Conditions: Low Back Pain
Keywords: Chronic low back pain Chronic pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 277
Healthy volunteers: no

Brief summary:
This study will investigate the long-term safety and efficacy of a fixed dose of tanezumab 5 mg and 10 mg administered subcutaneously (SC) seven times at 8 week intervals. The primary objective of this study is to evaluate the long term safety of tanezumab 5 mg and 10 mg administrated SC every 8 weeks (7 administrations). In addition, the study will evaluate the long term analgesic efficacy of tanezumab 5 mg and 10 mg SC administered every 8 weeks (7 administrations).

Detailed description:
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 up to 56 weeks in subjects with chronic low back pain. Subjects will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio. Treatment groups will include: 1) Placebo SC matching tanezumab administered at an 8-week interval (total of 7 times) plus celecoxib 100 mg twice a day (BID) to be administered orally for 56 weeks; 2) Tanezumab 5 mg SC administered at an 8-week interval (total of 7 times) plus placebo matching celecoxib to be administered orally BID for 56 weeks; 3) Tanezumab 10 mg SC administered at an 8-week interval (total of 7 times) plus placebo matching celecoxib to be administered orally BID for 56 weeks. The study is designed with a total duration (post-randomization) of up to 80 weeks and will consist of three periods: Screening (up to 37 days; includes a Washout Period and an Initial Pain Assessment Period \[IPAP\]), a Double-blind Treatment Period (56 weeks) and a Follow-up Period (24 weeks). The Screening Period (beginning up to 37 days prior to Randomization) includes a Washout Period (lasting 2 to 32 days), if required, and an IPAP (the 5 days prior to Randomization/Baseline). Prior to entering the study, subjects must be experiencing some benefit (eg, analgesic effect) from their current stable dose regimen of oral NSAID (celecoxib, loxoprofen or meloxicam) treatment, be tolerating their NSAID regimen, 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.

Arms:
arm 1: Subcutaneous injection of placebo for tanezumab every 8 weeks plus oral celecoxib 100 mg twice daily for 56 weeks arm 2: Subcutaneous injection of tanezumab 5 mg every 8 weeks plus oral placebo for celecoxib twice daily for 56 weeks arm 3: Subcutaneous injection of tanezumab 10 mg every 8 weeks plus oral placebo for celecoxib twice daily for 56 weeks

Interventions: intervention 1: Celecoxib intervention 2: Tanezumab 5 mg intervention 3: Tanezumab 10 mg intervention 4: Placebo for celecoxib intervention 5: Placebo for tanezumab
Intervention descriptions: intervention 1: Orally administered Celecoxib 100 mg twice daily for 56 weeks intervention 2: Subcutaneous injection of tanezumab 5 mg every 8 weeks for 56 weeks intervention 3: Subcutaneous injection of tanezumab 10 mg every 8 weeks for 56 weeks intervention 4: Orally administered the placebo twice daily for 56 weeks intervention 5: Subcutaneous injection of the placebo every 8 weeks for 56 weeks

Protocol document:
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 JAPANESE ADULT 
SUBJECTS WITH CHRONIC LOW BACK PAIN
Compound:
PF-04383119
Compound Name:
Tanezumab
United States (US) Investigational New 
Drug (IND) Number:
NA
European Clinical Trials Database 
(EudraCT) Number:
NA
Protocol Number:
A4091063
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Amendment 2
14 September 2017
Considering study feasibility, number of subjects
with 1-year exposure and capability of safety 
evaluation with the data from this study, the 
target sample size was changed to approximately 
200 (170-220) subjects and Section 9.1 and 
associated texts throughout the protocol were 
updated. Additionally, it is acceptable to 
randomize more than 220 subjects from the 
safety perspective.
Per change of target sample size, analysis of 
serum tanezumab and NGF levels at Weeks 2 
and 4 were changed to be conducted for part of 
subjects (i.e. approximately 30% of subjects 
randomized at selected sites) to all subjects
randomized.
In order to clarify study procedure and 
description, administrative changes are added in 
Protocol Summary (Study Design), schedule of 
activities, Section 3 Study Design, Section 4.4 
Life Style Guidelines and Section 5.6 
Investigational Product Storage.
Amendment 1
02 August 2016
Inclusion criterion #6 and associated text 
throughout the protocol has been updated to 
expand the number of pre-study, non-steroidal 
anti-inflammatory drug (NSAID) chronic low 
back 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:  
Loxoprofen 120 - 180 mg/day
Meloxicam 5 - 15 mg/day
Administrative updates in the Schedule of 
Activities and Sections 5.8.1.4, 6.7 and 7.4.4 to:

Provide flexibility in the allowance of 


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screening stage 2.

Clarify that facet joint injections and nerve 
blocks are prohibited beginning 30 days 
prior to IPAP and through Week 64.

Correct the activity in telephone contacts at 
Weeks 68, 72 and 76. 

Provide clarification of the intended follow-
up for subjects with severe and persistent 
joint pain.
Original protocol
28 August 2015
N/A


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Rationale for protocol amendment 2
Background
Although inclusion criterion #6 has been updated to expand the number of pre-study non-
steroidal anti-inflammatory drug (NSAID) for chronic low back pain treatment regimens that 
are considered to be qualifying in the amendment 1 (version date: 2 August 2016), an 
expected effect of enhancement of patient enrolment has not been achieved. Considering 
study feasibility, number of subjects with 1-year exposure and capability of safety evaluation 
with the data from this study, the protocol was amended to revise the target sample size.
Amendment 2
Considering study feasibility, number of subjects with 1-year exposure and capability of 
safety evaluation with the data from this study, the target sample size was updated to 
approximately 200 (170-220) subjects.  However, it is acceptable to randomize more than 
220 subjects from the safety perspective because primary objective is to evaluate the long-
term safety.


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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 (CLBP).
This study will investigate the long term safety and efficacy of a fixed dose of tanezumab 
5 mg and 10 mg administered subcutaneously (SC) seven times at 8-week intervals.  The 
primary objective of this study is to evaluate the long-term safety of tanezumab 5 mg and 
10 mg administrated SC every 8 weeks (7 administrations).  In addition, the study will 
evaluate the long-term analgesic efficacy of tanezumab 5 mg and 10 mg SC administered 
every 8 weeks (7 administrations).
STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:

Evaluate the long-term safety of tanezumab 10 mg and 5 mg SC administrated every 
8 weeks (7 administrations).
Secondary Objective:

Demonstrate the long-term analgesic efficacy of tanezumab 10 mg and 5 mg SC 
administered every 8 weeks (7 administrations).
Primary Endpoints:
Safety Measures

Adverse events.

Standard safety assessments (safety laboratory testing [chemistry and hematology], 
vital signs).

Orthostatic (supine/standing) blood pressure assessments.

Survey of Autonomic Symptoms (SAS) scores.

Electrocardiogram (ECG, 12-lead) assessments.

Joint Safety adjudication outcomes.


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
Total joint replacements.

Neurologic examination (Neuropathy Impairment Score [NIS]).

Anti-drug antibody assessments (ADA).

Physical examinations.
Secondary Endpoints:
Efficacy-Related Endpoints

Change from Baseline to Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64 in average 
Low Back Pain Intensity (LBPI) score as measured by an 11-point Numeric Rating 
Scale (NRS).

Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in the 
Roland-Morris Disability Questionnaire (RMDQ) total score.

Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in Patient’s 
Global Assessment of Low Back Pain.

Cumulative distribution of percent change from Baseline in average LBPI score to 
Weeks 16, 24 and 56.

Response as defined by a ≥30%, ≥50%, ≥70% and a ≥90% reduction from Baseline in 
weekly average LBPI score derived from the subject diary at Weeks 16, 24, 40 and 56.

Change from Baseline to Weeks 2, 4, 8, 16, 24, 40, 56 and 64 in the Brief Pain 
Inventory-short form (BPI-sf) scores for Worst Pain, Average Pain, Pain Interference 
Index (composite function score), Pain Interference with General Activity, Pain 
Interference with Walking Ability, Pain Interference with Sleep, and Pain 
Interference with Normal Work.

Chronic Low Back Pain Responder Index analysis (composite endpoint of average 
LBPI score, Patient’s Global Assessment of Low Back Pain, and RMDQ total score)
at Weeks 16, 24, 40 and 56.

Treatment Response:  Improvement of ≥2 points in Patient’s Global Assessment of 
Low Back Pain at Weeks 16, 24, 40 and 56.

Euro Quality of Life Health State Profile (EQ-5D-5L) dimensions and overall 
health utility score at Baseline, Weeks 16 and 56.

Work Productivity and Activity Impairment Questionnaire: Low Back Pain 
(WPAI:LBP) change from Baseline to Week 16, 56 and 64, in the percent work time 
missed due to chronic low back pain, percent impairment while working due to 


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chronic low back pain, percent overall work impairment due to chronic low back 
pain, and percent activity impairment due to chronic low back pain.

Incidence of and time to discontinuation due to lack of efficacy.

Usage of rescue medication (incidence, and number of days of usage) during Weeks 
2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64.

Usage of rescue medication (amount taken) during Weeks 2, 4, 8, 12, and 16.

Health Care Resource Utilization (HCRU) at Baseline, Weeks 64 and 80.
Treatment Satisfaction Measures

Treatment Satisfaction Questionnaire for Medication v.II (TSQM) score at Weeks 16 
and 56.

Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 
56.
Tertiary Endpoints

Plasma tanezumab concentrations.

Serum NGF assessments.

Serum and urine osteoarthritis biomarker concentrations.
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 up to 56 
weeks in subjects with chronic low back pain.  Subjects will be randomized to 1 of 
3 treatment groups in a 1:1:1 ratio.  Treatment groups will include:
1. Placebo SC matching tanezumab administered at an 8-week interval (total of 7 times)
plus celecoxib 100 mg twice a day (BID) to be administered orally for 56 weeks.
2. Tanezumab 5 mg SC administered at an 8-week interval (total of 7 times) plus
placebo matching celecoxib to be administered orally BID for 56 weeks.
3. Tanezumab 10 mg SC administered at an 8-week interval (total of 7 times) plus
placebo matching celecoxib to be administered orally BID for 56 weeks.
The study is designed with a total duration (post randomization) of up to 80 weeks and will 
consist of three periods: Screening (up to 37 days; includes a Washout Period and an Initial 
Pain Assessment Period), Double-blind Treatment (56 weeks) and Follow-up (24 weeks).


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STATISTICAL METHOD
In terms of study feasibility and safety evaluation, the total sample size will be approximately 
200 subjects (170-220 subjects, approximately 66 subjects [56-73 subjects] per treatment 
group).  However, it is acceptable to randomize more than 220 subjects from the safety 
perspective as described below because primary objective is to evaluate the long-term safety.
Japanese CLBP subjects are enrolled in two studies (A4091059 and this study). In ongoing 
A4091059 study (randomization was finished in June 2017), 129 Japanese subjects were 
randomized and approximately 57 Japanese CLBP subjects are expected to be initially 
randomized to the tanezumab arm. Considering approximately 133 (113-146) subjects are 
expected to be randomized to the tanezumab arm in this study, the safety data will be 
collected from approximately 190 (170-203) Japanese CLBP subjects treated with tanezumab.
The proportion of subjects expected to complete this study was calculated as approximately 
54% based on two OA phase 3 studies (A4091011, A4091014) and approximately 34% 
based on one CLBP phase 3 study (A4091012), and therefore the proportion of completers of 
this study is estimated to be between 34% and 54%.  If the proportion of completers is at 
least 43% in CLBP program, approaching 100 subjects would be treated with tanezumab for 
a minimum of one year.
As described below, when approximately 200 (170-220) Japanese subjects are enrolled in 
this study, the adverse events related to abnormal peripheral sensation and decreased 
sympathetic function are expected to occur in several Japanese subjects, so neurological 
safety can be evaluated with high probability in Japanese subjects.
Assuming that the true incidence of adverse events related to abnormal peripheral sensation
in CLBP subjects enrolled in A4091059 and this study is 10%, when 170 subjects are 
enrolled in this study (approximately 113 subjects will be treated with tanezumab), these 
adverse events are expected to occur in 7 to 15 subjects (6%-13%) in this study at a 
probability of ≥80%, and in 12 to 22 subjects (7%-13%) in combined A4091059 and this 
study (approximately 170 subjects will be treated with tanezumab) at a probability of ≥80%.
Assuming that the true incidence of adverse events related to decreased sympathetic function
in CLBP subjects enrolled in A4091059 and this study is 6%, when 170 subjects are enrolled 
in this study, these adverse events are expected to occur in 4 to 10 subjects (4%-9%) in this 
study at a probability of ≥80%, and in 6 to 14 subjects (4%-8%) in combined A4091059 and 
this study at a probability of ≥80%.


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Main Safety and Efficacy Analysis
The efficacy and safety population will be the ITT population, defined as all randomized 
subjects who received SC investigational product (either tanezumab or matching placebo).
Adverse events, concomitant medications, laboratory safety tests, physical and neurological 
examinations, vital signs, electrocardiogram (ECG), and the anti-drug antibody test will be 
collected for each subject during the study according to the Schedule of Assessments.  
Standard safety reporting tables will summarize and list the safety data.  
The incidence of subjects with any of the adjudication outcomes of rapidly progressive 
osteoarthritis (type-1 and type-2), subchondral insufficiency fracture (or SPONK), primary 
osteonecrosis, or pathological fracture 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 celecoxib treatment group.  The 
risk ratio and risk difference with 95% confidence intervals will be calculated for the 
comparisons of each tanezumab group versus the celecoxib group.
For the efficacy endpoints, summary statistics will be shown by timepoints and by treatment 
group.  For the continuous endpoints and the binary endpoints, the difference with 95% 
confidence intervals between tanezumab treatment groups and the celecoxib treatment group 
will be calculated, but no inferential testing will be performed.
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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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 well-being of the subject.
Table 1.
Schedule of Activities: Screening through Week 56
Screen
Treatment Period
Visit Indentifiers
SC.
Stage 1
SC.
Stage 2
IPAP
Baselinea
Week 2
Week 4
Week 8a Week 12b Week 16a Week 24a
Weeks 
32, 40, 
48a
Weeks 
20, 28, 
36, 44, 
52b
Week 56/
End of 
Treatment
Study Activities
Day - 37 to -5
Day-5 
to -1
Day 1 
Dosing 
Visit
Day 15 
(2 days)
Day 29 
(3 days)
Day 57 
(7 days) 
Dosing 
Visit
(7 days) 
Telephone
Contact
Day 113 
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visits
(7 days) 
Telephone
Contact
Day 393 
(7 days)
Informed Consent
X
Inclusion/Exclusion 
Criteria/
subject eligibility
X
X
Demographics, General 
and Musculoskeletal 
Specific Medical History 
and Prior/Current 
Medication Use
X
Primary Diagnosis
X
Quebec Task Force 
Category
X
Height/BMI/
Smoking Status/Female 
Hormonal Status/Alcohol 
Use
X
Body Weight
X
X


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Screen
Treatment Period
Visit Indentifiers
SC.
Stage 1
SC.
Stage 2
IPAP
Baselinea
Week 2
Week 4
Week 8a Week 12b Week 16a Week 24a
Weeks 
32, 40, 
48a
Weeks 
20, 28, 
36, 44, 
52b
Week 56/
End of 
Treatment
Study Activities
Day - 37 to -5
Day-5 
to -1
Day 1 
Dosing 
Visit
Day 15 
(2 days)
Day 29 
(3 days)
Day 57 
(7 days) 
Dosing 
Visit
(7 days) 
Telephone
Contact
Day 113 
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visits
(7 days) 
Telephone
Contact
Day 393 
(7 days)
Vital Signs (sitting BP, 
HR)
X
X
X
X
X
X
X
X
X
Orthostatic Blood 
Pressure 
(supine/standing)
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(12-lead)
X
X
X
General Physical 
Examination
X
X
Musculoskeletal Physical 
Examination
X
X
X
X
X
X
X
X
X
Neurologic 
Exam/Neuropathy 
Impairment Score (NIS)c
X
X
X
X
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
X
Review weekly joint pain 
scores
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
review
X
X
X
X
X
X
X
X
X
X
Washout of prohibited 
Pain Medications (Prior 
to Day -5)
Subject Reported Assessments Completed at Study Visits (collected via tablet device at site)
BPI-sf
X
X
X
X
X
X
Xd
X
RMDQ
X
X
X
X
X
X
X
X
Patient Global 
Assessment of Low Back 
Pain
X
X
X
X
X
X
X
X
Pain DETECT
X
WPAI:LBP
X
X
X
EQ-5D-5L
X
X
X


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Screen
Treatment Period
Visit Indentifiers
SC.
Stage 1
SC.
Stage 2
IPAP
Baselinea
Week 2
Week 4
Week 8a Week 12b Week 16a Week 24a
Weeks 
32, 40, 
48a
Weeks 
20, 28, 
36, 44, 
52b
Week 56/
End of 
Treatment
Study Activities
Day - 37 to -5
Day-5 
to -1
Day 1 
Dosing 
Visit
Day 15 
(2 days)
Day 29 
(3 days)
Day 57 
(7 days) 
Dosing 
Visit
(7 days) 
Telephone
Contact
Day 113 
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visits
(7 days) 
Telephone
Contact
Day 393 
(7 days)
Health Care Resource 
Utilization (HCRU)
X
TSQM
X
X
mPRTI
X
X
Survey of Autonomic 
Symptoms (SAS)
X
X
X
Subject Daily and Weekly Assessments (IRT)
LBPI scoree
Xf
Xf
-------------------- (Weekly via IRT [handheld device]) ------------------
Rescue medication usagee
-------------------- (Daily via IRT [handheld device]) ------------------
--- (Weekly via IRT [handheld device]) ---
Record joint pain, if 
applicableg
X
-------------------- (Weekly via IRT [handheld device]) ------------------
Concomitant NSAID 
(outside of oral 
investigational product)
usage
-------------------- (Weekly via IRT [handheld device]) ------------------
Radiographic Assessments
X-rays of the hips, knees 
and shoulders
X
Xh
X
Central reader to confirm 
radiologic eligibility
X
Xh
Compliance assessments
Assess compliance with 
oral investigational 
product (Celecoxib or 
placebo matching for 
Celecoxib)
X
X
X
X
X
X
X
X
X
Compliance with daily 
and weekly diary entries 
via IRT
X
X
X
X
X
X
X
X
X
X
Rescue medication 
compliance
X
X
X
X
X
X
X
X
X
X


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Screen
Treatment Period
Visit Indentifiers
SC.
Stage 1
SC.
Stage 2
IPAP
Baselinea
Week 2
Week 4
Week 8a Week 12b Week 16a Week 24a
Weeks 
32, 40, 
48a
Weeks 
20, 28, 
36, 44, 
52b
Week 56/
End of 
Treatment
Study Activities
Day - 37 to -5
Day-5 
to -1
Day 1 
Dosing 
Visit
Day 15 
(2 days)
Day 29 
(3 days)
Day 57 
(7 days) 
Dosing 
Visit
(7 days) 
Telephone
Contact
Day 113 
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visits
(7 days) 
Telephone
Contact
Day 393 
(7 days)
NSAID (outside of oral 
investigational product)
limit compliance
X
X
X
X
X
X
X
X
X
Remind subject of
contraceptive 
requirements
X
X
X
X
X
X
X
X
X
X
X
Laboratory
Hepatitis Screen 
(Hepatitis B & C); HIV, 
Urine Toxicology screen
X
Hemoglobin A1c
X
Serum FSH testingi
X
Serum/Urine Pregnancy 
Testj
X
X
X
X
X
X
X
Hematology
X
X
X
Blood Chemistry
X
X
X
Urinalysis
X
Serum/Plasma Retention 
Sample
X
X
X
Plasma Pharmacokinetic 
samplek
X
X
X
X
X
Xl
X
Serum Pharmacodynamic 
sample (NGF)k
X
X
X
X
Xl
X
Serum Anti-Drug 
Antibodyk
X
X
X
Xl
X
Serum and urine 
biomarkersm
X
Banked biospecimen 
(whole blood)
X


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Screen
Treatment Period
Visit Indentifiers
SC.
Stage 1
SC.
Stage 2
IPAP
Baselinea
Week 2
Week 4
Week 8a Week 12b Week 16a Week 24a
Weeks 
32, 40, 
48a
Weeks 
20, 28, 
36, 44, 
52b
Week 56/
End of 
Treatment
Study Activities
Day - 37 to -5
Day-5 
to -1
Day 1 
Dosing 
Visit
Day 15 
(2 days)
Day 29 
(3 days)
Day 57 
(7 days) 
Dosing 
Visit
(7 days) 
Telephone
Contact
Day 113 
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visit
(7 days) 
Dosing 
Visits
(7 days) 
Telephone
Contact
Day 393 
(7 days)
Trial Treatment
Pre-study Celecoxib
Dispensed/Regimen 
Stabilization
X
At least 2 or 3 
weeks prior to 
Baseline (Day 1) 
visitn
Assess treatment 
response and eligibility to 
continue in the trialo
Xo
Randomization
X
SC investigational 
productp
X
X
X
X
X
Blinded Celecoxib (Oral 
investigational product)
--------------------------------------------------------------------X--------------------------------------------------------
Dispense Blinded 
Celecoxib (Oral 
investigational product)
X
X
X
X
X
X
X
Dispense rescue 
medication
X
X
X
X
X
X
X
X
X


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Table 2.
Schedule of Activities: Follow-up Period
Follow-up Period
Early Termination (ET) Procedure
Visit Indentifiers
Week 60
Week 64
Week 68, 
72, 76
Week 80 
End of 
Study
ET Visit 1
ET 
Telephone 
Contact 1
ET Visit 2
ET 
Telephone 
Contact 2
ET Visit 3
Study Activities
(7 days) 
Telephone 
Contact
Day 449 
(7 days)
(7 days) 
Telephone 
Contact
Day 560
(7 days)
8 weeks after 
last dose of 
SC Study 
Med
(7 days)
12 weeks 
after last 
dose of SC 
Study Med 
(7 days)
16 Weeks 
after last 
dose of SC 
Study Med 
(7 days)
20 weeks 
after last 
dose of SC 
Study Med 
(7 days)
24 Weeks 
after last 
dose of SC 
Study Med 
(7 days)
Vital Signs (sitting BP, HR) 
X
X
X
X
X
Orthostatic Blood Pressure 
(supine/standing)
X
X
X
X
X
Electrocardiogram (12-lead)
X
X
X
Body weight
X
General Physical Examination
X
Musculoskeletal Physical Examination
X
X
X
X
X
Neurologic Exam/Neuropathy 
Impairment Score (NIS)c
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
Review weekly joint pain scores 
X
X
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
Subject Reported Assessments Completed at Study Visits (collected via tablet device at site)
BPI-sf
X
X
X
RMDQ
X
X
X
Patient Global Assessment of Low 
Back Pain
X
X
X
WPAI:LBP
X
X
X
EQ-5D-5L
X
HCRU
X
X
X
X
TSQM
X
mPRTI
X
Survey of Autonomic Symptoms 
(SAS)
X
X
X


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Follow-up Period
Early Termination (ET) Procedure
Visit Indentifiers
Week 60
Week 64
Week 68, 
72, 76
Week 80 
End of 
Study
ET Visit 1
ET 
Telephone 
Contact 1
ET Visit 2
ET 
Telephone 
Contact 2
ET Visit 3
Study Activities
(7 days) 
Telephone 
Contact
Day 449 
(7 days)
(7 days) 
Telephone 
Contact
Day 560
(7 days)
8 weeks after 
last dose of 
SC Study 
Med
(7 days)
12 weeks 
after last 
dose of SC 
Study Med 
(7 days)
16 Weeks 
after last 
dose of SC 
Study Med 
(7 days)
20 weeks 
after last 
dose of SC 
Study Med 
(7 days)
24 Weeks 
after last 
dose of SC 
Study Med 
(7 days)
Subject Weekly Assessments (IRT)
LBPI scoree
----------- X -----------
---------------------- X -----------------------
Rescue medication usee
--------------------------- X ---------------------------
---------------------------------------- X ----------------------------------------
Record joint pain, if applicableg
--------------------------- X ---------------------------
---------------------------------------- X ----------------------------------------
Concomitant NSAID (outside of oral 
investigational product) usage
--------------------------- X ---------------------------
---------------------------------------- X ----------------------------------------
Radiographic Assessments
X-rays of the hips, knees and 
shoulders 
X
X
X
Compliance assessments
Compliance with weekly diary entries 
via IRT
X
X
X
X
X
X
X
Rescue medication compliance
X
X
X
X
X
NSAID (outside of oral investigational 
product) limit compliance
X
X
X
X
X
Remind subject of contraceptive 
requirements
X
X
X
X
X
Laboratory
Serum/Urine Pregnancy Testj
X
X
X
Hematology
X
X
Blood Chemistry
X
X
Serum/Plasma Retention Sample
X
X
X
Plasma Pharmacokinetic samplek
X
X
X
Serum Pharmacodynamic sample 
(NGF)k
X
X
X
Serum Anti-Drug Antibodyk
X
X
X
X
X


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Follow-up Period
Early Termination (ET) Procedure
Visit Indentifiers
Week 60
Week 64
Week 68, 
72, 76
Week 80 
End of 
Study
ET Visit 1
ET 
Telephone 
Contact 1
ET Visit 2
ET 
Telephone 
Contact 2
ET Visit 3
Study Activities
(7 days) 
Telephone 
Contact
Day 449 
(7 days)
(7 days) 
Telephone 
Contact
Day 560
(7 days)
8 weeks after 
last dose of 
SC Study 
Med
(7 days)
12 weeks 
after last 
dose of SC 
Study Med 
(7 days)
16 Weeks 
after last 
dose of SC 
Study Med 
(7 days)
20 weeks 
after last 
dose of SC 
Study Med 
(7 days)
24 Weeks 
after last 
dose of SC 
Study Med 
(7 days)
Trial Treatment
Dispense rescue medication
X
X
X
Assign standard of care treatment as 
needed
X
X
Abbreviations: = Ongoing/Continuous event; BMI = body mass index;  BP = Blood Pressure;  BPI-sf = Brief Pain Inventory-Short Form, ECG = Electrocardiogram; 
EQ-5D-5L = EuroQol 5 Dimension ; FSH = Follicle Stimulating Hormone; HCRU = Health Care Resource Utilization; HIV = Human Immunodeficiency Virus; HR = Heart Rate; 
IPAP = Initial Pain Assessment Priod; IRT = Interactive Response Technology; LBPI = Low Back Pain Intensity; mPRTI = Patient Reported Treatment Impact 
assessment-modified; NGF = Nerve Growth Factor; NIS = Neuropathy Impairment Score; NSAID = Non-Steroidal Anti-Inflammatory Drug; PD = Pharmacodynamics; PK = 
Pharmakokinetic; RMDQ = Roland-Morris Disability Questionnaire; SAS = Survey of Autonomic Symptoms; SC = Subcutaneous; SC. = Screening; TSQM (v.II) = Treatment 
Satisfaction Questionnaire Medicine version II; WPAI:LBP = Work Productivity and Activity Impairment Questionnaire: Low Back Pain
a.
All study activities at Baseline (Day 1), Weeks 8, 16, 24, 32, 40 and 48 should be performed prior to dosing with investigational product, unless 
otherwise noted.
b.
Telephone Contact Visit: Contact subject and review adverse events (including any new or persistent joint pain, joint procedures or surgeries), 
compliance with contraceptive requirements, concomitant medications and concomitant use of analgesics for chronic low back pain, as appropriate.  If 
adverse events dictate that the subject should be seen, an unscheduled visit may be conducted and pertinent exams conducted (eg, physical exam, 
neurological exam, ECG, clinical laboratory testing) depending on the nature of the event and the investigator’s clinical judgment.
c.
A neurological examination (NIS) will be performed by the investigator (or designated physician) and assessed for clinically significant changes from 
Baseline. 
d.
BPI-sf to be conducted at Week 40 only.
e.
LBPI scores will be collected daily during the Intial Pain Assessment Period (IPAP) and weekly from Baseline through to Week 64 using IRT. Rescue 
medication use will be collected daily up to Week 16 and weekly from Week 16 to 64 via IRT.
f.
At the Screening stage 1 visit only, in order to determine eligibility, the LBPI score will be collected via the IRT. During the IPAP (within a 5 day 
consecutive period prior to Baseline), the subjects will record their daily LBPI score use by the IRT.
g.
Collected at Screening and then weekly thereafter as described Section 7.3.2.


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h.
At Week 24, sites must receive confirmation of continued radiologic eligibility from the Central Reader prior to administering the Week 24 SC 
investigational product.  Refer to Section 6.4.7.
i.
FSH testing in female subjects as described in Section 7.3.4.4.
j.
Serum pregnancy tests are obtained at Screening, Weeks 56 and 64 or Early Termination Visits 1 and 2 for subjects who discontinue (Refer to Section 
6.9).  A urine pregnancy test will be obtained at Baseline prior to initial dosing, and pre-dose at Weeks 8, 16, 24, 32, 40, and 48. 
k.
On dosing visits, samples for ADA should be obtained pre-dose at Baseline and Weeks 8, 16, 32 and 48, and at Weeks 56, 64 and 80, or at early 
termination. Samples for PK should be obtained pre-dose at Baseline and Weeks 8, 16, 32 and 48, and at Weeks 2, 4, 56 and 64, or early termination. 
samples for NGF should be obtained pre-dose at Baseline and Weeks 8, 48, and at Weeks 2, 4, 56 and 64, or early termination.
l.
Of the 3 dosing visits listed, obtain a sample for ADA, PK, at Weeks 32 and 48 and PD (NGF) at Week 48 only.
m. Biomarker samples should be collected prior to dosing and if possible, following a fasting period of at least 8 hours at approximately the same time of 
day at all scheduled timepoints.  Urine collected for biomarkers should be the second or later void of the day.
n.
Pre-study NSAID (Celecoxib) will be dispensed in the Screening period and subjects will be reqired to maintain 70% (5 of 7 days per week) compliance 
during the final two weeks (subjects who were receiving celecoxib as pre-study treatment) or three weeks (subjects who were receiving loxoprofen or 
meloxicam as pre-study treatment) of the Screening period immediately prior to Baseline (Day1) (refer to Section 6.1.2 for additional detail regarding 
Celecoxib regimen stabilization).
o.
At the Week 16 visit, all subjects must have at least a 30% reduction in weekly average LBPI score relative to Baseline and at least a 15% reduction in 
weekly average LBPI score from Baseline at any week from Week 1 to Week 15 in order to continue order to continue investigational product.  Subjects 
who do not meet these response criteria will be discontinued from the Treatment Period and enter Early Termination Follow-up Period.
p.
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 SC investigational product.


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TABLE OF CONTENTS
1. INTRODUCTION .................................................................................................................... 27
1.1. Mechanism of Action/Indication.................................................................................. 27
1.2. Background and Rationale ........................................................................................... 27
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain ................................ 27
1.2.2. Description of Investigational Product ............................................................ 27
1.2.3. Chronic Low Back Pain................................................................................... 27
1.2.4. Overview of Clinical Studies........................................................................... 28
1.2.4.1. Efficacy of Tanezumab in the Treatment of Chronic Low 
Back Pain ........................................................................................... 28
1.2.4.2. Overview of Safety in Clinical Studies............................................... 29
1.2.4.3. Sympathetic Nervous System.............................................................. 31
1.2.4.4. Subcutaneous Administration of Tanezumab in Clinical 
Studies................................................................................................ 31
1.2.4.5. Joint Safety.......................................................................................... 31
1.2.4.6. Experience in Japanese Subjects......................................................... 33
1.2.5. Dose Selection Rationale................................................................................. 34
1.2.6. Rationale for Celecoxib as an Active Comparator .......................................... 38
1.2.7. Subject Population Selection Rationale........................................................... 38
2. STUDY OBJECTIVES AND ENDPOINTS............................................................................ 38
2.1. Objectives..................................................................................................................... 38
2.2. Endpoints...................................................................................................................... 39
2.2.1. Primary Endpoints ........................................................................................... 39
2.2.2. Secondary Endpoints ....................................................................................... 39
2.2.3. Tertiary Endpoints ........................................................................................... 40
3. STUDY DESIGN...................................................................................................................... 41
4. SUBJECT SELECTION........................................................................................................... 42
4.1. Inclusion Criteria.......................................................................................................... 42
4.2. Exclusion Criteria......................................................................................................... 44
4.3. Randomization Criteria ................................................................................................ 48
4.4. Life Style Guidelines.................................................................................................... 49
4.5. Sponsor Qualified Medical Personnel.......................................................................... 50


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5. STUDY TREATMENTS.......................................................................................................... 51
5.1. Allocation to Treatment................................................................................................ 51
5.2. Breaking the Blind........................................................................................................ 51
5.3. Subject Compliance...................................................................................................... 52
5.4. Drug Supplies............................................................................................................... 52
5.4.1. Dosage Form(s) and Packaging....................................................................... 52
5.4.1.1. Tanezumab .......................................................................................... 52
5.4.1.2. Placebo for Tanezumab....................................................................... 52
5.4.1.3. Non-steroidal Anti-inflammatory Drugs (NSAID)............................. 53
5.4.1.4. Acetaminophen/paracetamol (Rescue Therapy) ................................. 53
5.4.2. Preparation and Dispensing ............................................................................. 53
5.5. Administration.............................................................................................................. 53
5.5.1. SC Investigational Product Administration..................................................... 53
5.5.2. Oral Investigational Product Administration................................................... 53
5.6. Investigational Product Storage.................................................................................... 54
5.7. Investigational Product Accountability........................................................................ 55
5.7.1. Destruction of Investigational Product Supplies ............................................. 55
5.8. Concomitant Treatment(s)............................................................................................ 55
5.8.1. Prohibited Medications.................................................................................... 55
5.8.1.1. Medications Prohibited through Week 80........................................... 55
5.8.1.2. Medications Prohibited During Entire Treatment Period
through Week 64................................................................................ 55
5.8.1.3. Prohibited Medications from Washout until Week 16........................ 56
5.8.1.4. Prohibited Non-pharmacological Therapies........................................ 57
5.8.2. Permitted Medications..................................................................................... 58
5.9. Rescue Therapy............................................................................................................ 59
6. STUDY PROCEDURES .......................................................................................................... 60
6.1. Screening Period........................................................................................................... 61
6.1.1. Screening Period Stage 1 (Initial Screening Visit):......................................... 61
6.1.2. Screening Period Stage 2................................................................................. 61
6.2. Washout Period ............................................................................................................ 62
6.3. Initial Pain Assessment Period..................................................................................... 62


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6.4. Double-Blind Treatment Period................................................................................... 63
6.4.1. Baseline Visit (Day 1) ..................................................................................... 63
6.4.1.1. Assessment of Randomization Criteria and Randomization............... 63
6.4.1.2. Dosing (Day 1).................................................................................... 63
6.4.1.3. Post Dosing (Day 1) ............................................................................ 64
6.4.2. Week 2 and 4 Visits......................................................................................... 64
6.4.3. Week 8 Dosing Visit........................................................................................ 64
6.4.4. Week 12 Telephone Visit ................................................................................ 64
6.4.5. Week 16 Dosing Visit...................................................................................... 64
6.4.6. Weeks 20 Telephone Visit............................................................................... 65
6.4.7. Week 24 Dosing Visit...................................................................................... 65
6.4.8. Weeks 28, 36, 44 and 52 Telephone Visits ..................................................... 65
6.4.9. Weeks 32, 40 and 48 Dosing Visits................................................................. 65
6.4.10. Week 56 Visit-End of Treatment Visit.......................................................... 65
6.5. Week 60 Telephone Visit............................................................................................. 66
6.6. Week 64 Visit-Safety Follow-up Period ...................................................................... 66
6.7. Weeks 68, 72, and 76 Telephone Visits....................................................................... 66
6.8. Week 80 Visit-End of Study Visit................................................................................ 66
6.9. Subject Withdrawal/Early Termination Visits ............................................................. 66
6.9.1. Early Termination Follow-up Procedures ....................................................... 68
6.9.1.1. Early Termination Follow-up Period Visit 1 (8 weeks after 
the last dose of SC Investigational Product)...................................... 68
6.9.1.2. Early Termination Follow-up Period Telephone Visit 1
(12 weeks after last dose of SC investigational product)................... 68
6.9.1.3. Early Termination Follow-up Period Visit 2 (16 weeks after 
last dose of SC investigational product) ............................................ 69
6.9.1.4. Early Termination Follow-up Period Telephone Visit 2
(20 weeks after last dose of SC investigational product)................... 69
6.9.1.5. Early Termination Follow-up Period Visit 3 (24 Weeks after 
last dose of SC investigational product) ............................................ 69
6.9.2. Procedures for Subjects Undergoing Joint Replacement................................. 69
7. ASSESSMENTS....................................................................................................................... 70
7.1. Subject Collected Efficacy Assessments...................................................................... 70


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7.1.1. Low Back Pain Intensity (LBPI) Score ........................................................... 70
7.1.2. Rescue Medication and Amount...................................................................... 71
7.2. Study Efficacy Assessments......................................................................................... 71
7.2.1. Roland-Morris Disability Questionnaire (RMDQ).......................................... 71
7.2.2. Patient’s Global Assessment of Low Back Pain.............................................. 71
7.2.3. Brief Pain Inventory-short form (BPI-sf) ........................................................ 72
7.2.4. Work Productivity and Activity Impairment Questionnaire: Low 
Back Pain (WPAI:LBP) .............................................................................. 72
7.2.5. Euro Quality of Life Health State Profile (EQ-5D-5L) ............................... 73
7.2.6. Treatment Satisfaction Questionnaire for Medication v.II (TSQM) ............... 73
7.2.7. Patient Reported Treatment Impact Assessment-modified (mPRTI).............. 73
7.2.8. Health Care Resource Utilization (HCRU) ..................................................... 73
7.3. Safety Assessments ...................................................................................................... 73
7.3.1. Physical Examination ...................................................................................... 74
7.3.1.1. General Physical Examination ............................................................ 74
7.3.1.2. Musculoskeletal History and Physical Examination........................... 74
7.3.2. Joint Pain Weekly Assessments....................................................................... 74
7.3.3. Collection of concomitant NSAID use............................................................ 74
7.3.4. Laboratory Safety Assessments....................................................................... 75
7.3.4.1. Blood tests........................................................................................... 76
7.3.4.2. Urinalysis and Urine Toxicology Screen ............................................ 76
7.3.4.3. Pregnancy Testing............................................................................... 76
7.3.4.4. Serum FSH Testing ............................................................................. 76
7.3.5. Vital Signs ....................................................................................................... 77
7.3.5.1. Orthostatic Blood Pressure Measurements ......................................... 77
7.3.6. 12-Lead Electrocardiogram ............................................................................. 78
7.3.7. Survey of Autonomic Symptoms (SAS).......................................................... 79
7.3.8. Radiographic Assessments .............................................................................. 79
7.3.8.1. Radiation Exposure ............................................................................. 80
7.3.9. Neurologic Examination.................................................................................. 81
7.3.10. Anti-Drug Antibody Testing.......................................................................... 82


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7.3.10.1. Serum for Analysis of Anti-Drug Antibodies (ADA) 
Against Tanezumab ........................................................................... 82
7.4. Triggered Requirements and Subject Level Stopping Rules ....................................... 82
7.4.1. Dysesthesia/Allodynia ..................................................................................... 82
7.4.2. Hypersensitivity or Injection Site Reactions ................................................... 83
7.4.3. Orthostatic Hypotension and Sympathetic Function Adverse Events............. 83
7.4.4. Evaluation and Follow-up for Increased, Severe Persistent Joint Pain ........... 86
7.4.5. Central Reader and Subject-Level Stopping Criteria for Joint Safety 
Events.......................................................................................................... 86
7.4.6. Procedures for Subjects Undergoing Joint Replacement................................. 87
7.5. Pharmacokinetics (PK) and Pharmacodynamics (PD)................................................. 87
7.5.1. Plasma for Analysis of Tanezumab ................................................................. 87
7.5.2. Nerve Growth Factor (NGF) for Pharmacodynamic Analyses ....................... 88
7.6. Biomarkers ................................................................................................................... 88
7.6.1. Serum Biomarkers ........................................................................................... 88
7.6.2. Urine Biomarkers............................................................................................. 89
7.7. Banked Biospecimens .................................................................................................. 89
7.7.1. Markers of Drug Response .............................................................................. 89
7.7.2. Additional Research......................................................................................... 91
7.8. Other Assessments ....................................................................................................... 91
7.8.1. PainDETECT................................................................................................... 91
8. ADVERSE EVENT REPORTING........................................................................................... 91
8.1. Adverse Events............................................................................................................. 91
8.2. Reporting Period........................................................................................................... 92
8.3. Definition of an Adverse Event.................................................................................... 92
8.4. Medication Errors......................................................................................................... 93
8.5. Abnormal Test Findings............................................................................................... 93
8.6. Serious Adverse Events................................................................................................ 94
8.6.1. Protocol-Specified Serious Adverse Events .................................................... 95
8.6.2. Potential Cases of Drug-Induced Liver Injury................................................. 95
8.7. Hospitalization.............................................................................................................. 96
8.8. Severity Assessment..................................................................................................... 97


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8.9. Causality Assessment................................................................................................... 97
8.10. Exposure During Pregnancy....................................................................................... 98
8.10.1. Additional Postnatal Follow-up..................................................................... 99
8.11. Occupational Exposure............................................................................................... 99
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal) ............................................................................................................... 99
8.13. Eliciting Adverse Event Information ....................................................................... 100
8.14. Reporting Requirements........................................................................................... 100
8.14.1. Serious Adverse Event Reporting Requirements ........................................ 100
8.14.2. Non-Serious Adverse Event Reporting Requirements ................................ 100
8.14.3. Medical Device Complaint Reporting Requirements.................................. 101
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ................... 101
9. DATA ANALYSIS/STATISTICAL METHODS.................................................................. 101
9.1. Sample Size Determination........................................................................................ 101
9.2. Analysis of Safety Endpoints ..................................................................................... 103
9.3. Analysis of Efficacy Endpoints.................................................................................. 105
9.4. Analysis of Other Endpoints ...................................................................................... 106
9.4.1. Pharmacokinetic Data.................................................................................... 106
9.4.2. Pharmacodynamic (NGF) Data ..................................................................... 106
9.4.3. Biomarker Data.............................................................................................. 106
9.5. External Adjudication Committee.............................................................................. 106
9.6. Data Monitoring Committee ...................................................................................... 107
9.6.1. Protocol Level Rules for Dosing Suspension/Safety Assessment................. 108
9.6.1.1. Serious Adverse Events..................................................................... 108
9.6.1.2. Events Consistent with Hy’s Law ..................................................... 109
9.6.1.3. Joint Safety Events............................................................................ 109
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................... 110
11. DATA HANDLING AND RECORD KEEPING ................................................................ 110
11.1. Case Report Forms/Electronic Data Record ............................................................ 110
11.2. Record Retention...................................................................................................... 111
12. ETHICS................................................................................................................................. 111
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)................ 111


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12.2. Ethical Conduct of the Study.................................................................................... 112
12.3. Subject Information and Consent............................................................................. 112
12.4. Subject Recruitment ................................................................................................. 113
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP.......................................................................................................................... 113
13. DEFINITION OF END OF TRIAL...................................................................................... 113
14. SPONSOR DISCONTINUATION CRITERIA ................................................................... 113
15. PUBLICATION OF STUDY RESULTS ............................................................................. 114
15.1. Communication of Results by Pfizer........................................................................ 114
15.2. Publications by Investigators.................................................................................... 114
16. REFERENCES ..................................................................................................................... 116
LIST OF TABLES
Table 1.
Schedule of Activities: Screening through Week 56 ............................................ 10
Table 2.
Schedule of Activities: Follow-up Period ............................................................. 15
Table 3.
Adverse Drug Reactions in Subjects All Subjects Receiving Tanezumab ........... 29
Table 4.
Study Treatments................................................................................................... 51
Table 5.
Orthostatic Blood Pressure Changes and Subject Management ........................... 78
Table 6.
The relationship between the proportion of completer and number of 
subjects with one year exposure.......................................................................... 102
LIST OF FIGURES
Figure 1.
Comparison of individual Cmax and AUCinf from Studies A4091006 
(non-Japanese OA subjects) and A4091022 (Japanese OA subjects) -
Cmax or AUCinf vs. fixed dose (mg)....................................................................... 34
Figure 2.
Simulated AUCs across the doses (fixed dose) for Japanese and non-
Japanese OA subjects............................................................................................ 35
Figure 3.
Simulated dose response for WOMAC pain (change from placebo) in 
typical Japanese and non-Japanese OA patients* at Week 16.............................. 36
Figure 4.
Dose-response relationship based on Emax model [relationship between 
total daily dose and change of WOMAC pain (LOCF) at Week 8]...................... 37
Figure 5.
Study Schematic.................................................................................................... 41
Figure 6.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events ............... 85


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APPENDICES
Appendix 1. Quebec Task Force Classification.......................................................................... 123
Appendix 2. American College of Rheumatology (ACR) Classification Criteria for 
Osteoarthritis ....................................................................................................... 124
Appendix 3. American Society of Anesthesiologists (ASA) Physical Status 
Classification....................................................................................................... 125
Appendix 4. Half-Lives of Prohibited Prior and Concomitant Medications .............................. 126
Appendix 5. Patient Health Questionnaire (PHQ-9)................................................................... 132
Appendix 6. Roland-Morris Disability Questionnaire (RMDQ) ................................................ 133
Appendix 7. Neuropathy Impairment Score (NIS) Sample........................................................ 134
Appendix 8. Patient’s Global Assessment of Low Back Pain.................................................... 136
Appendix 10. Work Productivity and Activity Impairment Questionnaire: Low Back 
Pain (WPAI:LBP) ............................................................................................... 139
Appendix 11. Subject Daily/Weekly Assessments of Low Back Pain....................................... 141
Appendix 12. Euro Quality of Life Health State Profile (EQ-5D-5L™).................................... 142
Appendix 13. Pain DETECT Questionnaire............................................................................... 144
Appendix 14. Adjudication Categories....................................................................................... 146
Appendix 15. Survey of Autonomic Symptoms (SAS).............................................................. 147
Appendix 16. Patient reported treatment impact assessment-modified (mPRTI) ...................... 148
Appendix 17. Treatment Satisfaction Questionnaire for Medication v.II .................................. 149
Appendix 18. Substudy- Follow-up for Subjects Undergoing Total Joint Replacement 
of The Hip, Knee or Shoulder ............................................................................. 152
Appendix 20. The Shoulder Pain and Disability Index (SPADI) ............................................... 183
CCI
CCI


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1. INTRODUCTION 
1.1. Mechanism of Action/Indication
Tanezumab (PF-04383119, formerly RN624) is an anti-nerve growth factor monoclonal 
antibody under development for the management of chronic low back pain.
1.2. Background and Rationale
1.2.1. Role of Nerve Growth Factor in the Modulation of Pain
During mammalian development, nerve growth factor (NGF) is required for the survival and 
growth of several populations of neurons. In adults, the effect of NGF signaling shifts from 
the regulation of neuronal survival to the regulation of neuronal phenotype and function.  The 
role of NGF in the adult mammal appears to principally be as a modulator of nociceptive 
neuronal activity and modulation of the pain response.1,2 Many non-clinical 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.2,3  Together these observations suggest 
that NGF may play a role in pain secondary to inflammation or injury.
1.2.2. Description of Investigational Product
Tanezumab is a humanized immunoglobulin G Type 2 (IgG2) monoclonal antibody, derived 
from a murine precursor with a mutation  in the Fc portion of the antibody to decrease its 
ability to activate complement or to support antibody dependent cell-mediated cytotoxicity.4,5
Tanezumab is highly potent in sequestering NGF and preventing interaction with the trkA or 
p75 receptors.
1.2.3. Chronic Low Back Pain
Chronic low back pain, generally defined as back pain that persists more than 12 weeks, 
represents a significant cause of morbidity, disability, and lost productivity world-wide.6  
Estimates of the prevalence of chronic low back pain vary by study and by geographic 
region, but chronic low back pain is a common cause of chronic pain and disability in all 
regions studied.  In the United States, the prevalence of chronic low back pain derived from 
the 1988 United States National Health Interview Survey was 6.4%7 and a recent survey in 
2008 estimated the prevalence of chronic low back pain to be 8.1%.8 Estimates in Europe 
suggest that the prevalence of non-specific chronic low back pain is 23%; with 11-12% of the 
population being disabled by low back pain.9 In Japan, a large population-based survey 
found that 3.87% of the population had experienced chronic, disabling low back pain during 
their lifetime.10
The majority of chronic low back pain cannot be attributed to a single pathophysiological or 
anatomical cause but is usually multifactorial in nature.  This back pain is often called 
“mechanical” or “non-specific” low back pain.11 Back pain may originate from many spinal 
structures including facet joints, ligaments, paravertebral musculature, intervertebral discs, 
and nerves.  Common causes of low back pain include injuries to the musculoligamentous 


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structures, age-related degenerative processes of the discs and facet joints, spinal stenosis, 
and disc herniation.11 Given the lack of a specific etiology in most cases, therapeutic 
measures are aimed at providing symptomatic relief and restoring function.
Pharmacological agents commonly used to treat chronic low back pain include nonsteroidal 
anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, muscle relaxants, opioid 
analgesics, and other drugs active in the central nervous system.  However, these agents are 
not fully effective in many patients, and the use of these agents can be limited by side effects 
such as gastrointestinal bleeding, somnolence and cognitive impairment.  There are, in 
addition, a variety of other care modalities, such as epidural injections, nerve blocks, facet 
joint injections, implanted electrical stimulators and pumps, physical therapy, chiropractic 
and acupuncture, which are expensive and unproven and still leave many patients with 
inadequate pain relief.  Pharmacologic management of pain not responsive to NSAIDs 
without the toxicities of opiates is needed for patients experiencing moderate-to-severe 
chronic low back pain.
1.2.4. Overview of Clinical Studies
A total of 32 clinical studies involving over 11,000 patients have been conducted with 
tanezumab as of September 2014.  Most of these studies were conducted in subjects with 
osteoarthritis of the knee or hip.  A total of 17 clinical studies overall (4 Phase 2 studies and 
13 Phase 3 studies), were initiated to provide evidence of efficacy and safety of tanezumab 
with intravenous (IV) or subcutaneous (SC) administration for the relief of the signs and 
symptoms of osteoarthritis alone or in combination with NSAIDs. The efficacy and safety of 
tanezumab IV in chronic low back pain has been evaluated in 3 Phase 2 studies (N=1564).  
The first was a small Phase 2 proof-of-concept study (A4091004;12 N=217) which evaluated 
the efficacy and safety of tanezumab 200 g/kg IV relative to placebo or naproxen 500 mg 
twice a day (BID). This study was followed by a Phase 2 dose-ranging study (A4091012;13
N=1347) that evaluated the efficacy and safety of fixed doses of tanezumab of 5 mg, 10 mg, 
and 20 mg IV relative to placebo or naproxen 500 mg BID and a long term safety extension 
study (A4091039;14 N=848) which evaluated the safety and efficacy of tanezumab 10 mg and 
20 mg IV and SC administered every 8 weeks for 56 weeks.
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 two 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.
1.2.4.1. Efficacy of Tanezumab in the Treatment of Chronic Low Back Pain
The efficacy of tanezumab in chronic low back pain has been evaluated in a double-blind, 
randomized, placebo- and active- controlled Phase 2 study (A4091012).13
Study A4091012 evaluated the efficacy and safety of multiple doses of tanezumab 5 mg, 
10 mg, or 20 mg administered IV every 8 weeks compared to placebo or naproxen 
500 mg BID in treating subjects with chronic low back pain.  The primary endpoint of the 


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study was the mean change in the daily average Low Back Pain Intensity score from Baseline 
to Week 16 with Baseline Observation Carried Forward (BOCF) imputation.  Key secondary 
efficacy endpoints were the Roland-Morris Disability Questionnaire (a measure of function 
used for low back pain) and Patient Global Assessment of Low Back Pain.
A total of 1347 subjects were randomized and treated and by definition comprised the ITT 
cohort in the study.
Tanezumab 10 mg and 20 mg provided significant improvement across the pain, function, 
and global efficacy domains at Week 16 compared to both placebo and naproxen treatment.  
The magnitude of efficacy was similar between these tanezumab doses.  The observed 
treatment differences between tanezumab 5 mg and placebo treatment reached statistical 
significance for only one of three primary measures of efficacy.  Naproxen treatment was 
associated with a significant reduction in pain versus placebo treatment.
Further efficacy and safety results from chronic low back pain studies with tanezumab are 
described in the tanezumab Investigator’s Brochure.
1.2.4.2. 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 3 are considered to be
expected in subjects who are treated with tanezumab.
Table 3.
Adverse Drug Reactions in Subjects All Subjects Receiving Tanezumab
System Organ Class
Adverse Drug Reaction
Frequency2
Nervous system disorders
Burning sensation
Carpal tunnel syndrome
Hyperesthesia 
Hypoesthesia
Paraesthesia
Common
Allodynia
Neuropathy peripheral
Uncommon
Musculoskeletal and connective 
tissue disorders
Rapidly Progressive Osteoarthritis
(in patients with underlying osteoarthritis1)
Uncommon
Arthralgia
Joint swelling
Myalgia
Pain in extremity
Common
General disorders and 
administration site conditions
Oedema peripheral
Common
1 Rapidly Progressive Osteoarthritis may occur in subjects with underlying osteoarthritis.  The frequency is 
estimated from adjudicated events of rapidly progressive osteoarthritis in historic clinical studies of tanezumab, 
which did not include specific risk minimization measures for this adverse reaction.
2 Common (1% and <10%); Uncommon (0.1% and <1%).
The majority of information regarding the safety profile of tanezumab comes from studies 
conducted in subjects with osteoarthritis.  The safety profile observed to date in chronic low 


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back pain and other chronic pain patient populations does not differ markedly from the 
results observed in the osteoarthritis studies.
A total of 7491 subjects were treated in 9 controlled Phase 3 osteoarthritis studies.  The 
majority of these subjects were treated in studies using IV administration of tanezumab; 
however, N=985 subjects with osteoarthritis were treated in 2 studies using SC 
administration.  The adverse event profile of SC administration of tanezumab is comparable 
to the IV route 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. Across the tanezumab monotherapy doses, the rates 
of adverse events, withdrawals due to adverse events, and serious adverse events, were 
similar with tanezumab 5 mg and 10 mg, and elevated in comparison to tanezumab 2.5 mg.  
Tanezumab/NSAID combination therapy was associated with higher overall adverse event
rates.  The relationship of incidence to the dose of tanezumab administered was similar to 
that observed with tanezumab monotherapy.
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 patients receiving either placebo or active 
comparator treatment.  The incidence of peripheral edema, arthralgia, joint swelling, pain in 
extremity, and paresthesia increased with increasing doses of tanezumab monotherapy.  The 
adverse events with increased incidence observed with active comparator over tanezumab 
monotherapy included the following: constipation, nausea, urinary tract infection, 
nasopharyngitis, osteoarthritis, and hypertension.
The most common adverse events reported in the non-controlled, long-term Phase 
3 osteoarthritis studies were similar to those seen in the controlled Phase 3 osteoarthritis 
studies with the exception of the inclusion of musculoskeletal pain and exclusion of 
hypertension and nasopharyngitis and all gastrointestinal-related adverse events.  
Dose-related increases in the incidence of peripheral edema, joint swelling, osteoarthritis and 
paresthesia were observed.
In general, the adverse event profile observed in subjects with chronic low back pain is 
similar to that observed in the osteoarthritis patient population.  The tanezumab 10 mg 
treatment had a better tolerability profile than the tanezumab 20 mg treatment.  The 
tanezumab 20 mg treatment group had a higher overall incidence of adverse events, a higher 
incidence of severe adverse events, and a higher incidence of subjects who withdrew due to 
an adverse event.  There were no investigator-reports of osteonecrosis or total joint 
replacements in Study A4091012.  In Study A4091039, there was one event of rapidly 
progressive osteoarthritis in a chronic low back pain subject treated with tanezumab 20 mg 
who had severe osteoarthritis in the affected knee prior to study entry.


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Based on data from the Phase 3 osteoarthritis studies and results of an independent 
adjudication of investigator-reported adverse events of osteonecrosis and total joint 
replacements, the risk of rapidly progressive osteoarthritis with tanezumab treatment is 
greater than with placebo or active comparator treatment.
1.2.4.3. Sympathetic Nervous System
In completed Phase 3 osteoarthritis studies, the incidence and discontinuation rates due to 
adverse events consistent with decreased sympathetic function associated with tanezumab 
monotherapy (combined doses of 2.5 to 10 mg) were less than or equal to rates with placebo 
or active comparator.  No evidence of dose related elevations in the frequency of adverse 
events suggestive of decreased sympathetic nervous system function were observed at 
tanezumab doses of 2.5 to 10 mg in subjects with osteoarthritis or chronic low back pain.  
Tanezumab 20 mg in chronic low back pain had marginally higher event rates compared to 
placebo and active comparator treatment groups.
Based on completed osteoarthritis studies where orthostatic blood pressure, heart rate deep 
breathing, or autonomic symptoms captured with the Neuropathy Symptom Change (NSC) 
questionnaire.were specifically assessed, the data are not suggestive of an adverse effect of 
tanezumab on autonomic function.
1.2.4.4. Subcutaneous Administration of Tanezumab in Clinical Studies
The formulation of the tanezumab drug product for SC injection is identical to that used for 
IV administration 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, A4091027 and A4091043, and in subjects with chronic 
low back pain in one study (A4091039).14,15,16  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.
In Study A4091039, tanezumab was planned to be administered IV every 8 weeks for 
3 administrations followed by SC every 8 weeks for 4 administrations.  A total of 
848 subjects were treated with tanezumab in this study of which of 240 (28%) received 
≥1 dose of SC tanezumab.  The planned duration of the study was 64 weeks; however, due to 
the FDA-imposed clinical hold, the majority of the subjects received only 1 dose of SC 
tanezumab.  SC administration of tanezumab was well tolerated in this study and provided 
durable pain relief, improvement in physical functioning and Patient’s Global Assessment of 
Low Back Pain.  All injection site reactions were mild in severity and the proportion of 
subjects who experienced injection site reactions was similar between treatment groups.
1.2.4.5. Joint Safety 
A comprehensive investigation and analyses related to joint-safety has been conducted, based 
on tanezumab monotherapy exposure in over 6400 subjects and tanezumab/NSAID 
combination therapy in 3400 subjects.  There were over 5000 subjects who received 
tanezumab treatment alone or in combination with NSAIDs for 6 months or longer.  These 
data were sufficient to define and characterize the adverse event of concern - rapidly 


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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.17
After careful investigation no evidence was found to indicate that tanezumab is associated 
with an increased risk of osteonecrosis, a disease process quite distinct from osteoarthritis.  A 
risk of rapidly progressive osteoarthritis was identified.  The risk of rapidly progressive 
osteoarthritis with tanezumab monotherapy was well below that observed with 
tanezumab/NSAID combination therapy but greater than with placebo or active comparator 
treatment.  A majority of subjects identified with rapidly progressive osteoarthritis had 
advanced osteoarthritis of the affected joint prior to treatment.  The event rate of all-cause 
joint replacements in subjects with osteoarthritis was comparable among placebo, active 
comparator, and tanezumab monotherapy treatment groups.
Risk mitigation measures have been developed as an outgrowth of the joint-related safety 
analyses to reduce the risk of rapidly progressive osteoarthritis.  Risk mitigation measures 
were developed using recommendations from discussions with European agencies (United 
Kingdom’s Medicines and Healthcare products Regulatory Agency [MHRA], Germany’s 
Paul Ehrlich Institute [PEI] and Spain’s Agency on Medicinal Products and Medical Devices 
[AEMPS]) as well as the FDA Arthritis Advisory Committee and interactions with FDA. 
These risk mitigation measures have been included in the tanezumab clinical development 
program and those applicable to 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 osteoarthritis of the knees and hips as 
defined by American College of Rheumatology (ACR) clinical and radiographic criteria;
subjects with Kellgren Lawrence Grade 2 or greater hip osteoarthritis, subjects with Kellgren 
Lawrence Grade 3 or greater knee osteoarthritis, and subjects with evidence of shoulder 
osteoarthritis (as determined by the presence of symptoms and radiologic findings consistent 
with osteoarthritis), (4) exclude subjects with evidence of rapidly progressive osteoarthritis or 
risk factors for such from participating in clinical studies, (5) discontinue treatment with 
investigational product in subjects who fail to achieve adequate pain relief and (6) exclude 
subjects who are not suitable candidates for total joint replacement from study participation.
Risk Identification and Management: (1) evaluation and follow-up for severe persistent 
joint pain, (2) extended post-treatment follow-up, (3) a program-level Central Radiograph 
Reader and subject-level stopping criteria, (4) an Adjudication Committee, and (5) a Data 
Monitoring Committee and protocol-level stopping rules.
Risk Characterization: (1) Comprehensive evaluation of osteoarthritis medical history prior 
to study entry, (2) scheduled radiographic assessments during the studies, (3) surgical and 
post-operative total joint replacement outcomes, and (4) biomarker determinations.


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1.2.4.6. Experience in Japanese Subjects
1.2.4.6.1. Study A4091013 in Healthy Volunteers
Study A409101318 was an absolute bioavailability study in which a total of 76 subjects, 
including 17 Japanese subjects, received tanezumab either intravenously or subcutaneously 
via a single injection in the abdomen.  Dose levels were 10 mg IV (n=19), 5 mg SC (n=20), 
10 mg SC (n=19) or 19 mg SC (n=18).  Based on geometric mean Cmax values, peak 
exposure for the 10 mg IV treatment was more than 3-fold higher than that for the 10 mg SC 
treatment.  However, comparison of median concentrations for the 10 mg doses shows that 
after approximately 4 weeks, tanezumab exposure was comparable between the IV and SC 
routes for the remaining 12 weeks of the study.  Terminal half-life was comparable after IV 
and SC administration in the range of 17 to 24 days.  Following IV administration of 
tanezumab, median Tmax for the combined Japanese and non-Japanese population was 0.17 
hours, corresponding to the first postdose sample (10 minutes after the start of the 1 minute 
IV push).  Subcutaneous absorption of tanezumab into the systemic circulation was relatively 
slow, with median Tmax values of 10 to 12 days for the combined population following SC 
administration.  Comparison of geometric mean Cmax and AUCinf values after SC 
administration suggests exposure increased proportionally with increasing dose across the 
dose levels tested.  Based on the observed dose linearity, data for all 3 SC treatments were 
combined for the statistical assessment of absolute bioavailability.  The ratio (90% CI) of 
adjusted geometric means for SC versus IV AUCinf was 68.27% (62.05%, 75.11%), 
indicating an absolute bioavailability of 68% for the SC treatments in this study.
1.2.4.6.2. Study A4091022 in Osteoarthritis Subjects
A total of 83 Japanese subjects were enrolled in Study A409102219, a study designed to 
examine the safety and efficacy of tanezumab in Japanese subjects with osteoarthritis of the 
knee. In part 1 of the study, 42 subjects were randomized to receive a single IV dose of 
tanezumab or placebo. Subjects randomized to tanezumab received one of five possible 
doses (10 μg/kg, 25 μg/kg, 50 μg/kg, 100 μg/kg or 200 μg/kg). Assuming a 100 kg subject, 
these tanezumab doses represent fixed doses of approximately 1 mg, 2.5 mg, 5 mg, 10 mg 
and 20 mg, respectively. In part 2 of the study, 41 other subjects were randomized to receive 
a single IV dose of tanezumab or placebo. Subjects randomized to tanezumab received one 
of four possible doses (10 μg/kg, 25 μg/kg, 50 μg/kg, or 100 μg/kg). In total, 67 subjects 
received a single dose of tanezumab and 16 received placebo.
Tanezumab PK were evaluated over the 16 week duration of the study after administration of 
a single IV dose of tanezumab at either 10 µg/kg (n=6), 25 µg/kg (n=4), 50 µg/kg (n=5), 
100 µg/kg (n=5), or 200 µg/kg (n=6).  Systemic exposure of tanezumab generally appeared 
to increase dose-proportionally across the dose range studied. Plasma tanezumab 
concentrations declined over time with an apparent mean elimination half-life of 
approximately 12.5 to 23.5 days.  The geometric mean clearance of tanezumab from plasma 
ranged from 2.55 to 3.84 mL/kg/day across dose levels.  The geometric mean Vss ranged 
from 50.0 to 82.6 mL/kg.  In addition, after a single IV administration of tanezumab the  
geometric mean Cmax were 309, 682, 1050, 2400, and 4790 ng/mL for doses 10, 25, 50, 100, 
and 200 µg/kg, respectively.


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Tanezumab (25, 100, and 200 µg/kg) showed preliminary efficacy against placebo in all the 
WOMAC subscales (pain, stiffness, and physical function). Of all the tanezumab treatment 
groups, the percentage of subjects experiencing at least one all-causality adverse event was 
lowest in the 25 μg/kg treatment group (26.7%) and highest in the 200 μg/kg treatment group 
(100%). In the placebo treatment group, 13 out of 16 subjects (81.3%) had at least one 
adverse event. The frequency of overall adverse events was smaller in the combined 
tanezumab treatment groups (36 out of 67 subjects, 53.7%) than in the placebo treatment 
group (13 out of 16 subjects, 81.3%). The most frequently reported all-causality adverse 
event was nasopharyngitis in 9.0% and 31.3% of subjects who received tanezumab or 
placebo, respectively. Most of the adverse events were mild or moderate in severity. There 
were no subjects who permanently discontinued the study due to adverse events. Three 
serious adverse events were reported, and none of these events were considered to be related 
to the investigational product.
1.2.5. Dose Selection Rationale
Based on the similarity of PK and PK-PD between Japanese and non-Japanese, the same 
dose selection rationale as study A4091059 was applied for the study.
Individual Cmax and AUCinf were compared between Japanese (study A4091022, OA 
subjects) and non-Japanese (study A4091006, OA subjects) populations using non-
compartmental analysis data from phase 1/2a studies. PK parameters plotted by the actual 
total dose for each individual are shown in Figure 1.  In Figure 1, linear regression curves 
were drawn based on parameters from Japanese subjects. The relationship between dose and 
plasma tanezumab exposure parameters (Cmax and AUCinf) was almost linear. In addition, 
individual parameters from Japanese OA subjects were generally within the range of non-
Japanese data.
Figure 1.
Comparison of individual Cmax and AUCinf from Studies A4091006 (non-
Japanese OA subjects) and A4091022 (Japanese OA subjects) - Cmax or 
AUCinf vs. fixed dose (mg)
Source:Briefing document for Tanezumab PMDA consultation (8Apr 2010) Appendix 5: Summary of Clinical 
Pharmacology
Non-Japanese (A4091006)
Japanese (A4091022)


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Simulations were performed to compare the AUC distribution between Japanese and non-
Japanese based on a Japanese/non-Japanese population PK (PopPK) model using data from 
Japanese (study A4091022) and non-Japanese subjects (A4091006 and A4091008 studies).
In the PopPK model, race on PK parameters did not remain as a significant covariate effect.
Figure 2 displays the range of predicted AUCs for the tanezumab doses of 2.5, 5 and 10 mg 
in both the Japanese and non-Japanese OA populations using the PopPK model.  The range 
of predicted tanezumab AUCs largely overlapped between Japanese and non-Japanese.  
These simulations based on the PopPK model show that the exposure following an 
intravenous administration of a fixed dose is comparable between the Japanese and non-
Japanese OA subjects.
Figure 2.
Simulated AUCs across the doses (fixed dose) for Japanese and non-
Japanese OA subjects
Each box plot indicated the 25% tile (upper quartile, median, lower quartile). W=non-Japanese, J=Japanese
Source: Population modeling analysis report PMAR-00156, Figure 16
The mean dose-response for WOMAC pain change from placebo for Japanese and non-
Japanese populations for fixed dose at Week 16 was simulatied based on PK-PD model using 
WOMAC pain subscale in Japanese (from Study A4091022) and non-Japanese OA (from 
Study A4091008) subjects. When the dose response was plotted as the change form placebo, 
the curves overlap further between the populations (Figure 3). As the results of PK-PD 


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model building, no race effect (Japanese vs. non-Japanese) on each PD parameter was 
included to the model.
Figure 3.
Simulated dose response for WOMAC pain (change from placebo) in typical 
Japanese and non-Japanese OA patients* at Week 16
: non-Japanese (A4091008)
     : Japanese (A4091022)
95% PI with consideration of RSE for the parameter estimation
*Used typical body weight of 66 kg and 89 kg for Japanese and non-Japanese OA patients, respectively, and 
mean WOMAC baseline of 60 and 67 for Japanese and non-Japanese OA patients, respectively.
Source: /A409 RN624 tanezumab/A4091022/PKPD Analysis/PMDA BD&TLR/PKPD/dose response/Run18
The relationship between total daily dose and change of WOMAC  pain (LOCF) at Week 8 
were estimated using Emax model besed on results of Study A4091022 and Study A4091008
(Figure 4).   This results show a similar trend between Japanese and non-Japanese although
limited sample size made large range of 95% CI.  


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Figure 4.
Dose-response relationship based on Emax model [relationship between total 
daily dose and change of WOMAC pain (LOCF) at Week 8]
  : non-Japanese (A4091008)
     : : Japanese (A4091022)
Source:Briefing document for Tanezumab PMDA consultation (8Apr 2010) Appendix 5: Summary of Clinical 
Pharmacology
Previous PopPK analyses were conducted to show the similarity in the PK of tanezumab 
between OA and CLBP subjects and ultimately support the dose regiments for CLBP studies 
in the non-Japanese. Given the similarity of the PK-PD in Japanese OA subjects to non-
Japaese OA subjects, these simulations are also relevant to dose regimen selection for 
Japanese CLBP subjects.
Intravenous administration of tanezumab at doses of 5 mg, 10 mg, and 20 mg was shown to 
reduce pain and improve function in a dose-related manner in the chronic low back pain 
study A4091012.  Both the tanezumab 10 mg and 20 mg doses demonstrated superior 
efficacy compared to placebo and to naproxen.  There was little incremental benefit in 
efficacy with tanezumab 20 mg treatment compared to tanezumab 10 mg.  The tanezumab 
5 mg dose did not achieve statistically significant superiority versus placebo in the primary 
endpoint of pain or the key secondary endpoint of function at Week 16 although significant 
differences versus placebo were observed at interim timepoints up to Week 12 and the 
overall efficacy profile of tanezumab 5 mg was similar to naproxen.
In contrast to the efficacy data, tanezumab 10 mg had a better safety profile compared with 
tanezumab 20 mg treatment.  No further study of the tanezumab 20 mg dose will be 
conducted in subjects with chronic low back pain as this dose did not provide sufficient 
additional efficacy benefit over the 10 mg dose.
This study will investigate the safety and efficacy of a fixed dose of tanezumab 5 mg and 
10 mg administered up to 7 times at 8-week intervals relative to an active comparator 


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treatment group (celecoxib). Patients randomized to the active comparator treatment group 
will receive celecoxib they were receiving prior to study entry.  Patients randomized to 
receive celecoxib in the current study will receive it at the protocol specified dose (100 mg 
BID).  This dose represents the labeled dose used for the treatment of low back pain in Japan.
1.2.6. Rationale for Celecoxib as an Active Comparator
The primary objective of this study is to evaluate the long-term safety of tanezumab in 
chronic low back pain patients. The secondary objective is to demonstrate the long-term 
analgesic efficacy. 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. For most subjects, first line medication options for chronic low 
back pain are NSAIDs/coxibs and acetaminophen. Celecoxib is selected as an active 
comparator because celecoxib is commonly used in Japan.
1.2.7. Subject Population Selection Rationale
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 chronic low back pain and be experiencing at least some 
benefit from their current stable dosing regimen of oral NSAID (celecoxib, loxoprofen or 
meloxicam), be tolerating their NSAID regimen and be taking this medication regularly 
during the 30-day period prior to the Screening Visit.
In order to reduce risk in this population, the tanezumab doses tested in this study will be 
limited to tanezumab 5 mg and 10 mg. Subjects with symptomatic osteoarthritis of the knees, 
hips or shoulders (as defined by American College of Rheumatology clinical and 
radiographic criteria) and subjects with Kellgren Lawrence Grade 2 or greater hip 
osteoarthritis, or Kellgren Lawrence Grade 3 or greater knee osteoarthritis will be excluded 
from participation.
Complete information for tanezumab may be found in the Single Reference Safety 
Document, which for this study is the Investigator’s Brochure.  The Single Reference Safety 
Document for celecoxib is the Company Core Data sheet.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

Evaluate the long-term safety of tanezumab 10 mg and 5 mg SC administered every 8 
weeks (7 administrations).
Secondary Objective

Demonstrate the long-term analgesic efficacy of tanezumab 10 mg and 5 mg SC 
administered every 8 weeks (7 administrations).


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2.2. Endpoints
2.2.1. Primary Endpoints
Safety Measures

Adverse events.

Standard safety assessments (safety laboratory testing [chemistry, and hematology], vital 
signs).

Orthostatic (supine/standing) blood pressure assessments.

Survey of Autonomic Symptoms (SAS) scores.

Electrocardiogram (ECG, 12-lead) assessments.

Joint Safety adjudication outcomes.

Total joint replacements.

Neurologic examination (Neuropathy Impairment Score [NIS]).

Anti-drug antibody assessments (ADA).

Physical examinations.
2.2.2. Secondary Endpoints
Efficacy-Related Endpoints

Change from Baseline to Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64 in average Low 
Back Pain Intensity (LBPI) score as measured by an 11-point Numeric Rating Scale 
(NRS).

Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in the 
Roland-Morris Disability Questionnaire (RMDQ) total score.

Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in Patient’s Global 
Assessment of Low Back Pain.

Cumulative distribution of percent change from Baseline in average LBPI score to 
Weeks 16, 24 and 56.

Response as defined by a ≥30%, ≥50%, ≥70% and a ≥90% reduction from Baseline in 
weekly average LBPI score derived from the subject diary at Weeks 16, 24, 40 and 56.


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
Change from Baseline to Weeks 2, 4, 8, 16, 24, 40, 56 and 64 in the Brief Pain 
Inventory-short form (BPI-sf) scores for Worst Pain, Average Pain, Pain Interference 
Index (composite function score), Pain Interference with General Activity, Pain 
Interference with Walking Ability, Pain Interference with Sleep, and Pain Interference 
with Normal Work.

Chronic Low Back Pain Responder Index analysis (composite endpoint of average LBPI 
score, Patient’s Global Assessment of Low Back Pain, and RMDQ total score) at Weeks 
16, 24, 40 and 56.

Treatment Response: Improvement of ≥2 points in Patient’s Global Assessment of Low 
Back Pain at Weeks 16, 24, 40 and 56.

Euro Quality of Life Health State Profile (EQ-5D-5L) dimensions and overall health 
utility score at Baseline, Weeks 16 and 56.

Work Productivity and Activity Impairment Questionnaire: Low Back Pain 
(WPAI:LBP) change from Baseline to Week 16, 56 and 64, in the percent work time 
missed due to chronic low back pain, percent impairment while working due to chronic 
low back pain, percent overall work impairment due to chronic low back pain, and 
percent activity impairment due to chronic low back pain.

Incidence of and time to discontinuation due to lack of efficacy.

Usage of rescue medication (incidence, and number of days of usage) during Weeks 2, 
4, 8, 12, 16, 24, 32, 40, 48, 56 and 64.

Usage of rescue medication (amount taken) during Weeks 2, 4, 8, 12 and 16.

Health Care Resource Utilization (HCRU) at Baseline, Weeks 64 and 80.
Treatment Satisfaction Measures

Treatment Satisfaction Questionnaire for Medication v.II (TSQM) score at Weeks 16 
and 56.

Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 56.
2.2.3. Tertiary Endpoints

Plasma tanezumab concentrations.

Serum NGF assessments.

Serum and urine osteoarthritis biomarker concentrations.


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3. STUDY DESIGN
Figure 5.
Study Schematic
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 up to 56 
weeks in subjects with chronic low back pain.  Subjects will be randomized to 1 of 
3 treatment groups in a 1:1:1 ratio.  Treatment groups will include:
1. Placebo SC matching tanezumab administered at an 8-week interval (total of 7 
times) plus celecoxib 100 mg BID to be administered orally for 56 weeks.
2. Tanezumab 5 mg SC administered at an 8-week interval (total of 7 times) plus
placebo matching celecoxib to be administered orally BID for 56 weeks.
3. Tanezumab 10 mg SC administered at an 8-week interval (total of 7 times) plus
placebo matching celecoxib to be administered orally BID for 56 weeks.
The study is designed with a total duration (post-randomization) of up to 80 weeks and will 
consist of three periods: Screening (up to 37 days; includes a Washout Period and an Initial 
Pain Assessment Period [IPAP] ), Double-blind Treatment (56 weeks) and Follow-up (24 
SC tanezumab 5 mg + Oral placebo (matching celecoxib)
SC tanezumab 10 mg + Oral placebo (matching celecoxib)
SC placebo (matching tanezumab) + Oral celecoxib
Day -5 to -1 
(IPAP)
16
Day  -37   -5 1


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weeks).  The Screening Period (beginning up to 37 days prior to Randomization) includes a 
Washout Period (lasting 2-32 days), if required, and an IPAP (the 5 days prior to 
Randomization/Baseline).
Prior to entering the study, subjects must be experiencing some benefit (eg, analgesic effect) 
from their current stable dose regimen of oral therapy of NSAID (celecoxib 200 mg/day 
[100 mg BID], loxoprofen 120 to 180 mg/day or meloxicam 5 to 15 mg/day) treatment, be 
tolerating their NSAID regimen, 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.  
At the Week 16 visit, subjects must have at least a 30% reduction in weekly average LBPI 
score relative to Baseline and at least a 15% reduction in weekly average LBPI score relative 
to Baseline at any week from Week 1 to Week 15 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 (See Section
6.9.1).
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 
that 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.  Subjects that do 
not complete the Double-blind Treatment period but who enter and complete the 24-week 
Early-termination follow-up period will be considered to have completed the study while 
those subjects who do not complete the 24-week Early-termination follow-up period will not 
be considered to have completed the study.
For subjects who withdraw from the study, see Section 6.9.1. Every effort should be made to 
have the subject agree to complete the entire 24-week Early Termination Safety Follow-up.
Details relevant to the study design can be found in Sections 6 and 7 and the SUBSTUDY 
SCHEDULE OF ACTIVITIES (Appendix 18, Table 7)
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 nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:


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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.
Japanese males or females, ≥18 years of age.
3.
Duration of chronic low back pain for ≥3 months.
4.
Treatment with agents for low back pain for ≥3 months.
5.
Primary location of low back pain must be between the 12th thoracic vertebra and the 
lower gluteal folds, with or without radiation into the posterior thigh, classified as 
Category 1 or 2 according to the classification of the Quebec Task Force in Spinal 
Disorders (Appendix 1).
6.
Be experiencing some benefit from their current stable dose regimen of oral therapy of 
NSAID (celecoxib 200 mg/day [100 mg BID], loxoprofen 120 to 180 mg/day or 
meloxicam 5 to 15 mg/day) treatment, be tolerating their NSAID regimen, 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 and must have had some improvement in low 
back pain, but still require additional pain relief at Screening.
7.
Maintain a stabilized dose regimen of celecoxib 100 mg BID with a minimum 
compliance of 70% (ie, 5 of 7 days per week) for at least the final 2 weeks (subjects who 
were receiving celecoxib as pre-study treatment) or 3 weeks (subjects who were 
receiving loxoprofen or meloxicam as pre-study treatment) of the Screening period 
directly prior to the Baseline (Day 1) visit.
8.
LBPI score of ≥5 at Screening (See Section 7.1.1).
9.
Completes at least 4 daily pain diaries during the 5 days prior to the day of 
Randomization, with an average LBPI score of ≥5.
10. Patient’s Global Assessment of Low Back Pain must be “fair”, “poor” or “very poor” at 
Baseline (Appendix 8).
11. Subjects must be willing to discontinue all pain medications for chronic low back pain 
except rescue medication and investigational product and not use prohibited pain 
medications throughout the duration of the study except as permitted per Protocol (refer 
to Section 5.8.1 for details regarding prohibited medications).
12. 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 treatment (See Section 4.4).
13. Female subjects who are not of childbearing potential (ie, meet at least 1 of the 
following criteria):


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
Have undergone a documented total hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure;

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological cause 
and confirmed by having a serum follicle stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women.
14. 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.
3.
Diagnosis of osteoarthritis of the knee or hip as defined by the ACR combined clinical 
and radiographic criteria (Appendix 2); Radiographic criteria will be assessed by the 
Central Reader:

Subjects who have Kellgren Lawrence Grade ≥2 radiographic evidence of hip 
osteoarthritis will be excluded.

Subjects who have Kellgren Lawrence Grade ≥3 radiographic evidence of knee 
osteoarthritis will be excluded.

Subjects who have Kellgren Lawrence Grade 2 radiographic evidence of knee 
osteoarthritis but who do not meet ACR criteria and do not have pain associated with 
their knee osteoarthritis will be allowed.
4.
Subjects with symptoms and radiologic findings (ie, joint space narrowing, osteophytes) 
consistent with osteoarthritis in the shoulder.
5.
History of lumbosacral radiculopathy within the past 2 years, history of spinal stenosis 
associated with neurological impairment, or history of neurogenic claudication.


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6.
Back pain due to recent major trauma (eg, vertebral fracture, post-traumatic 
spondylolisthesis).  Subjects with trauma occurring >6 months prior to Screening are 
eligible to be considered for entry into the study.
7.
Current or pending worker’s compensation, litigation, disability, or any other monetary 
settlement regarding his/her chronic low back pain or any other pain condition, or any 
closed claim within the past 5 years.
8.
Surgical intervention including, but not limited to, procedures such as discectomy, nerve 
ablation, kyphoplasty, or nucleoplasty during the past 6 months for the treatment of low 
back pain.
9.
Planned surgical procedure during the duration of the study.
10. Fibromyalgia, back pain due to a visceral disorder (eg, endometriosis), or other 
moderate-to-severe pain that may confound assessments or self-evaluation of the pain 
associated with chronic low back pain.
11. History of disease that may involve the spine, including inflammatory joint diseases 
such as seronegative spondyloarthropathy (eg, ankylosing spondylitis), rheumatoid 
arthritis, infections or tumors of the spinal cord, or Paget’s disease of the spine, pelvis or 
femur.
12. 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; or stress or traumatic fracture.
13. Subjects with radiographic evidence of any one 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.
14. Subjects with a history of osteonecrosis or osteoporotic fracture (ie, a subject with a 
history of osteoporosis and a minimally traumatic or atraumatic fracture).
15. History of significant trauma or surgery to a knee, hip, or shoulder within the previous 
year.
16. Subjects with a past history of carpal tunnel syndrome (CTS) with signs or symptoms of 
CTS in the one year prior to Screening.


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17. Subject considered unfit for surgery, defined as a Grade >3 on the American Society of 
Anesthesiologists (ASA) physical classification system for surgery (See Appendix 3) or
subjects who would not be prepared to undergo joint replacement surgery if required.
18. History of intolerance or hypersensitivity to the relevant oral celecoxib 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 celecoxib is contraindicated (refer to 
product labeling).
19. 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).
20. Use of prohibited medications or prohibited non-pharmacological treatments without the 
appropriate washout period (if applicable) prior to Screening or IPAP.  Prohibited 
medications and non-pharmacological treatments and the required washout periods are 
described in Section 5.8.1.
21. History of known alcohol, analgesic or narcotic abuse within 2 years of Screening.
22. Presence of drugs of abuse (including prescription medications without a valid 
prescription) or illegal drugs in the urine toxicology screen obtained at Screening.
23. History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal 
antibody or IgG-fusion protein.
24. 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.


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Subjects with a history of heart block now controlled by a functioning cardiac pacemaker 
are eligible.
25. Resting, sitting blood pressure 160 mmHg in systolic pressure or 100 mmHg 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 blood pressure 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.
26. Subjects who have evidence of orthostatic hypotension based upon replicate orthostatic 
blood pressure measurements (See 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 the subject is not eligible for the study.
27. Subjects with a total impact score of >7 on the Survey of Autonomic Symptoms (SAS)
(See Appendix 15).
28. 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.
29. History of cancer within 5 years prior to Screening, except for cutaneous basal cell or 
squamous cell cancer resolved by excision.
30. Is expected to undergo a therapeutic procedure or to use any analgesic other than those 
specified in the protocol throughout the pre-treatment and treatment periods that is likely 
to confound assessment of analgesic efficacy or safety.
31. Previous exposure to exogenous NGF or to an anti-NGF antibody.
32. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3.0 times the 
upper limit of normal, or creatinine exceeding 1.7 mg/dL (150 mol/L) in men or 
1.5 mg/dL (133 mol/L) in women, or hemoglobin (Hb) A1c 10% at Screening.  
Repeat confirmatory tests may be performed.
33. Positive Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV) tests at 
screening indicative of current infection.
34. 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.


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
Peripheral or autonomic neuropathy.

Multiple sclerosis.

Epilepsy or seizure disorder with seizure within the last 2 years.

Myopathy.
35. History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder, 
including but not limited to:

Psychotic disorders.

Somatoform disorders.

Bipolar disorders.

Any other psychiatric illness that in the opinion of the investigator would render a 
subject unsuitable to participate in the study.
36. 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]).20 A score 15 on questions 1-9 of the PHQ-9 corresponds to severe 
depression (See Appendix 5).
37. Likelihood of being non-compliant with study procedures.
38. 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.
39. 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.
40. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
30 days (or 90 days for biologics) before Screening and/or during study participation.
4.3. Randomization Criteria
At the Baseline/Randomization visit, in addition to meeting all inclusion and exclusion 
criteria requirements listed above, the following randomization criteria must be met before 


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randomization can be called into the Interactive Response Technology (IRT) system at the 
Baseline visit:
1.
Subject must have completed appropriate washout of analgesics;
2.
Subject must have entered at least 4 LBPI scores on the daily pain diary in the 5 days 
prior to the Baseline (Day 1) visit;
3.
Subjects must have maintained a stabilized dose regimen of celecoxib 100 mg BID with 
a minimum compliance of 70% (ie, 5 of 7 days per week) for at least the final 2 weeks 
(subjects who were receiving celecoxib as pre-study treatment) or 3 weeks (subjects who 
were receiving loxoprofen or meloxicam as pre-study treatment) of the Screening period 
directly prior to the Baseline (Day 1) visit.
4.
Subject must have abstained from taking rescue medication 
(acetaminophen/paracetamol) within the 24 hours that precede dosing; 
5.
Subjects must meet the Baseline LBPI score and Patient’s Global Assessment of 
Chronic Low Back Pain Baseline requirements (Inclusion Criteria 9 and 10).
6.
Review of the ECG and laboratory results and confirmation that there are no clinically 
significant or exclusionary findings.
7.
Radiographic eligibility must have been confirmed by the Central Reader.
4.4. Life Style Guidelines
Subjects should maintain their normal daily routine, including stable doses of permitted 
medications and exercise program(s).  Subjects are also permitted to continue with stable 
non-pharmacologic treatments (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. Refer to Sections 5.8.1 and 
5.8.2 for guidance on prohibited and permitted medications.
Subjects will be advised to avoid elective surgery during the study if possible; the study 
monitor or Pfizer clinician should be contacted for discussion prior to surgery whenever
possible.  Subjects who undergo joint replacement or arthroplasty will be discontinued from 
investigational product and followed as described in Section 6.9.2.
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 that the subject has selected the most appropriate 
methods of contraception for the individual subject from the permitted list of contraception 
methods (see below) and instruct the subject in its consistent and correct use.  Subjects need 
to affirm that they meet the criteria for correct use of at least two of the selected methods of 


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contraception.  The investigator or his or her designee will discuss with the subject the need 
to use highly effective contraception consistently and correctly according to the schedule of 
activities and document such conversation in the subject’s chart.  In addition, the investigator 
or his or her designee will instruct the subject to call immediately if the selected 
contraception methods are discontinued or if pregnancy is known or suspected in the subject
or the subject’s partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted, or transdermal hormonal methods 
of contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
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 postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
4.5. Sponsor 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 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 


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site and the study team are not available.  It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Subjects will be randomized at Baseline to one of the following treatment groups, all subjects 
will receive SC and PO treatment during the Double-blind Treatment period of the study: 
Table 4.
Study Treatments
Treatment Group
Subcutaneous Investigational Product (SC)
Oral Investigational Product (PO)
1
Placebo for tanezumab once every 8 weeks x 
7 doses
Celecoxib 100 mg BID through Week 
56
2
Tanezumab 5 mg once every 8 weeks x 7 
doses
Placebo for celecoxib through Week 56
3
Tanezumab 10 mg once every 8 weeks x 7 
doses
Placebo for celecoxib through Week 56
Subjects will be randomly assigned in a 1:1:1 ratio to the above treatment regimens 
according to a computer generated randomization code. The randomization will not be 
stratified.  Randomization will be coordinated centrally through 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 from the IRT.  Further details will be 
provided in the Pharmacy 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. 


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Blinding should only be broken in emergency situations for reasons of subject safety.  
Whenever possible, the investigator should consult with a member of the study team prior to 
breaking the blind. When the blinding code is broken at the investigator site, the reason must 
be fully documented and entered on the CRF.
5.3. Subject Compliance
Tanezumab and celecoxib 100 mg 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 celecoxib treatments (celecoxib or corresponding placebo) and rescue medication 
(acetaminophen/paracetamol), compliance will be reviewed and reconciled at each study visit. 
For oral investigational product (celecoxib 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 5.8.1.2.
Protocol rules governing the use of rescue medication are described in Section 5.9.
5.4. Drug Supplies
5.4.1. Dosage Form(s) and Packaging
Tanezumab, placebo for tanezumab, celecoxib and placebo for celecoxib will be supplied by 
the Sponsor or designee.
5.4.1.1. Tanezumab
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.
Tanezumab 10 mg is presented as a sterile solution for subcutaneous administration, in a 
glass PFS.  Each PFS contains a sufficient amount of tanezumab to provide the intended dose 
of drug at a concentration of 10 mg/mL.
Each PFS is packed in an individual carton.  Each PFS has a unique container number.
5.4.1.2. Placebo for Tanezumab
Placebo for tanezumab is presented as a sterile solution for subcutaneous administration, in a 
matching glass PFS.  Each PFS is packaged in an individual carton.  Each PFS has a unique 
container number.


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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 
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).
5.4.1.4. Acetaminophen/paracetamol (Rescue Therapy)
Acetaminophen/paracetamol tablets will be issued by the study sites in its approved marketed 
product dress.  Any approved commercial product of acetaminophen/paracetamol tablet is 
permitted.
5.4.2. Preparation and Dispensing
See the Dosage and Administration Instructions (DAI) for instructions on how to prepare 
tanezumab 5 mg SC, 10 mg SC and placebo SC for administration.  Investigational product 
should be prepared and dispensed by an appropriately qualified and experienced member of 
the study staff (eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as per
Japan regulations.
5.5. Administration
5.5.1. SC Investigational Product Administration
Tanezumab or matching placebo for tanezumab will be administered via SC injection by a 
medical staff (as per Japan regulations) and where facilities to handle allergic reactions are 
available.  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.  All Japan regulations must be complied with in assigning administration duties. 
5.5.2. Oral Investigational Product Administration
During the Screening period of the study, subjects will be provided with celecoxib and will 
maintain a stabilized dose regimen of celecoxib 100 mg BID for at least the final 2 weeks 
(subjects who were receiving celecoxib as pre-study treatment) or 3 weeks (subjects who 
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directly prior to the Baseline (Randomization/Day 1) visit.  Subjects should be advised to 
take their morning dose of this celecoxib before arriving for the Randomization/Day 1 clinic 
visit.
Celecoxib 100 mg 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.  On 
Study Day 1, a morning dose of oral investigational product (celecoxib 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 celecoxib 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. 
Storage conditions stated in the single reference safety document (SRSD) (ie, investigator’s 
brochure [IB]; core data sheets [CDS]), will be superseded by the storage conditions stated in 
the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
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 intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations. The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order.
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to 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 


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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.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products.
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. Subjects should be instructed to bring all untaken oral 
study medication dispensed at prior visits to each subsequent visit so that compliance can be 
assessed and drug accountability can be performed by the site.
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 destruction to is authorized take place at the study 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,  and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
5.8.1. Prohibited Medications
5.8.1.1. Medications Prohibited through Week 80
The following medications are prohibited from the time period specified until Week 80 or the
final Early Termination Visit.

Biologics (Refer to Appendix 4) other than investigational product (eg, TNF-α inhibitors 
such as adalimumab, etanercept, infliximab), including any live vaccines, within 
3 months of the IPAP or during the study.

Systemic corticosteroid therapy within 30 days prior to Screening (inhaled and topical 
corticosteroids are permitted).

Local or epidural injection of corticosteroids, as well as injections of corticosteroids in 
the facet joint or elsewhere in the back within 3 months prior to Screening.
5.8.1.2. Medications Prohibited During Entire Treatment Period through Week 64
In addition to the prohibited medications listed in Section 5.8.1.1, the following medications 
are prohibited from the time period specified through Week 64:

Aspirin at doses >324 mg/day or salicylate containing medications.


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
Opioid analgesics are prohibited beginning 48 hours prior to the start of the IPAP 
through Week 64.
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, dosage and reason for use 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 chronic low back 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 6.9).

Subjects who reported greater than 10 days (aggregate total) of concomitant NSAID use 
(any dosage of NSAIDs, for conditions other than chronic low back pain) 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 6.9).
Subjects will be instructed that many OTC medications contain NSAIDs and to be aware of 
this during their selection of OTC medications.
5.8.1.3. Prohibited Medications from Washout until Week 16
In addition to the prohibited medications listed in Sections 5.8.1.1 and 5.8.1.2, the following 
medications are prohibited from Washout through Week 16:

Analgesics for chronic low back pain by any route (ie, oral, inhaled, topical, injected, 
rectal) except investigational product (tanezumab and celecoxib) and provided rescue 
medication (acetaminophen/paracetamol). Use of analgesics except celecoxib as 
investigational product and acetaminophen/paracetamol are prohibited beginning 48 
hours prior to the start of the IPAP (the 5 days prior to Randomization/Baseline) or at 
the period of time prior to the start of the IPAP that is 5 times the half-life of the 
particular analgesic used, whichever is greater. Refer to Appendix 4: Half-Lives of 
Prohibited Prior and Concomitant Medications, for a detailed washout schedule for 
prohibited medications.  This is not an exhaustive list and the study monitor or Pfizer 
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 


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taper according to the product instructions if a taper is required.  Subjects will be 
counseled to review ingredients of OTC products and to report their use as concomitant 
medications.

Botulinum toxin (Botox®) injection for chronic low back pain within 4 months prior to 
Screening.
To investigate the response criteria (see Sections 3 and 6.4.5), initiation of the following 
medicines is prohibited through Week 16. However, subjects who have taken a stable dose of 
these medications for at least 30 days prior to Screening will be allowed to continue their 
regimen.

Muscle relaxants (Refer to Appendix 4) are prohibited beginning 48 hours prior to the 
start of the IPAP (the 5 days prior to Randomization/Baseline) or at the period of time 
prior to the start of the IPAP that is 5 times the half-life of the particular muscle relaxant 
used, whichever is greater.

Pregabalin and gabapentin are prohibited beginning within 48 hours prior to the start of 
the IPAP (the 5 days prior to Randomization/Baseline) .

All anti-depressants for the treatment of depression are prohibited beginning within 
30 days prior to Screening (Refer to Appendix 4).

Anti-depressants prescribed for the treatment of chronic low back pain are prohibited 
beginning 48 hours to start of the IPAP or at the period of time prior to the start of the 
IPAP that is 5 times the half-life of the particular anti-depressant, whichever is greater.

Centrally acting agents such as sedatives/hypnotics, anxiolytics, tranquilizers, or 
benzodiazepines are prohibited beginning within 30 days prior to the Screening (Refer to
Appendix 4). Benzodiazepines prescribed as a muscle relaxant are prohibited and must 
be discontinued via washout.  In this case, refer to Appendix 4, Muscle Relaxants.

Herbal, homeopathic, and naturopathic remedies should not be initiated from the IPAP
until Week 16. Subjects should be advised that St. John’s wort may interfere with the 
efficacy of hormonal contraceptive products.
5.8.1.4. Prohibited Non-pharmacological Therapies
To investigate the response criteria (see Sections 3 and 6.4.5), initiation of 
non-pharmacological therapies is prohibited through Week 16.

Commencing of physiotherapy is not allowed from the beginning of the IPAP through 
Week 16.  This involves the requirement for new, concomitant physiotherapy including, 
but not limited to, transdermal electroneural stimulation (TENS), physical therapy, 
massage, acupuncture, and spinal manipulation.  If the subject has had physiotherapy 
regularly for at least 4 weeks prior to Screening, the subject may participate in the study 


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but should maintain this therapy at least through Week 16. Facet joint injections and 
nerve blocks are prohibited beginning 30 days prior to IPAP and through Week 64.  
5.8.2. Permitted Medications
Medications for other (non-chronic low back pain, 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 (including starting a new therapy)
during the study can be made if required, and recorded on the concomitant medication CRF.  
Subjects taking cytochrome (CYP3A4/5) enzyme inducers (eg, carbamazepine and rifampin) 
should be advised that these agents may interfere with the efficacy of hormonal contraceptive 
products. 

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).  The subject should be 
counseled to avoid scheduling prospective procedures such that pain medications would 
be needed within 48 hours of a study visit.  Contact the study monitor 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.

Low-dose aspirin therapy for cardiac prophylaxis (324 mg per day).

After the Week 16 visit, subjects may initiate skeletal muscle relaxants, pregabalin, 
gabapentin, benzodiazepines, sedative/hypnotics, anxiolytics and anti-depressants, 
herbal, homeopathic, and naturopathic remedies and topical analgesics (except for 
NSAIDs and Opioids [eg, Fentanyl and Buprenorphine]).  However, the analgesics for 
chronic low back pain (NSAIDs and opioids, Refer to Appendix 4) except 
investigational product (tanezumab and celecoxib) are prohibited through Week 64. 
Subjects should be counseled to consult with the study site before initiating any new 
therapy and investigators should evaluate any new therapy for potential adverse 
interactions with celecoxib or rescue therapy by consulting the product labeling.  
Furthemore, subjects who have taken a stable dose of these products for at least 30 days 
prior to Screening will be allowed to continue their regimen.

At the discretion of the investigator, standard of care treatments for chronic low back 
pain may be initiated for subjects who have completed the Week 64 visit or for subjects 
who have prematurely discontinued investigational product provided 16 weeks have 
elapsed since the last dose of SC investigational product.  In this study, standard of care 
treatment refers to analgesics or other treatments approved by MHLW and generally 
considered effective therapy for chronic low back pain.  These medications include but 
are not limited to opioids, topical analgesics, NSAIDs, coxibs, tapentadol, tricyclic 
anti-depressants, benzodiazepines, or tramadol, and are prescribed at the discretion of 


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the investigator.  Standard of care treatments are not considered investigational product
but the cost of pre-specified analgesics will be paid for by Pfizer while the subject is 
participating in the Follow-up Period.  Their use will be recorded on the concomitant 
medication CRF. 
5.9. Rescue Therapy
Subjects will be provided with rescue medication (acetaminophen/paracetamol tablets).
During the Washout Period and the IPAP (ie, prior to Baseline [Randomization]), subjects 
may take rescue medication as needed up to a maximum daily dose of 3000 mg per day. 
Rescue medication must be discontinued 24 hours prior to the Baseline (Randomization) 
visit.
In the event of inadequate pain relief for chronic low back pain during the double-blind 
treatment period beginning at the Baseline (Randomization) visit through Week 16, Subjects 
may take acetaminophen/paracetamol up to 3 days per week up to a maximum daily dose of 
3000 mg per day.  Subjects must discontinue rescue medication within 24 hours of any 
scheduled site visit 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).
From the Baseline (Randomization) visit through Week 16, subjects taking greater than 
3 days per week of rescue medication (any level of acetaminophen/paracetamol used 
specifically for chronic low back 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 records.  Up to Week 16, subjects who have taken rescue medication 
more frequently than specified in the protocol and indicate that they cannot or will not follow 
the rescue medication protocol requirements because of insufficient pain relief for chronic 
low back pain should be withdrawn from investigational product and entered in the Early 
Termination Follow-up Period (See Section 6.9.1).  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 remain in the study.  However, if these subjects continue to take rescue 
medication more than 3 days per week, they should be withdrawn from investigational 
product.
After the Week 16 visit, subjects may take acetaminophen/paracetamol rescue medication 
daily, up to the maximum permitted dose of 3000 mg per day.  After Week 64, subjects may 
be started on standard of care treatments for low back pain.  After Week 64, subjects may 
continue to use acetaminophen/paracetamol as needed up to the maximum dose per day as 
permitted by national labeling.
Up to 16 weeks after the last dose of SC investigational product, subjects who discontinue 
treatment and enter the Early Termination Follow-up Period may take 
acetaminophen/paracetamol rescue medication daily up to the maximum permitted dose of 
3000 mg per day.  After the second Early Termination Follow-up visit occurring 
approximately 16 weeks after the last SC dose of investigational product, subjects may be 


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started on standard of care treatments for low back pain.  After the second Early Termination 
Follow-up visit, subjects may continue to use acetaminophen/paracetamol as needed up to 
the maximum dose per day as permitted by national labeling.
Subjects should return rescue medication bottles at each study visit for assessment of 
compliance.
Subjects will be instructed that many OTC medications contain acetaminophen/paracetamol, 
and to guard against overuse.  Subjects will be instructed to keep a daily record of their 
acetaminophen/paracetamol rescue medication usage via the 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.  Subjects must discontinue rescue 
medication within 24 hours of any scheduled site visit 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).  Use of acetaminophen/paracetamol for other types 
of pain or illness during the study (eg, toothache, headache, fever) should be recorded as a 
concomitant medication on the appropriate CRF page.
6. STUDY PROCEDURES
Refer to Schedule of Activities (Table 1 and Table 2) for the lists of procedures to be 
performed throughout the study.
If possible, each subject’s clinic visit should be conducted at approximately the same time of 
day throughout their participation in the study.  As a general rule, scales/instruments should 
be completed first by the subject upon arrival at the clinic and vital signs should be assessed 
prior to blood draws at non-dosing visits.
The study visit windows are 2 days for the visit at Week 2 and 3 days for the visit at Week 
4.  The study visit windows are 7 days for the clinic visits at Weeks 8, 16, 24, 32, 40, 
48 and 56 and for the visits during the Follow-up Period and for the Early Termination 
Visits.  The study visit windows are 7 days for the telephone visits at Weeks 12, 20, 28, 36, 
44, 52, 60, 68, 72, 76 and during the Early Termination Follow-up.  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 study monitor 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 to any 
study visit at which efficacy data is collected.


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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 2-week period of pre-randomization, celecoxib regimen 
stabilization.  The length of the celecoxib regimen stabilization period will depend on the 
NSAID subjects are receiving in the 30 days prior to screening.  The celecoxib regimen 
stabilization period will be a minimum of 2 weeks if the pre-study NSAID is celecoxib or a 
minimum of 3 weeks if the pre-study NSAID is loxoprofen or meloxicam.  Prior to entering 
the 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 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.
Subject demographics and the date of onset and primary etiology of primary diagnosis 
(chronic low back pain) 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 7.3.1.2). X-rays of the hips, knees and shoulders and other major joints 
exhibiting signs or symptoms suggestive of osteoarthritis should be obtained and sent to the 
Central Reader for assessment of joint-related eligibility.  It is recommended that the 
radiographs required at Screening be obtained at least two weeks prior to the Baseline visit to 
permit central radiology review of the images and to establish subject eligibility for initial 
dosing in the study.  Confirmation of radiologic eligibility from the Central Reader is 
required before the subject is randomized.
Clinically significant abnormal laboratory tests or tests not meeting inclusion/exclusion 
criteria may be repeated for verification prior to Baseline.
6.1.1. Screening Period Stage 1 (Initial Screening Visit):
After obtaining informed consent at Screening, the investigator will obtain information and 
perform activities listed in the Schedule of Activities.  Refer to Schedule of Activities 
(Table 1) for an all-inclusive list of procedures to be performed at the Screening Period Stage 
1 visit and Section 7 for descriptions of the assessments. 
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 screening procedures:

Subjects will be instructed in the use of the IRT system to record daily (during IPAP) 
/weekly LBPI scores, daily/weekly rescue medication use, weekly joint pain entries, 


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weekly concomitant NSAID (outside of oral investigational product) use entries 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 for at least the final 
2 or 3-weeks (average of 5 of 7 days per week at minimum; ie, minimum 70% 
compliance) of the Screening period directly prior to the Baseline (Day 1) visit.
NOTE: Beginning at Screening, subjects should use study-supplied oral investigational 
product (celecoxib during Screening and celecoxib or matching placebo post-randomization) 
through Week 56.
Subjects who were receiving celecoxib will receive the same oral celecoxib 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 for at least the final 2 weeks of the 
Screening period directly prior to the Baseline (Randomization/Day 1) Visit.
Subjects who were receiving loxoprofen or meloxicam prior to Screening will discontinue 
their prior NSAID and begin celecoxib dosing during the Screening period.  Subjects will use 
celecoxib for the remainder of the Screening period and will be stabilized on a dosing 
regimen of celecoxib 100 mg BID for at least the final 3 weeks of the Screening period 
directly prior to the Baseline (Randomization/Day 1) visit.
6.2. Washout Period
Subjects who satisfy inclusion/exclusion criteria (to this point) will be provided with a 
washout schedule for current pain medications.  The beginning of the Washout Period will 
preferably be scheduled based on the planned Baseline Visit so as to minimize the time spent 
without analgesic medications prior to Randomization.  The Washout Period will include the 
discontinuation and washout of all pain medications, muscle relaxants, and anti-depressants 
for the treatment of low back pain for at least 5 half-lives prior to the IPAP and will be at a 
minimum 2 days or 48 hours (Refer to Appendix 4).  Acetaminophen/paracetamol rescue 
medication will be dispensed.  Subjects experiencing pain during the Washout Period may 
take acetaminophen/paracetamol as needed up to a maximum daily dose of 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), however the total duration of 
the Screening period should not exceed 37 days.  Contact the the study monitor for guidance.
6.3. Initial Pain Assessment Period
The IPAP will begin 5 days prior to the Randomization/Baseline Visit (Day 1).  Subjects who 
do not require a washout of prohibited pain medications may begin the IPAP the day after 
X-ray confirmation of radiographic eligibility has been received from the Central Reader.  
During this time, the subject will record his/her daily LBPI scores and rescue medication use 
via the IRT.  In the event the subject misses an assessment entry in this period the schedule 
may be adjusted to acquire at least 4 days of daily LBPI score entries into the IRT (within a 


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5 day consecutive period prior to Baseline).  Study sites will monitor the IRT reports for 
compliance with diary recordings and rescue medication use and reschedule those subjects 
who fail to provide at least 4 days of diary entries or fail to refrain from rescue medication 
use 24 hours prior to Baseline.
6.4. 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 and 52) between site staff and 
study subjects.  
6.4.1. Baseline Visit (Day 1)
6.4.1.1. 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 should be assessed before carrying out randomization in the IRT system. Full 
eligibility, including (but not limited to) confirmation of appropriate washout of concomitant 
medication, compliance with celecoxib treatment regimen stabilization, abstinence from 
acetaminophen/paracetamol in the previous 24 hours, completion of at least 4 LBPI scores on 
the daily pain diary in the 5 days prior to the Baseline visit, required LBPI and PGA of LBP
scores and that no adverse events occurred since signing informed consent that would render 
the subject ineligible for randomization, should be assessed before carrying out 
randomization in the IRT system.
Refer to the Schedule of Activities Table 1 for the Baseline activities which should be 
completed prior to randomization to confirm eligibility for randomization. 
6.4.1.2. Dosing (Day 1)
Subjects will receive a single SC injection of blinded investigational product according to the 
treatment assigned by the IRT system (see Section 5.1).
The administration of study drug must be performed by medical staff (as per Japanese
regulations) 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 study 
drug administration should be discontinued immediately and permanently.  Subjects will 
receive appropriate treatment such as corticosteroids, antihistamine, or 
acetaminophen/paracetamol at the discretion of the investigator.  No other dosage 
modifications are allowed.


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6.4.1.3. Post Dosing (Day 1)
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.
6.4.2. Week 2 and 4 Visits
The subject will return for clinic visits at Week 2 and Week 4 to be assessed for efficacy and 
safety.  Refer to Schedule of Activities Table 1 for the procedures to be performed at the 
Week 2 and Week 4 Visits.
6.4.3. Week 8 Dosing Visit
The subject will return for clinic visits at Week 8 to be assessed for efficacy and safety.  
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 8
Visit.
The dosing and post-dosing procedures are the same as those as described in Section 6.4.1.2
and 6.4.1.3.
6.4.4. Week 12 Telephone Visit
The subject will be contacted by telephone at Week 12 to review adverse events, concomitant 
medications, compliance with weekly IRT entries and to remind female subjects of 
contraceptive requirements.
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 12 
Telephone Contact.
6.4.5. Week 16 Dosing Visit
The subject will return for clinic visits at Week 16 to be assessed for efficacy and safety.
Treatment response will be calculated by the IRT.  Subjects must have 30% reduction in 
weekly average LBPI score relative to Baseline and 15% reduction in weekly average LBPI 
score relative to Baseline at any week from Week 1 to Week 15, in order to continue 
investigational product.  Subjects who do not meet this response criterion will be 
discontinued from the Treatment Period and will enter the 24 week Early Termination 
Follow-up (See Section 6.9).
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 16
Visit.


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The dosing and post-dosing procedures are the same as those as described in Section 6.4.1.2
and 6.4.1.3.
6.4.6. Weeks 20 Telephone Visit
The subject will be contacted by telephone at Week 20 to review adverse events, concomitant 
medications, compliance with weekly IRT entries and to remind female subjects of 
contraceptive requirements.
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 20
Telephone Contact.
6.4.7. Week 24 Dosing Visit 
The subject will return for clinic visits at Week 24 to be assessed for efficacy and safety.  
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 24
Visit.
Radiographic assessment (X-rays) of hips, knees, and shoulders, and any other major joint 
imaged at Screening or at-risk joint identified during the study period.  Confirmation of 
continued radiographic eligibility from the Central Reader is required prior to Week 24 SC 
dosing.  The X-rays may be obtained up to 30 days before the Week 24 visit in order to allow 
confirmation of continued radiographic eligibility from the Central Reader.
The dosing and post-dosing procedures are the same as those as described in Sections 6.4.1.2
and 6.4.1.3.
6.4.8. Weeks 28, 36, 44 and 52 Telephone Visits
The subject will be contacted by telephone at Week 28, 36, 44 and 52 to review adverse 
events, concomitant medications, compliance with weekly IRT entries and to remind female 
subjects of contraceptive requirements.
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 28, 
36, 44 and 52 Telephone Contacts.
6.4.9. Weeks 32, 40 and 48 Dosing Visits
The subject will return for clinic visits at Week 32, 40 and 48 to be assessed for efficacy and 
safety.  Refer to Schedule of Activities Table 1 for the procedures to be performed at the 
Week 32, 40 and 48 Visits.
The dosing and post-dosing procedures are the same as those as described in Section 6.4.1.2
and 6.4.1.3.
6.4.10. Week 56 Visit-End of Treatment Visit 
The subject will return for clinic visits at Week 56 to be assessed for efficacy and safety.  
Refer to Schedule of Activities Table 1 for the procedures to be performed at the Week 56
Visit.


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Radiographic assessment (X-rays) of  hips, knees, and shoulders, and any major other joint 
imaged at Screening or at-risk joint identified during the study period.  The X-rays may be 
obtained within 30 days of the Week 56 visit.  Radiographs must be sent to the Central 
Reader for assessment.
At Week 56, subjects will enter the Follow-up Period which lasts until Week 80.
6.5. Week 60 Telephone Visit
The subject will be contacted by telephone at Week 60 to review adverse events, concomitant 
medications, compliance with weekly IRT entries and to remind female subjects of 
contraceptive requirements.
Refer to Schedule of Activities Table 2 for the procedures to be performed at the Week 60
Telephone Contact.
6.6. Week 64 Visit-Safety Follow-up Period
The subject will return for clinic visits at Week 64 to be assessed for efficacy and safety.  
Refer to Schedule of Activities Table 2 for the procedures to be performed at the Week 64
Visit.
6.7. Weeks 68, 72, and 76 Telephone Visits
The subject will be contacted by telephone at Week 68, 72 and 76 to review adverse events, 
concomitant medications and compliance with weekly IRT entries.
Refer to Schedule of Activities Table 2 for the procedures to be performed at the Week 68, 
72 and 76 Telephone Contacts.
Week 76: Verify that follow-up radiographs required for the Week 80 visit have been 
scheduled and will be completed (refer to Section 7.3.8).
6.8. Week 80 Visit-End of Study Visit
The subject will return for clinic visits at Week 80 to be assessed for safety.  Refer to 
Schedule of Activities Table 2 for the procedures to be performed at the Week 80 Visit.
Radiographic assessment (X-rays) of hips, knees, and shoulders, and any other major joint 
imaged at Screening or at-risk joint identified during the study period.  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.
6.9. Subject Withdrawal/Early Termination Visits
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.


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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  A subject thought lost to follow-up must be contacted through a minimum of 
3 documented phone call attempts and, if phone calls are unsuccessful, a certified letter sent 
to the subject.  In any circumstance, every effort should be made to document subject
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return 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.  Female subjects 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.  The sponser may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who discontinue 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 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, as described in
6.9.1.  In addition, subjects will be asked about the presence and severity of joint pain (hips, 
knees and shoulders), rescue medication use, and NSAID (outside of oral investigational 
product) use once per week via IRT through the end of the 24-week follow-up period.
X-rays of the hips, knees and shoulders (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.  The remainder of efficacy and safety assessments 
should be done at scheduled first visit, which is to occur 8 weeks after the last dose of 
investigational product (as described in 6.9.1.1).
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 to collect safety and efficacy data.  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.  Standard of care 
treatment may be initiated as needed and recorded on the concomitant medication 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, (described in 6.9.1.5), 
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.  The window for obtaining 
end of study X-rays is 30 days before or 14 days after the nominal time of the visit.
Telephone contact will be made with subjects at approximately 12 and 20 weeks following 


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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 above.
In the event that a subject refuses the Early Termination safety follow-up or chooses to 
discontinue during the Safety Follow-up Period (after Week 56 of the study 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 Week 
64 has already been completed; in that 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, TSQM, 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 SC 
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 Visit 2 that 
occurs 16 weeks after the last dose of investigational product, but will be advised not to 
exceed the maximum daily dose of 3000 mg.  Subjects will be requested not to take 
acetaminophen/paracetamol (or any other analgesic) in the 24 hours that precede in-clinic 
visits at which efficacy assessments are collected (Up to and including Week 64 and 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 low back pain.  Subjects may 
continue to use acetaminophen/paracetamol as needed up to 3000 mg per day.
6.9.1. Early Termination Follow-up Procedures
6.9.1.1. Early Termination Follow-up Period Visit 1 (8 weeks after the last dose of SC 
Investigational Product)
Refer to the Early Termination Schedule of Activities Table 2 and Section 7 for information 
on the procedures to be performed at Early Termination Follow-up Period Visit 1.
X-rays of the hips, knees and shoulders and all joints for which X-rays were obtained at 
Screening and other at risk joints identified during the study period, provided 30 days have 
elapsed since the last set of study X-rays were collected.  These X-rays should be collected as 
soon as possible after the decision to withdraw was made, provided that 30 days have elapsed 
since the last set of study X-rays were collected.
6.9.1.2. Early Termination Follow-up Period Telephone Visit 1 (12 weeks after last dose 
of SC investigational product)
The subject will be contacted by telephone (12 weeks after the last dose of SC investigational
product) to review adverse events, concomitant medications, compliance with weekly IRT 
entries and, at Telephone contact 1, to remind female subjects of contraceptive requirements.


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Refer to the Early Termination Schedule of Activities Table 2 for the procedures to be 
performed at the Early Termination Follow-up Period Telephone Contact 1, to remind female 
subjects of contraceptive requirements.
6.9.1.3. Early Termination Follow-up Period Visit 2 (16 weeks after last dose of SC 
investigational product)
Refer to the Early Termination Schedule of Activities Table 2 and Section 7 for information 
on the procedures to be performed at Early Termination Follow-up Period Visit 2
6.9.1.4. Early Termination Follow-up Period Telephone Visit 2 (20 weeks after last dose
of SC investigational product)
The subject will be contacted by telephone (20 weeks after the last dose of SC investigational 
product) to review adverse events, concomitant medications, compliance with weekly IRT 
entries at Telephone contact 2.
Refer to the Early Termination Schedule of Activities Table 2 for the procedures to be 
performed at the Early Termination Follow-up Period Telephone Contact.
6.9.1.5. Early Termination Follow-up Period Visit 3 (24 Weeks after last dose of SC
investigational product)
Refer to the Early Termination Schedule of Activities Table 2 and Section 7 for information 
on the procedures to be performed at Early Termination Follow-up Period Visit 3.
Radiographic assessment (X-rays) of hips, knees, and shoulders and any other major joint for 
which a radiograph was obtained at the Screening visit, and any other at risk joint identified 
as at risk during the study period.  The window for the Early Termination Visit 3 X-rays is 
30 days of the visit, but the X-rays should be obtained as close as possible to the Early 
Termination Visit 3, but not more than 30 days before or preferably 14 days after the visit.
6.9.2. 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 
(Treatment Period or Follow-up Period) will be followed for 24 weeks after the procedure 
(See Appendix 18), as part of the substudy or in a separate protocol, provided the subject 
consents.  The follow up will be conducted as part of a substudy if the total joint replacement 
occurs before the last subject enrolled in Study A4091063 has completed the treatment 
period.  Subjects undergoing total joint replacements after the last subject completes the 
treatment period may be followed in a separate protocol (Study A4091064).
Transition procedures into the substudy or Study A4091064 are determined by the timing of 
total joint replacement surgery:


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
Subjects who have undergone or plan an immediate total joint replacement procedure 
will be discontinued from the treatment period and enter into the substudy or Study 
A4091064.  At the discontinuation visit, all End of Treatment (Week 56) and Week 64 
procedures should be completed (Sections 6.4.10 and 6.6); unless the Subject has 
already completed the Week 56 and Week 64 visits, in which case only the Week 80 
visit procedures should be completed (Section 6.8). Baseline visit activities (See
Appendix 18, Schedule of Activities) should be completed on the same days as the End 
of Treatment Visit.  Female subjects of child-bearing potential will be advised to 
continue their contraception regimen during a period of 112 days (16 weeks) after the 
last dose of investigational product.

Subjects who plan to undergo total joint replacement during the study will be 
discontinued from the treatment period and entered into Early Termination Follow-up 
(See Section 6.9) until their joint replacement or other arthroplasty procedure.  For these 
subjects, a complete early termination visit (which includes all Week 56 and Week 64 
activities) should be conducted prior to the total joint replacement or arthroplasty 
procedure (Section 6.9) and entrance into the substudy or Study A4091064.  Substudy or 
Study A4091064 Baseline visit activities (See Appendix 18, Schedule of Activities) 
should be completed on the same day as the 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 the total joint 
replacement substudy or 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 the substudy or Study A4091064 
for follow-up.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion.
7.1. Subject Collected Efficacy Assessments
7.1.1. Low Back Pain Intensity (LBPI) Score
Average back pain will be assessed with an 11-point Numeric Rating Scale ranging from 
zero (no pain) to 10 (worst possible pain) captured through an IRT on a daily basis during the 
IPAP then assessed weekly from Baseline through to Week 64 or Early Termination Visit 2.


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The subjects should describe their average low back pain during the past 24 hours by 
choosing the appropriate number from 0 to 10.  If possible, the subject should conduct the 
self-assessment in the evening prior to midnight (Refer to Appendix 11).
Example Question:
“Select the number that best describes average low back pain in the past 24 hours.”
0
1
2
3
4
5
6
7
8
9
10
No 
Pain
Worst 
Possible 
Pain
If an IRT is used, additional instructional language may need to be added to the question 
such as “Using a scale from 0 to 10, with 0 meaning no pain and 10 meaning worst possible 
pain; please enter the number that best describes your average low back pain in the past 
24 hours.”
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/paracetamol tablets will be 
captured.  The subject should note the number of tablets of rescue medication taken during 
the last 24 hours.
Following the Week 16 visit up to and including the Week 80 visit and up to and including 
the Early Termination Visit 3 for subjects that have entered the Early Termination Follow-up 
Period, 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.
7.2. Study Efficacy Assessments
7.2.1. Roland-Morris Disability Questionnaire (RMDQ) 
The RMDQ is an index of how well subjects with low back pain are able to function with 
regard to daily activities.21  The score for the index ranges from 0 to 24 with a lower score 
indicating better function.  All subjects will complete the RMDQ via IRT at the study center 
at Baseline, and Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 (or Early Termination visits 1
and 2) visits.  An example of the RMDQ can be found in Appendix 6.
7.2.2. Patient’s Global Assessment of Low Back Pain 
The Patient’s Global Assessment of Low Back Pain (Appendix 8) is a global evaluation that 
utilizes a 5-point Likert scale with a score of 1 being the best (Very Good) and a score of 
5 being the worst (Very Poor).  It was adapted from a scale developed by Pfizer (Pharmacia) 
for studies in osteoarthritis (OA) and rheumatoid arthritis (RA).  The original question asked 


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in the OA/RA studies was modified to refer to low back pain rather than arthritis, otherwise 
the scale was unchanged.  It is intended to provide a qualitative measurement of the subject’s 
overall impression of disease activity.  The Patient’s Global Assessment of Low Back Pain 
will be completed by the subject via IRT at Baseline and the Weeks 2, 4, 8, 16, 24, 32, 40, 
48, 56 and 64 visits (or Early Termination visits 1 and 2).  The subjects will answer the 
following question:
“Considering all the ways your low back pain affects you, how are you doing today?”
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. Brief Pain Inventory-short form (BPI-sf)
The BPI-sf was derived from the Brief Pain Inventory (BPI) developed for use in clinical 
research by Charles Cleeland.  It is a self-administered questionnaire developed to assess the 
severity of pain and the impact of pain on daily functions during the 24-hour period prior to 
evaluation.  It consists of 5 questions.  Questions 1-4 measure the magnitude of pain at its 
worst, least, average, and ‘right now’.  Responses are provided by the subject on an 11-point 
Numeric Rating Scale with anchors at 0 (No Pain) and 10 (Pain as bad as you can imagine).  
Question 5 consists of 7 item subsets (A to G) which measure the level of interference of 
pain on daily functions.  Responses are given on an 11-point Numeric Rating Scale with 
anchors at 0 (Does not interfere) and 10 (Completely interferes).  The instrument is scored by 
item and by dimension, with lower scores indicating less pain or pain interference.  The BPI 
will be completed by the subject via IRT at Baseline and the Weeks 2, 4, 8, 16, 24, 40, 56 
and 64 (or Early Termination Visits 1 and 2) visits.  Refer to Appendix 9 for the BPI-sf 
questionnaire.
7.2.4. Work Productivity and Activity Impairment Questionnaire: Low Back Pain
(WPAI:LBP)
Subjects will complete the WPAI:LBP (See Appendix 10) prior to SC dosing at Baseline, 
Week 16 , 56 and 64 (or at Early Termination Visits 1 and 2).  Subjects will record their 
responses using IRT.
The WPAI:LBP is a self-administered questionnaire that measures the effect of general 
health and symptom severity on work productivity and regular activities.  Unlike general 
health or disease-specific measures, the WPAI:LBP assesses function-related endpoints to 
allow a measure of the economic impact of relative differences in either the safety or efficacy 
of therapeutic endpoints.22 In this study, the WPAI:LBP will measure the effect of the 
subject’s chronic low back pain on work productivity and regular activities.


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7.2.5. Euro Quality of Life Health State Profile (EQ-5D-5L) 
The EQ-5D-5Lis a subject completed questionnaire designed to assess the subject’s 
current health and translate that score into an index value or utility score.  Health status is 
described in terms of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression.  There are two components to the EQ-5D-5L: a Health State Profile and a 
visual analog scale (VAS) item (see Appendix 12). The 5 item health state profile will be 
assessed to calculate a single index value.  This instrument provides a mechanism for 
conducting cost-effectiveness and cost-utility analyses.23 The 5-item Health State Profile and 
the VAS will be administered in this study at Baseline, Weeks 16 and 56 (or at Early 
Termination Visits 1).  Subjects will record their responses using IRT.
7.2.6. Treatment Satisfaction Questionnaire for Medication v.II (TSQM)
Subjects will complete the Treatment Satisfaction Questionnaire for Medication v.II 
(Appendix 17) via IRT at Weeks 16 and 56 (or at Early Termination Visit 1).
The TSQM is an 11-item validated scale that quantifies the subject’s level of satisfaction 
with investigational product, 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 is self-administered by the subject and takes less than 5 minutes to complete.24
7.2.7. Patient Reported Treatment Impact Assessment-modified (mPRTI)
The mPRTI is a self-administered questionnaire containing four items to assess patient
satisfaction, previous treatment, preference and willingness to continue using the 
investigational product.  In this study, three items are being collected: previous treatment, 
preference and willingness to continue using the investigational product. Higher scores 
indicate greater satisfaction, preference or willingness to use the investigational product; see
Appendix 16. The questionnaire will be self-completed by the subject using IRT at Week 16 
and Week 56 or at Early Termination Visit 1.
7.2.8. Health Care Resource Utilization (HCRU)
The HCRU (eg, doctor office visits, hospitalizations, surgeries or procedures) during the 
3 month period prior to Baseline will be collected by a questionnaire via IRT.  In addition, 
HCRU will be collected at study visits at baseline, Week 64 and Week 80 (or at Early 
Termination, Visits 2 and 3).
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 chronic low back pain), non-pharmacologic 
therapies, supplements and concomitant medication use will be collected at Screening and 


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concomitant medication at each scheduled study visit.  Information regarding tobacco and 
alcohol use and dependency will also be collected at Screening.
7.3.1. Physical Examination
7.3.1.1. General Physical Examination
Each subject will undergo a general physical examination at Screening, Week 56 or at Early 
Termination Visit 1.
7.3.1.2. Musculoskeletal History and Physical Examination
Each subject will also undergo a musculoskeletal physical examination at Screening, 
Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 (or Early Termination Visits).  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, or 
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 exam should evaluate the joints for 
swelling, redness, tenderness, deformity, osteophytes or nodes, crepitus and range of 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.
7.3.2. Joint Pain Weekly Assessments
At the Screening visit, subjects will record via IRT if they are experiencing pain in the hips, 
knees, shoulders or any other major joint.  Pain will be rated on an 11 point numeric rating 
scale, using a 24 hour recall.  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.  The subject should record a score for any major joint that has signs and symptoms of 
osteoarthritis and thus will be undergoing X-ray. 
On a weekly basis beginning at the IPAP and through Week 80 of the study (or through the 
last Early Termination Follow-up visit), the subject will be asked via the IRT if he/she 
experienced new onset or increased pain in any major joint.  If a subject responds that he/she 
has experienced new onset or increased pain in a major joint (post-baseline), the subject will 
be asked to rate his/her pain in that joint on the same 11-point numeric rating scale, using a 
24-hour recall and will be asked to rate his/her pain in that joint for the remainder of the 
study.
7.3.3. Collection of concomitant NSAID use
Use of OTC or prescription NSAID (outside of oral investigational product) use will be 
collected weekly via IRT from Screening period Stage 2 visit until the Week 80 visit.  During 
the Early Termination Follow-up Period, for subjects who discontinue treatment, the use of 


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OTC or prescription NSAID will be collected once weekly using IRT.  Subjects will record 
the number of days of NSAID use in the past week.  Via telephone contact or at clinic visits, 
sites will interview the subject regarding his/her 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 the subject’s NSAID use to detect subjects 
who are at risk of exceeding the protocol-defined limits on NSAID use (See Section 5.8.1.2).
7.3.4. Laboratory Safety Assessments
Blood and urine tests for safety assessments and/or determination of eligibility will be 
performed as indicated in this table and described in the subsections below:
Chemistry
Hematology
Other
Urinalysis
Screening, Baseline, Weeks 
16 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, 
Weeks 16 and 64 (or 
Early Termination 
Visit 2):
Complete blood count 
with differential
Screening only:
HbA1c
Serum FSH, if 
applicable
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).
Screening, Weeks 56 
and 64 (or Early 
Termination Visits 1 
and 2):
Serum Pregnancy Test
Baseline, Weeks 8, 16, 
24, 32, 40, and 48 
(Pre-dose at dosing 
visits): Urine 
Pregnancy Test
Baseline, Weeks 16, 
56 and 64 (or Early 
Termination Visits 1 
and 2):
Serum and plasma 
retention samples
Screening only:
pH, 
protein, 
glucose, 
ketones, 
blood, 
bilirubin, 
nitrite, 
specific gravity and 
leukocytes. 
Microscopic 
analysis performed 
if abnormalities are 
present on the above 
components.
Does not include PK, PD (NGF), ADA and biomarkers (refer to sections below for collection details).


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7.3.4.1. Blood tests
Blood tests for clinical laboratory testing (chemistry, hematology) will be performed at 
Screening, Baseline, Week 16, and Week 64 (or at Early Termination Visit 2).  An 
unscheduled visit(s) may be necessary for follow-up of abnormal test results.
Serum and plasma retention samples will be collected at Baseline, Weeks 16, 56 and 64 (or at 
Early Termination Visits 1 and 2).
See Section 7.3.4.3 for sample collected for serum pregnancy test and 7.3.4.4 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 7.3.10.
7.3.4.2. 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.
7.3.4.3. Pregnancy Testing
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.  Urine pregnancy tests with 
sensitivity of at least 25 mIU/mL
 will be performed at Baseline (Day 1, pre-dose), 
Weeks 8, 16, 24, 32, 40, and 48.  A negative pregnancy result is required before the subject
may receive the investigational product.  Additional serum pregnancy tests will be conducted 
at Week 56 and 64 (to confirm the subject has not become pregnant during the study period) 
or at Early Termination Visits 1 and 2.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected), and may also be repeated as per request of Institutional Review 
Boards/Ethics Committees (IRB/ECs) or if required by Japanese regulations. 
 
Refer to Sections 8.10 and 8.10.1 for guidance pertaining to exposure during pregnancy and 
post-natal follow-up.
7.3.4.4. Serum FSH Testing
Female subjects of non-child bearing 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 who are considered of 
childbearing potential do not require FSH testing.
CCI
CCI


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7.3.5. Vital Signs
Vital signs (including systolic blood pressure, diastolic blood pressure and pulse rate) will be 
collected and recorded at Screening, Baseline, prior to SC dosing at Weeks 2, 4, 8, 16, 24, 
32, 40, 48, 56, 64 and 80 (or at Early Termination).  Vital signs will be collected after the 
subject has been in a sitting position for at least five minutes at each visit.
7.3.5.1. Orthostatic Blood Pressure Measurements
In addition to sitting vital sign measurements, orthostatic blood pressure measurements will 
be obtained using a standard manual sphygmomanometer at Screening, Baseline and at 
Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 (or Early Termination).  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 8̽16 ounces (240̽480 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 timepoints.  If 
the measurements do not meet the criteria for orthostatic (postural) hypotension, no further 
measurements are needed. If either the 1 minute or 3 minute standing blood pressure
measurements show decreases meeting the criteria shown in Table 5, the sequence of supine 
and standing measurements should be repeated up to 2 more times.  Refer to Table 5 for the 
criteria defining orthostatic hypotension and actions that should be taken when orthostatic 
hypotension criteria are met.


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Table 5.
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
OR
>150 mmHg
20 mmHg systolic or
10 mmHg diastolic
30 mmHg systolic or
15 mmHg diastolic
- Repeat the sequence of measurements (supine and standing) 
up to 2-times.  If either the 1 minute or 3 minutes 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.
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, Weeks 16, 56 and 80 (or Early Termination 
Visits 1 and 3) for determination of ECG-related eligibility and safety monitoring.  Post-
Screening ECGs may be collected during the study, if needed (for cause), at the discretion of 
the investigator.
A 12-lead ECG should be recorded after subjects have been resting at least 5 minutes in the 
supine position in a quiet environment.  Digital ECG tracings will be performed using 
equipment from and analyzed by a central ECG laboratory.  All standard intervals (PR, QRS, 
QT, QTcF, QTcB, RR intervals, and heart rate [HR]) will be collected.  The QTc interval 
reading produced by machine will be listed in the data listings.  The QT interval will be 
manually measured by the central laboratory.  The cardiologist at the central ECG laboratory 
reading the ECGs will be blinded regarding investigational product.  In the event a clinically 
significant ECG abnormality is seen at a visit on a post treatment ECG, the investigator 
should consider evaluation of the subject by a cardiologist.
Investigators will also be alerted of subjects with evidence of the following as a potential 
indicator of sympathetic nervous system dysfunction:

Significant bradycardia (heart rate of 45 beats per minute on an ECG, exclusionary 
at Screening)

Heart rate decrease from Screening of ≥25% with resulting heart rate <60 bpm.
Investigators should report adverse events of bradycardia for subjects who meet the ECG 
criteria listed above.  Refer to Section 7.4.3 for additional details pertaining to subject
evaluation and dosing in subjects with sympathetic function adverse events.


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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 Weeks 24, 56 and 80 (or 
at Early Termination Visits 1 and 3).  Subjects will enter responses in IRT.
7.3.8. Radiographic Assessments
A central radiology reader (Central Reader) will review the radiology images for assessment 
of eligibility including determination 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, or pathological fractures.
During the study, the Central Reader will review radiology images for continued radiologic 
eligibility and for diagnosis of joint conditions that would warrant further evaluation by the 
Adjudication Committee such as rapidly progressive osteoarthritis, subchondral insufficiency 
fractures, spontaneous osteonecrosis of the knee (SPONK), primary osteonecrosis, or 
pathological fracture.
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.
The X-ray technologists, in addition to their professional training and certifications, will be 
trained in performing the radiographic protocols for the hips, knees, 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 and 
hips, a standardized subject and joint positioning protocol will be utilized.  The Core Imaging 
Laboratory will be responsible for working with the sites to ensure quality, standardization 
and reproducibility of the radiographic images/assessments made at the Screening and 
follow-up time-points.  Additional details regarding the required X-rays will be provided in a 
site imaging manual.
Radiographic assessments (X-rays) of the hips, knees and shoulders will be obtained at 
Screening, Weeks 24, 56 and 80 (or at Early Termination Visit 1 and 3).  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 the same 
intervals as the knees, hips, and shoulders.
It is recommended that the radiographs required at Screening be obtained at least two weeks 
prior to the Baseline visit to permit central radiology review of the images and to establish 


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subject eligibility for initial dosing in the study.  Subjects will not be permitted to start dosing 
in the study until the Screening radiographs are reviewed by the Central Reader and 
eligibility is established.  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).  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.
The Central Reader will review the Week 24 knee X-rays to confirm continued radiologic 
eligibility and for evidence of radiographic progression of knee osteoarthritis.  The Central 
Reader will identify subjects entering the study with asymptomatic knee osteoarthritis 
Kellgren Lawrence Grade 2 who progress to Kellgren Lawrence Grade ≥3 at Week 24.  
These subjects should be discontinued from tanezumab treatment and entered into the Early 
Termination Follow-up.  The images from these patients will not be reviewed by the 
Adjudication Committee unless the Central Reader determines the subject has developed a 
joint condition that would require evaluation by the Adjudication Committee such as rapidly 
progressive osteoarthritis, subchondral insufficiency fractures, spontaneous osteonecrosis of 
the knee (SPONK), primary osteonecrosis or, pathological fracture.
For subjects discontinued prior to the Week 56 visit, follow-up radiographs of the hips, knees 
and shoulders should be performed as soon as possible (refer to Section 6.9.1) after the 
decision to withdraw from the study has been made, provided at least 30 days have passed 
since the last set of X-rays were collected.  A final set of follow-up radiographs of the hips, 
knees and shoulders should be obtained 24 weeks (Early Termination Visit 3, Section
6.9.1.5) after the last dose of SC investigational product was administered.  Any joint imaged 
at Screening or other at risk joints identified during the study period should also be imaged at 
Early Termination Visits 1 and 3.
For subjects who are identified by the Central Readers as having a possible or probable joint 
event (ie, 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.
7.3.8.1. 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 
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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)
Knee
0.024 mSV
Hip
1.9 mSV
Shoulder
0.04 mSV
Total
1.964 mSV
The average annual subject exposure per body part imaged is shown in the table above.25,26  
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.  In some cases, it is expected that a repeat image of a 
joint may necessary due to the quality of the X-ray images.
7.3.9. Neurologic Examination
Neurologic examinations will be performed by the investigator or 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) and the Neuropathy Impairment Score (NIS) will be completed at these 
time points based on this neurological exam (refer to Appendix 7).  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.27 Investigators and other designated physicians performing the neurologic 
examination 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.


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
A new or worsened clinically significant abnormality on the neurologic exam should be 
reported as an adverse event and may result in a neurologic evaluation/consult further to 
the guidance above.

A neurological adverse event which is non-neuropathic (eg, stroke, seizure) but which 
the investigator considers medically important should also result in a neurological 
consultation.
In these cases, a neurologic evaluation should be obtained as soon as possible after these 
signs and symptoms are known.  The results of the neurological consultation will be recorded 
on the appropriate CRF and adverse event (if applicable) forms.  Adverse events will be 
reported where applicable as described in Section 8.
7.3.10. Anti-Drug Antibody Testing
7.3.10.1. Serum for Analysis of Anti-Drug Antibodies (ADA) Against Tanezumab
Blood samples for the assessment of ADA against tanezumab (anti-tanezumab antibodies) 
will be collected at Baseline (Day 1; pre-dose) and Weeks 8 (pre-dose), 16 (pre-dose), 
32 (pre-dose), 48 (pre-dose), 56, 64 and 80. If subjects terminate prior to Week 56, ADA 
will be determined at approximately 8, 16 and 24 weeks after the last SC investigational 
product was administered (or at Early Termination).
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 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 


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date, the subject will not receive any additional doses of investigational product and will 
enter the Early Termination Follow-up Period (see Section 6.9).
7.4.2. Hypersensitivity or Injection Site Reactions
If a severe hypersensitivity reaction or severe injection reaction occurs following any
administration of SC investigational product, the investigational product should be 
discontinued immediately and no further administrations of SC investigational product will 
be allowed.  Subjects experiencing these types of reactions will enter the Early Termination 
Follow-up Period (see Section 6.9).
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 6 provides a flow diagram for the processes 
described below.
1. If no apparent medical cause (eg, dehydration, illness, medications) is identified at the 
time the orthostatic hypotension criterion is met and the subject is symptomatic, the 
subject should be further evaluated for the presence of sympathetic autonomic 
neuropathy by a cardiologist or neurologist as soon as possible.  See “Sympathetic 
function adverse events” below for decisions regarding subject management and 
continued dosing with investigational product.
2. If an apparent medical cause is identified at the time the orthostatic hypotension 
criterion is met or if 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 


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bradycardia), syncope, orthostatic hypotension (as described above and in boxes C and E of 
flow diagram Figure 6), anhidrosis or hypohidrosis should be further evaluated for the 
presence of sympathetic autonomic neuropathy by a cardiologist or neurologist as soon as 
possible.
The investigator should determine the appropriate type of consultation (neurology or 
cardiology) depending on the subject’s symptom presentation and the investigator’s 
assessment as to the specialist best able to evaluate the subject.  Pfizer will provide a 
guidance document which outlines appropriate recommendations regarding tests to consider 
for subject work-up.
These subjects should not be dosed with SC investigational product until the absence of 
sympathetic autonomic neuropathy has been confirmed.  Subjects who are not deemed to 
have a sympathetic autonomic neuropathy based on this evaluation can continue the study 
provided no more than 12 weeks have elapsed since the last dose of SC treatment (Boxes H 
and K of flow diagram Figure 6).  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, he/she should not receive additional investigational 
product; even if a sympathetic autonomic neuropathy has not been confirmed (Boxes J and L 
of flow diagram Figure 6), and will enter the Early Termination Follow-up Period (refer to 
Section 6.9).  Subjects found to have a sympathetic autonomic neuropathy (Boxes I and L of 
flow diagram Figure 6), should not receive additional investigational product and will enter 
the Early Termination Follow-up Period (see Section 6.9).


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Figure 6.
Follow-up Procedures for Confirmed Orthostatic Hypotension Events
OH=Orthostatic Hypotension
6.9


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7.4.4. Evaluation and Follow-up for Increased, Severe Persistent Joint Pain
On a weekly basis beginning at the IPAP and through Week 80 of the study, the subject will 
be asked via the IRT if he/she experienced new onset or increased pain in a major joint (refer 
to Section 7.3.2).  If a subject responds that he/she has experienced new onset or increased 
pain in a major joint (post-baseline), the subject will be asked to rate his/her pain in that joint 
on the same 11-point numeric rating scale, using a 24-hour recall 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 (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 (e.g., 
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 joint 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 osteoarthritis symptoms will be evaluated by the 
site personnel.  An assessment of the subjects’ general health and major joints for any 
changes in their joint 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.  Magnetic Resonance Imaging (MRI) scans will not be 
required but may be obtained if warranted for diagnostic purposes.  If warranted, the subject 
should be referred to an orthopedic surgeon for evaluation.
Radiographic and any MRI images collected as part of follow-up procedures for reports of 
increased severe or persistent pain or clinically significant findings of the investigator will be 
assessed by the Central Reader for possible or probable events of rapidly progressive 
osteoarthritis, subchondral insufficiency fractures (spontaneous osteonecrosis of the knee 
[SPONK]), primary osteonecrosis, or pathological fracture (Refer to Sections 7.4.5 and 9.5).
7.4.5. Central Reader and Subject-Level Stopping Criteria for Joint Safety Events 
Subjects identified through the measures described above (in Section 7.4.4) who are
determined by the Central Reader to have 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 


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fracture will be withdrawn from treatment and enter the Early Termination Follow-up period 
(see Section 6.9).
The Central Reader will review the radiology images on an ongoing basis and provide 
assessments to the investigator and Pfizer.  For subjects who are identified with a possible or 
probable event described above and for subjects undergoing total joint replacement for any 
reason, all images and other source documentation will be provided to the blinded tanezumab 
Adjudication Committee for review and adjudication of the event.  The Adjudication 
Committee’s assessment of the event will represent the final classification of the event (refer 
to Appendix 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 (see Section 6.9).
The Central Reader will review the Week 24 knee X-rays for evidence of radiographic 
progression of osteoarthritis.  The Central Reader will identify subjects entering the study 
with asymptomatic knee osteoarthritis Kellgren Lawrence Grade 2 who progress to Kellgren 
Lawrence Grade 3 at Week 24.  These subjects should be discontinued from tanezumab 
treatment and entered in the Early Termination Follow-up phase.  Unless the Central Reader 
determines the subject has developed a joint condition that would warrant further evaluation 
by the Adjudication Committee such as rapidly progressive osteoarthritis, subchondral 
insufficiency fractures, spontaneous osteonecrosis of the knee (SPONK), primary 
osteonecrosis or pathological fracture, the images will not be further reviewed by the 
Adjudication Committee.
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 treatment.  Follow-up procedures for 
these subjects are described in Section 6.9.2. The follow-up will be conducted as part of a 
substudy (Refer to Appendix 18) if the total joint replacement occurs before the last subject 
enrolled in Study A4091063 has completed the treatment period.  Subjects undergoing total 
joint replacements after the last subject completes the treatment period may be followed in a 
separate protocol (Study A4091064).
7.5. Pharmacokinetics (PK) and Pharmacodynamics (PD)
7.5.1. Plasma for Analysis of Tanezumab
Blood samples for the assessment of the PK of tanezumab will be collected at Baseline (Day 
1; pre-dose) and at Weeks 2 and 4, Week 8 (pre-dose), Week 16 (pre-dose), Week 
32 (pre-dose), Week 48 (pre-dose), Week 56, and Week 64.  If subjects terminate prior to 
Week 56, PK will be determined at approximately 8 and 16 weeks after the last SC dose was 
administered (as described in Section 6.9, Early Termination).


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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.
7.5.2. Nerve Growth Factor (NGF) for Pharmacodynamic Analyses
Blood samples will be collected for the assessment of NGF.  NGF can exist in different 
forms including, but not limited to, NGF bound to drug or not bound to drug, NGF bound to 
soluble p75, and proNGF.  Blood volume collected 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 final set of NGF forms, including total NGF, that will be measured will depend 
on the availability of the analytical assay that can reliably measure the NGF concentration.  
The time points of NGF sample collection will be at Baseline (Day 1; pre-dose), at Weeks 2
and 4, Week 8 (pre-dose), Week 48 (pre-dose) and at Weeks 56 and 64 (or at Early 
Termination, as described in Section 6.9). If subjects terminate prior to Week 56, NGF will 
be determined at approximately 8 and 16 weeks after the last SC dose was administered (or at 
Early Termination, as described in Section 6.9).
Instructions regarding sample processing (eg, sample volumes, tube types, storage 
temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
NGF samples may be used for further evaluation of the bioanalytical methods used for 
measuring NGF.  These data will be used for internal exploratory purposes and will not be 
included in the clinical report.
The shipment address 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 will be collected at Baseline (Day 1; 
pre-dose in all subjects). 
If possible, the samples should be obtained following a fasting period of at least 8 hours.  
Fasting status should be recorded on the eCRF.
Currently the measurement of 12 biomarkers are planned:
 
 
CCI


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  This selection of biomarkers could change due to 
blood volume limitations and/or assay performance issues.  OA biomarkers different from 
the ones listed could be added or substituted if considered informative to further understand
the osteoarthritis condition.
Instructions regarding sample processing (eg, sample volumes, tube types, storage
temperatures) will be provided in the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 
Biomarker samples may be used for further evaluation of the bioanalytical methods. 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 in all subjects.
The urine sample should be collected from the second void of the day or later. If possible, 
the samples should be obtained at approximately the same time at each study visit and 
following a fasting period of at least 8 hours in order to control for diurnal variations in the 
biomarkers.  Fasting status should be recorded on the eCRF. Sites will provide collection 
containers and storage instructions for subjects doing home collection. Instructions regarding 
sample processing (eg, sample volumes, tube types, storage temperatures) will be provided in 
the laboratory manual.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
Biomarker samples may be used for further evaluation of biomarkers other than the ones 
listed that could improve the understanding of the safety and efficacy profile of tanezumab.
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.
7.7. 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 deoxyribonucleic acid (DNA), 
CCI
CCI


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ribonucleic acid (RNA), 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 swiping a badge, Data will be stored on password-protected 
computer systems.  The key between the code and the subject’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information.  Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/subject information sheet; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
postmarketing 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 edetic acid [ethylenediaminetetraacetic acid]
[EDTA] whole blood collection optimized for DNA analysis) will be collected at the 
Baseline 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 biospecimen will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
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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.
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.
7.8. Other Assessments
7.8.1. PainDETECT
The painDETECT questionnaire was developed with the aim of detecting neuropathic pain 
components in pain patients, especially in chronic low back pain patients.  The questionnaire 
was developed and validated in a prospective, multicenter study and subsequently applied to 
approximately 8000 low back pain subjects.28 It is a reliable screening tool with high 
sensitivity and predictive accuracy and can be used to determine the prevalence of 
neuropathic pain components in low back pain subjects.  The painDETECT questionnaire 
will be administered at Baseline.  Refer to Appendix 13 for the painDETECT questionnaire.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events (AEs) regardless of treatment group or suspected 
causal relationship to the investigational product(s) will be reported as described in the 
following sections.
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the adverse event 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 adverse event.  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.


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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:

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;


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
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;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event 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 adverse event by the investigator or sponsor.


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Medical device complaints may meet the SAE reporting requirement criteria (see the section 
on Medical Device 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 
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
any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

fetal distress, fetal death, or any congenital abnormality or birth defects.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see 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:

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 values 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 1x 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 
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In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/International normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen/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.
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 a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event 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);


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
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 adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical adverse event;

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 adverse event.
8.8. Severity Assessment
If required on the adverse event CRFs, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  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 event reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an AE; generally the facts (evidence) or arguments to suggest a causal 
relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (see the section on


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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; 
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (SAE) report form 
and an Exposure During Pregnancy (EDP) Supplemental Form, regardless of whether an 
SAE has occurred.  In addition, the investigator must submit information regarding 
environmental exposure to a Pfizer product in a pregnant woman (eg, a subject reports that 
she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) using 
the EDP Supplemental Form.  This must be done irrespective of whether an AE has occurred 
and within 24 hours of awareness of the exposure.  The information submitted should include 
the anticipated date of delivery (see below for information related to termination of 
pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EDP Supplemental Form.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).


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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.
8.10.1. Additional Postnatal 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 on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of adverse event noted earlier, and recorded on the appropriate 
adverse event CRF page.


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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.
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.


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8.14.3. Medical Device Complaint 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 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
The efficacy and safety population will be the ITT population, defined as all randomized 
subjects who received SC investigational product (either tanezumab or matching placebo).
9.1. Sample Size Determination
In terms of the study feasibility and the safety evaluation described below, the total sample 
size will be approximately 200 subjects (170-220 subjects, approximately 66 subjects [56-73
subjects] per treatment group). However, it is acceptable to randomize more than 220 
subjects from the safety perspective as described below because primary objective is to 
evaluate the long-term safety.
Japanese subjects are enrolled in two studies within the tanezumab CLBP program
(A4091059 and this study). In ongoing A4091059 study (randomization was finished in June 
2017), 129 Japanese subjects were randomized and appropriately 57 Japanese CLBP subjects 
are expected to be initially randomized to the tanezumab arm. Considering approximately 
133 (113-146) subjects are expected to be randomized to the tanezumab arm in this study, the 
safety data will be collected from approximately 190 (170-203) Japanese CLBP subjects 
treated with tanezumab.
The primary objective of this study is the evaluation of long term safety. The number of 
subjects who complete this study is estimated as described below. Both these protocols 


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require subjects to meet the efficacy response criteria (defined as at least a 30% reduction in 
weekly average LBPI score at week 16 relative to Baseline and at least a 15% reduction in 
weekly average LBPI score from Baseline at any week from week 1 to week 15) at week 16 
in order to continue in the study. The proportion of 30% responders at week 16 was 
approximately 60% in two OA phase 3 studies (A4091011, A4091014) and approximately 
42% in one CLBP phase 3 study (A4091012). On the other hand, the proportion of subejcts 
discontinuing after week 16 is assumed to be approximately 10% for OA and approximately 
20% for CLBP based on the results of discontinuation for reasons other than insufficient 
clinical response in these studies.
Therefore, the proportion of subjects expected to complete this study was calculated as 
approximately 54% (=100*0.6*0.9) based on the two OA studies and approximately 34% 
(=100*0.42*0.8) based on the CLBP study, and the proportion of completers of this study is 
estimated to be between 34% and 54%.  Table 6 shows the relationship between the 
proportion of completers and the number of subjects with one year exposure.
From Table 6, if the proportion of completers is at least 43% in the CLBP program, 
approaching 100 subjects are expected to be treated with tanezumab for a minimum of one 
year.
Table 6.
The relationship between the proportion of completer and number of 
subjects with one year exposure
Proportion of
completers
Tanezumab treated Japanese sample size
with 1 year of treatment exposure
CLBP program total
A4091063 only
54 %
91-109
61-78
50 %
85-101
56-73
45 %
76-91
50-65
43 %
73-87
48-62
40 %
68-81
45-58
34 %
57-69
38-49
(randomized 170 subjects in this study – randomized 220 subjects in this study)
As described below, when approximately 200 (170-220) Japanese subjects are enrolled in 
this study, the adverse events related to abnormal peripheral sensation and decreased 
sympathetic function are expected to occur in several Japanese subjects, so neurological 
safety can be evaluated with high probability in Japanese subjects.
Adverse events related to abnormal peripheral sensation1
The incidence of adverse events related to abnormal peripheral sensation was 8.6% in the 
tanezumab 5 mg group and 15.6% in 10 mg group of the phase II controlled study of 
                                                
1 Details are described in section 7.3.9.


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tanezumab conducted in CLBP subjects (A4091012). Also, the incidence was 15.6% in 10 
mg group of the phase II uncontrolled study (A4091039). Assuming that the true incidence 
rate of these events in the subjects enrolled in A4091059 and this study is nearly equal (10% 
in tanezumab treated subjects), when 170 subjects are enrolled in this study (approximately 
113 subjects will be treated with tanezumab), these adverse events are expected to occur in 7
to 15 subjects (6%-13%) in this study at a probability of ≥80%, and in 12 to 22 subjects (7%-
13%) in combined A4091059 and this study (approximately 170 subjects will be treated with 
tanezumab) at a probability of ≥80%.
Adverse events related to decreased sympathetic function 2
The incidence of adverse events related to decreased sympathetic function was 6.0% in the 
tanezumab 5 mg group and 5.1% in 10 mg group of the phase II controlled study of 
tanezumab conducted in CLBP subjects (A4091012). Also, the incidence was 4.1% in 10 mg 
group of the phase II uncontrolled study (A4091039). Assuming that the true incidence rate 
of these events in the subjects enrolled in A4091059 and this study is nearly equal (6% in 
tanezumab treated subjects), when 170 subjects are enrolled in this study, these adverse 
events are expected to occur in 4 to 10 subjects (4%-9%) in this study at a probability of 
≥80%, and in 6 to 14 subjects (4%-8%) in combined A4091059 and this study at a 
probability of ≥80%.
9.2. Analysis of Safety Endpoints

Adverse events, concomitant medications, laboratory safety tests, physical and 
neurological examinations, vital signs, electrocardiogram (ECG), and the anti-drug 
antibody test will be collected for each subject during the study according to the 
Schedule of Assessments.  Standard safety reporting tables will summarize and list the 
safety data.

Adverse events of interest and common adverse events will be summarized using Risk 
Differences between each tanezumab group and the celecoxib group, together with 95% 
confidence interval, using exact methods.

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 
                                                
2 Details are described in section 9.2.


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necessary, this list of preferred terms may be adjusted for updates made to the MedDRA 
dictionary versions used for reporting.

In addition to summaries of adverse events considered to represent adverse events of 
decreased sympathetic function noted above, adverse events of syncope, bradycardia, 
orthostatic hypotension, anhidrosis, or hypohidrosis are designated as adverse events of 
interest that will be reviewed by the unblinded E-DMC (See Section 9.6).

Incidence of orthostatic hypotension using postural changes in blood pressure, in 
addition to mean changes in postural blood pressure will be summarized.

The 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 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 will be summarized.  The 
change from Baseline to each study visit, and to Worst (largest) change from Baseline 
(over all post-Baseline visits) will be summarized.  

The neurological consultation data will be summarized all subjects, and for subjects with 
adverse events of abnormal peripheral sensation, which are described in the 
Neurological Examination Section (Section 7.3.9).  The “conclusion from the 
neurological examination” data will be summarized for each timepoint, and as well as a 
summary of the final assessment over all neurological examinations for each subject.

The incidence of subjects with any of the joint safety adjudication outcomes of rapidly 
progressive osteoarthritis (type-1 and type-2), subchondral insufficiency fracture (or 
SPONK), primary osteonecrosis, or pathological fracture 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 celecoxib treatment group. The risk ratio and risk difference with 95% Confidence 
intervals will be calculated for the comparisons of each tanezumab group versus the 
celecoxib group. 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.

The incidence of subjects with any of the joint safety adjudication outcomes of rapidly 
progressive osteoarthritis (type-2), subchondral insufficiency fracture (or SPONK), 
primary osteonecrosis, or pathological fracture will be analyzed as described above. 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.


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
A listing of the subjects who develop anti-tanezumab antibodies after treatment for each 
dose, and the proportion of subjects who develop anti-tanezumab will be summarized for 
each dose.

The PK profile will be examined for subjects with anti-tanezumab antibodies.

Individual subjects with positive ADA results will be evaluated for potential ADA 
impact on the individual’s efficacy and safety profile.
9.3. Analysis of Efficacy Endpoints
Efficacy endpoints regarding the continuos data will examine the change from Baseline to 
each timepoints (Week 2, 4, 8, 12 [LBPI score only], 16, 24, 32, 40, 48, 56 and 64) in LBPI 
score, RMDQ total score, Patient Global Assessment of Low back Pain and BPI-sf measures. 
The differences with 95% confidence intervals will be calculated for the comparisons of each 
tanezumab group versus the celecoxib group.  Detailes for the missing handling will be 
documented in the Statiltical Analysis Plan.
Subject response endpoints of improvement in the average LBPI score of ≥ 30, 50, 70 and 
90%, improvement in the Patient’s Global Assessment of Low Back Pain ≥2 points and the 
Chronic Low Back Pain Responder Index will be summarized to Weeks 16, 24, 40 and 56.  
The differences with 95% confidence intervals will be calculated for the comparisons of each 
tanezumab group versus the celecoxib group.  Detailes for the missing handling will be 
documented in the Statiltical Analysis Plan.  Cumulative average LBPI response at Week 16, 
24 and 56 using response definitions from a reduction of >0% to =100% (in steps of 10%) 
will be summarized.
A two-way table showing number and percentage of subjects will summarize the response 
for each dimension (item) for the EQ-5D-5L at Baseline versus Weeks 16 and 56.  These 
summary tables will be shown by treatment group.  In addition, the EQ-5D-5L overall health 
utility score will be summarized for each treatment and for each time point assessed.
Summaries of the change from Baseline to Week 16, 56 and 64 or Early Termination in the 
WPAI:LBP impairment scores will be shown by treatment group.
All data from TSQM and mPRTI will be summarized by visit. The HCRU data will be 
reported as outlined in the SAP.
The incidence of and time to withdrawal due to lack of efficacy will also be summarized for 
discontinuations up to Week 16 and 56.  Kaplan-Meier estimates of the time to 
discontinuation will be 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.


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The incidence and number of days of rescue medication use will be summarized during 
Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64, and the amount of rescue medication taken 
in a week summarized during Weeks 2, 4, 8, 12 and 16.
For the efficacy analysis, the observed data (no imputation for missing data) will be 
summarized.  Additional analyses may explore the sensitivity of the efficacy analysis results 
to missing data.  The details will be provided in the Statistical Analysis Plan.
Any efficacy data collected at an Early Termination visit will be excluded from summary and 
analyses of efficacy with the following exception: Any efficacy data collected at the Early 
Termination 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.
9.4. 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.
The following reporting of PK data will be done:

A listing of all 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.
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.
9.5. External Adjudication Committee
A blinded Adjudication Committee consisting of external experts in orthopedic surgery, 
rheumatology, orthopedic pathology, or radiology with expertise in patients with end stage 
osteoarthritis and osteonecrosis will be convened.  The Adjudication Committee will have 
written operating procedures and a Charter, including a specific description of the scope of 
their responsibilities.  In general, the Adjudication Committee will be asked to review all 
possible or probable joint-related safety events identified by the Central Reader, total joint 


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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 (see Section 7.4.5).
Prior to the Adjudication Committee’s review of a given event, the Committee will be 
provided with blinded, available source documentation of progress reports from the 
investigator, orthopedic consult reports, operative reports, radiology reports, pathology 
reports, X-ray images, MRI images, and pathology specimens for review. Copies of all 
relevant clinical information including the items listed above should be provided to Pfizer or 
its designee for review by the external Adjudication Committee. Copies of the information 
should include the study number, site number and subject number, but it should not include 
the subject’s name or initials.
The external Data Monitoring Committee (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.
The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision. Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of endpoint events and of safety data which are not 
endpoints, to regulatory authorities, as appropriate.
Pfizer Standard Operating Procedures regarding periodic safety reviews by the study team 
and the Tanezumab Risk Management Committee will be followed. This committee will be 
composed of members inside and outside the immediate study team who will review blinded 
safety data from individual studies as well as data pooled across the studies on an ongoing 


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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 or more subjects in any individual tanezumab treatment group than for 
placebo or active control-treated subjects, the protocol-based rule for dosing suspension will 
be triggered.
The pre-specified serious adverse events are:

Sudden cardiac death or cardiac death.

Acute renal failure.

Anaphylactic shock or severe anaphylactic reaction.

Neuropathic joint or neuropathic arthropathy (ie, Charcot joint).

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, anhidrosia, 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 or whether the study should be terminated completely.  This decision will 
be made by the Sponsor in consultation with the tanezumab E-DMC.
If the protocol-based stopping rule is triggered, the E-DMC will consider the implications of 
this action on a program-level basis and formulate a recommendation whether it is safe to 
continue dosing (for some or all treatment groups) in other ongoing tanezumab clinical 
studies.  Decisions regarding stopping treatment in other ongoing tanezumab clinical studies 
will be made by the Sponsor in consultation with the E-DMC.


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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 (5 mg or 10 mg) and distribution of adverse events across 
tanezumab dose arms.

Possible differences in the baseline demographics between study 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.
9.6.1.3. Joint Safety Events
If the blinded Adjudication Committee identifies adjudicated events of rapidly progressive 
osteoarthritis type 2, subchondral insufficiency fractures (or spontaneous osteonecrosis of the 
knee [SPONK]), primary osteonecrosis, or pathological fracture, occurring at a rate that 
could trigger the protocol-based stopping criteria, an urgent, ad hoc assessment of the events 
will be made by the E-DMC.
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 celecoxib treatment 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 


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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.
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.
CC
IC
CI
CCI


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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.
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)/Independent Ethics Committee (IEC)
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/IEC approvals should be 
forwarded to Pfizer.


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The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC 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, 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.
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 


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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
End of trial is defined as database lock.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product 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.


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


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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 CSA between Pfizer and the 
institution.  In this section entitled Publications by investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1
Bennett DLH, McMahon SB, Rattray M, et al.  Nerve growth factor and sensory nerve 
function.  In:Brain SD, Moore PK editors. Pain and Neurogenic Inflammation. Basel: 
Birkhäuser; 1999: 167-93.
2
Woolf CJ, Safieh-Garabedian B, Ma QP, et al.  Nerve growth factor contributes to the 
generation of inflammatory sensory hypersensitivity.  Neuroscience 1994; 62(2):327-31.
3
McMahon SB, Bennett DLH, Priestley JV, et al.  The biological effects of endogenous 
nerve growth factor on adult sensory neurons revealed by a trkA IgG fusion molecule.  
Nature Med 1995; 1(8):774-80.
4
Armour KL, Clark MR, Hadley AG, et al.  Recombinant human IgG molecules lacking 
Fcgamma receptor I binding and monocyte triggering activities.  Eur J Immunol 1999;
29(8):2613-24.
5
Armour KL, van de Winkel JG, Williamson LM, et al.  Differential binding to human 
FcgammaRIIa and FcgammaRIIb receptors by human IgG wild type and mutant 
antibodies.  Mol Immunol 2003; 40(9):585-93.
6
Borenstein D.  Chronic low back pain.  Musculoskeletal Medicine 1996; 22 (3);439-56.
7
Praemer A, Furnos S, Rice DP.  Musculoskeletal conditions in the United States.  
Rosemont: AAOS; 1992: 1-99.
8
Johannes C, Le TK, Zhou X, et al.  The prevalence of chronic pain in the United Stated 
adults: results of an internet-based survey.  Journal of Pain 2010; 11(11):1230-9.
9
Airakinsinen O, Brox JI, Hildebrandt, et al.  European guidelines for the management of 
chronic non specific low back pain.  Eur Spine J 2006; 15 (Suppl. 2):S192-300.
10
Fujii T, Matsudaira K.  Prevalence of low back pain and factors associated with chronic 
disabling pain in Japan.  Eur Spine J. Published online: 07 Aug 2012.
11
Deyo RA, Weinstein JN.  Low back pain.  N Engl J Med 2001; 344(5):363-70.
12
Pfizer Data on File A4091004 CSR approved 8 July 2009.
13
Pfizer Data on File A4091012 CSR approved 21 Dec 2011.
14
Pfizer Data on File A4091039 CSR approved 11 May 2012.
15
Pfizer Data on File A4091027 CSR approved 01 Feb 2012.
16
Pfizer Data on File A4091043 CSR approved 03 Feb 2011.


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17
Pfizer. TANEZUMAB ARTHRITIS ADVISORY COMMITTEE BRIEFING 
DOCUMENT. February 8, 2012; In 2012. URL: 
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm286556.htm?utm_source=fdaSe
rch&utm_medium=website&utm_term=March 12, 2012&utm_content=1. Access Date: 
April 4, 2012.
18
Pfizer Data on File A4091013 CSR approved 22 Mar 2010.
19
Pfizer Data on File A4091022 CSR approved 7 July 2010.
20
Spitzer RL, Kroenke K, Williams J. Validation and utility of a self-report version of 
PRIME-MD. JAMA 1999; 282(18):1737-44.
21
Roland M, Fairbank.  The Roland-Morris Questionnaire and the Oswestry Disability 
Questionnaire.  Spine. 2000; 25(4)3115-24.
22
Reilly MC, Zbrozek AS, Dukes, EM.  The validity and reproducibility of a work 
productivity and activity impairment instrument. PharmacoEconomics 1993; 4(5):353-
65.
23
Devlin NJ, Krabbe PF. The development of new research methods for the valuation of 
EQ-5D-5L. Eur J Health Econ 2013; 14 Suppl 1:S1-3.
24
Atkinson MJ, Kumar R, Cappellari JC, et al. Hierarchical Construct Validity of the 
Treatment Satisfaction Questionnaire for Medication (TSQM Version II) Among 
Outpatient Pharmacy Consumers. Value in Health 2005; 8 Suppl 1:S9-24.
25
Okkalides D, Fotakis M. Patient effective dose resulting from radiographic 
examinations. Br J Radiol. 1994; 67(798):564-72.
26
Huda W, Gkanatsios NA. Radiation dosimetry for extremity radiographs. Health Phys. 
1998; 75(5):492-9.
27
Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, and O’Brien PC. Variables 
influencing neuropathic endpoints: The Rochester Diabetic Neuropathy Study of 
Healthy Subjects. Neurology 1995; 45(6):1115-21.
28
Freynhagen R, BaronR, Gockel U, and Tolle TR.  painDETECT: a new screening 
questionnaire to identify neuropathic components in patients with back pain.  Curr Med 
Res Opin 2006; 22(10):1911-20.
29
Altman R, Asch E, Bloch D, et al. The American College of Rheumatology criteria for 
the classification and reporting of osteoarthritis of the knee. Arthritis Rheum 1986; 
29(8):1039-49.


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30
Dripps RD. New classification of physical status. Anesthesiol 1963; 24:111.


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Abbreviations
This is a list of abbreviations that may or may not be used in the protocol.  
Abbreviation
Term
ACR
American College of Rheumatology
ADA
Anti-drug antibody
AE
Adverse event
AEMPS
Agency on Medicinal Products and Medical 
Devices
ALT
Alanine aminotransferase
ASA
American Society of Anesthesiologists
AST
Aspartate aminotransferase
AUC
Area under the concentration -time curve
AUCinf
Area under the concentration -time curve 
from time zero to infinity
BID
Twice a day
BMI
Body mass index
BOCF
Baseline observation carried forward
BP
Blood pressure
BPI
Brief Pain Inventory
BUN
Blood urea nitrogen
CDS
Core data sheets
CI
Confidence interval
CLBP
Chronic low back pain
Cmax
Maximum observed concentration
COX-2
Cyclooxygenase 2
CPK
Creatine phosphokinase
CRF
Case report form
CRA
Clinical Research Associate
CSA
Clinical study agreement
CTS
Carpal tunnel syndrome
CYP
Cytochrome
DAI
Dosage and administration instructions
DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
CCI
CCI
CCI


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Abbreviation
Term
E-DMC
External Data Monitoring Committee
EDP
Exposure during pregnancy
EDTA
Edetic acid (ethylenediaminetetraacetic 
acid)
Emax
Maximum observed  pharmacodynamic
effect
EQ-5D-5L
EuroQol 5 Dimension
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United 
States)
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
Hb
Hemoglobin
HCRU
Health Care Resources Utilization
HDPE
High-density polyethylene
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiation 
Protection
ID
Identification
IND
Investigational New Drug application
INR
International Normalized Ratio
IgG
Immunoglobulin G
IgG2
Immunoglobulin G Type 2
IRB
Institutional review board
IPAP
Initial Pain Assessment Period
IRT
Interactive response technology
ITT
Intent to treat
IUD
Intrauterine device
IV
Intravenous 
IWRS
Interactive web response system
LBPI
Low Back Pain Intensity
LDH
Lactate dehydrogenase
LFT
Liver function test
CCI
CCI
CCI
CCI


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Abbreviation
Term
LOCF
Last observation carried forward
MHLW
Ministry of Health, Labour and Welfare
MHRA
United Kingdom’s Medicines and 
Healthcare products Regulatory Agency
mPRTI
Patient Reported Treatment Impact 
Assessment-Modified
MRI
Magnetic resonance imaging
mSv
Millisievert
N/A
Not applicable
NGF
Nerve growth factor
NGFI
Nerve growth factor inhibitor
NIH
National Institutes of Health
NIS
Neuropathy Impairment Score
NRS
Numeric rating scale
NSAID
Non-steroidal anti-inflammatory drug
NSC
Neuropathy Symptom Change 
Questionnaire
NYHA
New York Heart Association
OA
Osteoarthritis
OTC
Over-the-counter
PD
Pharmacodynamic
PEI
Paul Ehrlich Institute
PHQ-9
Patient Health Questionnaire-9
PFS
Pre-filled syringe
PGA
Patient Global Assessment
PK
Pharmacokinetic
PPK
Population pharmacokinetics
PT
Prothrombin time
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
CCI
CCI
CCI


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Abbreviation
Term
RA
Rheumatoid Arthritis
RMDQ
Roland-Morris Disability Questionnaire
RNA
Ribonucleic acid
RD
Risk difference
RR
Risk ratio
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Survey of Autonomic Symptoms
SC
Subcutaneous
SPONK
Spontaneous osteonecrosis of the knee
SRSD
Single reference safety document
Tmax
Time to first occurrence of Cmax
TENS
Transdermal electroneural stimulation
TNF-α
Tumor necrosis factor alpha
trkA
Tropomyosin receptor kinase A
TSQM
Treatment Satisfaction Questionnaire for 
Medication 
ULN
Upper limit of normal
US
United States
VAS
Visual analog scale
Vss
Steady-state volume of distribution
WOMAC
Western Ontario and McMaster University 
Osteoarthritis Index
WPAI:LBP
Work Productivity and Activity Impairment 
Questionnaire: Low Back Pain
CCI


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Appendix 1. Quebec Task Force Classification


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Appendix 2. American College of Rheumatology (ACR) Classification Criteria for 
Osteoarthritis
OA Hip Criteria29
Combined clinical (history, physical examination, laboratory) and radiographic criteria for 
osteoarthritis of the hip, traditional format.
1. Hip pain;
2. AND at least 2 of the 3 following features:

Erythrocyte sedimentation rate (ESR) less than 20 mm/hour;

Radiographic femoral or acetabular osteophytes;

Radiographic joint space narrowing (superior, axial, and/or medial).
ESR testing may be conducted at the local laboratory.
1986 OA Knee Criteria29
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.


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Appendix 3. 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;30 a sixth category was later added.  These 
are:
1.  A normal healthy patient
2.  A patient with mild systemic disease
3.  A patient with severe systemic disease
4.  A patient with severe systemic disease that is a constant threat to life
5.  A moribund patient who is not expected to survive without the operation
6.  A declared brain-dead patients whose organs are being removed for donor 
purposes.


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Appendix 4. Half-Lives of Prohibited Prior and Concomitant Medications
NSAIDs and Other Analgesics
Use of analgesics except acetaminophen/paracetamol is prohibited through Week 64 of the 
study beginning 48 hours prior to the start of the IPAP (the 5 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 324 mg/day is permitted 
throughout the study.
These lists are not all-inclusive and include unapproved medications in Japan. The 
Physician’s Desk Reference provides half-life information.
HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
Analgesic
Half-life (hours)
Minimum Washout Period
Aspirin >324 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
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
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
Mefenamic acid
2.0
2 days
Meperidine
3.7
2 days
Mexiletine
6.0-17.0
4 days


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HALF-LIVES OF NSAIDs AND OTHER ANALGESICS
Analgesic
Half-life (hours)
Minimum Washout Period
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


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Muscle Relaxants
Use of any muscle relaxants is prohibited during the Treatment Period up to Week 16
beginning 48 hours prior to the start of the IPAP (the 5 days prior to 
Randomization/Baseline) or at the period of time prior to the start of the IPAP that is 5 times 
the half-life of the particular muscle relaxant used, whichever is greater.
Subjects who have taken a stable dose of the particular muscle relaxants for at least 30 days 
prior to Screening will be allowed to continue their regimen.
These lists are not all-inclusive and include unapproved medications in Japan.  The 
Physician’s Desk Reference provides half-life information.
HALF-LIVES OF MUSCLE RELAXANTS
Muscle Relaxant
Half-life (hours)
Minimum Washout Period
Baclofen
3.0-6.8
2 days
Carisoprodol
8.0
2 days
Clorzoxazone
1.1
2 days
Cyclobenzaprine
18.0-33.0
7 days
Dantrolene
8.7
2 days
Diazepam
20.0-54.0
12 days
Flupirtine
7.0-10.0
3 days
Meprobamate
9.0-11.0
3 days
Methocarbamol
0.9-2.0
2 days
Metaxalone
2.4-9.2
2 days
Orphenadrine
13.2-20.1
5 days
Tetrazepam
13.0-45.0
10 days
Tizanidine
2.0
2 days


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Anti-depressants
All anti-depressants for the treatment of depression are prohibited beginning within 30 days 
prior to Screening.
Anti-depressants prescribed for the treatment of chronic low back pain are prohibited 
beginning 48 hours to start of the IPAP or at the period of time prior to the start of the IPAP
that is 5 times the half-life of the particular anti-depressants used, whichever is greater.
Subjects who are anticipated to need to initiate treatment with an antidepressant from 
Baseline to Week 16 should not be enrolled.
Subjects who have taken a stable dose of the anti depressants for the treatment of depression
and low back pain for at least 30 days prior to Screening will be allowed to continue their 
regimen.
These lists are not all-inclusive and include unapproved medications in Japan.  The 
Physician’s Desk Reference provides half-life information.
PROHIBITED ANTI-DEPRESSANTS
Tricyclic and Related 
Cyclic Antidepressants
Serotonin and Norepinephrine 
Reuptake Inhibitors
Amitriptyline
Venlafaxine
Amoxapine
Nefazodone
Clomipramine
Reboxetine
Desipramine
Atomoxetine
Doxepin
Duloxetine
Imipramine
Maprotiline
Reversible Inhibitors of Monoamine
Oxidase Type A (RIMAs)
Nortriptyline
Protriptyline
Brofaromine
Ttrimipramine
Moclobemide
Monoamine Oxidase Inhibitors (MAOIs)
Miscellaneous Antidepressants
Phenelzine
Bupropion
Selegiline
Mirtazapine
Tranylcypromine
St John’s Wort
Trazodone
Selective Serotonin Reuptake Inhibitors 
(SSRIs)
Citalopram
Escitalopram
Fluoxetine 
Fluvoxamine
Paroxetine
Sertraline


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Centrally Acting Agents 
Other centrally acting agents are allowed with limitations. The use of any
sedatives/hypnotics, anxiolytics, tranquilizers, or benzodiazepines are prohibited beginning
within 30 days prior to the Screening. Benzodiazepines prescribed as a muscle relaxant are 
prohibited and must be discontinued via washout.  In this case, refer to Muscle Relaxants.
Subjects who have taken a stable dose of the centrally acting agents for at least 30 days prior 
to Screening will be allowed to continue their regimen.
These lists are not all-inclusive and include unapproved medications in Japan.  The 
Physician’s Desk Reference provides half-life information.
Anxiolytics
Sedatives/Hypnotics
Benzodiazepines
Alprazolam
Amobarbital
Alprazolam
Buspirone
Butabarbital
Bromazepam
Clonazepam
Chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide
Clorazepate
Clonazepam
Diazepam
Diazepam
Clorazepate
Doxepin
Estazolam
Diazepam
Halazepam
Flurazepam
Estazolam
Hydroxyzine
Lorazepam
Flurazepam
Lorazepam
Mephobarbital
Halazepam
Meprobamate
Midazolam
Ketazolam
Oxazepam
Phenobarbital
Lorazepam
Trifluoperazine
Quazepam
Midazolam
Secobarbital
Oxazepam
Temazepam
Quazepam
Triazolam
Temazepam
Zolpidem
Triazolam


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Biologicals
Use of biologicals is prohibited within 3 months of the IPAP 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.
TNF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/intranasal live influenza vaccines [these vaccines are not
approved in Japan]) is prohibited within 3 months of IPAP and during the study. 
These lists are not all-inclusive.  The Physician’s Desk Reference provides half-life 
information.
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 5. 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.
Patient Health Questionnaire (Version 2.1.0)


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Appendix 6. Roland-Morris Disability Questionnaire (RMDQ)
Instructions:
When your back hurts, you may find it difficult to do some of the things you normally do.  
This list contains some sentences that people have used to describe themselves when they 
have back pain.  When you read them, you may find that some stand out because they 
describe you today.  As you read the list, think of yourself today.  When you read a sentence 
that describes you today, put a check in the yes box.  If the sentence does not describe you, 
then leave the space blank and go on to the next one.  Remember, only check the box if you 
are sure it describes you today.
Questionnaire:
YES
1.
I stay at home most of the time because of my back.
□
2.
I change position frequently to try and get my back comfortable.
□
3.
I walk more slowly than usual because of my back.
□
4.
Because of my back, I am not doing any of the jobs that I usually do around the 
house.
□
5.
Because of my back, I use a handrail to get upstairs.
□
6.
Because of my back, I lie down to rest more often.
□
7.
Because of my back, I have to hold on to something to get out of an easy chair.
□
8.
Because of my back, I try to get other people to do things for me.
□
9.
I get dressed more slowly than usual because of my back.
□
10.
I only stand for short periods of time because of my back.
□
11.
Because of my back, I try not to bend or kneel down.
□
12.
I find it difficult to get out of a chair because of my back.
□
13.
My back is painful almost all the time.
□
14.
I find it difficult to turn over in bed because of my back.
□
15.
My appetite is not very good because of my back pain.
□
16.
I have trouble putting on my socks (or stockings) because of pain in my back.
□
17.
I only walk short distances because of my back.
□
18.
I sleep less well because of my back.
□
19.
Because of my back pain, I get dressed with help from someone else.
□
20.
I sit down for most of the day because of my back.
□
21.
I avoid heavy jobs around the house because of my back.
□
22.
Because of my back pain, I am more irritable and bad tempered with people than 
usual.
□
23.
Because of my back, I go upstairs more slowly than usual.
□
24.
I stay in bed most of the time because of my back.
□


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Appendix 7. Neuropathy Impairment Score (NIS) Sample


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Appendix 8. Patient’s Global Assessment of Low Back Pain 
The patient’s response using the 5-point Likert scale of 1 being the best (very good) and a 
score of 5 being the worst (very poor) will be recorded in the CRF.
The subjects will answer the following question: 
“Considering all the ways your low back pain affects you, how are you doing today?”
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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CCI


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CCI


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Appendix 10. Work Productivity and Activity Impairment Questionnaire: Low Back 
Pain (WPAI:LBP)
The following questions ask about the effect of your LOW BACK PAIN on your ability to 
work and perform regular activities.  Please fill in the blanks or circle a number, as 
indicated.
1. Are you currently employed (working for pay)? _____ NO ___ YES
If NO, check “NO” and skip to question 6.
The next questions are about the past seven days, not including today.
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your LOW BACK PAIN?  Include hours you missed on sick days, times you 
went in late, left early, etc., because of your LOW BACK PAIN.  Do not include time you 
missed to participate in this study.
_____HOURS
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?
_____HOURS
4. During the past seven days, how many hours did you actually work?
_____HOURS  (If “0”, skip to question 6).
5. During the past seven days, how much did your LOW BACK PAIN affect your 
productivity while you were working?  
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual.  If LOW BACK PAIN affected your work only a little, choose a low number.  Choose a 
high number if LOW BACK PAIN affected your work a great deal. 
Consider only how much LOW BACK PAIN affected 
productivity while you were working.
LOW BACK PAIN 
had no effect on my 
work
LOW BACK 
PAIN completely 
prevented me 
from working
0
1
2
3
4
5
6
7
8
9
10
CROSS A NUMBER
6. During the past seven days, how much did your LOW BACK PAIN affect your ability to 
do your regular daily activities, other than work at a job?  


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By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc.  Think about times you were limited in the 
amount or kind of activities you could do and times you accomplished less than you would 
like.  If LOW BACK PAIN affected your activities only a little, choose a low number.  Choose 
a high number if LOW BACK PAIN affected your activities a great deal. 
Consider only how much LOW BACK PAIN affected your ability
to do your regular daily activities, other than work at a job.
LOW BACK PAIN 
had no effect on my 
daily activities
LOW BACK 
PAIN completely 
prevented me 
from doing my 
daily activities
0
1
2
3
4
5
6
7
8
9
10
CROSS A NUMBER
WPAI:LBP V2.0 (US English) 


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Appendix 11. Subject Daily/Weekly Assessments of Low Back Pain
Daily and Weekly Assessments
Subjects will use IRT to complete questionnaires recording subject average daily low back 
pain intensity (LBPI) scores with a 24-hour recall.  The LBPI score will be captured once 
daily during the Initial Pain Assessment Period, and weekly from Baseline through to Week 
64 or Early Termination Visit 2, in the evening if possible.
Low Back Pain Intensity (from the beginning of the Initial Pain Assessment Period to 
Week 64 or Early Termination Visit 2):
Low Back Pain Intensity
“Select the number that best describes average low back pain in the past 24 hours.”
0
1
2
3
4
5
6
7
8
9
10
No 
Pain
Worst 
Possible 
Pain
If an IRT is used, additional instructional language may need to be added to the question 
such as “Using a scale from 0 to 10, with 0 meaning no pain and 10 meaning worst possible 
pain; please enter the number that best describes your average low back pain in the past 
24 hours.”


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Appendix 12. Euro Quality of Life Health State Profile (EQ-5D-5L)
Sample


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Sample


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Appendix 13. Pain DETECT Questionnaire


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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)


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Appendix 16. Patient reported treatment impact assessment-modified (mPRTI)
PATIENT GLOBAL PREFERENCE ASSESSMENT
Before enrolling in this clinical trial, what treatment were you receiving for your low back pain?
Please Check (X) ONE only:

(1) Injectable prescription medicines

(2) Prescription medicines taken by mouth 

(3) Surgery

(4) Prescription medicines and surgery

(5) No treatment
Overall, do you prefer the drug that you received in this study to the treatment you received before this clinical 
trial?
Please Check (X) ONE only:

(1) Yes, I definitely prefer the drug that I am receiving now

(2) I have a slight preference for the drug that I am receiving now

(3) I have no preference either way

(4) I have a slight preference for my previous treatment

(5) No, I definitely prefer my previous treatment
PATIENT WILLINGNESS TO USE DRUG AGAIN ASSESSMENT
In the future, would you be willing to use the same drug that you have received in this study for your low back 
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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Appendix 17. Treatment Satisfaction Questionnaire for Medication v.II


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Appendix 18. Substudy- Follow-up for Subjects Undergoing Total Joint Replacement of 
The Hip, Knee or Shoulder
SUBSTUDY SUMMARY
Measures to better characterize the joint safety issue have been developed and agreed with 
FDA.  The post-arthroplasty data collected within this substudy, when aggregated with 
similar data from other tanezumab clinical studies, fulfills one component of the agreed risk 
characterization measures and is an attempt to address the potential concern that subjects 
treated with tanezumab have a different post-surgical outcome than those not treated with 
tanezumab.  The total joint replacement data from completed tanezumab studies does not 
suggest a different post-surgical outcome in tanezumab treated subjects however those data 
were gathered retrospectively.  The types of endpoints to be assessed in this prospective 
substudy and the duration of this substudy have been agreed to with the FDA.  Every effort 
will be made to enroll all A4091063 subjects who undergo a qualifying total joint 
replacement into this substudy however it is acknowledged that to a certain extent the 
population enrolled in this substudy will be 'self-selected' and thus there maybe subjects with 
a qualifying total joint replacement who choose not to enter the substudy.
This substudy is a long-term observational study of subjects from tanezumab Study 
A4091063 (regardless of treatment group) who undergo a total knee, hip or shoulder 
replacement during participation in the study (treatment period or safety follow-up period).  
If while the subject is participating in this substudy, the subject undergoes an additional total 
joint replacement surgery or the site becomes aware that an additional total joint replacement 
surgery has been scheduled for the subject, the subject will be requested to provide 
information on the additional total joint replacement surgery as well.  Finally, any subject 
with a qualifying total joint replacement after the last subject completes the treatment period 
in study A4091063 may be followed in Study A4091064.
This substudy is designed with a total duration of subject follow-up of 24 weeks after the 
total joint replacement surgery.  There will be two methods of data collection utilized in this 
substudy: interview by site staff via the telephone and interactive web response system 
(IWRS) accessed by desktop, laptop or tablet computer (or paper if the subject has no access 
to the internet via a desktop, laptop or tablet computer).  Following the surgery, the subject 
will be contacted monthly via telephone by study site personnel to ascertain whether the 
subject has experienced any adverse events and to record any concomitant analgesic 
medications the subject is taking as well as the reason for the medication use.  An assessment 
of the subject’s overall satisfaction with his/her total joint replacement (IWRS), average pain 
in the replaced joint (IWRS), the subject’s level of function and activity in the replaced joint 
(IWRS) and physical rehabilitation activities (telephone interview) will be made at Weeks 4, 
12 and 24.  At Weeks 12 and 24, subjects will be queried during the telephone interview as to 
whether any additional or corrective procedures related to the total joint replacement are 
planned.
All events of total knee, hip or shoulder replacement will be reviewed by the Joint Safety 
Adjudication Committee (Adjudication Committee) established for the tanezumab clinical 


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program.  This Committee will adjudicate in an independent and blinded fashion if the event 
is primary osteonecrosis, worsening OA (further sub-divided into rapidly progressive OA 
(RPOA) type 1 or type 2, normal progression of OA or not enough information to distinguish 
between RPOA and normal progression of OA), subchondral insufficiency fracture, 
pathologic fracture, other (with diagnosis specified) or not enough information to specify a 
diagnosis.  Prior to the Adjudication Committee’s review of a given event, Committee 
members will be provided with blinded, available source documentation of progress reports 
from the investigator, orthopedic consult reports, operative reports, the pathology report from 
the central laboratory, radiology reports, Dual Energy X-ray Absorptiometry (DXA) reports, 
x-ray images and MRI for review.  In addition, blinded summaries of the following data from 
Study A4091063 will be provided to the Committee members for review for each event 
undergoing adjudication: demographic and baseline characteristics, medical history and 
concomitant medications, study medication administration, non-drug treatments, subject 
disposition, efficacy data, adverse event information, neurological safety data and a serious 
adverse event narrative (if applicable).
Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons, and 
clinical research associates (CRAs), staff directly involved with this substudy at Pfizer and its 
designees will be blinded to treatment assignment in Study A4091063.
The number of subjects who will enroll in this substudy is unknown but is estimated to be 
less than 25 subjects.  Also unknown is the distribution of subjects across treatment groups 
(ie, the treatment given in Study A4091063).  Therefore, it is predicted that there will be 
insufficient statistical power to perform statistical inferential analyses.  All analyses will be 
descriptive in nature.  The data collected in this substudy will be combined with similar data 
collected in other tanezumab studies for further analysis.  These aggregate analyses will be 
reported separately.


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SUBSTUDY SCHEDULE OF ACTIVITIES
The Schedule of Activities table (Table 7) provides an overview of the substudy visits and procedures.  Refer to the Procedures and 
Assessments sections of this appendix for detailed information on each procedure and assessment.
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.
Table 7.
SUBSTUDY SCHEDULE OF ACTIVITIES
Substudy Activities
Post-Surgery
Baselinea
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 
24/ET
Last visit in the 
A4091063 studyb
or when notified 
of TJR surgery 
Day of 
Surgery 
(+10 days)
Day 29
(5 days)
Day 57
(5 days)
Day 85
(5 days)
Day 113
(5 days)
Days 141
(5 days)
Day 169
(5 days)
Pre-surgery Activities
Informed Consent
X
Inclusion Criteria Review 
X
Record ongoing adverse events and 
concomitant analgesic medication 
X
Train subject in the use of the interactive 
web response system (IWRS) if applicablec
X
Assessment of Pain in Joint to be Replaced 
(11-point NRS)d
X
Assessment of Functional Status
(WOMAC [total hip or knee replacement 
candidates] or SPADI [total shoulder 
replacement candidates ])d
X


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Substudy Activities
Post-Surgery
Baselinea
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 
24/ET
Last visit in the 
A4091063 studyb
or when notified 
of TJR surgery 
Day of 
Surgery 
(+10 days)
Day 29
(5 days)
Day 57
(5 days)
Day 85
(5 days)
Day 113
(5 days)
Days 141
(5 days)
Day 169
(5 days)
Provide surgery-related documents 
(Surgeon’s Assessment of Procedural 
Difficulty and Pathology Specimen 
Collection/Shipment Guidelines to Surgeon
X
Surgery - related Activities
Obtain Surgeon’s Assessment of 
Procedural Difficulty
X
Confirm that pathologic specimens were 
shipped according to instructions 
X
Ensure required source documents are 
provided to Endpoint Management Team
X
Post-Surgery Subject Follow-up Activities
Telephone-based Assessments
Adverse events
X
X
X
X
X
X
Concomitant analgesic medication use
X
X
X
X
X
X
Participation in physical rehabilitation 
activities related to the replaced joint
X
X
X
Additional or corrective procedures related 
to the replaced joint
X
X
Remind subjects not utilizing the IWRS to 
return paper-based assessments to the site 
within 5 days
X
X
X
Remind female subjects of contraceptive 
requirements (if applicable)e
X
X
X
X


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Substudy Activities
Post-Surgery
Baselinea
Day 1
Week 4
Week 8
Week 12
Week 16
Week 20
Week 
24/ET
Last visit in the 
A4091063 studyb
or when notified 
of TJR surgery 
Day of 
Surgery 
(+10 days)
Day 29
(5 days)
Day 57
(5 days)
Day 85
(5 days)
Day 113
(5 days)
Days 141
(5 days)
Day 169
(5 days)
Web-based Assessmentsf
Subject’s overall satisfaction with joint 
replacement surgery (SAPS)
X
X
X
Pain in replaced joint (11-point NRS)
X
X
X
Functional status (WOMAC [total hip and 
knee replacement subjects] or SPADI [total 
shoulder replacement subjects]g
X
X
X
a.
Baseline activities must be conducted at the site.
b.
Last visit in StudyA4091063 can be either the end of study visit or early termination visit.
c.
Training in the use of the ePRO system (IWRS) is appropriate for subjects who will have access to the internet via a desktop, laptop or tablet computer for the duration of the 
substudy.
d.
To be collected via the Interactive Web Response System (IWRS).  If the subject will not have access to the IWRS via a desktop, laptop or tablet computer for the duration of 
the substudy, paper versions of the assessment should be completed by the subject with subsequent entry into the IWRS by site staff.  Note:  the WOMAC and SPADI should 
be completed in their entirety.
e.
Female subjects of child-bearing potential should be reminded of contraception requirements if less than 112 days (16 weeks) have elapsed since the last dose of 
subcutaneous study medication in Study A4091063.
f.
If the subject does not have access to the IWRS via a desktop, laptop or tablet computer for the duration of the substudy, paper versions of the assessments should be 
completed by the subject.  Completed paper assessments should be returned to the clinical site within 5 days of assessment completion.  Site staff will enter the subject 
reported outcomes into the IWRS upon receipt of the completed assessment.
g.
The WOMAC and SPADI should be completed in their entirety.


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101. SUBSTUDY INTRODUCTION
Measures to better characterize the joint safety issue identified in 2010 have been developed 
and agreed with FDA.  The post-arthroplasty data collected within this substudy, when 
aggregated with similar data from other tanezumab clinical studies, fulfills one component of 
the agreed risk characterization measures and is an attempt to address the potential concern 
that subjects treated with tanezumab have a different post-surgical outcome than those not 
treated with tanezumab.  The total joint replacement data from completed tanezumab studies 
does not suggest a different post-surgical outcome in tanezumab treated subjects however 
those data were gathered retrospectively from previous studies.  The types of endpoints to be 
assessed in this prospective substudy and the duration of the substudy have been agreed to 
with the FDA.  Every effort will be made to enroll all Study A4091063 subjects who undergo 
a qualifying total joint replacement into this substudy however it is acknowledged that to a 
certain extent the population enrolled in this substudy will be 'self-selected' and thus there 
maybe subjects with a qualifying total joint replacement who choose not to enter the 
substudy.
101.1. Rationale for Selected Patient Reported Outcomes
Subject-based measures of health-related quality of life have increasingly been used by the 
orthopedic research community as a means to define a successful intervention.a  Subject 
reported outcomes typically assessed post-arthroplasty include overall satisfaction with the 
joint replacement, pain and function. 
The Self-Administered Patient Satisfaction Scale (SAPS) will be utilized to assess subject 
satisfaction with the joint replacement in this substudy.  The SAPS is a multidimensional, 
disease specific measure that evaluates subject satisfaction with the outcome of hip or knee 
arthroplasty and was designed to be used in conjunction with other clinical measures and 
functional health status instruments to evaluate the results of hip and knee arthroplasty.  The 
validity and reliability of the scale has been demonstrated.b The scale consists of four items 
focusing on satisfaction with the extent of pain relief, improvement in ability to perform 
home or yard work, ability to perform recreational activities and overall satisfaction with 
joint replacement.
Average pain in the joint to be replaced (pre-surgery) and the replaced joint (post-surgery) 
will be assessed with an 11-point Numeric Rating Scale (NRS) ranging from zero (no pain) 
to 10 (worst possible pain).  The validity and reliability of the scale has been demonstrated.c
The functional measures chosen for this substudy were those which have been shown to be 
valid, reliable and sensitive and in addition were region-specific and easy to administer.  
Subjects undergoing total knee or hip replacement will be asked to complete the Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with the knee or hip that 
was replaced serving as the “index joint”.  Subjects undergoing total shoulder replacement 
will be asked to complete the Shoulder Pain and Disability Index (SPADI).


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The WOMAC is a self-administered condition-specific instrument which assesses pain, 
disability and joint stiffness in knee and hip osteoarthritis.  It is a valid, reliable and 
responsive measure of outcome in subjects with arthritis and has been used extensively.d,e,f
The SPADI is a self-administered questionnaire that was developed to measure the pain and 
disability associated with shoulder pathology in people with shoulder pain of 
musculoskeletal, neurogenic or undetermined origin.  The psychometric properties of the 
SPADI have been shown to be acceptable for research use and the SPADI has been 
recommended to assess outcomes in subjects undergoing shoulder arthroplasty.g,h The 
instrument consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use.
101.2. Interactive Web Response System
To avoid a social desirability bias in the subject reported outcomes, an Interactive Web 
Response System (IWRS) will be utilized in this substudy.  Contingency plans will be in 
place to address system and/or connectivity issues with the IWRS. 
However, eligibility for this substudy does not require access to the internet via a desktop, 
laptop or tablet computer so, for those subjects without access to the internet via a desktop, 
laptop or tablet computer, paper versions of the assessments will be utilized.  Though not 
optimal, the use of two methods to collect subject reported outcomes will maximize the 
ability to capture information from all subjects who undergo a total knee, hip, or shoulder 
replacement surgery while participating in tanezumab StudyA4091063.  Additional 
considerations which mitigate the concerns about using two methods to collect subject 
reported outcomes in the same substudy include that this substudy has not been formally 
powered and all analyses will be descriptive rather than inferential.
102. SUBSTUDY STUDY OBJECTIVE AND ENDPOINTS
102.1. Objective

To describe the post-operative outcome of subjects who underwent a total knee, hip, or 
shoulder replacement while participating in tanezumab Study A4091063 (treatment 
period or safety follow-up period).
102.2. Endpoints
The following endpoints will be assessed in this substudy:

Surgeon’s Assessment of Procedural Difficulty: number and percentage of surgeries 
assessed as uneventful, minor complications or major complications.

Subjects’s overall satisfaction with surgery as assessed by the Self-Administered Patient 
Satisfaction (SAPS) Scale: number and percentage of subjects satisfied vs unsatisfied 
with their total joint replacement at Week 24.


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


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Any subject who expresses a desire to leave this substudy before 24 weeks of follow-up have 
been completed should be asked to complete all assessments scheduled for Week 24.
All events of total knee, hip or shoulder joint replacement will be reviewed by the Joint 
Safety Adjudication Committee (Adjudication Committee) established for the tanezumab 
clinical program.  This Committee will adjudicate in an independent and blinded fashion if 
the event is primary osteonecrosis, worsening OA (further sub-divided into rapidly 
progressive OA (RPOA) type 1 or type 2, normal progression of OA or not enough 
information to distinguish between RPOA and normal progression of OA), subchondral 
insufficiency fracture, pathologic fracture, other (with diagnosis specified) or not enough 
information to specify a diagnosis.  Prior to the Adjudication Committee’s review of a given 
event, Committee members will be provided with blinded, available source documentation of 
progress reports from the investigator, orthopedic consult reports, operative reports, the 
pathology report from the central laboratory, radiology reports, DXA reports, x-ray images 
and MRI images for review.  Sites will be requested to submit required source documentation 
to the Endpoint Management Team as soon as possible, and ideally within 29 5 days, after 
the total joint replacement surgery (ie, by the time the Week 4 visit occurs provided the 
source documentation has been completed).  In addition, blinded summaries of the following 
data from Study A4091063 will be provided to the Committee members for review for each 
event undergoing adjudication: demographic and baseline characteristics, medical history and 
concomitant medications, study medication administration, non-drug treatments, subject 
disposition, efficacy data, adverse event information, neurological safety data and a serious 
adverse event narrative (if applicable). 
The Adjudication Committee, in coordination with the Data Monitoring Committee (DMC), 
is responsible for ongoing analysis of these outcomes and for informing the sponsor of 
recommendations made.
Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons, clinical 
research associates (CRAs) staff directly involved with this substudy at Pfizer and its 
designees will be blinded to treatment assignment in Study A4091063.  The data collected in 
this substudy will be combined with similar data collected in other tanezumab studies for 
analysis.  Data analyses will be reported separately.
104. SUBSTUDY SUBJECT SELECTION
This substudy can fulfill its objectives only if appropriate subjects are enrolled.  The 
following eligibility criteria are designed to select subjects for whom the substudy is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this substudy is suitable for a particular subject.
104.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team (ie, the investigator or a sub-investigator) before subjects are 
included in this substudy.


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Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
substudy:
1. Evidence of a personally signed and dated informed consent document indicating the 
subject (or a legal representative) has been informed of all pertinent aspects of the 
substudy. 
2. Subject has been randomized and treated with SC study medication in tanezumab Study 
A4091063 and has completed the study or has been withdrawn from the study. 
3. Actual or planned total knee, hip or shoulder replacement surgery during tanezumab 
Study A4091063.  Subjects undergoing total knee, hip or shoulder replacement surgery 
after the last subject completes the treatment period in Study A4091063 may be enrolled 
in Study A4091064 in order to complete the total joint replacement follow-up. 
Note: additional procedures in a subject undergoing total joint replacement surgery 
(eg, revision of a previously replaced joint in addition to a new total joint replacement) will 
be allowed, but subjects undergoing solely sub-total arthroplastic procedures 
(eg, hemi-arthroplasty) will not be eligible.
4. Subject is willing and able to comply with scheduled visits and other substudy 
procedures.
104.2. Life Style Guidelines 
All female subjects who, in the opinion of the investigator, are biologically capable of having 
children, and are sexually active, who withdraw from Study A4091063 less than 16 weeks 
after the last dose of subcutaneous study medication must agree to use two (2) methods of 
highly effective contraception until 112 days (16 weeks) after the last dose of 
subcutaneous study medication.  Refer to Section 4.4 of the A4091063 protocol for 
guidance on appropriate methods of contraception. 
There are no contraception requirements for sexually active female subjects of childbearing 
potential who withdraw from Study A4091063 more than 16 weeks after the last dose of 
subcutaneous study medication.
104.3. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for this 
substudy is documented in the study contact list located in the Study Manual (see also 
Section 4.5 of the A4091063 protocol).
105. SUBSTUDY STUDY TREATMENTS
This is an observational study of subjects who were randomized and treated in tanezumab 
Study A4091063 and who subsequently underwent a total knee, hip or shoulder replacement 
during the treatment or safety follow-up period.  There are no study medications in this 
observational study. 


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Subjects, investigators, study coordinators, clinical site staff, orthopedic surgeons and clinical 
research associates (CRAs) and IWstaff directly involved with this substudy at Pfizer and its 
designees will be blinded to treatment assignment in Study A4091063.
105.1. Concomitant Medication(s)
No medications are specifically prohibited in this observational substudy. 
Subjects who enter into this substudy <16 weeks after their last dose of subcutaneous study 
medication in Study A4091063 will be advised to avoid chronic non-steroidal 
anti-inflammatory drug (NSAID) use, until at least 16 weeks has elapsed, if possible.
Subjects will be instructed to keep a record of concomitant analgesic medication usage 
(including dose, dosing regimen and reason for use).  This information will be recorded on 
the appropriate concomitant medication case report form (CRF) during the monthly 
telephone interviews.
106. SUBSTUDY STUDY PROCEDURES
The site monitor should be consulted in the event that site layout, logistics, or equipment 
require adjustment to the ordering of study procedures or resolution of technical difficulties 
to enable performance of this substudy.  Such changes will be implemented administratively 
and documented in the appropriate venue (eg, site trial documentation and/or clinical study 
report). 
Study visit windows are +10 days for activities related to the total joint replacement surgery 
and 5 days for activities performed on Weeks 4, 8, 12, 16, 20 and 24.  Site staff should 
make every effort to contact the subject within the defined visit window for Weeks 4, 8, 12, 
16, 20 and 24 however, data obtained outside of the visit window while a deviation, should 
still be recorded.  In the event that the activities related to a visit are performed within the 
extremes of the visit windows, following study visits and associated activities should be 
scheduled with reference to the total joint replacement surgery date.  Subject scheduling 
issues should be brought to the attention of the study monitor for resolution. 
The investigator must make sure that delegations of responsibility to site staff for 
administering the IWRS or entering data into the IWRS are specifically documented using 
the appropriate forms and are based on documented evidence of adequate training in 
administration and use of the IWRS.  The investigator (or other site staff specifically 
delegated by the investigator) is responsible for regular monitoring of the compliance of the 
subjects with the required data entry by means of reports in the IWRS.  The IWRS will also 
be programmed to notify designated site staff when data has not been recorded within the 
requested timeframe.  Regardless of how the investigator delegates responsibility for 
administering the IWRS or entering data into the IWRS, the investigator remains responsible 
for providing adequate supervision and oversight of the investigator’s colleagues, employees 
and any third parties as per FDA regulations and guidelines and Good Clinical Practice.


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106.1. Baseline Visit
Baseline information for this substudy should be obtained as close as possible to, and prior 
to, the total joint replacement surgery.  The Baseline Visit may coincide with the last visit in 
Study A4091063 (End of Study or Early Termination Visit) or occur when the site is notified 
of a planned total joint replacement surgery.  Baseline Visit activities must be conducted at 
the clinical site. 
Subjects should be queried about their access to the internet via a desktop, laptop or tablet 
computer so as to determine the appropriate format for the subject reported outcomes of pain 
in the joint to be (or post-surgery, that has been) replaced, functional status and, post-surgery, 
satisfaction with surgery. 
Subjects with access to the internet via a desktop, laptop or tablet computer should be trained 
in the use of the IWRS and in their responsibilities for data entry in compliance with this 
substudy protocol.  IWRS technical support (Help Desk) will be available to the subject for 
the duration of the study.  Beginning with the Baseline Visit, subjects with access to the 
internet via a desktop, laptop or tablet computer should complete the aforementioned 
assessments via the IWRS.  In the event of internet connectivity issues at the Baseline Visit, 
paper versions of the assessments should be completed.
Only subjects without access to the internet via a desktop, laptop or tablet computer during 
this substudy should complete the aforementioned assessments on paper for the duration of 
the substudy.  Simple preference for the use of paper is not sufficient to allow its use by the 
subject who has access to the internet via a desktop, laptop or tablet computer during this 
substudy.
Except in unusual circumstances, subjects should not switch between paper-based and 
web-based completion of the subject reported outcome measures. 
Thorough instruction should be provided for completion of self-administered scales (subject 
reported outcomes) however, no coaching or other interpretative assistance should be given 
to the subject during the completion of the questionnaires. 
Telephone contact information should also be confirmed at the Baseline Visit.
106.1.1. Activities at the Baseline Visit

Informed consent.

Review of inclusion criteria.

Record ongoing adverse events and concomitant analgesic medications.

Assessment of pain in the joint to be replaced (11-point NRS).


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
Assessment of functional status in the joint to be replaced (WOMAC for subjects 
undergoing total knee or hip replacement or SPADI for subjects undergoing total 
shoulder replacement).  NOTE: the WOMAC and SPADI should be completed in their 
entirety.

Subjects without access to the internet via a desktop, laptop or tablet computer should be 
provided with paper copies of the subject reported outcomes assessments.  Subjects 
should be instructed on the timing of assessments and the need to return the assessments 
to the site as soon as possible, but no later than 5 days, after completion of the 
assessment.  Site staff will enter the subject reported outcomes into the IWRS upon 
receipt of the completed assessment.

Study site staff must contact the subject’s orthopedic surgeon to discuss the completion 
of the required forms and specimen collection and handling.  The surgeon will be 
provided with the surgery related documents (Surgeon’s Assessment of Procedural 
Difficulty and instructions for the shipment of pathology specimens). 

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous study 
medication in Study A4091063, female subjects of child-bearing potential should be 
reminded of contraceptive requirements.
106.2. Day of Surgery (+10 days)
During this interval, sites should ensure receipt of a completed Surgeon’s Assessment of 
Procedural Difficulty and confirm that pathology specimens were shipped according to 
instructions.  Required source document collection (eg, operative report and discharge 
summary) should begin in this interval.
Sites will be requested to submit required source documentation to the Endpoint 
Management Team as soon as possible, and ideally within 29 5 days, after the total joint 
replacement surgery (ie, by the time the Week 4 visit occurs provided the source 
documentation has been completed).
106.3. Week 4 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).

Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.


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During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or SPADI 
for subjects with a total shoulder replacement); NOTE: the WOMAC and SPADI should 
be completed in their entirety.

Overall satisfaction with joint replacement surgery measured by the Self-Administered 
Patient Satisfaction Scale (SAPS).
At the conclusion of the telephone call, site staff should:

Remind subjects not utilizing the IWRS to return paper-based assessments to the site as 
soon as possible, but no later than 5 days, after completion of the assessment.

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous study 
medication in Study A4091063, remind female subjects of child-bearing potential of 
contraceptive requirements.

Confirm the approximate timing of the next telephone call.
106.4. Week 8 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous study 
medication in Study A4091063, remind female subjects of child-bearing potential of 
contraceptive requirements.

Confirm the approximate timing of the next telephone call.
106.5. Week 12 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).


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
Query about physical rehabilitation activities subsequent to the total joint replacement 
surgery.

Query for additional or corrective procedures related to the total joint replacement 
surgery.
During the telephone call, site staff should instruct the subject to complete the following 
assessments either via the IWRS or via paper, as established at the Baseline Visit:

Pain in Replaced Joint (11-point NRS).

Functional status (WOMAC for subjects with a total knee or hip replacement or SPADI 
for subjects with a total shoulder replacement); NOTE: the WOMAC and SPADI should 
be completed in their entirety.

Overall satisfaction with joint replacement surgery measured by the SAPS.
At the conclusion of the telephone call, site staff should:

Remind subjects not utilizing the IWRS to return paper-based assessments to the site as 
soon as possible, but no later than 5 days, after completion of the assessment.

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous study 
medication in Study A4091063, remind female subjects of child-bearing potential of 
contraceptive requirements.

Confirm the approximate timing of the next telephone call.
106.6. Week 16 (5 days)
Site staff should contact the subject via telephone to:

Query for adverse events.

Query for concomitant analgesic medication use (record dose, dosing regimen and 
reason for use).
At the conclusion of the telephone call, site staff should:

If less than 112 days (16 weeks) have elapsed since the last dose of subcutaneous study 
medication in Study A4091063, remind female subjects of child-bearing potential of 
contraceptive requirements.

Confirm the approximate timing of the next telephone call.


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


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


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4. Uneventful; or 
5. Minor complications; or
6. Major complications
If the category of minor or major complications is chosen, the surgeon will be requested to
specify the complication(s).
107.2. Pathology Specimens
Surgeons will be requested to ship pathology specimens from the total joint replacement 
surgery to a central laboratory for analysis.  Detailed instructions for the shipping of 
pathology specimens will be provided.  Identification of specimens of adequate quality, 
preparation and histopathologic examination of the specimens will be performed in a 
standardized manner by the central laboratory under the direction of an expert orthopedic 
pathologist.  Pathology reports will generally be returned to the referring site within 
7-10 days following completion of the report by the central laboratory. 
107.3. Telephone-based Assessments
Post-surgery, subjects will be contacted monthly via telephone by study site personnel.
107.3.1. Adverse Events
At each post-surgery telephone contact, subjects will be queried for the occurrence of adverse 
events.  All adverse events reported by the subject must be recorded on the appropriate case 
report form (CRF).
A neurologic evaluation should be performed by a consulting neurologist if any of the 
following occurs: 

If an adverse event suggestive of new or worsening peripheral neuropathy or an adverse 
event of abnormal peripheral sensation (eg, allodynia, burning sensation, carpal tunnel 
syndrome, dysesthesia, hyperesthesia, hyperpathia, hypoesthesia, neuralgia, neuritis, 
neuropathy peripheral, pallanesthesia, paresthesia, peripheral sensory neuropathy, 
sciatica, sensory disturbance, sensory loss, tarsal tunnel syndrome) is reported as: 1) a 
serious adverse event or 2) an adverse event which has resulted in the subject being 
withdrawn from the study, or 3) an adverse event ongoing at the end of the subject’s 
participation in the study, or 4) an adverse event of severe intensity. 

A 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.  Adverse events will be reported where applicable as described in 
Section 8.
Subjects reporting adverse events with preferred terms of bradycardia, syncope, orthostatic 
hypotension (as defined in Section 7.3.5.1 of the A4091063 protocol), anhidrosis or 
hypohidrosis (any seriousness or severity) will be further evaluated for the presence of 
sympathetic autonomic neuropathy.  Subjects will be referred for neurologic or cardiologic 
evaluation depending on symptom presentation and the investigator’s assessment as to the 
specialist best able to evaluate the subject.
107.3.2. Concomitant Analgesic Medication
At each post-surgery telephone contact, subjects will be queried about concomitant analgesic 
medication usage including dose, dosing regimen and reason for use.  This information 
should be recorded on the appropriate case report form (CRF).
107.3.3. Physical Rehabilitation Activities
At the Week 4, 12 and 24 post-surgery telephone contacts, subjects will be queried for 
physical rehabilitation activities related to the replaced joint.  Specifically, subjects will be 
asked to respond yes or no to the following question:

Are you participating in physical rehabilitation activities related to your replaced joint?
Subjects will be queried for details if the answer to the question is yes.  This information 
should be recorded on the appropriate case report form (CRF).
107.3.4. Additional or Corrective Procedures
At the Week 12 and 24 post-surgery telephone contacts, subjects will be queried for 
additional or corrective procedures related to the total joint replacement surgery.  Specifically, 
subjects will be asked to respond yes or no to the following question:

Have you been told by your orthopedic surgeon that additional or corrective procedures 
(for example a revision or implant replacement) are necessary for your total joint 
replacement?
Subjects will be queried for details if the answer to the question is yes.  If necessary, the 
orthopedic surgeon may be contacted to confirm/expand upon the information regarding 
additional or corrective procedures.  This information should be recorded on the appropriate 
case report form (CRF).
107.4. Web-based Assessments
107.4.1. Overall Satisfaction with Joint Replacement Surgery
The Self-Administered Patient Satisfaction Scale (SAPS) evaluates subject satisfaction with 
the outcome of hip and knee arthroplasty and was designed to be used in conjunction with 


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other clinical measures and functional health status instruments to evaluate the results of hip 
and knee arthroplasty. 
The scale consists of four items focusing on satisfaction with the extent of pain relief, 
improvement in ability to perform home or yard work, ability to perform recreational 
activities and overall satisfaction with joint replacement. 
Specifically, subjects will be asked to respond to the following questions:

How satisfied are you with the results of your surgery?

How satisfied are you with the results of your surgery for improving your pain?

How satisfied are you with the results of surgery for improving your ability to do home 
or yard work?

How satisfied are you with the results of surgery for improving your ability to do 
recreational activities?
Items are scored on a 4-point Likert scale with response categories consisting of ‘very 
satisfied’ (100 points), ‘somewhat satisfied’ (75 points), ‘somewhat dissatisfied’ (50 points), 
and ‘very dissatisfied’ (25 points).  The scale score is the unweighted mean of the scores 
from the individual items, ranging from 25 to 100 per item with higher scores indicating 
greater satisfaction.
Subjects will be requested to complete the SAPS at Weeks 4, 12, and 24 either via the IWRS 
or by paper if the subject does not have access to the internet via a desktop, laptop or tablet 
computer.  When completed on paper, the subject will be requested to return the assessment 
to the site as soon as possible, but no later than 5 days, after completion of the assessment.
107.4.2. Pain in Replaced Joint
Average pain in the joint to be replaced (pre-surgery) and average pain in the replaced joint 
(post-surgery) will be assessed with an 11-point Numeric Rating Scale (NRS) ranging from 
zero (no pain) to 10 (worst possible pain).
Question:
Select the number that best describes your average pain in the (joint to be replaced or your 
replaced joint) the past 24 hours. 
0
1
2
3
4
5
6
7
8
9
10
No Pain
Worst 
Possible 
Pain


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At Baseline and at Weeks 4, 12 and 24 following total joint replacement surgery, subjects 
will be asked to indicate their average pain in the joint to be replaced (pre-surgery) or the 
replaced joint (post-surgery) via the IWRS or by paper if the subject does not have access to 
the internet via a desktop, laptop or tablet computer.  When completed on paper, the subject 
will be requested to return the assessment to the as soon as possible, but no later than 5 days, 
after completion of the assessment.
107.4.3. Assessment of Functional Activity 
Subjects undergoing total knee or hip replacement will be asked to complete the Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with the knee or hip that 
was replaced serving as the “index joint”.  Subjects undergoing total shoulder replacement 
will be asked to complete the Shoulder Pain and Disability Index (SPADI).  Descriptions of 
these assessments are provided below.
107.4.3.1. WOMAC
Subjects who will be proceeding to total knee or hip arthroplasty will be requested to 
complete all subscales of the WOMAC (ie, pain, physical function and stiffness) at Baseline 
and Weeks 4, 12, and 24 following total joint replacement surgery either via the IWRS or by 
paper if the subject does not have access to the internet via a desktop, laptop or tablet 
computer.  When completed on paper, the subject will be requested to return the assessment 
to the site as soon as possible, but no later than 5 days, after completion of the assessment. 
107.4.3.1.1. WOMAC Pain Subscale
The WOMAC Pain subscale is comprised of 5 questions regarding the amount of pain 
experienced due to OA in the index joint (selected study knee or hip) in the past 48 hours.  
For this study, the index joint (selected study knee or hip) is defined as the joint to be or 
that has been replaced.  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.
107.4.3.1.2. WOMAC Physical Function Subscale
The WOMAC Physical Function subscale is comprised of 17 questions regarding the degree 
of difficulty experienced due to arthritis in the index joint (selected study knee or hip) in the 
past 48 hours.  For this study, the index joint (selected study knee or hip) is defined as 
the joint to be or that has been replaced.  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.


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107.4.3.1.3. WOMAC Stiffness Subscale
The WOMAC Stiffness subscale is comprised of 2 questions regarding the amount of 
stiffness experienced in the index joint (selected study knee or hip) in the past 48 hours.  For 
this study, the index joint (selected study knee or hip) is defined as the joint to be or 
that has been replaced.  The WOMAC Stiffness subscale is calculated as the mean of the 
scores from the two individual questions, which may not be a whole (integer) number.  The 
WOMAC Stiffness subscale NRS scores for each question, and the WOMAC Stiffness 
subscale score, range from 0 to 10 with higher scores indicating more stiffness.  Stiffness is 
defined as a sensation of decreased ease with which the subject moves the index knee or hip.
A copy of the WOMAC can be found in Appendix 19.
107.4.3.2. The Shoulder Pain and Disability Index (SPADI)
Subjects who will be proceeding to shoulder arthroplasty will be requested to complete both 
dimensions of the SPADI (ie, pain and function) at Baseline and Weeks 4, 12, and 
24 following total joint replacement surgery either via the IWRS or by paper if the subject 
does not have access to the internet via a desktop, laptop or tablet computer.  When 
completed on paper, the subject will be requested to return the assessment to the site as soon 
as possible, but no later than 5 days, after completion of the assessment.
The SPADI consists of two dimensions (pain and function).  The pain dimension consists of 
five questions regarding the severity of an individual’s pain.  Functional activities are 
assessed with eight questions designed to measure the degree of difficulty an individual has 
with various activities of daily living that require upper extremity use.  The scores from both 
dimensions are averaged to derive a total score from 0 (best) to 100 (worst).
A copy of the SPADI can be found in Appendix 20.
108. SUBSTUDY ADVERSE EVENT REPORTING
Refer to Section 8 of the A4091063 protocol.
109. SUBSTUDY DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for the summary and descriptive analyses of the data collected in this 
substudy will be documented in a Statistical Analysis Plan, which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
109.1. Sample Size Determination
This substudy is designed to collect information sufficient to describe the post-operative 
outcome of subjects who underwent a total knee, hip, or shoulder replacement while 
participating in tanezumab Study A4091063. The number of subjects who will enroll in this 
substudy is unknown but is estimated to be less than 25 subjects.  Also unknown is the 
distribution of subjects across treatment groups (ie, the treatment given in Study A4091063).  


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Therefore, it is predicted that there will be insufficient statistical power to perform statistical 
inferential analyses.  All analyses will be descriptive in nature.  The data collected in this 
substudy will be combined with similar data collected in other tanezumab studies for further 
analysis.  These aggregate analyses will be reported separately. 
109.2. Analysis of Endpoints
Data from the substudy of subjects with total joint replacement of the knee, hip or shoulder 
will be presented at substudy Baseline or Day 1 (day of surgery) and each post-surgery visit 
using observed data (no imputation for missing data), and at Week 24 using Last Observation 
Carried Forward (LOCF) for missing data.  Data will be shown at the timepoints specified 
and also using change from (pre-surgery) Baseline where relevant.  Data will be shown 
overall, and split by treatment group.
For the Surgeon’s Assessment of Procedural Difficulty, the number and percentage of 
subjects in each category (Uneventful, Minor complications, Major complications) will be 
presented.  Complications reported by the surgeon will be listed. 
For the Subject’s Overall Satisfaction with Surgery assessments (using the Self-Administered 
Patient Satisfaction scale, SAPS), the responses [score] for each category (Very Satisfied 
[100], Somewhat Satisfied [75], Somewhat Dissatisfied [50], Very Dissatisfied [25]) will be 
summarized for each of the four items.  The scale score is the unweighted mean of the scores 
from the individual items, ranging from 25 to 100 per item with higher scores indicating 
greater satisfaction.  This total score will be summarized.  Reponses to the question “How 
satisfied are you with the results of your surgery?” will also be summarized as satisfied (very 
satisfied and somewhat satisfied categories combined) and dissatisfied (somewhat 
dissatisfied and very dissatisfied categories combined).
Similarly, the number and percentage of subjects who have required (i) additional or 
corrective procedures related to their total joint replacement and (ii) participating in physical 
rehabilitation activities related to their replaced joint will be presented.
Average pain (NRS) in the replaced joint for all subjects, WOMAC Pain, Stiffness and 
Physical Function sub-scale scores for subjects who had total knee or hip replacement and 
SPADI Pain, function and total score for subjects who had total shoulder replacement will be 
summarized (including change from substudy Baseline summaries).
The number and percent of subjects with specified post-surgical complications will be 
presented.  The list of post-surgical complications will be derived from reported adverse 
events and will consist of complications that are clinically significant and attributable to the 
total arthroplasty procedure eg, periprosthetic joint infection/wound infection, periprosthetic 
fracture, pulmonary embolism or sepsis/septicemia/shock.  Literature reported analyses of 
post-surgical complicationsi,j will be used for guidance in developing the list of post-surgical 
complications.  The list of post-surgical complications will be developed prior to database
lock. 


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109.3. Data Monitoring Committee 
Refer to Section 9.6 of the A4091063 protocol. 
109.4. External Adjudication Committee
Refer to Section 9.5 of the A4091063 protocol.
110. SUBSTUDY QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Section 10 of the A4091063 protocol.
111. SUBSTUDY DATA HANDLING AND RECORD KEEPING
Refer to Section 11 of the A4091063 protocol.
112. SUBSTUDY ETHICS
Refer to Section 12 of the A4091063 protocol.
113. SUBSTUDY DEFINITION OF END OF TRIAL
Refer to Section 13 of the A4091063 protocol.
114. SUBSTUDY SPONSOR DISCONTINUATION CRITERIA
Refer to Section 14 of the A4091063 protocol.
115. SUBSTUDY PUBLICATION OF STUDY RESULTS
Refer to Section 15 of the A4091063 protocol.
116. SUBSTUDY REFERENCES
a.
Beaton DE, and Schemitsch E. Measures of Health-Related Quality of Life and 
Physical Function. Clin Orth and Rel Research 413:2003; 90-105.
b. Mahomed N, et al. The self-administered patient satisfaction scale for primary hip 
and knee arthroplasty. Arthritis 2011; doi:10.1155/2011/591253.
c.
Hawker GA, et al. Measures of adult pain. Arthritis Care Res 2011;63:S240-52.
d. Rolfson O, et al. Use of patient-reported outcomes in the context of different levels of 
data. J Bone Joint Surg Am 2011; 93 Suppl3(E):66-71. 
e.
Beaton DE and Schemitsch E. Measures of health-related quality of life and physical 
function. Clin Orth Rel Res 2003; 413:90-105. 
f.
Rogers JC and Irrgang JJ.  Measures of adult lower extremity function. Arthritis Care 
Res 2003;49:S67-84.
g. Angst F, et al. Measures of adult shoulder function.  Arthritis Care Res
2011;63:S174-88.


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h. Roy J-S, MacDermid JC and Woodhouse LJ. Measuring shoulder function: a 
systemic review of four questionnaires. Arthritis Care Res 2009; 61:623-32.
i.
Grosso, LM et al., Hospital-Level Risk-Standardized Complication Rate Following 
Elective Primary Total Hip Arthroplasty and/or Total Knee Arthroplasty Measure 
Methodology Report 25 June 2012. 
j.
Bohsali KI, Wirth MA and Rockwood CA. Complications of total shoulder 
arthroplasty. J Bone Joint Surgery 88:2006; 2279-92.


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Appendix 20. The Shoulder Pain and Disability Index (SPADI)

SAP_000.pdf: 
Protocol A4091063 (PF-04383119) Statistical Analysis Plan
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Protocol A4091063
A PHASE 3 RANDOMIZED, DOUBLE BLIND, ACTIVE CONTROLLED, 
MULTICENTER STUDY OF THE LONG TERM SAFETY AND EFFICACY OF 
SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN JAPANESE ADULT 
SUBJECTS WITH CHRONIC LOW BACK PAIN
Statistical Analysis Plan 
(SAP)
Version:
3
Date:
4-Jul-2019


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION ...............................................................................................................10
2.1. Study Objectives .....................................................................................................10
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Primary Endpoints...................................................................................................13
3.2. Secondary Endpoints...............................................................................................13
3.3. Tertiary Endpoints...................................................................................................15
3.4. Baseline Variables...................................................................................................15
3.5. Safety Endpoints .....................................................................................................15
3.5.1. Adverse Events...........................................................................................15
3.5.2. Laboratory Tests .........................................................................................17
3.5.3. Orthostatic (supine/standing) Blood Pressure Assessments.......................17
3.5.4. Survey of Autonomic Symptoms (SAS) Scores.........................................17
3.5.5. Electrocardiogram (ECG, 12-lead) Data ....................................................17
3.5.6. Joint Safety Adjudication Outcomes and Total Joint Replacements..........17
3.5.7. Neurologic Examination (Neuropathy Impairment Score [NIS]) ..............18
3.5.8. Anti Drug Antibody Assessments (ADA) ..................................................18
3.5.9. Physical Examinations................................................................................18
4. ANALYSIS SETS ...............................................................................................................18
4.1. Intent To Treat Analysis Set....................................................................................18
4.2. Safety Analysis Set..................................................................................................19
4.3. Other Analysis Sets .................................................................................................19
4.4. Treatment Misallocations........................................................................................19
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.2. General Methods .....................................................................................................19
5.2.1. Analyses for Binary Data............................................................................19


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5.2.2. Analyses for Continuous Data....................................................................19
5.2.3. Analyses for Categorical Data....................................................................20
5.2.4. Analyses for Time to Event Data................................................................20
5.3. Methods to Manage Missing Data ..........................................................................20
6. ANALYSES AND SUMMARIES ......................................................................................23
6.1. Primary Endpoints...................................................................................................23
6.1.1. Safety Measures: Adverse Events ..............................................................24
6.1.2. Safety Measures: Standard Safety Assessments (safety laboratory 
testing [chemistry, and hematology], vital signs)............................................25
6.1.3. Safety Measures: Orthostatic (supine/standing) Blood Pressure 
Assessments.....................................................................................................25
6.1.4. Safety Measures: Survey of Autonomic Symptoms (SAS) Scores ............26
6.1.5. Safety Measures: Electrocardiogram (ECG, 12-lead) Assessments...........26
6.1.6. Safety Measures: Joint Safety Adjudication Outcomes and Total 
Joint Replacements ..........................................................................................26
6.1.7. Safety Measures: Neurologic Examination (Neuropathy Impairment 
Score [NIS]).....................................................................................................27
6.1.8. Safety Measures: Outcome of Consultation ...............................................27
6.1.9. Safety Measures: Anti-drug Antibody Assessments (ADA)......................27
6.1.10. Safety Measures: Physical Examinations.................................................28
6.2. Secondary Endpoints...............................................................................................28
6.2.1. Average Low Back Pain Intensity (LBPI) Score........................................28
6.2.2. Roland-Morris Disability Questionnaire (RMDQ) total score ...................29
6.2.3. Patient’s Global Assessment of Low Back Pain (PGA-LBP) ....................30
6.2.4. Brief Pain Inventory-short form (BPI-sf) scores ........................................30
6.2.5. Chronic Low Back Pain Responder Index (CLBP-RI) Analysis................30
6.2.6. Euro Quality of Life Health State Profile (EQ-5D-5L) ..........................30
6.2.7. Work Productivity and Activity Impairment Questionnaire: Low 
Back Pain (WPAI:LBP)...................................................................................31
6.2.8. Discontinuation Due to Lack of Efficacy...................................................31
6.2.9. Usage of Rescue Medication ......................................................................32
6.2.10. Health Care Resource Utilization (HCRU) ..............................................33
6.2.11. Treatment Satisfaction Questionnaire for Medication v.II (TSQM) 
Score ................................................................................................................33


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6.2.12. Patient Reported Treatment Impact Assessment-Modified (mPRTI) ......33
6.3. Other Endpoints: Tertiary Endpoints ......................................................................34
6.3.1. Plasma Tanezumab Concentrations............................................................34
6.3.2. Serum NGF Assessments ...........................................................................34
6.4. Subset Analyses.......................................................................................................34
6.5. Baseline and Other Summaries and Analyses.........................................................35
6.5.1. Baseline Summaries....................................................................................35
6.5.2. Study Conduct and Subject Disposition .....................................................35
6.5.3. Study Treatment Exposure .........................................................................35
6.5.4. Concomitant Medications, Non-Drug Treatments and Drug 
Treatments Prior to Start of Study Treatment..................................................36
7. INTERIM ANALYSES.......................................................................................................36
7.1. Introduction .............................................................................................................36
7.2. Interim Analyses and Summaries............................................................................36
8. REFERENCES ....................................................................................................................38
9. APPENDICES .....................................................................................................................39
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................................6
LIST OF FIGURES
Figure 1.
Study Schematic....................................................................................................12
APPENDICES
Appendix 1. SUMMARY OF EFFICACY ANALYSES........................................................39
Appendix 2. DATA DERIVATION DETAILS ......................................................................47
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................47
Appendix 2.2. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations............................................................................................51
Appendix 2.3. Further Definition of Endpoints.......................................................................51
Appendix 3. DATA SET DESCRIPTIONS ............................................................................57
Appendix 4. STATISTICAL METHODOLOGY DETAILS..................................................57
Appendix 4.1. Further Details of Interim Analyses.................................................................57


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Appendix 4.2. Further Details of Statistical Methods..............................................................57
Appendix 4.3. painDETECT Questionnaire5...........................................................................58


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Original
25 Dec 2015
Original 
28 Aug 2015
N/A
N/A
Version 2
14 Jun 2019
Amendment 2
14 Sep 2017
The changes reflect 
protocol amendment, 
updates from blinded 
data review and 
program decisions for 
alignment of analysis. 
Additionally, 
clarifications, removal 
of 
redundant/duplicated 
text have been 
implemented.

Various formatting and editorial clarifications 
were made (throughout).

Section 2.2: Updated the study design according 
to the change made in Protocol amendment 2.

Section 2.2: Clarified that most safety results 
will be presented for the treatment period. 

Section 3.1 and 6.1: Specified the outcome of 
consultation as safety endpoints. 

Section 3.2: Added change from baseline to 
Week 1 in low back pain intensity (LBPI). 
Added cumulative distribution of percent change 
from Baseline in RMDQ score to Weeks 16 and 
56. Added usage of rescue medication 
(incidence, number of days of usage and amount 
taken) during Week 1.

Section 3.4: Modified description. Moved the 
description on how to summary baseline 
variables to Section 6.5.1.

Section 3.5.1: Clarified the Tier-1 events. 
Section 3.5.1: Changed the Tier-2 AE cutoff 
from 1% to 3%. Updated definitions for 
Abnormal Peripheral Sensation and Sympathetic 
Nervous System.  A smaller set of the AEs of 
Sympathetic Nervous System (AEs of 
Decreased Sympathetic Function) is deleted.

Section 4: Clafied the definitions of analysis 
sets.

Section 5.2.1: Removed the calculation of 
treatment difference. Changed the calculation of 
95% CI for response rate.

Section 5.2.2: Added mixed model ANCOVA
for aLBPI and RMDQ.  Removed the 
calculation of treatment differences, except for 
aLBPI and RMDQ ANCOVA analyses.

Section 5.2.3: Moved the description on NIS and 
PGA-LBP to section 6 with some modification.
Removed the summary of WPAI parameters 
using categories.


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
Section 5.3: Added the analysis with multiple 
imputation, BOCF and LOCF for the summary 
for LBPI, RMDQ, PGA and BPI-sf. 

Section 6.1.1: P-value and 95% CI for risk 
difference will be shown for pooled Tier 1 
adverse events and will not be shown for each 
adverse event within Tier 1 event. Updated the 
description of footnote for 3-tier AE tables.  
Removed the following analyses: Tier 1 and 
Tier 2 AE graphs, the comparison between the 
number of subjects with AEs of APS against the 
number of subjects with the AE of Oedema
peripheral, the plots of the start and stop study
day of specified individual AES of APS, the 
summary of start day and AE duration for five 
AEs of APS (Paraesthesia, Hyperaesthesia, 
Hypoaesthesia, Allodynia and Dysaesthesia), 
AEs of DSF and Oedema peripheral, summary 
of AEs and serious AEs by 1000 patient years of 
exposure, ‘incidence and severity’ table for 
decreased sympathetic function (DSF), and 
listing of AEs for subjects who are not 
randomized and those randomized and not 
treated. Added the summary for adverse events 
associated with laboratory abnormalities, vital 
signs, and ECG measurement.

Section 6.1.2: Changed the category of blood 
pressure.

Section 6.1.3: Removed the summary of mean 
change in postural blood pressure. Clarified the 
detail of analysis.

Section 6.1.6: Updated the analysis plan for joint 
safety adjudication outcomes and total joint 
replacement.

Section 6.1.7: Separate section (6.1.8) was made 
for outcome of consultation and moved the 
description on outcome of consultation to 
Section 6.1.8.

Section 6.1.9: Specified that ADA assessments 
will be made using all available data.

Section 6.1.10: Updated the analysis plan for 
physical examination.

Section 6.2: Clarified the definition of ‘on-
treatment’ and ‘off-treatment’.


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
Section 6.2.1: Added the ANCOVA analysis for 
change from baseline for aLBPI. Updated the 
description on handling of missing data based on 
the modification in section 5.3.  Added plots of 
cumulative distribution of percent change from 
Baseline in aLBPI score. Removed the
calculation of treatment differences in mean of 
change from baseline for aLBPI and in response 
rate in each aLBPI response category.  Added
the summary of change from baseline of aLBPI 
at Week 1. Removed the summary of 
proportion of subjects who meet a aLBPI 
response definition at Week 16.  Added the 
description on the handling of aLBPI data 
obtaining after the early termination visit.

Section 6.2.2: Added the ANCOVA analysis for 
change from baseline for RMDQ.  Added the 
description on handling of missing data based on 
the modification in section 5.3.  Removed the 
calculation of treatment differences in mean of 
change from baseline for RMDQ. Added
treatment response analysis for RMDQ. 

Section 6.2.3: Updated the description on 
handling of missing data based on the 
modification in section 5.3. Removed the 
calculation of treatment differences in mean of 
change from baseline for PGA of LBP and in 
response rate in PGA of LBP response category.

Section 6.2.4: Updated the description on 
handling of missing data based on the 
modification in section 5.3. Removed the 
calculation of treatment differences in mean of 
change from baseline for BPI-sf.

Section 6.2.5: Removed the calculation of 
treatment differences in response rate in CLBP-
RI. Added a plot of CLBP-RI analysis.

Section 6.2.7: Modified the description on 
analyses.

Section 6.2.8: Clarified the definition of event 
“discontinuation from treatment due to lack of 
efficacy”.

Section 6.2.9: Added usage of rescue medication 
(incidence, number of days of usage and amount 
taken) during Week 1. Clafiried the summary of 
rescue medication.


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
Section 6.2.10: Clarified the analyses for health 
care resource utilization.

Section 6.2.12: Removed the summary splitted 
by response to question 1.

Section 6.3.1: Clarified PK data summaries.

Section 6.3.2: Clarified NGF data summaries.

Section 6.3.3: Removed as biomarker data are 
not generated.

Section 6.4: Removed Subset analysis using 
NGF subset analysis dataset and biomarker 
subset analysis dataset.

Section 6.5.1: Added baseline summaries for 
diabetes status and painDetect score.

Section 6.5.2: Removed cumulative summary of 
discontinuation by treatment group and reason, 
study week of discontinuation, and summary 
table and listing of demographic details for 
subjects who are not randomized and those 
randomized but not treated.

Section 6.5.3: Modified the summary of study 
treatment exposure.

Section 6.5.4: Added NSAID use summaries.

Section 8: Updated the references.

Appendix 1: Updated the summary of efficacy 
analyses.

Appendix 2.1: Clarified the windows for various 
data types.

Appendix 2.3: Some modifications and 
clarifications were made.

Appendix 4.2: Added the details of the statistical 
method.

Appendix 4.3: Added the detail of painDETECT 
questionnaire.

Delete Appendix 5 (immunogenicity data 
reporting detail).


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Version 3
4 Jul 2019
N/A
The changes reflect 
updates from blinded 
data review. 
Additionally, 
clarifications, removal 
of 
redundant/duplicated 
text have been 
implemented.

Section 5.2.2: Clafiried the explanation on the 
ANCOVA analyses.

Section 6.1.4: Modified the explanation.

Section 6.1.7: Added the analysis on Neuropathy 
impairment score (NIS). 

Section 6.2.1: Added the treatment difference of 
proportion of responder in weekly average LBPI 
score.

Section 6.2.6: Modified the descriptive statistics 
shown in the summary table.

Section 6.5.2: Modified the study week 
categories in the summary of time to 
discontinuation.

Section 6.5.3: Added the description on the 
summary of number of SC doses taken and 
duration in phases. Updated the description on 
the summary of oral study medication 
compliance.

Section 6.5.4: Added the description on the 
summary for treatments prior to start of study 
treatment. Clarified the summary for 
concomitant medications and non-drug 
treatments.

Appendix 1: Modified the time point for 
efficacy analyses.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A4091063.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Primary Objective:

Evaluate the long-term safety of tanezumab 10 mg and 5 mg SC administered every 
8 weeks (7 administrations).


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Secondary Objective:

Demonstrate the long-term analgesic efficacy of tanezumab 10 mg and 5 mg 
SC administered every 8 weeks (7 administrations).
2.2. 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 up to 
56 weeks in subjects with chronic low back pain.  Subjects will be randomized to 1 of 
3 treatment groups in a 1:1:1 ratio.  Treatment groups will include:
1. Placebo SC matching tanezumab administered at an 8-week interval (total of 7 times)
plus celecoxib 100 mg twice a day (BID) to be administered orally for 56 weeks.
2. Tanezumab 5 mg SC administered at an 8-week interval (total of 7 times) plus
placebo matching celecoxib to be administered orally BID for 56 weeks.
3. Tanezumab 10 mg SC administered at an 8-week interval (total of 7 times) plus
placebo matching celecoxib to be administered orally BID for 56 weeks.
The study is designed with a total duration (post randomization) of up to 80 weeks and will 
consist of three periods: Screening (up to 37 days; includes a Washout Period and an Initial 
Pain Assessment Period), Double-blind Treatment (56 weeks) and Follow-up (24 weeks).  
The total sample size will be approximately 200 subjects (170-220 subjects, approximately 
66 subjects [56-73 subjects] per treatment group).  However, it is acceptable to randomize 
more than 220 subjects from the safety perspective as described below because primary 
objective is to evaluate the long-term safety.
The period of interest for most safety results is the treatment period. Selected safety results 
will be provided separately for the safety follow-up period and for the combined overall 
study period comprising the treatment and safety follow-up periods.


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Figure 1.
Study Schematic
SC tanezumab 5 mg + Oral placebo (matching celecoxib)
SC tanezumab 10 mg + Oral placebo (matching celecoxib)
SC placebo (matching tanezumab) + Oral celecoxib
Day -5 to -1 
(IPAP)
16
Day  -37   -5 1


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
Safety Measures

Adverse events.

Standard safety assessments (safety laboratory testing [chemistry, and hematology], 
vital signs).

Orthostatic (supine/standing) blood pressure assessments.

Survey of Autonomic Symptoms (SAS) scores.

Electrocardiogram (ECG, 12-lead) assessments.

Joint Safety adjudication outcomes.

Total joint replacements.

Neurologic examination (Neuropathy Impairment Score [NIS]).

Anti-drug antibody assessments (ADA).

Physical examinations.

Outcome of Consultation
The details of the safety endpoints are described in Section 3.5.
3.2. Secondary Endpoints
Efficacy-Related Endpoints

Change from Baseline to Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64 in 
average Low Back Pain Intensity (LBPI) score as measured by an 11-point Numeric 
Rating Scale (NRS).

Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in the 
Roland-Morris Disability Questionnaire (RMDQ) total score.

Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in Patient’s 
Global Assessment of Low Back Pain.

Cumulative distribution of percent change from Baseline in average LBPI score to 
Weeks 16, 24 and 56.


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•
Cumulative distribution of percent change from Baseline in RMDQ score to Weeks 
16 and 56.
•
Response as defined by a ≥30%, ≥50%, ≥70% and a ≥90% reduction from Baseline 
in weekly average LBPI score derived from the subject diary at Weeks 16, 24, 40 and
56.
•
Change from Baseline to Weeks 2, 4, 8, 16, 24, 40, 56 and 64 in the Brief Pain 
Inventory-short form (BPI-sf) scores for Worst Pain, Average Pain, Pain Interference 
Index (composite function score), Pain Interference with General Activity, Pain 
Interference with Walking Ability, Pain Interference with Sleep, and Pain 
Interference with Normal Work.
•
The BPI-sf Pain interference index is calculated as the mean of the seven BPI-sf Pain 
interference items (question 5a to g), being Pain interference with General Activity; 
Mood; Walking Ability; Normal work; Relations with other people; Sleep; Enjoyment 
of life.
•
Chronic Low Back Pain Responder Index analysis (composite endpoint of average 
LBPI score, Patient’s Global Assessment of Low Back Pain, and RMDQ total score)
at Weeks 16, 24, 40 and 56.
For the definition of the Chronic Low Back Pain Responder Index, a responder is 
defined as:
•
A reduction of ≥30% in weekly average LBPI  from baseline to that week, and 
•
A decrease of ≥30% in Patient Global Assessment of low back pain from baseline 
to that week, and
•
No worsening (increase) in Roland-Morris Disability Questionnaire total score 
from baseline to that week
•
Treatment Response: Improvement of ≥2 points in Patient’s Global Assessment of 
Low Back Pain at Weeks 16, 24, 40 and 56.
•
Euro Quality of Life Health State Profile (EQ-5D-5L™) dimensions and overall 
health utility score at Baseline, Weeks 16 and 56.
•
Work Productivity and Activity Impairment Questionnaire: Low Back Pain 
(WPAI:LBP) change from Baseline to Week 16, 56 and 64, in the percent work time 
missed due to chronic low back pain, percent impairment while working due to 
chronic low back pain, percent overall work impairment due to chronic low back 
pain, and percent activity impairment due to chronic low back pain.
•
Incidence of and time to discontinuation due to lack of efficacy.


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
Usage of rescue medication (incidence, and number of days of usage) during 
Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64.

Usage of rescue medication (amount taken) during Weeks 1, 2, 4, 8, 12 and 16.

Health Care Resource Utilization (HCRU) at Baseline, Weeks 64 and 80.
Treatment Satisfaction Measures

Treatment Satisfaction Questionnaire for Medication v.II (TSQM) score at Weeks 16 
and 56.
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 2.3.

Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 
56.
3.3. Tertiary Endpoints

Plasma tanezumab concentrations.

Serum NGF assessments.

Serum and urine osteoarthritis biomarker concentrations.
3.4. Baseline Variables
Baseline variables are demographics, general and musculoskeletal specific medical history, 
Musculoskeletal baseline status, prior/current medication use, primary diagnosis and Quebec
Task Force (QTF) category.
The method and definition of reporting windows including Baseline for assigning efficacy 
data to particular time points is described in Appendix 2.1.  
3.5. Safety Endpoints
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to a given treatment if:

The event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment, or

The event was seen prior to the start of treatment but increased in severity during 
treatment.


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A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers. Different analyses will be performed for different tiers (See Section 6.1.1). 
Tier-1 events: These are pre-specified events of clinical importance.  Tier-1 events include 
syncope, bradycardia, orthostatic hypotension, anhidrosis, hypohidrosis.
Tier-2 events: These are events that are not Tier-1 but are “common”. A MedDRA PT is 
defined as a Tier-2 event with a frequency of >3% in any treatment group.
Tier-3 events: These are events that are neither Tier-1 nor Tier-2 events, 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).
The adverse events of Abnormal Peripheral Sensation (APS) are defined in the table below.  
Allodynia
Neuritis
Axonal neuropathy
Neuropathy peripheral
Burning sensation
Paraesthesia
Carpal Tunnel Syndrome
Paraesthesia oral
Decreased Vibratory Sense
Peripheral sensorimotor neuropathy
Demyelinating polyneuropathy
Peripheral sensory neuropathy
Dysaesthesia
Polyneuropathy
Formication
Polyneuropathy chronic
Hyperaesthesia
Sensory disturbance
Hyperpathia
Sensory loss
Hypoaesthesia
Thermohypoaesthesia
Hypoaesthesia oral
Sciatica
Intercostal neuralgia
Tarsal Tunnel Syndrome
Neuralgia
Adverse Events of Sympathetic Nervous System are defined in the table below.
Abdominal discomfort
Micturition urgency
Anal incontinence
Nausea
Anhidrosis
Nocturia
Blood pressure orthostatic decreased
Orthostatic hypotension
Bradycardia
Pollakiuria
Diarrhoea
Presyncope
Dizziness postural
Respiratory distress
Early satiety
Respiratory failure
Ejaculation delayed
Sinus bradycardia
Ejaculation disorder
Syncope
Ejaculation failure
Urinary hesitation
Heart rate decreased
Urinary incontinence
Hypertonic bladder
Vomiting
Hypohidrosis


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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.
3.5.2. Laboratory Tests
Larobatory tests will be summarized according to Pfizer standards.
3.5.3. Orthostatic (supine/standing) Blood Pressure Assessments
The incidence of orthostatic hypotension at each visit, at the last visit and for any post-
baseline incidence will be summarized.  The definition of orthostatic hypotension to be 
summarized is:

For patients with Baseline supine systolic Blood Pressure ≤150 mmHg: 

Reduction in sBP (standing minus supine) ≥20, OR

Reduction in dBP (standing minus supine) ≥10.

For patients with Baseline supine systolic Blood Pressure >150 mmHg: 

Reduction in sBP (standing minus supine) ≥30, OR

Reduction in dBP (standing minus supine) ≥15.
3.5.4. Survey of Autonomic Symptoms (SAS) Scores 
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 patient 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 patient does not have the particular symptom.  The range for the 
total impact score is 0-60 for males and 0-55 for females.
3.5.5. Electrocardiogram (ECG, 12-lead) Data
Electrocardiogram data including PR, QRS, QT, QTcF, QTcB, RR intervals, and heart rate 
[HR] will be summarized according to Pfizer standards.
3.5.6. Joint Safety Adjudication Outcomes and Total Joint Replacements
The following adjudication outcomes and total joint replacement endpoints are defined.

The composite endpoint consisting of adjudication outcomes of rapidly progressive 
osteoarthritis (type-1 or type-2), subchondral insufficiency fracture, primary 
osteonecrosis, or pathological fracture.


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
The composite endpoint consisting of adjudication outcomes of rapidly progressive 
osteoarthritis (type-2 only), subchondral insufficiency fracture, primary osteonecrosis, 
or pathological fracture.

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.

Total joint replacements.

Total joint replacements or any adjudication outcome (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).
3.5.7. Neurologic Examination (Neuropathy Impairment Score [NIS])
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.
3.5.8. Anti Drug Antibody Assessments (ADA)
The assessments of ADA data as described in Section 6.1.9 will be summarized.
3.5.9. Physical Examinations
The physical examination data as described in Section 6.1.10 will be summarized.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Intent To Treat 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
(subcutaneously) study medication (either tanezumab or placebo).  This analysis set is used 
in the presentations of all efficacy data, and all data listings, and labeled as the ‘ITT Analysis 
Set’ or ‘ITT population’. Subjects will be assigned per the treatment they were randomized 
to.
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 4.2). If the sets are the same, safety 
analyses may still refer to it as the ‘Safety Population’.


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4.2. Safety Analysis Set
The safety analysis set is defined as all subjects treated with tanezumab or placebo SC.  This 
analysis set will be labeled as the ‘Safety population’ in the corresponding safety data 
analyses, summaries, and listings. Subjects will be assigned per treatment they actually 
received. 
4.3. Other Analysis Sets
TJR (Total Joint Replacement) Subset Analysis Set: This analysis set includes all subjects 
who undergo total joint replacements of the hip, knee or shoulder during participation in the
study.
4.4. Treatment Misallocations 
If a subject was:

Randomized but not treated with SC study medication, 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 took incorrect treatment, then that subject 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 will be made in a timely manner and prior 
to database release.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
No formal hypotheses are to be tested.
5.2. General Methods 
5.2.1. Analyses for Binary Data
Output will show the number and percentage of subjects in each response category, and the 
response rate and its 95% confidence interval (CI) will be calculated.  The confidence 
interval of the response rate will be calculated based on Agresti & Coull method.
5.2.2. Analyses for Continuous Data
The descriptive statistics n, mean, median, standard deviation, minimum, maximum and 
95% CI will be used to summarize the endpoints.  
The analysis for change from baseline of aLBPI (average LBPI) will use mixed model 
ANCOVA with a fixed effect of treatment group, Baseline aLBPI as a covariate, and study 
site as a random effect. The analysis for change from baseline of RMDQ will use mixed 
model ANCOVA with a fixed effect of treatment group, Baseline score and Baseline aLBPI
as covariates, and study site as a random effect.  Change from baseline at each time point will 
be estimated using least squares means (LS means) with standard error (SE) and 95% CI.  


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Estimates of treatment differences between each tanezumab treatment group versus celecoxib 
group will also be done using least squares means (LS means) with SE and 95% CI.  P-value 
will not be shown.  Under the analysis using multiple imputation defined in Section 5.3, the 
multiple ANCOVA results will be combined using standard methods (Little & Rubin, 2002),4
which are described in Appendix 4.2.
5.2.3. Analyses for Categorical Data
Output will show number and percentage of subjects in each category. 
5.2.4. Analyses for Time to Event Data
Survival curve estimates (time to 1st, 2nd, 5th, 10th and 25th percentiles, and minimum and 
maximum values) and a plot of the time to event will be shown using the Kaplan-Meier 
estimates.  Only discontinuation up to the end of treatment period (Week 56 visit or early 
discontinuation) will be used in this analysis.  
Any subject who discontinues for any other reason 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.
5.3. Methods to Manage Missing Data
Missing values in standard summaries of AEs, lab values, vital signs and ECGs will be 
handled per Pfizer standard algorithms.  
The summary of LBPI, RMDQ, PGA and BPI-sf will use multiple imputation for missing 
data (where the method for imputation will be dependent on the reason for missing data). As 
for PGA and BPI-sf, the imputation will be used only for Week 16 and Week 56 analyses.
The imputation strategies are described in the following table. While the table describes the 
multiple imputation strategy specific for the Week 16 time point, it also applies to Week 56 
time point, eg, ‘Week 56’ would be substituted for ‘Week 16’ in the table, to describe the 
Week 56 multiple imputation strategy.  
Type of Missing Data
Imputation Method
Missing data resulting from discontinuation 
of treatment due to Death, Adverse Events 
(AEs) or Insufficient Clinical Response or 
Patient’s Meeting 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 overall 
ITT subjects.  This is a multiple imputation 
version of BOCF single imputation method.  
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*),
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 


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
Subject discontinued for a different 
reason prior to or during the Week 16 
visit reporting window*.
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.  
* See Appendix 2.1 for a definition of the reporting windows.
The imputation of baseline-like data for subjects with missing data due to discontinuation 
due to Death, AE or LoE is intended to impute conservative efficacy values for those subjects 
who discontinue because of a reason that is considered to be a poor outcome for the subject, 
and so a poor outcome is imputed.  For those subjects with missing data that is likely to not 
be related to treatment group, the intention is that missing data should be imputed based on a 
‘missing at random’ assumption taking into account the subject’s previous available data.
One hundred imputed samples will be used in this analysis.  In order to pre-define the 
analysis (and not to allow the results to change if run again), the following seeds will be used 
in the creation of the multiple imputed data: aLBPI: 1001-1100; RMDQ: 2001-2100; 
PGA-LBP: 3001-3100; BPI-sf scores for Worst Pain, Average Pain, Pain Interference Index 
(composite function score), Pain Interference with General Activity, Pain Interference with 
Walking Ability, Pain Interference with Sleep, and Pain Interference with Normal Work: 
4001-4100.  Imputed Week 16 and 56 data for the PGA-LBP will be rounded to integer 
scores in the range 1 to 5.  Imputed Week 16 and 56 data for the aLBPI that are <0 and 
>10 will be truncated to 0 and 10, respectively. 
Two 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 Week 16 and 
56 will impute the subject’s Baseline value for the Week 16 and 56 time point, respectively, 
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 Week 16 and 56 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). 
As for LBPI and RMDQ, ANCOVA with covariates described in Section 5.2.2 will be 
conducted for all time points up to week 56.  Study site will be fitted as a random effect in 
the ANCOVA model.  This analysis will use multiple imputation for missing data as 
described above.  While the table describes the multiple imputation strategy specific for the 
Week 16 time point, it also applies to all other analysis time points, eg, ‘Week 2’ would be 
substituted for ‘Week 16’ in the above table, to describe the Week 2 multiple imputation 
strategy. 


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The responder endpoints will be summarized, using both BOCF and LOCF 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, 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, patient’s not meeting protocol-specified pain criteria, 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 CLBP-RI (Chronic Low Back Pain Responder Index) is based on 3 parameters (aLBPI, 
RMDQ and PGA-LBP).  It is set to missing if any one out of these three parameters are 
missing at baseline or for the relevant post-Baseline timepoint (per its definition, a response 
can still be achieved if all three component parameters meet certain criteria).  
For the RMDQ, any missing items are treated as the patient not having that symptom, and so 
not included in the RMDQ total score.
The BPI-sf Pain interference index score is calculated from the seven BPI-sf pain 
interference items. The composite index score is calculated as the mean of the non-missing 
items as long as ≥4 of the 7 items are non-missing, otherwise (≤3 items non-missing) the 
index score is missing.
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 2.1 for definitions of the last study day in each 
week). For example if a subject discontinues on study day 10, then data up to the end of 
Week 2 will be imputed in this way. The weekly scores for the rescue medication endpoints 
can then be calculated for each week the subject is in the study. Rescue medication 
endpoints are summarized 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 -5 to -1) 
and subjects should not be taking rescue medication within 48 hours of the Baseline visit (so 
part of day -2, and 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 16 will use LOCF based on the last available weekly diary data score 
available. Imputation of weekly diary data after week 56 will not be performed.


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The Baseline mean will be calculated using potential five values of the Initial Pain 
Assessment Period (IPAP).  Note, for the weekly pain score, a pain score being carried 
forward with LOCF might not be a visit week assessment (eg, carry forward Week 3 for 
missing Week 4 data).  For the purposes of the imputation analyses, where there is no 
post-baseline observation available to carry forward, then the baseline score carried forward 
will be the baseline average pain score, being the mean of the expected five pain scores in the 
baseline assessment period.  If any of the baseline average pain scores are missing (or there 
are less than 5 pain scores) then the baseline is calculated over the remaining non-missing 
values.
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.
For the other efficacy and safety analyses, the observed data (no imputation for missing data) 
will be summarized if not otherwise specified.  Additional analyses will be performed in 
order to explore the sensitivity of the efficacy analysis results to missing data as described in 
this section.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
The primary objective of this study is to evaluate the long term safety of tanezumab 10 mg 
and 5 mg SC administered every 8 weeks (7 administrations). In this section, the safety 
measures are summarized.

Adverse events.

Standard safety assessments (safety laboratory testing [chemistry, and hematology], 
vital signs).

Orthostatic (supine/standing) blood pressure assessments.

Survey of Autonomic Symptoms (SAS) scores.

Electrocardiogram (ECG, 12-lead) assessments.

Joint Safety adjudication outcomes.

Total joint replacements.

Neurologic examination (Neuropathy Impairment Score [NIS]).

Outcome of consultation

Anti-drug antibody assessments (ADA).

Physical examinations.


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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.
Adverse events (AEs), concomitant medications, laboratory safety tests, physical and 
neurological examinations (NIS), vital signs, electrocardiogram (ECG), and the Anti-Drug 
Antibody (ADA) test will be collected for each subject during the study according to the 
schedule of assessments.
6.1.1. Safety Measures: Adverse Events
Pfizer standard safety data presentations will be made for adverse event data.
The details of Tier-1, Tier-2 and Tier-3 AEs are described in Section 3.5.1.
Treatment-emergent adverse events within Tier-1 will be summarized.  The combined Tier-1 
adverse events, but not each adverse event will be summarized using Risk Differences 
between each tanezumab group and celecoxib, together with 95% CI and p-value, using exact 
methods.  Treatment-emergent adverse events within Tier-2 will be summarized using Risk 
Differences between each tanezumab group and celecoxib, together with 95% CI, using exact 
methods.  There will be no multiplicity adjustment for these significance tests.  These tables 
will be produced for the comparisons of tanezumab 5mg versus celecoxib and tanezumab 
10mg versus celecoxib.
The following footnote will be used in the Tier-1 AE tables: “P-values and confidence 
interval 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.”
Similarly the following footnote will be used in the Tier-2 AE tables: “Confidence intervals 
are not adjusted for multiplicity and should be used for screening purpose only. 
95% Confidence intervals are provided to help gauge the precision of the estimates for Risk 
Difference.”
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.
Pfizer standard safety data presentations will be made for demography data, concomitant 
medications, discontinuation data, adverse event data, laboratory test data, vital sign data and 
ECG data. 
The non-standard safety tables as described in Section 3.5.1 will also be summarized.  The 
details are described below.
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) will be created.  


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The following non-standard safety tables will also be included:

Incidence and severity of adverse events leading to discontinuation.

Summary of AEs, Incidence of AEs, Incidence of AEs leading to discontinuation and 
summary of Serious AEs.

‘Incidence and severity’ tables of treatment-emergent adverse events of Abnormal 
Peripheral Sensation (APS), and Sympathetic Nervous system, 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.

Adverse events associated with laboratory abnormalities, vital signs, and ECG 
measurement may be summarized.
6.1.2. Safety Measures: Standard Safety Assessments (safety laboratory testing 
[chemistry, and hematology], vital signs)
Pfizer standard safety data presentations will be made for laboratory test data and vital signs 
data.  The following non-standard safety tables will also be included:

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, >30-40, and >40, and (diastolic BP) only decreases 
or no change, >0 to 10, >10-20, >20-30, and >30.

A summary of the maximum decrease from baseline in the sitting systolic and 
diastolic blood pressure.  The categories used are: (systolic BP) <-40, -40 to 
<-30, -30 to <-20, -20 to <-10, -10 to <0, only increases or no change, and (diastolic 
BP) <-30, -30 to <-20, -20 to <-10, -10 to <0, only increases or no change.

A summary of the change from baseline to last observation in the sitting systolic and 
diastolic blood pressure.  The categories used for these summaries are: (systolic BP) 
≤-40, >-40 to -30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to <10, 10-<20, 20-<30, 
30-<40, ≥40, and (diastolic BP) ≤-30, >-30 to -20, >-20 to -10, >-10 to 0, >0 to 
<10, 10-<20, 20-<30, ≥30.
6.1.3. Safety Measures: Orthostatic (supine/standing) Blood Pressure Assessments 
The following non-standard safety tables will be included

Incidence of subjects with orthostatic hypotension (defined in Section 3.5.3 above), 
for each visit and any post-baseline of orthostatic hypotension.  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.


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6.1.4. Safety Measures: Survey of Autonomic Symptoms (SAS) Scores
The following non-standard safety tables will be included:

Summary of the Survey of Autonomic Symptoms (SAS) number of symptoms 
reported and total symptom impact score as continuous data, at each visit, and for the 
change from Screening score (scores defined in Section 3.5.4 above).
6.1.5. Safety Measures: Electrocardiogram (ECG, 12-lead) Assessments
Pfizer standard safety data presentations will be made for ECG data such as PR, QRS, QT, 
QTcF, QTcB, RR intervals, and heart rate [HR].
6.1.6. Safety Measures: Joint Safety Adjudication Outcomes and Total Joint 
Replacements
Adjudication outcomes to be summarized include 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, 
pathological fracture, normal progression of OA and other joint outcomes.  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 
will also be summarized. Total joint replacement (TJR) will also be summarized. Output 
will show the number and percentage with 95% CI (exact confidence interval) of subjects for 
each outcome. In addition, subject years of exposure for individual treatment group and 
exposure adjusted event rates (number of subjects with an adjudicated joint safety event 
divided by exposure) of each outcome (with 95% CI) will also be shown. For each outcome, 
association with TJR, affected joint(s), and baseline Kellgren-Lawrence Grade of affected 
joint will be summarized. Number of TJRs during study, study period of first TJR 
occurrence, number of only elective TJR, number of joints with TJR prior to study, location 
of TJR prior to study will also be summarized. 
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.
Reporting of total joint replacement events including surgery will be described in a separate 
Statistical Analysis Plan that will cover patients in this subset from Studies 1059, 1061 and 
1063.  Corresponding data from Studies 1056, 1057 and 1058 will be reported under study 
1064.  Summary listings for the data from the 1063 substudy will be part of the 1063 study 
CSR as there are <10 total joint replacement events expected in the substudy.


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6.1.7. Safety Measures: Neurologic Examination (Neuropathy Impairment Score [NIS]) 
The change from Baseline in the NIS for Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 will 
be summarized. The number and percentage of subjects whose NIS score worsened 
(change>0), improved (change<0) or had no change will also be shown.  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 post baseline value.  The last post baseline value will only be used in the summary of 
change from baseline (not be used in the summary with change categories). 
Neurological-related safety data
The “conclusion from the neurological examination” data will be summarized for each 
timepoint and the final assessment over all neurological examinations for each subject.  In 
addition the persistence of any neurological examination finding will be summarized, 
showing the incidence of subjects with new or worsened neurological examination 
abnormality (both clinically significant only and also for any finding) for 2, 3, 4, and 
≥5 consecutive visits.
6.1.8. Safety Measures: Outcome of Consultation
Summary of neurological consultation will be shown.  The number of subjects with at least 
1 adverse event requiring neurological consult, and whether or not a neurologic consult 
performed, and the expert primary diagnosis will be summarized.  Further details of
neurological consultation will be summarized. 
Summary of incidence of sympathetic neuropathy based on investigator assessment and, if 
performed, expert consultant assessment will be shown.
6.1.9. Safety Measures: Anti-drug Antibody Assessments (ADA)
The following assessments of ADA data will be made using all available data:

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 efficacy and safety profile.


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6.1.10. Safety Measures: Physical Examinations
The following non-standard safety tables will also be included:

Incidence of physical examination findings at screening.

Incidence of musculoskeletal physical examination findings at screening.
6.2. Secondary Endpoints
All analyses in this section use the ITT analysis set, if not otherwise specified. If not 
otherwise specified, the observed data (no imputation for missing data) will be summarized.  
All efficacy assessments during the treatment period are made on the analysis windows 
defined in Appendix 2.1. Using these windows we find the analysis window for a patient’s 
last subcutaneous (SC) dose.  Any data included in a window that is up to 8 weeks from this 
last SC dose window is ‘on-treatment’, and any data included in a window that is more than 
8 weeks after the last SC dose window is off treatment.  Data in on-treatment analysis 
windows will be used in summaries and analyses, while data in off-treatment analysis 
windows will be excluded from all summaries and analyses of treatment period efficacy data, 
ie, up to Week 56.
Efficacy data collected via subject diary (aLBPI 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 84 calendar days after the last SC dose.  Diary efficacy data collected more 
than 84 calendar days after the last SC dose will be considered off-treatment and excluded 
from summaries and analyses of treatment period efficacy data.
6.2.1. Average Low Back Pain Intensity (LBPI) Score
Change from Baseline to Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64 in average LBPI 
score.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. Handling of missing data is described in Section 5.3.
The ANCOVA model for change from baseline of aLBPI up to week 56 described in 
section 5.2.2 will also be conducted.  The plot of LS mean (+/- SE) for change from baseline 
up to week 56 will also be prepared.
LBPI data obtained after the early termination visit and considered as off-treatment will be 
shown in the listing and not be included in any summaries and analyses.
Cumulative distribution of percent change from Baseline in average LBPI score to Weeks 16, 
24 and 56.
The cumulative aLBPI 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 observed data, 
mixed BOCF/LOCF, and also LOCF and BOCF imputation for aLBPI (see Section 5.3). 


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Imputation with BOCF for subjects with missing data at that timepoint will lead to the 
subjects being assessed as non-responders for the response endpoint.
Plots of cumulative distribution of percent change from Baseline in average LBPI score to 
Week 16 and Week 56 (mixed BOCF/LOCF) will be created.
Response as defined by a Ӌ30%, Ӌ50%, Ӌ70% and a Ӌ90% reduction from Baseline in weekly 
average LBPI score derived from the subject diary at Weeks 16, 24, 40 and 56.
For each treatment and each timepoint assessed, the number and percentage of subjects in 
each response category endpoint will be summarized along with 95% CIs. Treatment 
differences of proportion of responder between each tanezumab treatment group versus 
celecoxib group will be estimated with 95% CI of Agresti-Caffo method. These analyses use 
observed data, 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.
6.2.2. Roland-Morris Disability Questionnaire (RMDQ) total score
Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in the RMDQ total 
score.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. Handling of missing data is described in Section 5.3.
The ANCOVA model for change from baseline of RMDQ up to week 56 described in 
section 5.2.2 will also be conducted.  The plot of LS mean (+/- SE) for change from baseline 
up to week 56 will also be prepared.
Response as defined by a ≥30%, ≥50%, ≥70% and a ≥90% reduction from Baseline in the 
RMDQ score at Weeks 16, 24, 40 and 56.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. These analyses use observed data, 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.
Cumulative distribution of percent change from Baseline in RMDQ score to Weeks 16 and 
56.
The cumulative RMDQ response at Weeks 16 and 56 using response definitions from a 
reduction of >0% to =100% (in steps of 10%) will be summarized using mixed BOCF/LOCF 
imputation for RMDQ. Plots of cumulative distribution of percent change from Baseline in 
RMDQ score to Week 16 and Week 56 (mixed BOCF/LOCF) will also be created.


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6.2.3. Patient’s Global Assessment of Low Back Pain (PGA-LBP)
Change from Baseline to Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 in Patient’s Global 
Assessment of Low Back Pain.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. Handling of missing data is described in Section 5.3.
Treatment Response: Improvement of Ӌ2 points in Patient’s Global Assessment of Low Back 
Pain at Weeks 16, 24, 40 and 56.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. Handling of missing data is same with Section 5.3.
Treatment Response: Any improvement (change<0), no change (change=0), any worsening 
(change>0) at Weeks 16, 24, 40 and 56.
For each treatment and each timepoint assessed, the number and percentage of subjects in 
each category will be shown. Handling of missing data is same with Section 5.3.
6.2.4. Brief Pain Inventory-short form (BPI-sf) scores
Change from Baseline to Weeks 2, 4, 8, 16, 24, 40, 56 and 64 in the BPI-sf scores for Worst 
Pain, Average Pain, Pain Interference Index (composite function score), Pain Interference 
with General Activity, Pain Interference with Walking Ability, Pain Interference with Sleep, 
and Pain Interference with Normal Work.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. Handling of missing data is described in Section 5.3.
6.2.5. Chronic Low Back Pain Responder Index (CLBP-RI) Analysis
CLBP-RI analysis [composite endpoint of average LBPI score, Patient’s Global Assessment 
of Low Back Pain, and RMDQ total score] at Weeks 16, 24, 40 and 56.
For each treatment and each timepoint assessed, the endpoint will be summarized along with 
95% CIs. Handling of missing data is same with Section 5.3.
Plot of CLBP-RI analysis at week 16, 24, 40 and 56 (mixed BOCF/LOCF) will be created.
6.2.6. Euro Quality of Life Health State Profile (EQ-5D-5L™)
EQ-5D-5L™dimensions and overall health utility score at Baseline, Weeks 16 and 56
The Baseline and Weeks 16 and 56 responses in the five dimensions (mobility; self-care; 
usual activity; pain/discomfort; anxiety/depression) and overall health utility score from the 
EuroQol 5 Dimensions (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 2.3.


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An additional question, called the EQ-VAS asks the patient to rate their health today using a 
VAS scale from 0 (the worst health you can imagine) to 100 (the best health you can 
imagine).  This will be summarized along with the health utility score.
A table showing number and percentage of subjects will summarize the response for each 
dimension (item) of the EQ-5D-5L at each timepoint.  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, minimum, maximum, number of subjects) will 
be shown for the health utility score, and the EQ-VAS measure of health today.
6.2.7. Work Productivity and Activity Impairment Questionnaire: Low Back Pain 
(WPAI:LBP)
WPAI:LBP change from Baseline to Week 16, 56 and 64, in the percent work time missed 
due to chronic low back pain, percent impairment while working due to chronic low back 
pain, percent overall work impairment due to chronic low back pain, and percent activity 
impairment due to chronic low back pain.
This summary of WPAI:LBP will use observed data only (no imputation for missing data).  
These are listed below: 

Percent work time missed due to Low Back Pain.

Percent impairment while working due to Low Back Pain.

Percent overall work impairment due to Low Back Pain.

Percent activity impairment due to Low Back Pain.
The calculation of these endpoints is described in Appendix 2.3.  The change from Baseline 
in the impairment scores of the WPAI:LBP will be summarized by treatment group.
The summary will show number and percentage of patients with a decrease, no change, and 
an increase in score for the change from Baseline to each timepoint. In addition, descriptive 
statistics (mean, standard deviation, median, min, max, number of subjects) for the change 
from Baseline to each timepoint and the absolute scores at the individual timepoints of 
Baseline and Weeks 16, 56, and 64 will be calculated.
6.2.8. Discontinuation Due to Lack of Efficacy
Incidence of and time to discontinuation due to lack of efficacy
The incidence of discontinuation from treatment due to ‘INSUFFICIENT CLINICAL 
RESPONSE’ and ‘PATIENT MEETS PROTOCOL-SPECIFIED PAIN CRITERIA FOR 
DISCONTINUATION’ on the End of Treatment Subject Summary Case Report Form will 
be summarized along with 95% CIs 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.  The differences with 95% CIs will be calculated for the comparisons of each 


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tanezumab group versus the celecoxib group. A supplementary analysis for the incidence of 
discontinuation from treatment due to ‘INSUFFICIENT CLINICAL RESPONSE’ will also 
be performed.
The time to discontinuation due to lack of efficacy will be summarized 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.
6.2.9. Usage of Rescue Medication
Usage of rescue medication (incidence, and number of days of usage) during Weeks 1, 2, 4, 
8, 12, 16, 24, 32, 40, 48, 56 and 64.
Incidence of rescue medication use will be summarized up to Week 64 using observed data 
and LOCF imputation. Imputation of weekly diary data after week 56 will not be performed.
Number and percentage of subjects taking rescue medication will be shown.
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 2.3.
The number of days of rescue medication use per week endpoint will be summarized for the 
Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64 using observed data and LOCF
imputation.  Imputation of weekly diary data after week 56 will not be performed.  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.  Number of subjects, mean, median, standard deviation, 
minimum and maximum will be shown.


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Usage of rescue medication (amount taken) during Weeks 1, 2, 4, 8, 12, and 16.
The amount of rescue medication use per week will be summarized for the Weeks 1, 2, 4, 8, 
12 and 16 using observed data and LOCF imputation.  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.  Number of subjects, mean, median, standard deviation, minimum and maximum 
will be shown.
6.2.10. Health Care Resource Utilization (HCRU)
HCRU at Baseline, Weeks 64 and 80.
Individual items in HCRU at Baseline, Weeks 64 and 80 will be summarized as described in 
Appendix 2.3. As for questions obtaining number of visits and number of nights stayed in 
the hospital, n, mean, median, standard deviation, minimum and maximum will be shown.  
As for questions obtaining binary or categorical responses, number and percentage of each 
response category will be shown.
6.2.11. Treatment Satisfaction Questionnaire for Medication v.II (TSQM) Score
TSQM score at Weeks 16 and 56.
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.  
Summary tables showing number and percentage of patients by value and treatment group 
will be shown for TSQM items 1-2 and 4-11, and the four satisfaction parameters.
This summary and analysis will use observed data only (no imputation for missing data).  
The calculation of these endpoints are described in Appendix 2.3.
6.2.12. Patient Reported Treatment Impact Assessment-Modified (mPRTI)
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 low back 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’).


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Summary tables showing number and percentage of patients 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).
6.3. Other Endpoints: Tertiary Endpoints
6.3.1. Plasma Tanezumab Concentrations
The following reporting of PK data will be done using all available data:

A listing of all plasma tanezumab concentrations sorted by subject, active treatment
group and nominal time post dose. The listing of concentrations will also include the
actual times post dose.

A descriptive summary of the plasma tanezumab concentrations based on nominal
time post dose for each treatment group.

Boxplots of tanezumab plasma trough concentrations at the nominal times for the 
tanezumab treatment groups.
6.3.2. Serum NGF Assessments
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 NGF concentrations sorted by subject, active treatment group 
and time post dose.

Descriptive statistics of NGF concentrations based on time post dose for each 
treatment group.

Boxplots of NGF over time post dose for each treatment group.
6.4. Subset Analyses 
Analysis of the data relating to Total Joint Replacement surgery will be performed using the 
TJR subset analysis set.  Reporting of total joint replacement events including surgery and 
recovery will be described in a separate Statistical Analysis Plan that will cover patients in 
this subset from Studies 1059, 1061 and 1063.  Corresponding data from Studies 1056, 
1057 and 1058 will be reported under study 1064.  This data from Study 1063 will be 
reported separately.


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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following baseline characteristics will be summarized.

A summary of baseline characteristics.  This summary includes average LBPI, BPI-sf 
average pain and worst pain, RMDQ total score, PGA-LBP, Low back pain duration 
and etiology, Quebec Task Force (QTF) category, diabetes status (from medical 
history and/or pre-treatment HbA1c≥6.5%), and pain Detect score (Appendix 4.3).

Summaries of Baseline painDetect score in continuous scale (Mean/SD/Min/Max) 
and by painDetect category (painDetect score <= 12, 13 to 18, >=19).

Plot of the cumulative distribution function of painDetect score
6.5.2. Study Conduct and Subject Disposition
The following subject dispositions will be summarized.

Summary of number of patients treated by treatment group.

Summary table and listing of inclusion and exclusion criteria that are not met by 
subjects who were screened (but not randomized).

Summary of time to 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, total) and for the safety follow-up period (Weeks 
1-8, 9-16, 17-24, >24, total).

A summary of discontinuation up to End of Treatment period, and up to End of Study 
period.
6.5.3. Study Treatment Exposure
The following study treatment exposure will be summarized.

Number of SC doses taken. 

Summary of oral study medication compliance.  This is calculated for the interval 
from Baseline to 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 multiplied by 100, to get a 
percentage compliance for each patient.  The number and percentage of subjects in 
each category (>=50%, >=80% and >=100% compliance) will be shown.
In addition, summary of duration in treatment period and post-treatment follow-up period 
will be summarized.  The number and percentage of patients with each duration category will 
also be shown. The duration categories are 1-2, 3-4, 5-8, 9-12, 13-16, 17-24, 25-32, 33-40, 


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41-48, 49-56, >56 for duration in treatment period and 1-8, 9-16, 17-24, >24 for duration in 
post-treatment follow-up period, respectively.
6.5.4. Concomitant Medications, Non-Drug Treatments and Drug Treatments Prior to 
Start of Study Treatment
The following concomitant medications and non-drug treatment will be summarized.

Concomitant drug treatments during the treatment phase through week 64 or up to 
16 weeks post the last SC dose will be summarized. Summary of concomitant 
medications for non-NSAID medication and drug treatments for CLBP, concomitant 
NSAID medications, concomitant analgesics not used for CLBP, and concomitant 
non-drug treatments will be shown separately.

Concomitant drug treatments after 16 weeks post last SC dose will be summarized for 
analgesics and other treatment for CLBP.

Number of days of non-study NSAID use per dosing interval (eg, Baseline to Week 8 
and Week 8 to Week 16, up to Week 56) and for Week 56 to Week 64. This will 
show the number and percentage of subjects in a dosing interval who exceeded the 
limit of 10 days of NSAID use. If a dosing 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 each 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.
The treatment prior to start of study treatment will also be summarized. Summary of 
analgesics and drug treatments for CLBP, analgesics not used for CLBP, non-analgesics and 
non-CLBP medication, and non drug treatments prior to start of study treatment will be 
shown separately.
7. INTERIM ANALYSES
7.1. Introduction
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 external Data Monitoring Committee 
(E-DMC).
7.2. Interim Analyses and Summaries
Events relating to joint safety, including reported Osteonecrosis or events leading to Total 
Joint Replacement will be reviewed by a blinded expert adjudication panel.  A stopping rule 
relating to a set of adjudicated outcomes has been defined, and is described below.


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If the blinded Adjudication Committee identifies adjudicated events of rapidly progressive 
osteoarthritis type 2, subchondral insufficiency fractures, primary osteonecrosis, or 
pathological fracture, occurring at a rate that could trigger the protocol-based stopping 
criteria, an urgent, ad hoc assessment of the events will be made by the E-DMC.
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 celecoxib treatment 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. 
 
 and the RR is 
and the difference in the number of subjects with adjudicated events joint safety event 
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.
Separate sets of dosing suspension rules for specified Serious Adverse Events and events 
consistent with Hy’s Law are described in Sections 9.6.1.1 and 9.6.1.2 of the protocol, 
respectively.
CCI
C
CI
CC
I
CCI


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8. REFERENCES 
1.
Atkinson, MJ et al (2005).  Hierarchical construct validity of the treatment satisfaction 
questionnaire for medication (TSQM Version II) among outpatient 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.
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-1736.
4.
Little RJ & Rubin DB (2002).  Statistical Analysis with Missing Data.  New Jersey: 
Wiley.
5.
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).


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9. APPENDICES 
Appendix 1. SUMMARY OF EFFICACY ANALYSES
Note: BL=Baseline
Endpoint
Analysis 
Set
Statistical Method 
Model/Covariates
Missing 
Data
Objective
Change from Baseline to Weeks 1, 2, 4, 
8, 12, 16, 24, 32, 40, 48, 56 and 64 in 
aLBPI
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in aLBPI
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in aLBPI
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in aLBPI
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 1, 2, 4, 
8, 12, 16, 24, 32, 40, 48 and 56 in aLBPI
ITT
ANCOVA
BL score, 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, 56 and 64 in RMDQ 
total score
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in RMDQ total score
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in RMDQ total score
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in RMDQ total score
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis


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Change from Baseline to Weeks 2, 4, 8, 
16, 24, 32, 40, 48 and 56 in RMDQ total 
score
ITT
ANCOVA
BL score, BL LBPI score, 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, 56 and 64 in PGA-
LBP
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in PGA-LBP
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in PGA-LBP
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and
56 in PGA-LBP
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 aLBPI
ITT
None (summary)
NA
Observed
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 aLBPI
ITT
None (summary)
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 aLBPI
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 aLBPI
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in the aLBPI 
ITT
None (summary)
NA
Observed
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in the aLBPI 
ITT
None (summary)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis


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Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in the aLBPI
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in the aLBPI 
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in RMDQ total score
ITT
None (summary)
NA
Observed
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in RMDQ total score
ITT
None (summary)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in RMDQ total score
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with reduction of  
>30/50/70/90% from Baseline to Weeks 
16, 24, 40 and 56 in RMDQ total score 
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 and 56 in RMDQ total score
ITT
None (summary)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf 
Worst Pain 
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Worst Pain 
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Worst Pain 
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Worst Pain 
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis


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Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf 
Average Pain 
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Average Pain 
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Average Pain 
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Average Pain
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf Pain 
Interference Index
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference Index 
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference Index 
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference Index
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf Pain 
Interference with General Activity
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
General Activity
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
General Activity
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
General Activity
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis


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Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf Pain 
Interference with Walking Ability
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Walking Ability
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Walking Ability
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Walking Ability
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf Pain 
Interference with Sleep
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Sleep
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Sleep
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Sleep
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 2, 4, 8, 
16, 24, 40, 56 and 64 in the BPI-sf Pain 
Interference with Normal Work
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Normal Work
ITT
None (summary)
NA
Multiple 
imputation
Secondary Endpoint 
Analysis


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Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Normal Work
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16 and 
56 in the BPI-sf Pain Interference with 
Normal Work
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
The CLBP-RI response at Weeks 16, 24, 
40 and 56
ITT
None (summary)
NA
Observed
Secondary Endpoint 
Analysis
The CLBP-RI response at Weeks 16, 24, 
40 and 56  
ITT
None (summary)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
The CLBP-RI response at Weeks 16, 24, 
40 and 56  
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
The CLBP-RI response at Weeks 16, 24, 
40 and 56  
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 16, 24, 40 56 in the PGA-LBP  
ITT
None (summary)
NA
Observed
Secondary Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 16, 24, 40 56 in the PGA-LBP  
ITT
None (summary)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 16, 24, 40 56 in the PGA-LBP  
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with an 
improvement of ≥2 points from Baseline 
to Weeks 16, 24, 40 56 in the PGA-LBP  
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with any 
improvement (change<0), no change 
(change=0), any worsening (change>0) 
in the PGA-LBP at Weeks 16, 24, 40 
and 56
ITT
None (summary)
NA
Observed
Secondary Endpoint 
Analysis


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Percentage of subjects with any
improvement (change<0), no change 
(change=0), any worsening (change>0) 
in the PGA-LBP at Weeks 16, 24, 40 
and 56
ITT
None (summary)
NA
Mixed 
BOCF/LOCF
Secondary Endpoint 
Analysis
Percentage of subjects with any
improvement (change<0), no change 
(change=0), any worsening (change>0) 
in the PGA-LBP at Weeks 16, 24, 40 
and 56
ITT
None (summary)
NA
BOCF
Secondary Endpoint 
Analysis
Percentage of subjects with any
improvement (change<0), no change 
(change=0), any worsening (change>0) 
in the PGA-LBP at Weeks 16, 24, 40 
and 56
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Time to discontinuation due to lack of 
efficacy (up to Week 56/End of 
Treatment)
ITT
KM estimates
NA
Observed Data
Secondary Endpoint 
Analysis
Incidence of rescue medication use 
during Weeks 1, 2, 4, 8, 12, 16, 24, 32, 
40, 48, 56 and 64
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Number of days of rescue medication 
use during Weeks 1, 2, 4, 8, 12, 16, 24, 
32, 40, 48, 56 and 64
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Amount (mg) of rescue medication 
taken during Weeks 1, 2, 4, 8, 12, 16
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
Incidence of rescue medication use 
during Weeks 1, 2, 4, 8, 12, 16, 24, 32, 
40, 48 and 56
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Number of days of rescue medication 
use during Weeks 1, 2, 4, 8, 12, 16, 24, 
32, 40, 48 and 56
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis


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Amount (mg) of rescue medication 
taken during Weeks 1, 2, 4, 8, 12, 16
ITT
None (summary)
NA
LOCF
Secondary Endpoint 
Analysis
Change from Baseline to Weeks 16, 56
and 64 in WPAI Impairment scores 
(Percent work time missed due to Low 
Back Pain; Percent impairment while 
working due to Low Back Pain; Percent 
overall work impairment due to Low 
Back Pain; Percent activity impairment 
due to Low Back Pain)
ITT
None (summary)
NA
Observed Data
Secondary Endpoint 
Analysis
EQ-5D dimensions (Mobility; Self-care; 
Usual activity; Pain/Discomfort; 
Anxiety/Depression) and Overall Health 
Utility at Baseline and Weeks 16 and 56
ITT
Summary
NA
Observed Data
Secondary Endpoint 
Analysis
EQ-VAS at Baseline and Weeks 16 and 
56
ITT
Summary
NA
Observed Data
Secondary Endpoint 
Analysis
mPRTI endpoints (willingness to re-use; 
patient preference; patient satisfaction) 
at Weeks 16 and 56
ITT
Summary
NA
Observed
Secondary Endpoint 
Analysis
TSQM endpoints (satisfaction with 
effectiveness, side effects and 
convenience, and overall satisfaction) at 
Weeks 16 and 56
ITT
Summary
NA
Observed
Secondary Endpoint 
Analysis
Healthcare Resource Utilization at 
baseline, week 64 and 80
ITT
Descriptive 
Summary
NA
Observed
Secondary Endpoint 
Analysis


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Appendix 2. DATA DERIVATION DETAILS
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Study visits are planned at Screening, Baseline and then at post-baseline Weeks 2, 4, 8, 16, 
24, 32, 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, 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 study visits (eg, BPI-sf, PGA-LBP 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 30 days 
prior to baseline visit)
[No lower limit, Day -6]
Baseline
1 (defined as initial day of 
study drug administration)
[-5,1]
Week 2
15
[2,22]
Week 4
29
[23,43]
Week 8
57
[44,85]
Week 16
113
[86,141]
Week 24
169
[142,197]
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]
As for BPI-sf, the visit window is below.
Visit
Target Study Day
Window
Screening [1]
Variable (up to 30 days 
prior to baseline visit)
[No lower limit, Day -6]
Baseline
1 (defined as initial day of 
study drug administration)
[-5,1]
Week 2
15
[2,22]
Week 4
29
[23,43]
Week 8
57
[44,85]
Week 16
113
[86,141]
Week 24
169
[142,225]
Week 40
281
[226, 309]
Week 48
337
[310, 365]
Week 56
393
[366, 421]
Week 64
449
[422, 477]


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Besides the windows specified above, there is one additional window as defined as follows:
1. “16 Weeks after Last Dose”.  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 [86, 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.
EQ-5D-5L is collected at Baseline, Weeks 16 and 56, and ET1.  WPAI:LBP is collected at 
Baseline, Weeks 16, 56, 64, and ET1 and ET2.  HCRU is collected at Baseline, Weeks 64 
and 80, and ET2 and ET3.  TSQM and mPRTI are collected at Weeks 16 and 56, and ET1.  
The visit window for these visits will be defined below.
EQ-5D-5L, TSQM, mPRTI
Visit
Target Study Day
Window
Baseline
1 (defined as initial day of 
study drug administration)
[-7, 1]
Week 16
113
[2, 253]
Week 56
393
[254, no upper limit]]
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]
WPAI: OA,
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, 421]
Week 64
449
[422, no upper limit]
Data in on-treatment analysis windows will be used in summaries and analyses of treatment 
period efficacy data, ie, up to Week 56,  while data in off-treatment analysis windows will be 
only included in summaries (at Week 64, Week 80, 16 Weeks after Last Dose, and End of 
Study).  Data in off-treatment analysis windows will be imputed, if needed, in analyses.


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Any data collected up to 8 weeks (per the windowing rule above) from the last SC dose 
window is ‘on-treatment’, and any data collected more than 8 weeks (per the windowing rule 
above) after the last SC dose window is off treatment.  For example, for patients whose last 
SC dose is at Week 8 (per the windowing rule above), any data collected after Week 16 (per 
the windowing rule above) will be off-treatment.
For the weekly diary average Low Back Pain Intensity scores, the data will be allocated to 
study weeks based on calendar weeks relative to the baseline visit (study day 1) and not 
based on the post-baseline visit schedule.  The table below describes the visit days for each 
week.  The mean of available weekly data in each of the weekly intervals will be used to 
calculate the weekely diary average Low Back Pain Intensity scores.
Study 
Week
Days
1
1-7
2
8-14
3
15-21
4
22-28
5
29-35
6
36-42
7
43-49
8
50-56
9
57-63
10
64-70
11
71-77
12
78-84
13
85-91
14
92-98
15
99-105
16
106-112
At the Screening visit only, the Low Back Pain Intensity (Numeric Rating Scale) will be administered with a 
patient worksheet for screening purposes.Also, the daily LBPI scores collected during the Initial Pain 
Assessment Period (Days-5 to -1), will be averaged to assess versus study inclusion criteria.
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 Week 16
score, and the available scores from Days 99-101 will be used to calculate the Week 15 score.
After the Week 16 visit, 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.


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All available on- or off-treatment data will be used for these windows after the planned 
treatment period.
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
When multiple observations occur in a day for pain score collected weekly, the average of 
scores will be used.
For rescue medication, data are collected until the end of study (Week 80 or final ET).  
Additional windows are defined below
Summary 
Week
Includes 
Weeks
Days
68
65 - 68
449-476
72
69 – 72
477-504
76
73 – 76
505-532
80
77 – 80 
533-560
Besides the windows specified above, there is one additional window as defined as follows:
“16 Weeks after Last Dose”.  This window will include the average of all data 
collected from 13 to 16 calendar weeks (85 to 112 calendar 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.
Note that, similar to data collected at clinic visit, any data collected via diary up to 
84 calendar day (12 weeks, 8 weeks + a 4 week window) from the date of the last SC dose 
are ‘on-treatment’, and any data collected more than 84 calendar day (12 weeks, 
8 weeks + a 4 week window) from the date of the last SC dose are off treatment. 


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Appendix 2.2. Definition of Protocol Deviations that Relate to Statistical 
Analyses/Populations
Not applicable.
Appendix 2.3. 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.
It is intended that this study will recruit patients from Japan.
WPAI:LBP Endpoints
The tables below summarizes the 6 questions of the WPAI:LBP 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 Low Back Pain
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 Low Back Pain affect productivity while 
you were working?
0 to 10 scale with 0 being ‘Low Back 
Pain had no effect on my work’ and 10 
being ‘Low Back Pain completely 
prevented me from working’
6
During the past seven days, how much did 
your Low Back Pain affect your ability to do 
your regular daily activities, other than work 
at a job?
0 to 10 scale with 0 being ‘Low Back 
Pain had no effect on my daily 
activities’ and 10 being ‘Low Back Pain 
completely prevented me from doing 
my daily activities’


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WPAI endpoint
Calculation
Percent activity impairment due to Low Back 
Pain
Q6*10
Percent impairment while working due to Low 
Back Pain
Q5*10
Percent overall work impairment due to Low 
Back Pain
100
10
5
4
2
2
1
4
2
2




























Q
Q
Q
Q
Q
Q
Q
Percent work time missed due to Low Back 
Pain
4
2
2
Q
Q
Q

*100
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)


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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.
Healthcare Resource Utilization (example using 3 month recall – 8 week recall is also 
used in this study)
Question
Response
Scoring
During the last 3 months, what 
services did you receive directly 
related to your low back pain?

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 last 3 months, have you 
visited the emergency room due to
your low back pain?
Yes, No
No = 0
Yes = 1
How many times?
Number of visits
0-999 
During the last 3 months, have you 
been hospitalized due to your low 
back pain?
Yes, No
No = 0
Yes = 1
How many nights in total did you 
stay in hospital due to your low 
Number of Nights
0-999 (max should be 
92)


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back pain in the last 3 months?
Did you use these aids or devices 
to help you in doing things because 
of your low back pain 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 low back pain?
Yes, No
No = 0
Yes = 1
Not applicable = 2
How long ago did you quit your 
job because of your low back pain?
Years and Months
0-99 Years and 0-99 
Months (should be max 
of 11 months)
Rescue Medication Endpoints
Rescue medication data is collected daily using an electronic system up to Week 16, and 
weekly after Week 16 and up to Week 64.  Daily and Weekly collected data will be assigned 
to a specific study week for summary and reporting.  The assignment of daily and weekly 
data to weeks will use the same principle as described above in Appendix 2.1 for the weekly
aLBPI 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 5.3 above.  Imputation occurs for daily data up to Week 16 
where the patient 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 (Patient does not 
discontinue)
In this example, a patient has a Week 2 visit on study day 14 (slightly earlier than the 
nominal day 15).  Study days 8-14 would represent Week 2 data.
Using the Week 2 interval described above for a subject, ie, study days [8-14], we have the 
following rescue medication example data.


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The amount taken and number of days of rescue medication use is adjusted for the duration 
of the Weekly interval.  
Study Day (Week)
Number of Doses of 
RM taken [1]
Number of Doses of 
RM taken [1] with 
LOCF imputation
8 (Week 2)
2
2
9 (Week 2)
Missing
2 [2]
10 (Week 2)
0
0
11 (Week 2)
1
1
12 (Week 2)
Missing
1 [2]
13 (Week 2)
2
2
14 (Week 2)
0
0
[1] 500mg tablets of acetaminophen; [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 4000 mg.
Example of calculating rescue medication data from Daily Diary Data (Patient 
discontinues)
In this example, a patient 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 patient has rescue medication data as shown below.
Study Day (Week)
Number of Doses of 
RM taken [1]
Number of Doses of 
RM taken [1] with 
LOCF imputation
57 (Week 9)
1
1
58 (Week 9)
1
1
59 (Week 9)
Missing
1 [2]
60 (Week 9)
Missing
1 [2]
61 (Week 9)
Missing
1 [2]
62 (Week 9)
Missing
1 [2]
63 (Week 9)
Missing
1 [2]
[1] 500mg tablets of acetaminophen; [2] Using LOCF imputation for missing data.


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Week 9 is calculated as days 57 to 63.  The data up to the end of the last week the patient was 
in the trial is imputed using LOCF as shown above.  Therefore the Week 9 scores are then 
used to impute the Weekly data from summary and analysis for Weeks 10 to 56.
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=3500 mg for this week.


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Appendix 3. DATA SET DESCRIPTIONS
Not applicable.
Appendix 4. STATISTICAL METHODOLOGY DETAILS 
Appendix 4.1. 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 4.2. Further Details of 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),4 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 
ifor 
  .  The combined estimate is 



D
i
i
D
D
1
1


.  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


where 
i
W is the variance for the parameter 
i.
The total variance for 
D
is shown below:
D
D
D
B
D
D
W
T
1



.
The test statistic 

D
D
T


has a t-distribution with 
*
v degrees of freedom, which is defined 
below:
,
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





























This distribution can be used to construct the test statistics and 95% confidence intervals 
for θ.
Appendix 4.3. painDETECT Questionnaire5
PainDETECT score will be calculated based on the below table.
Item
Score
Gradation of pain*
Do you suffer from a burning sensation (eg, stinging nettles) in the 
marked areas?
0–5
Do you have a tingling or prickling sensation in the area of your 
pain (like crawling ants or electrical tingling)?
0–5
Is light touching (clothing, a blanket) in this area painful?
0–5
Do you have sudden pain attacks in the area of your pain, like 
electric shocks?
0–5
Is cold or heat (bath water) in this area occasionally painful?
0–5
Do you suffer from a sensation of numbness in the areas that you 
marked?
0–5
Does slight pressure in this area, eg, with a finger, trigger pain?
0–5


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Pain course pattern
Persistent pain with slight fluctuations
0
Persistent pain with pain attacks
-1
Pain attacks without pain between them
+1
Pain attacks with pain between them
+1
Radiating pain
Does your pain radiate to other regions of your body? Yes/No
+2/0
* For each question: never, 0; hardly noticed, 1; slightly, 2; moderately, 3; strongly, 4; very strongly, 5.