primary efficacy endpoints are the 
change from Baseline to Week 16 in the WOMAC Pain and Physical Function subscales.
The primary analysis of the co-primary endpoints will use multiple imputation for missing 
data at Week 16 (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 16 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 16’ in the table below.
Efficacy data missing from windows after the Week 56 window, eg, Week 64, will not be 
imputed for any summary or analysis unless otherwise indicated.
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Type of Missing Data
Imputation Method
Missing data resulting from discontinuation 
due to Death, Adverse Events (AEs) or 
Insufficient Clinical Response (Lack of 
Efficacy, LoE, including Patient meets 
protocol specified pain criteria for 
discontinuation) prior to or during the 
Week 16 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 16 over all 
ITT subjects. This is a multiple imputation 
version of BOCF single imputation method.  
[Seeds 1, 3, and 5 below].
Missing data for other reasons, ie,
•
Subject did not discontinue on or before 
Week 16 (includes discontinuation for 
any reason after the end of the Week 16 
visit reporting window*)
•
Subject discontinued for a different 
reason prior to or during the Week 16 
visit reporting window*.
Multiple imputations will be created by 
sampling from a normal distribution based on 
the subject’s last score and the standard 
deviation (over all treatment groups) of the
observed efficacy data at Week 16 over all 
ITT subjects. For example if last observation 
for a subject is at Week 12, then the 
imputation sample for that subject is created 
using the subject’s Week 12 observation and 
the standard deviation of the Week 16
observations for all subjects.  Note, a 
subject’s last observation may be the Baseline 
observation.  This is a multiple imputation 
version of LOCF single imputation method.  
[Seeds 2, 4, and 6 below].
* See Appendix 1.1 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: WOMAC scores [1] 7001-7100; and 
[2] 8001-8100; PGA scores: [3] 9001-9100 and [4] 10001-10100; and diary pain scores: 
[5] 11001-11100 and [6] 12001-12100.  Imputed data for the PGA will be rounded to integer 
scores in the range 1 to 5.  Imputed data for the WOMAC subscale and Average scores, and 
for the diary pain scores <0 and >10 will be truncated to 0 and 10, respectively.  Imputed 
data for the WOMAC items of Pain when Going Up or Down Stairs and Pain when Walking 
on a Flat Surface will be rounded to integer scores in the range 0 to 10.  The ANCOVA 
analysis described in Section 8.1.1 (with covariates in Section 6.4) 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 3.2.  
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This analysis will be used for the co-primary efficacy endpoints at Week 16, plus secondary 
analyses at other time points, and also for a range of secondary efficacy endpoints at all time
points up to Week 56.  When using the multiple imputation method described above for time 
points earlier than Week 56, then the reason for missing data is assessed up to the end of the 
window for that particular time point (see Appendix 1.1).
Three 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 16 will impute the subject’s Baseline value for the Week 16 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 16 will impute the subject’s last observed data value for the efficacy endpoint. With 
LOCF, if a subject is missing all post-baseline efficacy data for a given efficacy endpoint, 
then baseline will be carried forward (if baseline is 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 all observed 
data up to and including Week 16, including data considered off-treatment (retrieved 
dropout; see Appendix 1.1 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).  
Analyses of the three co-primary measures 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 (Insufficient clinical response on the end of treatment Subject 
Summary Case Report Form, and also including Patient meets protocol specified pain criteria 
for discontinuation), adverse event or death up to the time point of interest, and LOCF 
imputation would be used for missing data for any other reason.
Note, if Baseline is missing then the subject data for the change from Baseline will be set to 
missing for all efficacy analyses for that parameter.  A subject who has a missing Baseline 
score will be missing for the response criteria for endpoints where the response is based on 
one parameter. The OMERACT-OARSI responder index is based on 3 parameters.  It is set 
to missing if two or three out of these three parameters are missing at baseline (per its 
definition, a response can be still be achieved if only one parameter is missing, regardless of 
which one it is).  
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The individual WOMAC subscales are calculated as the mean of the individual items (5 for 
Pain, 17 for Physical Function and 2 for Stiffness). 
 
 
  The WOMAC Average score is 
calculated as the mean of the three WOMAC subscale scores of Pain, Physical Function and 
Stiffness.  
 
  Missing WOMAC subscale or WOMAC Average scores will be subject to the 
imputation method of the analysis as described above.  
For the analysis of the rescue medication endpoints, missing data is imputed for daily 
missing scores first, and then the last available weekly score (after daily missing data is 
imputed) will be used for subsequent missing weekly scores, as described below.  For the 
analysis of the rescue medication endpoints while subjects are still in the study any missing 
data will be imputed by carrying forward the last recorded daily data up to Week 16 (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 1.1 for definitions of the last study day in each 
week). For example if a subject discontinues on study day 10, then data up to the end of 
Week 2 will be imputed in this way. The weekly scores for the rescue medication endpoints 
can then be calculated for each week the subject is in the study. Rescue medication 
endpoints are summarized and analyzed using LOCF, and so the last weekly score for the 
rescue medication will be used for LOCF after the subject has discontinued from the study
(note, imputation is taken from the last week with non-missing data and not necessarily from 
the last available study week, eg, if Week 8 is missing then Week 7 data can be used). The 
baseline observation will not be carried forward in the case where a post-baseline observation 
is not available for the LOCF imputation.  In the example above, the subject who 
discontinued in Week 2 (Study Day 10) will have their Week 2 value used as the LOCF 
value for all Weeks 3-16.  The BOCF imputation rule will not be used for the subject because 
rescue medication is collected during the Initial Pain Assessment Period only (days -7 to -1) 
and subjects should not be taking rescue medication within 24 hours of the Baseline visit (so 
part of day -1), therefore Baseline rescue medication use is not an accurate reflection of 
subjects’ true Baseline use of rescue medication.  Imputation of weekly diary data after Week 
56 will not be performed. 
The electronic diary data are a mix of daily and weekly average pain assessments for the 
index hip or knee, although the recall assessment period is the past 24 hours for both daily 
and weekly assessments.  A weekly mean score will be calculated from the available daily 
pain scores.  Any missing daily pain scores will be left as missing in the weekly pain score 
calculated.  If there are no non-missing observations then the weekly score will be missing.  
The Baseline mean will be calculated using the last 3 actual values from the last 7 days of the 
Initial Pain Assessment Period (IPAP).  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 
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CCI
CCI
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carry forward, then the baseline score carried forward will be the baseline average pain score, 
being the mean of the last 3 pain scores in the baseline assessment period.  If there are less 
than 3 baseline pain scores then the baseline is calculated over the remaining non-missing 
values.
Missing values in standard summaries of AEs, lab values, vital signs and ECGs will be 
handled per Pfizer standard algorithms.  For the analysis of NIS the Baseline observation will 
not be carried forward in the case where a post-baseline observation is not available for the 
LOCF imputation.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
A modified treatment-policy estimands strategy is applied as the main strategy to assess 
effectiveness of tanezumab. Data collected will be included for efficacy assessment 
regardless of rescue medication being used or not. 
The general study design for efficacy includes a planned treatment period through the Week 
56 visit, and a planned 24-week post-treatment safety follow-up period.  Efficacy data 
planned to be collected during this post-treatment safety follow-up period are intended to 
have efficacy measures contemporaneous to safety observations during this period.  They are 
not intended to assess treatment effects or compare treatment groups.  All endpoints up to 
Week 64 will be summarized (where available), and endpoints up to Week 56 will be 
analyzed.  
The method and definition of reporting windows for assigning efficacy data to particular time
points is described in Appendix 1.1.
All efficacy assessments are made on the analysis windows defined in Appendix 1. Using 
these windows we find the analysis window for a patient’s last subcutaneous (SC) dose. Any 
data included in a window up to 8 weeks from this last SC dose window is ‘on-treatment’, 
and any in a window more than 8 weeks after the last SC dose window is off treatment.  Data 
in on-treatment analysis windows will be used in summaries and analyses, while data in off-
treatment analysis windows will be excluded from all summaries and analyses of treatment 
period efficacy data, ie, up to Week 56.
For example the table below shows on-treatment and off-treatment windows for the planned 
collection visits for the WOMAC data during the treatment period: 
Last SC Dose 
Analysis Window
On-treatment Analysis 
Window Data 
Off-treatment Analysis 
Window Data
Baseline
Weeks 2, 4, 8
Weeks 16, 24, 32, 40, 48, 56
Week 2
Weeks 2, 4, 8
Weeks 16, 24, 32, 40, 48, 56
Week 4
Weeks 2, 4, 8, 
Weeks 16, 24, 32, 40, 48, 56
Week 8
Weeks 2, 4, 8, 16
Weeks 24, 32, 40, 48, 56
Week 16
Weeks 2, 4, 8, 16, 24
Weeks 32, 40, 48, 56
Week 24
Weeks 2, 4, 8, 16, 24, 32
Weeks 40, 48, 56
Week 32
Weeks 2, 4, 8, 16, 24, 32, 40
Weeks 48, 56
Week 40
Weeks 2, 4, 8, 16, 24, 32, 40, 48
Week 56
Week 48
Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56
None
Week 56
Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56
None
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Efficacy data at Week 64 is planned to be off-treatment so will not be subject to the above 
handling, ie, all available data in the Week 64 window will be used in summaries.
Efficacy data collected via subject diary (NRS pain scores and rescue medication use) are 
collected daily or weekly, not at study visits.  Diary efficacy data will be considered on-
treatment if it is collected up to 12 weeks (84 days) after the last SC dose.  Diary efficacy 
data collected more than 12 weeks (84 days) after the last SC dose will be considered off-
treatment and excluded from summaries and analyses of treatment period efficacy data, 
ie, for presentations up to Week 56.
Diary data after Week 56 is planned to be off-treatment so will not be subject to the above 
handling, ie, all available data in windows after Week 56 will be used in summaries.
8.1. Statistical Methods 
8.1.1. Analyses for Continuous Data
The mixed model ANCOVA, with multiple imputation, will be used with continuous change 
from Baseline endpoints for landmark (single time point) analyses.  The model will include 
the covariates described in Section 6.4, including study site as a random effect.  Estimates of 
treatment effects and pair wise treatment comparisons will be done using least squares means
(LS means) and 95% CIs.  
Under the primary analysis using multiple imputation defined in Section 7, the multiple 
ANCOVA results will be combined using standard methods (Little & Rubin, 2002)3, which 
are described in Appendix 3.2.
A sensitivity analysis for the primary endpoints will use a mixed model repeated measures 
analysis, with covariate terms for Time (study week, treated as a categorical variable), 
Treatment Group and Time-by-Treatment interaction, as well as the covariates described in 
Section 6.4.  The unstructured covariance will be used in the modeling of the within-subject
errors in the analysis.  Even though this is a sensitivity analysis for the primary endpoints, 
estimates for the time points of Weeks 2, 4, and 8, in addition to Week 16 will be shown 
from this analysis.
Interaction analyses will be performed for the primary endpoints, exploring the effect of 
Study site and Country.  These analyses will fit the covariate terms described in Section 6.4
(except for use of Study site as a covariate in the Country interaction analysis, where Country 
will be used instead [as a fixed term]), in addition to the interaction term of treatment group 
by factor.
The interaction of Treatment with Study site will be fitted as a random effect (in addition to 
Study site itself), with the resulting estimated treatment differences being shown for the 
largest study sites to illustrate the level of consistency of treatment benefit across the larger 
study sites.  The study sites to be examined in this way will be any site with an average of ten
or more subjects per treatment group within the site, which for this study relates to any site 
with 30 or more subjects in total.  This assessment will be made prior to unblinding, therefore 
a study site in this group may still have fewer than ten subjects in one or more of the 
treatment groups, however that site will still be included in this summary of efficacy of the 
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largest study sites.  To aid the interpretation of the treatment-site and treatment-country 
interactions, a summary of the efficacy data for each co-primary endpoint by treatment group 
will be shown for the sites with ≥30 subjects and also for the countries with ≥30 subjects 
over all treatment groups.
The time to discontinuation from treatment due to lack of efficacy will be analyzed using the 
log-rank test, and estimated failure curves will be produced using Kaplan-Meier estimation.  
The time to selected percentiles will also be shown.  These are influenced by the frequency 
of discontinuation, but are expected to be shown for the 1st, 2nd, 5th, 10th and 25th percentiles, 
in addition to the minimum and maximum time to discontinuation.  Any subject who 
discontinues for any other reason prior to the planned Week 56 visit will be censored at the 
time of discontinuation.  Subjects who complete the study or who discontinue for any reason 
after the Week 56 visit (including lack of efficacy) will be censored at the Week 56 visit.  
This analysis will be performed using ‘Insufficient clinical response’ alone, and either 
‘Insufficient clinical response’ or ‘Patient meets protocol specified pain criteria for 
discontinuation’, as reasons for discontinuation.
The time to joint safety events will be summarized and analyzed in the same way as 
described above for the time to discontinuation due to lack of efficacy.  For these analyses, 
subjects without events would be censored up to the end of the observation period (defined as 
end of study completion or discontinuation for subjects who did not have an event). Time to 
the earliest event would be considered for those who had multiple events.
8.1.2. Analyses for Categorical Data 
The number of days and amount (mg of acetaminophen/paracetamol) of rescue medication 
used per week will be analyzed using a negative binomial model with model terms of 
treatment group and covariates as described in Section 6.4.  In this model the error term is 
defined with a negative binomial distribution, and ‘log’ is used as the link function. Output 
from this analysis will be the estimated number/amount of rescue medication use per week in 
each treatment group, and (following the exponential back transformation) the ratio of rescue 
medication use for the treatment comparisons shown in Section 4.1.  The 95% CIs will be 
given for the estimates of both the individual treatment groups and the treatment group ratios.
The change from Baseline in the NIS will be analyzed using a Cochran-Mantel-Haenszel 
(CMH) test for ‘row mean scores differ’, using change from Baseline categories as the scores 
in the analysis, and stratified by the combined levels of the three stratification factors
(Section 6.4).  Output will show number and percentage of subjects whose NIS score 
worsened (change>0), improved (change<0) or had no change, in addition to the mean (with 
standard deviation) and median change, and minimum and maximum change.  This analysis 
will be performed for the two treatment comparisons separately, and shown by visit and 
worst change (largest change from baseline to any post-baseline visit), and by last change 
(summary statistics only).
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The change from Baseline in the Patient’s Global Assessment of Osteoarthritis to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, and 56 will also be analyzed using the CMH test and stratified by the 
combined levels of the stratification factors.  Changes by each level of improvement will be 
summarized, as well as any improvement (change<0), and any worsening (change>0).  For 
this analysis imputation for missing data will use mixed BOCF/LOCF, BOCF, and LOCF.
The change from Baseline in the Lower Extremity Activity Scale to Weeks 4, 8, 16, 24, 
56 and 80 and worst post-Baseline score will be analyzed using CMH test and stratified by 
the combined levels of the three stratification factors (Section 6.4).  LOCF will be used for 
imputation of missing data.  The change from Baseline to all weeks (including Week 80) will 
be summarized showing the number and percentage of subjects with any worsening score 
(change<0), no change, or improvement (change>0), as well as each category of change, and 
mean (with standard deviation) and median change.
The CMH test will be stratified by the combinations of the three stratification factors
(Section 6.4).  For any analysis using the CMH test, if there are too few subjects in any 
stratification combination group (defined as <15 subjects in any stratification factor) then an 
unstratified test will be performed.
8.1.3. Analyses for Binary Endpoints
Binary response parameters, and the incidence of rescue medication use and treatment 
discontinuation due to lack of efficacy will be analyzed using logistic regression for binary 
data, with covariates described in Section 6.4.  Output will show the number and percentage 
of subjects in each response category, and odds ratios (with 95% CIs) for the treatment 
comparisons shown in Section 4.1.
Separate analyses of the joint safety endpoints will use exposure time as the denominator
(giving results in terms of events per 1000 patient years of exposure) and then number of 
subjects as the denominator (giving results in terms of percentages).  Both these analyses will 
be performed for risk difference and risk ratio.  The analyses using number of subjects as the 
denominator will analyze risk difference and ratio between both tanezumab groups and 
NSAID using exact methods.  The analyses using exposure as the denominator will analyze 
risks using Poisson models.  The model for risk difference will have a linear link, poisson 
errors, and model terms for exposure and exposure-by-treatment (where treatment is 1 for 
tanezumab group and 0 for NSAID).  The model for risk ratio will have a log-link, poisson 
errors, and model term for treatment group with log-exposure as the offset variable.
Results will show event rates by treatment group, and difference/ratio of tanezumab doses 
versus NSAID, all shown with 95% confidence intervals, and significance tests for the 
treatment comparisons.
Events will be included in summaries if they occur up to the end of the safety follow-up
period or 26 weeks (planned duration of the follow-up period + 2 weeks) after the end of the
treatment period, whichever is later.
For the joint safety event analyses, the observation period is defined as the time from first SC 
dose to study completion or discontinuation for subjects who did not have an event, or time 
from first SC dose to the earliest event for subjects who did have at least one event.
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8.2. Statistical Analyses 
A summary of all analyses is given in Section 8.2.5. In all tables the treatment group 
ordering will be: tanezumab 2.5 mg, tanezumab 5 mg, NSAID.
8.2.1. Primary Analysis (Efficacy)
The primary analysis for the co-primary endpoints will use ANCOVA with covariates of 
Baseline score, Baseline diary average pain, Index Joint (Knee or Hip), Highest KL grade 
(2, 3 or 4), NSAID cohort, Treatment Group, and study site as a random variable.  The 
primary analysis set is the ITT analysis set.  The primary analysis will use multiple 
imputation as described in Section 7, and analysis using the ANCOVA model, with 
combination of results from imputation analyses using standard methods as described in 
Section 8.1.1.  These three primary endpoint analyses (two for Japan) will be used to assess 
the primary objective of the study.
Primary Endpoint Sensitivity Analyses
A number of sensitivity analyses will be performed on the primary efficacy endpoints in 
order to assess the robustness of the conclusions for the primary objective.  These relate to 
the analyses for missing data and the analysis population, the homogeneity of the results 
across factors that may influence efficacy, and for a secondary analysis of the PGA.  The 
analyses described below will not be subject to the testing strategy described for multiple 
comparisons of the primary analyses (given in Section 4.2).  As such, assessment of all 
treatment comparisons will be made independent of results over the co-primary endpoints or 
the two treatment comparisons for each analysis.
The ITT analysis set is used in the analyses numbered 2 to 5 below, and the PP analysis set is
used in analysis number 1 below.
1. Per-Protocol Analysis Set.
The primary analysis described above will be repeated, but using the Per-Protocol analysis 
set (as described in Section 5.2 and Section 5.6) in place of the ITT analysis set.  This 
analysis will assess the robustness of the efficacy conclusions to subjects who have more 
strictly adhered to protocol inclusion and exclusion criteria, and to protocol defined study 
procedures.
2. Alternative Missing Data Analyses.
There are three 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.  
These analyses are described in detail in Section 7.
In the first and second analyses, the primary ANCOVA analysis model described in 
Section 8.1.1 will be repeated, but using BOCF and LOCF respectively for missing data 
(note these are single imputation analyses).
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In the third analysis the mixed model Repeated Measures (MMRM) analysis will be 
performed using observed data up to Week 16 (ie, retrieved dropout), as described in 
Section 8.1.1 (see Appendix 1.1 for details on windows).
A summary of the missing data pattern will be shown for the WOMAC Pain and Physical 
Function subscales, and the PGA for Baseline and Weeks 2, 4, 8 and 16.  This summary will 
show the incidence of subjects with each pattern of observed and missing data over these 
visits and endpoints.  This summary will be shown overall, and split by treatment group.
3. Sensitivity Analysis Excluding Subjects from Sites with Potential GCP Compliance
Issues.
During the conduct of the study, it was identified that there may be GCP compliance issues at
Sites 1714 and 1730. A sensitivity analysis will be performed excluding the patients from 
both sites, using the same approach as the primary analysis for the primary endpoint.  
Additional sites may be excluded from this sensitivity analysis prior to unblinding if other 
issues deemed important are identified.
4. Interaction Analyses.
There will be 2 analyses for each of the co-primary endpoints to explore the interaction of 
treatment with Study Site and Country, as described in Section 8.1.1.  Estimates for Study 
sites with 30 or more subjects, and for Countries with 30 or more subjects will be shown.  
Estimates will be shown within each level of each factor, ie,:
•
Study Site: Individual sites with ≥30 subjects in the ITT set;
•
Country: Individual countries with ≥30 subjects in the ITT set.
5. CMH test for PGA.
The CMH test stratified by the combined levels of the three stratification factors (Section 
6.4) will be performed for the PGA, with additional summaries for the change from Baseline 
to Week 16 as described in Section 8.1.2.  This analysis will provide a sensitivity analysis for 
the primary analysis of the PGA.  The missing data imputation used for this analysis will be 
mixed BOCF/LOCF.
8.2.2. Secondary Analyses (Efficacy)
The following secondary endpoint analyses support the primary endpoints in the assessment 
of efficacy.  All analyses in this section use the ITT analysis set only.  Unless otherwise 
stated, efficacy data will be summarized up to Week 64, and analyzed up to Week 56.
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1. Other time points for the primary efficacy measures.
The ANCOVA model described above for the co-primary endpoints, using covariates of 
Baseline score, Baseline diary average pain, Index Joint, Highest KL grade (2, 3 or 4), 
NSAID cohort and Treatment, with Study Site as a random effect, will be used in the analysis 
of WOMAC Pain, WOMAC Physical Function and PGA for the change from Baseline to 
Weeks 2, 4, 8, 24, 32, 40, 48, and 56.  This analysis will be produced using multiple 
imputation (as described in Section 7 and Section 8.1.1), and BOCF and LOCF for missing 
data.
The MMRM analysis described above in Section 8.1.1 will also analyze results for the 
secondary time points of Weeks 2, 4 and 8, for the co-primary efficacy endpoints.
The CMH test for the PGA with corresponding summary will be performed for the change 
from Baseline to Weeks 2, 4, 8, 24, 32, 40, 48, and 56, as described above for the primary 
PGA endpoint.
2. Secondary endpoints analyzed using ANCOVA.
The ANCOVA model described above for the primary endpoint using covariates of Baseline 
score, Baseline diary average pain, Index Joint, Highest KL grade (2, 3 or 4), NSAID cohort
and Treatment, with Study Site as a random variable, will be used in the analysis of
WOMAC Stiffness subscale, WOMAC Average score, WOMAC Pain item “Pain when 
walking on a flat surface”, WOMAC Pain item “Pain when going up or down stairs” for the 
change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 56.  This analysis will be 
produced using multiple imputation for missing data.
The ANCOVA analysis (with covariates of Baseline diary average pain, Index Joint, Highest 
KL grade (2, 3 or 4), NSAID cohort and Treatment, with Study Site as a random variable)
will be produced for the Average Pain in the Index Joint from the diary, for the change from 
Baseline to Days 1, 2, 3, 4, 5, 6, and 7, and to Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 
40, 48, and 56, using multiple imputation for missing data.
3. Response and Incidence endpoints.
The response endpoints of OMERACT, improvement in PGA ≥2 and WOMAC Pain and 
Physical Function ≥30, 50, 70 and 90% improvements are analyzed using logistic regression 
with covariates of Baseline score (WOMAC Pain for OMERACT), Baseline diary average 
pain, Index Joint, Highest KL grade (2, 3 or 4), NSAID cohort and Treatment Group, for 
response at Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 56.  These analyses use mixed 
BOCF/LOCF, and BOCF and 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.
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Incidence of rescue medication use will be analyzed using the logistic regression as described 
above up to Week 56, but only using LOCF imputation for missing data.
The incidence of treatment discontinuation due to lack of efficacy will be analyzed using 
logistic regression with model terms of Baseline WOMAC Pain, Baseline diary average pain, 
the three stratification parameters and treatment group, and using incidence up to the end of 
treatment period (the Week 56 visit or early termination).  Discontinuation in the 
post-treatment safety follow-up period will not be included in this endpoint for analysis, but 
will be summarized as part of the safety tables.  Lack of efficacy is indicated as ‘Insufficient 
Clinical Response’ on the Subject Summary Case Report Form.  An additional analysis will 
be performed also including the discontinuation reason of ‘Patient meets protocol specified 
pain criteria for discontinuation’.
The cumulative WOMAC Pain and Physical Function response at Weeks 16, 24 and 56 using 
response definitions from a reduction of >0% to =100% (in steps of 10%) will be 
summarized, using mixed BOCF/LOCF, and also LOCF and BOCF imputation. Imputation 
with BOCF for subjects with missing data at that time point will lead to the subjects being 
assessed as non-responders for the response endpoint.
4. Time to Event.
The time to treatment discontinuation due to lack of efficacy will use the log-rank test.  
Survival curve estimates (time to 1st, 2nd, 5th, 10th and 25th percentiles, and minimum and 
maximum values) and a plot of the time to discontinuation (failure) will be shown using the 
Kaplan-Meier estimates.  Only treatment discontinuation up to the end of treatment period 
(Week 56 visit or early discontinuation) will be used in this analysis.  Discontinuation due to 
lack of efficacy after the end of treatment visit will be included in the standard safety tables.  
Imputation of time to event for discontinued subjects (discontinuing for reasons other than 
lack of efficacy) prior to the Week 56 visit uses censoring at the time of discontinuation.
Imputation of time to event for completed subjects or discontinued subjects (for any reason) 
after the Week 56 visit uses censoring at the Week 56 visit time point.  Lack of efficacy is 
indicated as ‘Insufficient Clinical Response’ on the Subject Summary Case Report Form.  An 
additional analysis will be performed also including the discontinuation reason of ‘Patient 
meets protocol specified pain criteria for discontinuation’.
5. Number of Days and Amount of Rescue Medication Use.
The rescue medication data will be converted to Weekly scores for the week prior to the 
timepoint of interest.  Calculation of the endpoints for both the IPAP and the concomitant 
medication log data collection is described in Appendix 1.4.
The number of days and amount of rescue medication endpoints will be analyzed using the 
negative binomial model, with model terms for Baseline WOMAC Pain score, Baseline diary 
average pain, Index Joint, Highest KL grade (2, 3 or 4), NSAID cohort and Treatment Group 
as described in Section 8.1.2.
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The number of days of rescue medication use per week endpoint will be analyzed for the 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 56. The amount of rescue medication use per week 
will be analyzed for the Weeks 2, 4, 8 and 16.  Missing data will be imputed using LOCF 
only.  For this analysis, Baseline data will not be carried forward in the case of a 
post-Baseline observation not being available for use in LOCF.
6. EuroQol 5 Dimensions 5 Level (EQ-5D-5L).
The Baseline and Weeks 8, 16, 24, 40, 56 and 64 responses in the five dimensions (mobility; 
self-care; usual activities; pain/discomfort; anxiety/depression) and overall health utility 
score from the EuroQol 5 Dimensions 5 Level (EQ-5D-5L) will be summarized by treatment 
group.  This summary will use observed data only (no imputation for missing data).  The 
calculation of the overall health utility score is described in Appendix 1.4.
An additional question, called the EQ-VAS asks the subject to rate their health today using a 
VAS scale from 0 (the worst health you can imagine) to 100 (the best health you can 
imagine).  This will be summarized along with the health utility score.  A table showing 
number and percentage of subjects will summarize the response for each dimension (item) of 
the EQ-5D at each time point.  These summary tables will be shown by treatment group.  In 
addition, for each treatment and each time point assessed, descriptive statistics (mean, 
standard deviation, median, number of subjects) will be shown for the health utility score, 
and the EQ-VAS measure of health today.
7. Work Productivity and Activity Impairment Questionnaire for Osteoarthritis 
(WPAI:OA).
The change from Baseline to Weeks 16, 24, 56 and 64 in the 4 impairment scores of the 
Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) 
will be summarized by treatment group.  
This summary will use observed data only (no imputation for missing data).  The calculation 
of these endpoints is described in Appendix 1.4.
The summary will show number and percentage of subjects with a decrease, no change, and 
an increase in score for the change from Baseline to each time point, as well as descriptive 
statistics (mean, standard deviation, median, number of subjects) of the Baseline and change 
at Weeks 16, 24, 56, and 64.
Change from baseline at Weeks 16, 24, and 56 in the 4 parameters will be analyzed using the 
ANCOVA model described above for the primary endpoint using covariates of the 
corresponding Baseline score, Baseline diary average pain, Index Joint, Highest KL grade (2, 
3 or 4), NSAID cohort and Treatment, with Study Site as a random variable.
8. Health Care Resource Utilization.
The Health Care Resource Utilization data at Baseline, Weeks 64 and 80 will be summarized.
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9. Treatment Satisfaction Questionnaire Medicine v.II (TSQM v.II).
The Weeks 16 and 56 responses in the 4 TSQM parameters of satisfaction with effectiveness, 
side effects and convenience, and overall satisfaction will be summarized.  The 11 questions 
of the TSQM are used to calculate the 4 endpoints of Effectiveness, Side Effects, 
Convenience and Global Satisfaction, each scored on a 0-100 scale with 100 being the best 
level of satisfaction.
The four parameters of the TSQM will be analyzed using the ANCOVA model described 
above for the primary endpoint using covariates of the Baseline diary average pain, Index 
Joint, Highest KL grade (2, 3 or 4), NSAID cohort and Treatment, with Study Site as a 
random effect at both Weeks 16 and 56.  Summary tables showing number and percentage of 
subjects by value and treatment group will be shown for the TSQM items 1-11, and the four 
satisfaction parameters.
This summary and analysis will use observed data only (no imputation for missing data).  
The calculation of these endpoints is described in Appendix 1.4.
10. Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 
and 56.
The mPRTI is collected at Weeks 16 and 56.  The two endpoints derived from this 
questionnaire are described below:
•
Patient willingness to use drug again.  This comes from the question “In the future, 
would you be willing to use the same drug that you have received in this study for 
your osteoarthritis pain?”  This is rated on a 5 point Likert scale from 1 (‘Yes, I 
would definitely want to use the same drug again’) to 5 (‘No, I definitely would not 
want to use the same drug again’).
•
Patient preference of drug versus prior treatment.  This comes from the question 
“Overall, do you prefer the drug that you received in this study to the treatment you 
received before this clinical trial?”  This is rated on a 5 point Likert scale from 
1 (‘Yes, I definitely prefer the drug I am receiving now’) to 5 (‘No, I definitely prefer 
my previous treatment’).
The two parameters of the mPRTI will be analyzed using the CMH test (stratified by the 
combinations of the three stratification factors) at both Weeks 16 and 56.  If there are too few 
subjects in any stratification combination group (defined as <15 in any strata level) then the 
analysis will be modified to an unstratified test.  Summary tables showing number and 
percentage of subjects by value and treatment group will be shown for all mPRTI questions.
This summary and analysis will use observed data only (no imputation for missing data).  
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11. Lower Extremity Activity Scale.
The LEAS is an 18-point scale ranging from 1 (‘I am confined to bed all day’) to 18 (‘daily 
vigorous physical activity’), and is collected at Baseline and Weeks 4, 8, 16, 24, 56 and 80.  
The number and percentage of subjects whose activity score is improved (increased), 
worsened (decreased) or have no change, and each level of change will be shown by 
treatment group for each week, using LOCF for any missing data.  The mean (with standard 
deviation) and median change will also be summarized.  The change from baseline to each 
post-Baseline visit (using LOCF for missing data), and for the worst change from Baseline 
(over all post-Baseline visits) will be summarized, and analyzed using CMH test (stratified 
by the combinations of the three stratification factors) (note, Week 80 data will be
summarized, but not analyzed).  If there are too few subjects in any stratification combination 
group (defined as <15 in any strata level) then the analysis will be modified to an unstratified 
test.  
12. Accelerometry Endpoints.
The five accelerometry endpoints will be collected prior to Baseline (at least 4 days, with 
1 being a weekend day) and prior to Weeks 16 and 56 (at least 8 days, with 2 being weekend 
days).  The change from Baseline to Week 16 and 56 will be calculated for these parameters.  
Summaries and analyses of these endpoints will use observed data for change from Baseline 
to Weeks 16 and 56, and imputation using LOCF for Week 56.  
These parameters will be analyzed using a negative binomial model using covariates of the 
corresponding Baseline accelerometry score, Baseline diary average pain, Index Joint, 
Highest KL grade (2, 3 or 4), NSAID cohort and Treatment.
8.2.3. Safety Analyses
8.2.3.1. Safety Endpoints (including Primary Joint Safety Endpoint)
1. Joint Safety Endpoints.
The primary joint safety endpoint is the incidence of subjects with any of the adjudication 
outcomes of rapidly progressive osteoarthritis (type-1 or type-2), subchondral insufficiency 
fracture, primary osteonecrosis, or pathological fracture.
The primary endpoint will be shown by number of subjects treated and subject years of 
exposure (treatment plus follow-up periods), for individual treatment groups and differences 
between tanezumab treatment groups and the NSAID treatment group. The risk ratio and 
risk difference (using number of subjects as the denominator and then exposure as the 
denominator) with 95% confidence intervals will be calculated for the comparisons of each 
tanezumab treatment group versus the NSAID treatment group, as well as significance tests 
for each treatment comparison. The time to each event will be summarized, and (where there 
are sufficient numbers of subjects) Kaplan-Meier estimates of the time to event will be 
produced, together with an analysis of each tanezumab treatment group versus the NSAID 
treatment group using the log-rank test.
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The primary analysis of the primary joint safety endpoint is the analysis of the 
exposure-adjusted risk difference.  The analyses of the exposure-adjusted risk ratio, and risk 
difference and ratio based on percentage of subjects with the event will be secondary 
analyses.
The summary and analysis of the secondary joint safety endpoints will follow the same 
method described above for the primary joint safety endpoint.
2. Neuropathy Impairment Score.
The change from Baseline in the NIS for Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 will 
be analyzed using a CMH test (stratified by the levels of the stratification factors) with 
change categories.  Missing data will be imputed using LOCF only.  For this analysis, 
Baseline data will not be carried forward in the case of a post-Baseline observation not being 
available for use in LOCF.  An additional analysis will use the change from Baseline to the 
largest (worst) post-Baseline value and to the last value (summary, not analysis).
3. Radiographic Endpoints.
The change from Baseline to Weeks 56 and 80 in the Minimum Joint Space Width (JSW) for 
subjects with Kellgren-Lawrence grades of 2 or 3 in the index joint will be analyzed for 
subjects with measurements in the knee and hip separately.  The analysis will also be 
performed for subjects with a Kellgren-Lawrence grade of 3 in the index knee.  For subjects 
with an index joint of a knee, where both medial and lateral measurements are collected, if 
the baseline medial JSW is ≤ the baseline lateral JSW, the medial view will be followed 
through the study for these analyses.  If the baseline lateral JSW < the baseline medial JSW, 
the lateral view will be followed through the study for these analyses.  The percentage of 
subjects with narrowing over certain intervals will be shown, in addition to summary 
statistics of the mean (with standard deviation) and median change from Baseline.  
Significant progression of osteoarthritis will be defined using the Bland-Altman method, as 
proposed by OARSI-OMERACT.  Progression will be defined as 1.96 times the 
within-subject standard deviation of the change in JSW.  The incidence of subjects with JSW 
narrowing greater than or equal to these values will be shown (with Kellgren-Lawrence 
grades of 2 or 3 in the index joint, and separately with Kellgren-Lawrence grade of 3 in the 
index knee), and incidence analyzed using logistic regression for binary data, taking into 
account Baseline JSW as a covariate.  
The Radiographic endpoint summaries and analyses will be performed separately for subjects 
with osteoarthritis of the hip and knee.  These analyses will use the Week 56 End of 
Treatment/Early Termination data and then Week 80 End of Study/Early Termination Visit 3
regardless of the study day of assessment and/or where subjects have discontinued early from 
the study.  In the event of missing data, baseline data will not be carried forward for 
Radiographic data.  Additional analyses will be performed for assessments at Week 56 and 
Week 80 (equivalent to observed data analysis for subjects who reach these time points), 
subject to a window of ±4 weeks and ±6 weeks for the Week 56 and Week 80 analyses 
respectively.
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8.2.3.2. Other Safety Assessments
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.
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 1058
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.
Tier 3 AEs are those not in tier 1 or tier 2, and will be summarized using standard Pfizer data 
standards tables, where all Adverse Events will be included (ie, tier 3 AEs will not be shown 
separately).
Adverse events within tier 1 and 2 will be summarized using Risk Differences between each 
tanezumab group and NSAID, together with 95% confidence intervals, using exact methods.  
Significance tests will be performed for tanezumab versus NSAID comparisons using exact 
methods for the tier 1 adverse events.  There will be no multiplicity adjustment for these 
significance tests.  These tables will be produced for the comparisons of tanezumab 2.5 mg 
versus NSAID and tanezumab 5 mg versus NSAID.
The following footnote will be used in the Tier 1 AE tables: “P-values and confidence 
intervals are not adjusted for multiplicity and should be used for screening purpose only. 
95% CIs are provided to help gauge the precision of the estimates for Risk Difference. Risk 
Difference is computed as ‘Tanezumab 5 mg versus NSAID’ and ‘Tanezumab 2.5 mg versus 
NSAID’.  Exact methods are used for 95% confidence intervals and significance tests.”  
Similarly the following footnote will be used in the Tier 2 AE tables: “Confidence intervals 
are not adjusted for multiplicity and should be used for estimation purposes only. 95% CIs 
are provided to help gauge the precision of the estimates for Risk Difference. Risk Difference 
is computed as ‘Tanezumab 5 mg versus NSAID’ and ‘Tanezumab 2.5 mg versus NSAID’.  
Exact methods are used for 95% confidence intervals.”  
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this exploratory analysis.
All summaries of adverse events will be shown for adverse events that begin or worsen after 
the first dose of SC 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 safety follow-up period 
and for the whole period up to the end of the study, including the treatment period and safety 
follow-up period.
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Adverse events (AEs), concomitant medications, laboratory safety tests, physical and 
neurological examinations (NIS), vital signs, electrocardiogram (ECG), and the ADA test 
will be collected for each subject during the study according to the schedule of assessments.
The following non-standard safety tables will also be included 
1. A summary of baseline characteristics, including Kellgren-Lawrence grade of the 
index joint (for subjects with Hip and Knee OA separately and then overall), highest 
Kellgren-Lawrence grade for each subject, Summary of WOMAC subscales at 
Baseline and Screening (for Pain subscale only), diabetes status (from medical history 
and/or pre-treatment HbA1c≥6.5%), and the PGA at Baseline.  This summary will 
also include a summary of the number of subjects who are ≥75 years old.
2. Summary of number of subjects treated by country and treatment group, and by 
NSAID cohort.
3. Summary of failed drug treatments for protocol qualification, with reasons for 
discontinuation.
4. Incidence and severity of AEs leading to discontinuation.
5. 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).
6. Summary of AEs and Serious Adverse Events by 1000 patient years of exposure.
7. Summary of evidence of neurological examination abnormalities by visit and final 
assessment, and incidence of neurological findings over consecutive visits.  Further 
details of this summary are given below.
8. Summary of final outcome of neurological consultation. 
9. Summary of the Incidence of sympathetic neuropathy based on investigator 
assessment and, if performed, expert consultant assessment.
10. ‘Incidence and severity’ tables of treatment-emergent AEs 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.
11. Summary table and listing of inclusion and exclusion criteria that are not met by 
subjects who were screened (but not randomized).
12. 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, 
25-32, 33-40, 41-48, 49-56, >56) and for the safety follow-up period (Weeks 1-8, 9-
16, 17-24, >24).
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13. A summary of the maximum increase from baseline in the sitting systolic and 
diastolic blood pressure.  The categories used are: (systolic BP) only decreases or no 
change, >0 to 10, >10-20, >20-30, >30, and (diastolic BP) only decreases or no 
change, >0 to 10, >10-20, >20.
14. 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.
15. A summary of the change from baseline to last observation in the sitting systolic and 
diastolic blood pressure.  The categories used for these summaries are: (systolic BP) 
≤-40, >-40 to -30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to <10, 10-<20, 20-<30, 
30-<40, ≥40, and (diastolic BP) ≤-30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to <10, 
10-<20, 20-<30, ≥30.
16. A summary of incidence of subjects with confirmed orthostatic hypotension, for each 
visit and any post-baseline incidence of orthostatic hypotension.  
17. A summary of discontinuation up to End of Treatment period, and up to End of Study 
period.
18. Incidence of musculoskeletal physical examination findings at screening.
19. Summary of Dual Energy X-Ray Absorptiometry (DEXA) at screening, showing 
summary measures of bone mineral density, and t-scores of the spine and hip.
20. Summary of the Survey of Autonomic Symptoms (SAS) number of symptoms 
reported and total symptom impact score, at each visit, and for the change from 
Baseline score.
21. Summary of concomitant medications for Osteoarthritis for non-NSAID and NSAID 
medications (shown separately).
22. Summary of number of days of non-study NSAID use per dosing interval (eg, Day 1
to Week 8, Week 8 to Week 16, etc.) 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 
64 will be shown, as well as the number and percentage of subjects who exceeded the 
limit of 80 days of NSAID use during this interval.
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23. Summary of oral study medication compliance.  This is calculated for the interval 
from Baseline to Week 16 and the entire post-Baseline period up to Week 56 (or end 
of treatment visit).  Compliance is calculated as number of tablets dispensed minus 
the number returned divided by the number of days in the interval, all divided by 
2 (for the daily regimen frequency), multiplied by 100, to get a percentage 
compliance for each subject for each time period.
Neurological-related safety data
The “conclusion from the neurological examination” data will be summarized for each time
point and the last subject assessment.  In addition the persistence of any neurological
examination finding will be summarized, showing the incidence of subjects with new or 
worsened neurological examination abnormalities (both clinically significant only and also 
for any finding) for 2, 3, 4, and ≥5 consecutive visits.
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. 
•
The proportion of subjects who test positive (ie, develop anti-tanezumab antibodies) 
and negative will be summarized by treatment group and planned visit. The summary 
will also include the proportion of subjects who test positive and negative overall in 
the study.
•
Subjects who develop anti-tanezumab antibodies after treatment will be evaluated for 
the presence of anti-tanezumab neutralizing antibodies, and individual results will be 
listed.
•
Individual subjects with positive ADA results will be evaluated for potential ADA 
impact on the individual’s PK, efficacy and safety profile. 
8.2.4. Other Analyses
8.2.4.1. Pharmacokinetics
The following reporting of PK data will be done:
•
A listing of all plasma tanezumab concentrations sorted by subject, active treatment 
group and nominal time post dose.  The listing of concentrations will also include the 
actual times post dose.
•
A descriptive summary of the plasma tanezumab concentrations based on nominal 
time post dose for each treatment group.
•
Boxplots of plasma tanezumab concentrations at the nominal times for the tanezumab 
treatment groups.
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•
A listing of available synovial fluid tanezumab concentrations at the time of the 
arthrocentesis only sorted by subject, treatment group and actual collection date and 
time.
8.2.4.2. Pharmacodynamics (NGF)
Serum samples from a subset of patients will be run in the bioanalytical assays for 
assessment of NGF and the measurements will be summarized in the following tables and 
figures.
•
A listing of individual serum NGF concentrations sorted by subject, treatment group 
and time post dose.
•
Descriptive statistics of serum NGF concentrations based on time post dose for each 
treatment group.
•
Boxplots of serum NGF over time post dose for each treatment group.
If enough synovial fluid volume is left after determining the tanezumab concentration in the 
sample that is collected in subjects who have arthrocentesis performed, synovial fluid NGF 
concentrations will be determined as well at the time of the arthrocentesis only, and the 
measurements will be summarized as follows:
•
A listing of available synovial fluid NGF concentrations at the time of the 
arthrocentesis only sorted by subject, treatment group and actual collection date and 
time.
8.2.4.3. Osteoarthritis Biomarkers
The biomarker data analysis related to joint safety events will be performed separately from 
the A4091058 study CSR. 
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8.2.5. Summary of Efficacy Analyses 
Note: BL=Baseline
Endpoint
Analysis 
Set
Statistical Method 
Model/Covariates
Missing 
Data
Objective
Change from Baseline to Week 16 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Primary Analysis 
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Primary Analysis 
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Primary Analysis 
Change from Baseline to Week 16 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Study Site, 
Treatment Group, Study Site x 
Treatment Group (Study site and 
interaction as random effects)
Multiple 
Imputation
Additional 
(Interaction) Analysis
Change from Baseline to Week 16 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Country, 
Treatment Group, Country x 
Treatment Group.
Multiple 
Imputation
Additional 
(Interaction) Analysis
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Multiple 
Imputation
Additional 
(Interaction) Analysis
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NSAID cohort, Study Site, 
Treatment Group, Study Site x 
Treatment Group (Study site and 
interaction as random effects)
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Country, 
Treatment Group, Country x 
Treatment Group.
Multiple 
Imputation
Additional 
(Interaction) Analysis
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip),
Highest KL grade (2, 3 or 4), 
NSAID cohort, Study Site, 
Treatment Group, Study Site x 
Treatment Group (Study site and 
interaction as random effects)
Multiple 
Imputation
Additional 
(Interaction) Analysis
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip),
Highest KL grade (2, 3 or 4), 
NSAID cohort, Country, 
Treatment Group, Country x 
Treatment Group
Multiple 
Imputation
Additional 
(Interaction) Analysis
Change from Baseline to Week 16 in 
WOMAC Pain subscale
PP
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Sensitivity Analysis
(Per protocol)
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
PP
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Sensitivity Analysis
(Per protocol)
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis
PP
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
Multiple 
Imputation
Sensitivity Analysis
(Per protocol)
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
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(Study site as a random effect)
Change from Baseline to Week 16 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
BOCF
Sensitivity Analysis
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
BOCF
Sensitivity Analysis
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
BOCF
Sensitivity Analysis
Change from Baseline to Week 16 in 
WOMAC Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
LOCF
Sensitivity Analysis
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
LOCF
Sensitivity Analysis
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
LOCF
Sensitivity Analysis
Change from Baseline to Weeks 2, 4, 
8 and 16 in WOMAC Pain subscale
ITT
MMRM
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Time, Treatment 
Group, Time x Treatment Group
(Study site as a random effect)
Observed Data
Sensitivity Analysis
for Week 16 
(Secondary Endpoint 
Analysis for other time 
points)
Change from Baseline to Weeks 2, 4, 
ITT
MMRM
BL Score, BL Diary Average 
Observed Data
Sensitivity Analysis
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 47
8 and 16 in WOMAC Physical 
Function subscale
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Time, Treatment 
Group, Time x Treatment Group
(Study site as a random effect)
for Week 16 
(Secondary Endpoint 
Analysis for other time 
points)
Change from Baseline to Weeks 2, 4, 
8 and 16 in Patient Global Assessment 
of Osteoarthritis
ITT
MMRM
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Time, Treatment 
Group, Time x Treatment Group
(Study site as a random effect)
Observed Data
Sensitivity Analysis
for Week 16 
(Secondary Endpoint 
Analysis for other time 
points)
Change from Baseline to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, and 56 in Patient 
Global Assessment of Osteoarthritis
ITT
CMH test 
Treatment Group [1]
Mixed 
BOCF/LOCF
Sensitivity Analysis
for PGA
Change from Baseline to Week 16 in 
WOMAC Pain subscale, shown by 
site (sites with n≥30)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive summary 
for interaction analysis
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale, 
shown by site (sites with n≥30)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive summary 
for interaction analysis
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis, shown by site (sites 
with n≥30)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive summary 
for interaction analysis
Change from Baseline to Week 16 in 
WOMAC Pain subscale, shown by 
country (countries with n≥30)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive summary 
for interaction analysis
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale, 
shown by country (countries with 
n≥30)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive summary 
for interaction analysis
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis, shown by country 
(countries with n≥30)
ITT
None (summary)
NA
Multiple 
Imputation
Supportive summary 
for interaction analysis
Missing data pattern for WOMAC 
Pain subscale for Baseline and Weeks 
2, 4, 8 and 16
ITT
None (summary)
NA
Observed Data
Supportive summary 
for missing data
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
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Missing data pattern for WOMAC 
Physical Function subscale for 
Baseline and Weeks 2, 4, 8 and 16
ITT
None (summary)
NA
Observed Data
Supportive summary 
for missing data
Missing data pattern for Patient 
Global Assessment of Osteoarthritis
for Baseline and Weeks 2, 4, 8 and 16
ITT
None (summary)
NA
Observed Data
Supportive summary 
for missing data
Change from Baseline to Week 16 in 
WOMAC Pain subscale by NSAID 
cohort
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group (Study site as a 
random effect)
Multiple 
Imputation
Primary endpoint 
analysis for individual 
NSAID comparisons
Change from Baseline to Week 16 in 
WOMAC Physical Function subscale
by NSAID cohort
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group (Study site as a 
random effect)
Multiple 
Imputation
Primary endpoint 
analysis for individual 
NSAID comparisons
Change from Baseline to Week 16 in 
Patient Global Assessment of 
Osteoarthritis by NSAID cohort
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
Treatment Group (Study site as a 
random effect)
Multiple 
Imputation
Primary endpoint 
analysis for individual 
NSAID comparisons
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in WOMAC 
Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in WOMAC 
Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in WOMAC 
Pain subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
LOCF
Secondary Endpoint 
Analysis
090177e1907ea75f\Approved\Approved On: 04-Mar-2019 18:54 (GMT)
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 49
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in WOMAC 
Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in WOMAC 
Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in WOMAC 
Physical Function subscale
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in Patient 
Global Assessment of Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in Patient 
Global Assessment of Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 24, 32, 40, 48, and 56 in Patient 
Global Assessment of Osteoarthritis
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
LOCF
Secondary Endpoint 
Analysis
The OMERACT-OARSI response at 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and
56  
ITT
Logistic 
Regression
BL Score (WOMAC Pain), BL 
Diary Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
090177e1907ea75f\Approved\Approved On: 04-Mar-2019 18:54 (GMT)
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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The OMERACT-OARSI response at 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56  
ITT
Logistic 
Regression
BL Score (WOMAC Pain), BL 
Diary Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group
BOCF
Secondary Endpoint 
Analysis
The OMERACT-OARSI response at 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56  
ITT
Logistic 
Regression
BL Score (WOMAC Pain), BL 
Diary Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group
LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction 
of >30/50/70/90% from Baseline to 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56 in the WOMAC Pain subscale 
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction 
of >30/50/70/90% from Baseline to 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56 in the WOMAC Pain subscale 
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction 
of >30/50/70/90% from Baseline to 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56 in the WOMAC Pain subscale 
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction 
of >30/50/70/90% from Baseline to 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56 in the WOMAC Physical
Functioning subscale
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction 
of >30/50/70/90% from Baseline to 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56 in the WOMAC Physical
Functioning subscale
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction 
of >30/50/70/90% from Baseline to 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 
56 in the WOMAC Physical
Functioning subscale
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
LOCF
Secondary Endpoint 
Analysis
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
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Percentage of subjects with an 
improvement of ≥2 points from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 
40, 48, and 56 in the Patient Global
Assessment of Osteoarthritis  
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 
40, 48, and 56 in the Patient Global
Assessment of Osteoarthritis  
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from 
Baseline to Weeks 2, 4, 8, 16, 24, 32, 
40, 48, and 56 in the Patient Global
Assessment of Osteoarthritis  
ITT
Logistic 
Regression
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
LOCF
Secondary Endpoint 
Analysis
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from 
Baseline to Week 16, 24 and 56 in the 
WOMAC Pain subscale
ITT
None (summary 
and plot)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from 
Baseline to Week 16, 24 and 56 in the 
WOMAC Pain subscale
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Reduction of >0%, >10%, to ≥90% (in 
steps of 10%) and =100% from 
Baseline to Week 16, 24 and 56 in the 
WOMAC Pain subscale
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from 
Baseline to Week 16, 24 and 56 in the 
WOMAC Physical Function subscale
ITT
None (summary 
and plot)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Reduction of >0%, >10%, to >90% (in 
steps of 10%) and =100% from 
Baseline to Week 16, 24 and 56 in the 
WOMAC Physical Function subscale
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
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Reduction of >0%, >10%, to ≥90% (in 
steps of 10%) and =100% from 
Baseline to Week 16, 24 and 56 in the 
WOMAC Physical Function subscale
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, and 56 in the 
WOMAC Stiffness subscale 
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, and 56 in the 
WOMAC Average Score
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, and 56 in the 
WOMAC Item: Pain When Walking 
on a Flat Surface
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, and 56 in the 
WOMAC Item: Pain When Going Up 
or Down Stairs
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group 
(Study site as a random effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Change from Baseline to Days 1, 2, 3, 
4, 5, 6, 7, and to Weeks 1, 2, 3, 4, 6, 8, 
10, 12, 16, 20, 24, 32, 40, 48, and 56
in the weekly average pain score in 
the index joint
ITT
ANCOVA
BL Score, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group (Study site as a random 
effect)
Multiple 
Imputation
Secondary Endpoint 
Analysis
Time to treatment discontinuation due 
to lack of efficacy (up to Week 
56/End of Treatment)
ITT
Log-Rank (with 
KM estimates) 
Treatment Group
Observed 
Secondary Endpoint 
Analysis
Incidence of treatment discontinuation 
due to lack of efficacy (up to Week 
56/End of Treatment)
ITT
Logistic 
Regression
BL WOMAC Pain, BL Diary
Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group
Observed
Secondary Endpoint 
Analysis
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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Incidence of rescue medication use 
during Weeks 2, 4, 8, 16, 24, 32, 40, 
48, and 56
ITT
Logistic 
Regression
BL WOMAC Pain, BL Diary 
Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group
LOCF
Secondary Endpoint 
Analysis
Number of days of rescue medication 
use during Weeks 2, 4, 8, 16, 24, 32, 
40, 48, and 56
ITT
Negative Binomial
BL WOMAC Pain, BL Diary 
Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group 
LOCF
Secondary Endpoint 
Analysis
Amount (mg) of rescue medication 
taken during Weeks 2, 4, 8 and 16
ITT
Negative Binomial
BL WOMAC Pain, BL Diary 
Average Pain, Index Joint 
(Knee/Hip), Highest KL grade (2, 
3 or 4), NSAID cohort, Treatment 
Group 
LOCF
Secondary Endpoint 
Analysis
EQ-5D-5L dimensions (Mobility; 
Self-care; Usual activity; 
Pain/Discomfort; Anxiety/Depression) 
and Overall Health Utility at Baseline 
and Weeks 16, 24 and 56
ITT
Summary
NA
Observed
Secondary Endpoint 
Analysis
EQ-VAS at Baseline and Weeks 16, 
24 and 56
ITT
Summary
NA
Observed
Secondary Endpoint 
Analysis
mPRTI endpoints (willingness to 
re-use; patient preference) at Weeks 
16 and 56
ITT
CMH test
Treatment group [1]
Observed
Secondary Endpoint 
Analysis
TSQM endpoints (satisfaction with 
effectiveness, side effects and 
convenience, and overall satisfaction) 
at Weeks 16 and 56
ITT
ANCOVA
BL Diary Average Pain, Index 
Joint (Knee/Hip), Highest KL 
grade (2, 3 or 4), NSAID cohort, 
Treatment Group (Study site as a 
random effect)
Observed
Secondary Endpoint 
Analysis
WPAI endpoints (% work time 
missed; % impairment while working; 
% overall work impairment; % 
activity impairment) at Weeks 16, 24 
and 56
ITT
ANCOVA
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
(Study site as a random effect)
Observed
Secondary Endpoint 
Analysis
Healthcare Resource Utilization at 
baseline, weeks 56 and 64
ITT
Descriptive 
Summary
Treatment group
Observed
Secondary Endpoint 
Analysis
090177e1907ea75f\Approved\Approved On: 04-Mar-2019 18:54 (GMT)
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Protocol A4091058 (PF-04383119) Statistical Analysis Plan
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Change from Baseline in LEAS to 
Weeks 4, 8, 16, 24, and 56, and worst 
post-baseline score.
ITT
CMH test
Treatment group [1]
LOCF (weeks 4, 
8, 16, 24, and 
56) and worst 
score
Secondary Endpoint 
Analysis
Change from Baseline in 
Accelerometry endpoints (daily 
minutes of physical activity, MVPA 
and bouted MVPA; daily step count; 
daily physical activity counts) to 
Weeks 16 and 56
Accelerometry 
analysis set
negative binomial
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
Observed
Secondary Endpoint 
Analysis
Change from Baseline in 
Accelerometry endpoints (daily 
minutes of physical activity, MVPA 
and bouted MVPA; daily step count; 
daily physical activity counts) to 
Week 56
Accelerometry 
analysis set
negative binomial
BL Score, BL Diary Average 
Pain, Index Joint (Knee/Hip), 
Highest KL grade (2, 3 or 4), 
NSAID cohort, Treatment Group
LOCF
Secondary Endpoint 
Analysis
Incidence of primary composite 
adjudication joint safety endpoint
ITT
Poisson model for 
risk difference 
(exposure-adjusted)
Exposure, exposure*treatment
Observed
Primary Joint Safety 
Analyses
Incidence of primary composite 
adjudication joint safety endpoint
ITT
Poisson model for 
risk ratio 
(exposure-adjusted)
Treatment group, offset by 
log-exposure
Observed
Secondary Joint Safety 
Analyses
Incidence of primary composite 
adjudication joint safety endpoint
ITT
Exact analyses for 
risk difference and 
ratio (percentage)
Treatment group
Observed
Secondary Joint Safety 
Analyses
Incidence of secondary composite 
endpoint, individual adjudication joint 
safety endpoints (RPOA-1, RPOA-2, 
RPOA-1/2, SIF, Primary ON, 
Pathological fracture), TJR, and TJR 
and any adjudication outcome
ITT
Poisson model for 
risk difference 
(exposure-adjusted)
Exposure, exposure*treatment
Observed
Secondary Joint Safety 
Analyses
Incidence of secondary composite 
endpoint, individual adjudication joint 
safety endpoints (RPOA-1, RPOA-2, 
RPOA-1/2, SIF, Primary ON, 
Pathological fracture), TJR, and TJR 
and any adjudication outcome
ITT
Poisson model for 
risk ratio 
(exposure-adjusted)
Treatment group, offset by 
log-exposure
Observed
Secondary Joint Safety 
Analyses
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Incidence of secondary composite 
endpoint, individual adjudication joint 
safety endpoints (RPOA-1, RPOA-2, 
RPOA-1/2, SIF, Primary ON, 
Pathological fracture), TJR, and TJR 
and any adjudication outcome
ITT
Exact analyses for 
risk difference and 
ratio (percentage)
Treatment group
Observed
Secondary Joint Safety 
Analyses
Time to joint safety event (Primary 
Composite, Secondary Composite, 
Individual Adjudication Events, TJR, 
TJR and any adjudication outcome)
ITT
Log-Rank (with 
KM estimates) 
Treatment Group
Observed 
Secondary Joint Safety 
Analyses
Incidence of Bland-Altman defined 
progression of OA for subjects with 
OA of the Hip (KL2,3) at Weeks 
56/ET and 80/ET, and Weeks 56 and 
80 (based on window) 
ITT
Logistic 
Regression
BL JSW, Treatment Group
Observed
Radiographic safety 
endpoint
Incidence of Bland-Altman defined 
progression of OA for subjects with 
OA of the Knee (KL2,3) at Weeks 
56/ET and 80/ET, and Weeks 56 and 
80 (based on window) 
ITT
Logistic 
Regression
BL JSW, Treatment Group
Observed
Radiographic safety 
endpoint
Change from Baseline in JSW for 
subjects with OA of the Hip (KL 2, 3) 
at Weeks 56/ET and 80/ET, and 
Weeks 56 and 80 (based on window)
ITT
ANCOVA
BL JSW, Treatment Group 
(Study site as a random effect)
Observed
Radiographic safety 
endpoint
Change from Baseline in JSW for 
subjects with OA of the Knee (KL 2, 
3) at Weeks 56/ET and 80/ET, and 
Weeks 56 and 80 (based on window)
ITT
ANCOVA
BL JSW, Treatment Group 
(Study site as a random effect)
Observed
Radiographic safety 
endpoint
Change from baseline to Weeks 2, 4, 
8, 16, 24, 32, 40, 48, 56, 64 and 80 in 
the NIS score, and Change from 
Baseline to Worst post-Baseline NIS 
score
ITT
CMH test
Treatment Group [1]
LOCF (Weeks 2, 
4, 8, 16, 24, 32, 
40, 48, 56, 64, 
80), Worst 
post-baseline 
score
Safety Analysis
Survey of Autonomic Symptoms 
(SAS), number of symptoms and total 
impact score (by visit and change 
from Baseline)
ITT
Summary
NA
Observed
Safety Analysis
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[1] CMH test will be stratified by the levels of the combined stratification parameters (18 levels).  If there are <15 subjects in any combined stratification level 
then the CMH test will be unstratified.
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9. REFERENCES 
1.
Atkinson, MJ et al (2005).  Hierarchical construct validity of the treatment satisfaction 
questionnaire for medication (TSQM Version II) among outsubject pharmacy 
consumers.  Value in Health.  8(Supp 1), S9-24.
2.
EuroQol Group.  EuroQol: a new facility for the measurement of health related quality 
of life. Health Policy 1990; 16:199-208.
3.
Little RJ & Rubin DB (2002).  Statistical Analysis with Missing Data.  New Jersey: 
Wiley.
4.
Tudor-Locke C, et al.  A Catalog of Rules, Variables, Definitions Applied to 
Accelerometer Data in National Health and Nutrition Examination Survey, 2003-2006. 
Prev Chronic Dis 2012,9:110332. DOI: http://dx.doi.org/10.5888/pcd9.110332).
5.
Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical
trials. Statist. Med. (2014):33:693–713.
6.
Bretz F, Posch M, Glimm E, Klingmueller F, Maurer W, Rohmeyer K. Graphical
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or
parametric tests Biometrical Journal. 53(2011) 6, 894–913.
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10. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. 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, 40, 48, 56, 64 and 80.  If a subject discontinues from the trial then there will be an 
Early Termination Follow-Up period and for those who refuse, ideally, an Early termination 
visit.  To account for this visit and any early or late scheduled visits (compared to the target 
study days) we define ‘windows’ to be able to allocate each efficacy observation to a single
specific study visit.  For the assessments made at each planned study visit (eg, WOMAC 
subscales, Patient Global Assessment of Osteoarthritis etc.) these visit windows are shown 
below.  When multiple observations occur in a visit window, the observation closest to the 
protocol specified target day will be used, noting that the latter will be used in the case of a 
tie.
Visit
Target Study Day
Window
Screening [1]
Variable (up to 37 days 
prior to baseline visit)
[No lower limit, Day -8]
Baseline
1 (defined as initial day of 
study drug administration)
[-7,1]
Week 2
15
[2,22]
Week 4
29
[23,43]
Week 8
57
[44,85]
Week 16
113
[86,141]
Week 24
169
[142,197]
Week 32
225
[198, 253]
Week 40
281
[254, 309]
Week 48
337
[310, 365]
Week 56
393
[366, 421]
Week 64
449
[422, 477]
[1] Only efficacy data collected at screening is WOMAC Pain subscale.
One additional window will be created relative to the date of last SC dose for summaries of 
efficacy data collected beyond the planned treatment period.  This window will include data 
from 16 +/- 4 weeks past the date of the last SC dose.  The target day is 113 days after the 
last SC dose, with a window of [85, 141] days after the last SC dose.  If multiple 
observations occur in this visit window, the observation closest to the specified target day 
will be used, noting that the latter will be used in the case of a tie.
For the assessments not made at each planned study visit, broader visit windows are shown 
below.  When multiple observations occur in a visit window, the observation closest to the 
protocol specified target day will be used, noting that the latter will be used in the case of a 
tie.
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LEAS
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[-7,1]
Week 4
29
[2,43]
Week 8
57
[44,85]
Week 16
113
[86,141]
Week 24
169
[142,281]
Week 56
393
[282, 477]
Week 80/End of 
Study
561
[478, no upper limit]
EQ-5D-5L
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[-7, 1]
Week 8
57
[2, 85]
Week 16
113
[86, 141]
Week 24
169
[142, 225]
Week 40
281
[226, 337]
Week 56
393
[338, 421]
Week 64
449
[422, no upper limit]
WPAI: OA
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[-7,1]
Week 16
113
[2,141]
Week 24
169
[142,281]
Week 56
393
[282, 421]
Week 64
449
[422, no upper limit]
Actigraphy, TSQM, mPRTI
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[no lower limit, 1]
Week 16
113
[2,253]
Week 56
393
[254, no upper limit]
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HCRU
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[no lower limit, 1]
Week 64
449
[2,505]
Week 80
561
[506, no upper limit]
For the average pain in the index joint, the data are collected daily via electronic diary up to 
the end of Week 16, and thereafter weekly up to Week 80.  Data up to Week 64 will be 
reported as part of the efficacy assessment (summary up to Week 64; analysis up to Week 
56). 
The Baseline score is the mean of the last 3 non-missing pain scores over study days -7 to -1.  
If fewer than 3 are available between study days -7 and -1, the baseline will be the mean of 
the available scores.
The table below describes the visit days for each week (Weeks 1-16).  All available on-
treatment diary data in each of the weekly intervals will be used to calculate the mean daily 
pain score for that study week.
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Study 
Week
Days
Study 
Week
Days
1
1-7
9
57-63
2
8-14
10
64-70
3
15-21
11
71-77
4
22-28
12
78-84
5
29-35
13
85-91
6
36-42
14
92-98
7
43-49
15
99-105
8
50-56
16
106-112
However, if a subject receives the Week 16 injection dose prior to Day 113, the Week 16 
score will be calculated using the mean of the available scores from the 7 calendar days 
immediately prior to the Week 16 injection dose date.  Any scores used in this calculation of 
Week 16 will not also be used in an earlier week calculation, eg, if the Week 16 dose occurs 
on Day 109, the available scores from Days 102-108 will be used to calculate the average 
score for Week 16, and the available scores from Days 99-101 will be used to calculate the 
average score for Week 15.
After the Week 16 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 16 visit (or weekly diary is not activated at the visit), and so has daily diary data 
collected past Day 112, these data will be averaged with any data obtained weekly for any 
given interval.  All available on- or off-treatment data will be used for these windows after 
the planned treatment period, ie, after Week 56.
Summary 
Week
Includes 
Weeks
Days
20
17 - 20
113-140
24
21 - 24
141-168
28
25 - 28
169-196
32
29 - 32
197-224
36
33 - 36
225-252
40
37 – 40
253-280
44
41 – 44
281-308
48
45 – 48
309-336
52
49 – 52
337-364
56
53 – 56
365-392
60
57 – 60
393-420
64
61 – 64
421-448
One additional window will be created relative to the date of last SC dose for summaries of 
diary pain scores collected beyond the planned treatment period.  This window will be 
identified as 16 Weeks Post Last Dose, and will include the average of all data from 13 to 16 
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weeks (85 to 112 days)_past the date of the last SC dose. All available on- or off-treatment 
data will be used for this window after the planned treatment period.
Appendix 1.2. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations
Not applicable.
Appendix 1.3. Definition of Analysis Populations/Sets 
Not applicable.
Appendix 1.4. Further Definition of Endpoints
Health State Utility of the EQ-5D-5L
The EQ-5D-5L contains five questions that measure the following dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each of the five 
dimensions has five levels: (1) no problems; (2), slight problems; (3) moderate problems; (4) 
severe problems; and (5) extreme problems.  
The health utility scores are defined for every possible set of outcome combinations of the 
five dimensions for the following countries:
•
Denmark, France, Germany, Japan, the Netherlands, Spain, Thailand, UK, US and 
Zimbabwe
This study recruited treated subjects from the following countries.  
•
Australia, Bulgaria, Brazil, Colombia, Japan, New Zealand, Peru, Philippines, Russia, 
South Korea, Taiwan, Ukraine, US, Croatia, Lithuania, Serbia and Slovakia
Some of these may not actually recruit or treat subjects, and other countries may be added.  
As there is a mismatch between countries where subjects are being recruited and the 
currently available EQ-5D-5L health utility scoring, we will assign subjects to the following 
scoring countries based on the following assignments.
EQ-5D-5L Scoring Country
Study Recruitment Country
Denmark
-
France
-
Germany
Russia, Ukraine, Croatia, Lithuania, 
Serbia, Slovakia, Bulgaria
Japan
Japan, South Korea, Taiwan
The Netherlands
-
Spain
Colombia, Peru 
Thailand
-
UK
Australia, New Zealand
US
Brazil, US, Philippines
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Zimbabwe
-
If more EQ-5D-5L utility scores become available or other countries are added, then this 
assignment may be modified.
The health utility for a subject with no problems in all 5 items is 1 for all countries (except 
for Zimbabwe where it is 0.9), and is reduced where a subject reports greater levels of 
problems across the five dimensions.  The minimum score across the countries is -0.654.
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Appendix 2. WPAI:OA Endpoints
The tables below summarizes the 6 questions of the WPAI:OA questionnaire, and the four 
endpoints of the effect of impairment on activity and impairment.
Question
Question Wording
Scoring
1
Are you currently employed? [if No skip 
to question 6]
Yes, No
2
During the past seven days, how many 
hours did you miss from work due to 
problems associated with your OA of the 
knee or hip
number of hours (free text)
3
During the past seven days, how many 
hours did you miss from work because of 
any other reason, such as vacation, 
holidays, time off to participate in this 
study?
number of hours (free text)
4
During the past seven days, how many 
hours did you actually work (if ‘0’ skip to 
Question 6)
number of hours (free text)
5
During the past seven days, how much did 
your OA of the knee or hip affect 
productivity while you were working?
0 to 10 scale with 0 being ‘No effect 
on my work’ and 10 being 
‘Completely prevented me from 
working’
6
During the past seven days, how much did 
your OA of the knee or hip affect your 
ability to do your regular daily activities, 
other than work at a job?
0 to 10 scale with 0 being ‘No effect 
on my daily activities’ and 10 being 
‘Completely prevented me from 
doing my daily activities’
WPAI endpoint
Calculation
Percent activity impairment due to 
Osteoarthritis
Q6*10
Percent impairment while working due to 
osteoarthritis
Q5*10
Percent overall work impairment due to 
osteoarthritis 
100
10
5
4
2
2
1
4
2
2
×
⎪⎭
⎪⎬
⎫
⎪⎩
⎪⎨
⎧
⎟
⎠
⎞
⎜
⎝
⎛⎥
⎦
⎤
⎢
⎣
⎡
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
−
+
+
Q
Q
Q
Q
Q
Q
Q
Percent work time missed due to 
Osteoarthritis
4
2
2
Q
Q
Q
+
*100
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TSQM vII
The 11 questions of the TSQM and the scoring are shown below:
Item
Question wording
Likert Scoring
1
How satisfied or dissatisfied are you with the ability of the 
medication to prevent or treat the condition?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
2
How satisfied or dissatisfied are you with the way the 
medication relieves symptoms?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
3
As a result of taking this medication, do you experience any 
side effects at all?
0 (No), 1 (Yes)
4
How dissatisfied are you by side effects that interfere with 
your physical health and ability to function (eg, strength, 
energy levels)?
1 (Extremely dissatisfied) to 
5 (Not at all dissatisfied)
5
How dissatisfied are you by side effects that interfere with 
your mental function (eg, ability to think clearly, stay 
awake)?
1 (Extremely dissatisfied) to 
5 (Not at all dissatisfied)
6
How dissatisfied are you by side effects that interfere with 
your mood or emotions and ability to function (eg, 
anxiety/fear, sadness, irritation/anger)?
1 (Extremely dissatisfied) to 
5 (Not at all dissatisfied)
7
How satisfied or dissatisfied are you with how easy the 
medication is to use?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
8
How satisfied or dissatisfied are you with how easy it is to 
plan when you will use the medication each time?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
9
How satisfied or dissatisfied are you by how often you are 
expected to use/take the medication?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
10
How satisfied are you that the good things about this 
medication outweigh the bad things?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
11
Taking all things into account, how satisfied or dissatisfied 
are you with this medication?
1 (Extremely dissatisfied) to 
7 (Extremely satisfied)
The scoring of the 4 satisfaction parameters are shown in the table below.
TSQM Parameter
Scoring
Effectiveness
[(Item 1+Item 2) – 2 ]/12 *100
Side Effects
[(Item 4 + Item 5 + Item 6) – 3]/12 *100
If one item is missing then:
[(Sum of two completed items)-2]/8 *100
Convenience
[(Item 7 + Item 8 + Item 9) – 3]/18 *100
If one item is missing then:
[(Sum of two completed items)-2]/12 *100
Global Satisfaction
[(Item 10+Item 11) – 2 ]/12 *100
The four parameters have a scale of 0-100, with 100 being the best (most satisfied) score.
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Healthcare Resource Utilization (example using 3 month recall—8 week recall is also 
used in study)
Question
Response
Scoring
During the last 3 months, what services 
did you receive directly related to your 
osteoarthritis?
•
Primary Care Physician
•
Neurologist
•
Rhematologist
•
Physician Assistant or Nurse 
Practioner
•
Pain Specialist
•
Orthopedist
•
Physical Therapist
•
Chiropractor
•
Alternative Medicine or Therapy
•
Podiatrist
•
Nutritionist/Dietician
•
Radiologist
•
Home healthcare services
•
Other
Number of Visits
Response not selected = 
0
Number of visits = 
1-999
During the past 3 months, have you 
visited the emergency room due to your 
osteoarthritis?
Yes, No
No = 0
Yes = 1
How many times?
Number of visits
0-999 
During the past 3 months, have you been 
hospitalized due to your osteoarthritis?
Yes, No
No = 0
Yes = 1
How many nights in total did you stay in 
hospital due to your osteoarthritis in the 
last 3 months?
Number of Nights
0-999 (max should be 
92)
Did you use these aids or devices to help 
you in doing things because of your 
osteoarthritis in the last 3 months?
•
Walking Aid
•
Wheelchair
•
Devices or utensils to help you 
dress, eat or bathe
•
Other
Did not use any 
aids or devices
Never, rarely, 
sometimes, often, 
always
Did not use any aids or 
devices = 0
Device not selected = 0
Never = 1
Rarely = 2
Sometimes = 3
Often = 4
Always = 5
Did you quit your job because of your 
osteoarthritis?
Yes, No
No = 0
Yes = 1
Not applicable = 2
How long ago did you quit your job 
because of your osteoarthritis?
Years and Months
0-99 Years and 0-99 
Months (should be max 
of 11 months)
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Rescue Medication Endpoints
Rescue medication data is collected daily using an electronic system up to Week 16, and 
weekly after Week 16 and up to Week 80.  Daily and weekly collected data will be assigned 
to a specific study week for summary and reporting.  The assignment of daily and weekly 
data to weeks will use the same principle as described above in Appendix 1.1 for the daily
and weekly index joint pain data.  
The incidence of rescue medication use will look for any incidence in the week of interest 
(collected through daily or weekly diary data).  The number of days of RM use (using daily 
and weekly data) and the total amount taken (using daily data up to Week 16 only) over the 
week will be calculated for the assigned week algorithm described above.  
Imputation is described in Section 7 above.  Imputation occurs for daily data up to Week 16 
where the subject is in the trial and up to the end of that particular week.
An example of imputation and calculating the three endpoints using the daily diary data is 
shown below.
Example of calculating rescue medication data from Daily Diary Data (Subject does not 
discontinue)
In this example, a subject has a Week 2 visit on study day 14 (slightly earlier than the 
nominal day 15).  Study days 8-14 would represent Week 2 data.
Using the Week 2 interval described above for a subject, ie, study days [8-14], we have the 
following rescue medication example data.  
The amount taken and number of days of rescue medication use is adjusted for the duration 
of the Weekly interval. 
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Study Day (Week)
Number of Doses of 
RM taken [1]
Number of Doses of 
RM taken [1] with 
LOCF imputation
8 (Week 2)
2
2
9 (Week 2)
Missing
2 [2]
10 (Week 2)
0
0
11 (Week 2)
1
1
12 (Week 2)
Missing
1 [2]
13 (Week 2)
2
2
14 (Week 2)
0
0
[1] 500mg tablets of acetaminophen; [2] Using LOCF imputation for missing data
For this subject the following data will be calculated for Week 2:
•
Incidence of rescue medication taken in Week 2: Yes.  Rescue medication taken on 
days 8, 9 (imputed), 11, 12 (imputed), 13.
•
Number of days of rescue medication use in Week 2:   5. For days 8-14 we have 
rescue medication taken on days 8, 9 (imputed), 11, 12 (imputed), and 13.  The 
number of days taken for the 7 day period is 5/7*7=5.
•
Amount (mg) of rescue medication use in Week 2: For days 8-14 we have the number 
of doses taken of 2, 2 (imputed), 0, 1, 1 (imputed), 2, and 0.  The number of doses 
taken for the 7 day period is 8/7*7=8, making the amount of acetaminophen dosage 
of 4000mg.
Example of calculating rescue medication data from Daily Diary Data (Subject
discontinues)
In this example, a subject discontinues on study day 62, a few days after a Week 8 visit 
(which was on study day 60).  The Week 5-8 data is calculated as described above (eg, Week 
8 using days [50, 56]).  The subject has rescue medication data as shown below.
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Study Day (Week)
Number of Doses of 
RM taken [1]
Number of Doses of 
RM taken [1] with 
LOCF imputation
57 (Week 9)
1
1
58 (Week 9)
1
1
59 (Week 9)
Missing
1 [2]
60 (Week 9)
Missing
1 [2]
61 (Week 9)
Missing
1 [2]
62 (Week 9)
Missing
1 [2]
63 (Week 9)
Missing
1 [2]
[1] 500mg tablets of acetaminophen; [2] Using LOCF imputation for missing data
Week 9 is calculated as days 57 to 63.  The data up to the end of the last week the subject
was in the trial is imputed using LOCF as shown above.  Therefore the Week 9 scores are 
then used to impute the Weekly data for summary and analysis for Weeks 10 to 56 (up to 
Week 16 for the amount of rescue medication use).
As above the incidence of rescue medication for Week 9 would be ‘Yes’.  The number of 
days of rescue medication use would be 7, and the average dose would be 
7/7*7*500=3500mg for this week.
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Appendix 3. STATISTICAL METHODOLOGY DETAILS 
Appendix 3.1. Further Details of Interim Analyses
Details of the ongoing review of safety data (including joint safety events) are given in a 
separate statistical analysis plan for the Data Monitoring Committee.
Appendix 3.2. Further Details of the Statistical Methods
A description of the combination of the ANCOVA results from each of the multiple imputed 
datasets is given below, and taken from Little & Rubin (2002),3 page 86-7.
In this analysis we have defined the number of imputations (D) to be 100.
The treatment estimates for individual treatment groups and treatment contrasts are defined 
as 
iθ for 
D
i
K
1
=
.  The combined estimate is 
∑
=
=
D
i
i
D
D
1
1
θ
θ
.  The variability of the 
combined estimate contains components of both Within- (W) and Between- (B) imputation
dataset variability.  These are shown below:
∑
=
=
D
i
i
D
W
D
W
1
1
and 
(
)
∑
=
−
−
=
D
i
D
i
D
D
B
1
2
ˆ
1
1
θ
θ
where 
i
W is the variance for the parameter 
iθ .
The total variance for 
D
θ is shown below:
D
D
D
B
D
D
W
T
1
+
+
=
.
The test statistic (
)
D
D
T
θ
θ −
has a t-distribution with 
*
v degrees of freedom, which is defined 
below:
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
=
obs
v
v
v
ˆ
1
1
*
,
using
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(
)
(
)
.
1
1
ˆ
1
ˆ
1
ˆ
1
1
1
1
3
2
D
D
D
com
com
com
D
obs
D
D
T
B
D
v
v
v
v
B
W
D
D
v
⎟
⎠
⎞
⎜
⎝
⎛+
=
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
−
=
⎟⎟
⎠
⎞
⎜⎜
⎝
⎛
+
+
−
=
+
γ
γ
This distribution can be used to construct the test statistics and 95% confidence intervals for 
θ.
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