Final Clinical Study Report
Protocol A4091063

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Tanezumab/PF-04383119
Clinical Study Report Synopsis: Protocol A4091063
Protocol Title: A Phase 3 Randomized, Double-Blind, Active-Controlled, Multicenter Studyof the Long-Term Safety and Efficacy of Subcutaneous Administration of Tanezumab inJapanese Adult Subjects With Chronic Low Back Pain
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): A total of 58 sites randomized patients in this study. The study was
conducted at sites in Japan.
Publications Based on the Study: None
Study Initiation Date: 26 May 2016
Study Completion Date: 11 June 2019
Report Date: 08 July 2020
Previous Report Date(s): 20 November 2019
Phase of Development: Phase 3
Study Objectives
Primary ObjectiveTo evaluate the long-term safety of tanezumab 5 mg and tanezumab 10 mg
subcutaneously (SC) administrated every 8 weeks (7 administrations).

Secondary Objective

To demonstrate the long-term analgesic efficacy of tanezumab 5 mg and tanezumab
10 mg SC administered every 8 weeks (7 administrations).

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CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design
This was 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 patients with chronic low back pain (CLBP). Patients were randomized to one ofthree treatment groups in a 1:1:1 ratio. Treatment groups included:
1. Placebo matching tanezumab SC administered at 8-week intervals (up to 7 doses)
plus celecoxib 100 mg administered orally two times a day (BID) for 56 weeks.
2. Tanezumab 5 mg SC administered at 8-week intervals (up to 7 doses) plus placebo
matching celecoxib administered orally BID for 56 weeks.
3. Tanezumab 10 mg SC administered at 8-week intervals (up to 7 doses) plus placebo
matching celecoxib administered orally BID for 56 weeks.
The Double-blind Treatment period began with the Baseline (Day 1) visit and concluded
with completion of the Week 56 visit procedures.
The study was designed with a total duration (post randomization) of up to 80 weeks
including the 24-week Safety Follow-up Period.
Figure 1. Study Schematic
Double-blind Treatment Period

Safety Follow-up Period

SC Placebo (to match tanezumab) + PO celicoxib

Screening

SC Tanezumab 5 mg + PO Placebo (to match celecoxib)

SC Tanezumab 10 mg + PO Placebo (to match celecoxib)
0 24

8

12

Day -37 -5 1 1529

57

85 113

Week*

Baseline Pain Randomization
1st Dose ofDays -5 to -1
Study
Medication

24

16

32

169
*

40

225
*

48

281
*

56

337
*

Subcutaneous Administration of Study Medication

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64

393
*

80

449
*

561
*

*Phone Contact
with Patient**

End of Study

Final Clinical Study Report
Protocol A4091063

CLINICAL STUDY REPORT SYNOPSIS
Diagnosis and Main Criteria for InclusionJapanese males or females, ≥18 years of age.



Duration of CLBP for ≥3 months, and treatment with agents for low back pain (LBP) for≥3 months. Primary location of LBP must have been 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.



Patients must have experienced some benefit from their current stable dose regimen oforal therapy of non-steroidal anti-inflammatory drug (NSAID) (celecoxib 200 mg/day[100 mg BID], loxoprofen 120 to 180 mg/day, or meloxicam 5 to 15 mg/day) treatment,
have tolerated their NSAID regimen, have taken this medication regularly (defined as anaverage of at least five 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.



Patients must have maintained a stable dose regimen of celecoxib 100 mg BID with aminimum compliance of 70% (ie, five of seven days per week) for at least the final two
weeks (patients who were receiving celecoxib as pre-study treatment) or three weeks(patients who were receiving loxoprofen or meloxicam as pre-study treatment) of the
Screening Period immediately prior to the Baseline (Day 1) visit.

Patients must have had Low Back Pain Intensity (LBPI) score of ≥5 at Screening.



Patients must have completed at least 4 daily pain diaries during the 5 days prior to the
day of Randomization, with an average LBPI score of ≥5 and Patient’s Global
Assessment of Low Back Pain (PGA-LBP) must have been ‘Fair’, ‘Poor’ or ‘Very Poor’at Baseline.



Patients must have been willing to discontinue all pain medications for CLBP except
rescue medication and study medication and not use prohibited pain medications for theduration of the study.

Female patients of childbearing potential and at risk for pregnancy must have agreed tocomply with protocol-specified contraceptive requirements.

Female patients not of childbearing potential must have either: had a documented total
hysterectomy and/or bilateral oophorectomy; had medically confirmed ovarian failure; orachieved postmenopausal status.

Diagnosis and Main Criteria for ExclusionBody Mass Index (BMI) of >39 kg/m2.

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CLINICAL STUDY REPORT SYNOPSIS

Diagnosis of osteoarthritis (OA) of the knee or hip as defined by the American College of
Rheumatology (ACR) combined clinical and radiographic criteria. Radiographic criteria
were assessed by the Central Reader:o Patients who had Kellgren-Lawrence (KL) grade ≥2 radiographic evidence of hip
OA or KL grade ≥3 radiographic evidence of knee OA were excluded.
o Patients who had KL grade ≤2 radiographic evidence of knee OA but did not meet
ACR criteria and did not have pain associated with their knee OA were allowed.



Patients with symptoms and radiologic findings (ie, joint space narrowing, osteophytes)
consistent with OA in the shoulder.



History of lumbosacral radiculopathy within the past two years, history of spinal stenosis
associated with neurological impairment, or history of neurogenic claudication.

Back pain due to recent major trauma (eg, vertebral fracture, post-traumatic
spondylolisthesis) within six months prior to Screening.

Surgical intervention including, but not limited to, procedures such as discectomy, nerve
ablation, kyphoplasty, or nucleoplasty, during the past six months for the treatment of
low back pain.

Planned surgical procedure during the duration of the study.



Fibromyalgia, back pain due to a visceral disorder (eg, endometriosis), or othermoderate-to-severe pain that could have confounded assessments or self-evaluation of thepain associated with chronic low back pain.

History of disease that could have involved 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 thespine, pelvis, or femur.

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; otherarthropathies (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.



Patients with radiographic evidence of any one of the following conditions as determinedby the Central Radiology Reviewer and as defined in the tanezumab program imaging
atlas at Screening: 1) Rapidly progressive OA, 2) Atrophic or Hypotrophic OA,

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CLINICAL STUDY REPORT SYNOPSIS
3) Subchondral insufficiency fracture, 4) Spontaneous osteonecrosis of the knee,
5) Osteonecrosis, or 6) Pathologic fracture.


Patients with a history of osteonecrosis or osteoporotic fracture (ie, a patient with ahistory of osteoporosis and a minimally traumatic or atraumatic fracture).

History of significant trauma or surgery to a knee, hip, or shoulder within the previous
year.



Patients with a past history of carpal tunnel syndrome (CTS) with signs or symptoms of
CTS in the one year prior to Screening.



Patient considered unfit for surgery, defined as a Grade >3 on the American Society ofAnesthesiologists (ASA) physical classification system for surgery or patients who would
not be prepared to undergo joint replacement surgery if required.



History of intolerance or hypersensitivity to the relevant oral celecoxib the patient could
have been 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 iscontraindicated (refer to product labeling).



History of intolerance or hypersensitivity to acetaminophen (paracetamol) or any of its
excipients or existence of a medical condition or use of concomitant medication forwhich the use of acetaminophen/paracetamol was contraindicated (refer to productlabelling).



Use of prohibited medications or prohibited non-pharmacological treatments without theappropriate washout period (if applicable) prior to Screening or Initial Pain Assessment
Period (IPAP).



History of known alcohol, analgesic, or narcotic abuse within two years of Screening.

Presence of drugs of abuse (including prescription medications without a validprescription) or illegal drugs in the urine toxicology screen obtained at Screening.



History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal
antibody or IgG-fusion protein.



Signs and symptoms of clinically significant cardiac disease.

Resting, sitting blood pressure (BP) ≥160 mm Hg in systolic pressure or ≥100 mm Hg in
diastolic pressure at Screening. If a patient was found to have untreated significant
hypertension at Screening and antihypertensive treatment was initiated, assessment forstudy eligibility was deferred until BP and antihypertensive medication were stable for at

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CLINICAL STUDY REPORT SYNOPSIS
least one month. For patients with previously diagnosed hypertension, antihypertensive
medications must have been stable for at least one month prior to Screening.


Patients who had evidence of orthostatic hypotension (OH) based upon replicate
orthostatic BP measurements. If the orthostatic BP change could not be determined (eg,unable to establish a stable supine systolic and diastolic BP), then the patient was not
eligible for the study.

Patients with a total impact score of >7 on the Survey of Autonomic Symptoms (SAS).



Diagnosis of a transient ischemic attack in the six months prior to Screening, diagnosis ofstroke with residual deficits (eg, aphasia, substantial motor or sensory deficits) that could
preclude completion of required study activities.



Patient was expected to undergo a therapeutic procedure or to use any analgesic otherthan those specified in the protocol during the pre-treatment and treatment periods thatwas likely to confound assessment of analgesic efficacy or safety.

Previous exposure to exogenous nerve growth factor (NGF) or to an anti-NGF antibody.



Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3.0 times theupper limit of normal (ULN), or creatinine exceeding 1.7 mg/dL (150 µmol/L) in men or
1.5 mg/dL (133 µmol/L) in women, or hemoglobin (Hb) A1c ≥10% at Screening. Repeat
confirmatory tests could be performed.

Positive Hepatitis B, Hepatitis C virus (HCV), or human immunodeficiency virus (HIV)tests at screening indicative of current infection.



History, diagnosis, or signs and symptoms of clinically significant neurological disease or
clinically significant psychiatric disorder.

Pregnant female patients; breastfeeding female patients; female patients of childbearing
potential who were unwilling or unable to use two highly effective methods ofcontraception for the duration of the study and for 112 days (16 weeks) after the last doseof study medication.

Other severe acute or chronic medical or psychiatric condition or laboratory abnormalitythat could have increased the risk associated with study participation or study medication
administration or could have interfered with the interpretation of study results and, in the
judgment of the Investigator, could have made the patient inappropriate for entry into thisstudy.

Participation in other studies involving investigational drug(s) (Phase 1-4) within 30 days
(90 days for biologics) before Screening and/or during study participation.

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CLINICAL STUDY REPORT SYNOPSIS
Randomization Criteria

Patient must have completed appropriate washout of analgesics.

Patients must have entered at least four LBPI scores on the daily pain diary in the fivedays prior to the Baseline (Day 1) visit.

Patients must have maintained a stabilized dose regimen of celecoxib 100 mg BID with aminimum compliance of 70% (ie, five of seven days per week) for at least the final two
weeks (patients who were receiving celecoxib as pre-study treatment) or three weeks(patients who were receiving loxoprofen or meloxicam as pre-study treatment) of the
Screening period directly prior to the Baseline (Day 1) visit.

Patients must have abstained from taking rescue medication (acetaminophen/paracetamol) in the 24 hours that preceded dosing.



Patients must have met the Baseline LBPI score and PGA-LBP Baseline requirements.



Review of the electrocardiogram (ECG) and laboratory results and confirmation that
there were no clinically significant or exclusionary findings.

Radiographic eligibility must have been confirmed by the Central Reader.

Study Treatment
Tanezumab, placebo for tanezumab, celecoxib, and placebo for celecoxib were supplied by
the Sponsor or designee (Table S1).
Tanezumab 5 mg and tanezumab 10 mg were each presented as a sterile solution for SC
administration, in a glass pre-filled syringe (PFS). Each PFS contained a sufficient amount oftanezumab to provide the intended dose of drug at a concentration of 5 mg/mL or 10 mg/mL.
Each PFS was packed in an individual carton and had a unique container number.
Placebo for tanezumab was presented as a sterile solution for SC administration in amatching glass PFS. Each PFS was packaged in an individual carton and had a uniquecontainer number.
Celecoxib was provided as oral capsules containing 100 mg of active celecoxib. Celecoxib
100 mg was packaged in high-density polyethylene (HDPE) bottles with child-resistantclosures. The bottles used for the screening period contained 80 capsules (open-label supply)
and the bottles used for the treatment period contained 70 capsules (Double-blind supply).
Placebo for celecoxib was provided as oral capsules matching those used for celecoxib 100
mg capsules. Placebo to match celecoxib 100 mg was packaged in HDPE bottles with childresistant closures containing 70 capsules (Double-blind supply).

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Investigational Product Description
Investigational
Product Description

VendorLot
Number

Pfizer Lot
NumberStrength/Potency Dosage Form

PF-04383119 Solution for
Injection, 5 mg/mL
PF-04383119 Solution for
Injection, 10 mg/mL
Placebo for PF-04383119
Solution for Injection
Celecoxib, 100 mg

L5044715-002258

5 mg/mL

PFS

L5253915-002260

10 mg/mL

PFS

L3916815-002262

0 mg/mL

PFS

T0173V
H04083
S49797
H04007
H04009
S49791

12-004951
13-111559
17-000829
13-111563
13-111564
17-000830

100 mg
100 mg
100 mg
0 mg
0 mg
0 mg

CapsulePlacebo for 100 mg/200 mg
Celecoxib

CapsuleEFFICACY EVALUATIONS
Primary Endpoints
The primary endpoint in this study was safety.
Secondary Endpoints
Questionnaires for efficacy parameters were completed by the patients at the site via theInteractive Response Technology (IRT) (electronic tablets), or at home via electronic diaries.
Questionnaires at the site were completed prior to dosing on dosing days.
Efficacy endpoints included: Change from Baseline to Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40,
48, 56, and 64 in average 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 PGA-LBP; Cumulative distribution of percent
change from Baseline in average LBPI score to Weeks 16, 24, and 56; Response as definedby a ≥30%, ≥50%, ≥70%, and ≥90% reduction from Baseline in weekly average LBPI scorederived from the patient 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 Interferencewith General Activity, Pain Interference with Walking Ability, Pain Interference with Sleep,
and Pain Interference with Normal Work; CLBP Responder Index analysis (composite
endpoint of average LBPI score, PGA-LBP, and RMDQ total score) at Weeks 16, 24, 40, and56; Treatment Response: Improvement of ≥2 points in PGA-LBP at Weeks 16, 24, 40, and56; Euro Quality of Life Health State Profile™ (EQ-5D-5L) dimensions and overall healthutility 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 CLBP, percent impairment while working due to
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CLINICAL STUDY REPORT SYNOPSIS
CLBP, percent overall work impairment due to CLBP, and percent activity impairment due
to CLBP; Incidence of and time to discontinuation due to lack of efficacy; 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; and Health Care Resource Utilization (HCRU) at Baseline, Weeks 64, and 80.
Patient-reported outcome endpoints included Treatment Satisfaction Measures: Treatment
Satisfaction Questionnaire for Medication v. II (TSQM) score at Weeks 16 and 56; andPatient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 56.
Pharmacokinetic and Pharmacodynamic Evaluations
Pharmacokinetic (PK) blood samples were 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 (predose), Week 56, and Week 64. If participants terminated prior to Week 56, PK were
determined at approximately 8 and 16 weeks after the last SC dose was administered.
Tanezumab samples were assayed using a validated analytical method in compliance withSponsor standard operating procedures.
Tanezumab concentrations were measured to support the development of an SC
administration population PK model that allows for the prediction of the tanezumab
concentration over time in individuals. In addition, tanezumab concentrations were measured
to inform the immunogenicity profile of tanezumab.
Pharmacodynamic (PD) blood samples for the assessment of NGF (total NGF and proNGF)
and soluble p75 were collected 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). Bloodand urine samples for the assessment of biomarkers were collected at Baseline (Day 1; predose).
SAFETY EVALUATIONS
Safety evaluations for this study included assessment of adverse events (AEs); standard
safety assessments (safety laboratory testing [chemistry and hematology], vital signs);
orthostatic (supine/standing) BP assessments; SAS scores; ECG (12-lead) assessments; joint
safety adjudication outcomes; total joint replacements (TJRs); neurologic examination(Neuropathy Impairment Score [NIS]); anti-drug antibody (ADA) assessments; and physicalexaminations.
Safety Assessments
Adverse events (AEs), including serious adverse events (SAEs) and deaths, were collected
throughout the study. A general physical examination was performed at Screening and at
Week 56 or at Early Termination. Blood samples for clinical laboratory testing werecollected at Screening, Baseline, Week 16, and Week 64, or at Early Termination Visit 2. For
female patients of childbearing potential, serum pregnancy tests were conducted at
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CLINICAL STUDY REPORT SYNOPSIS
Screening, Weeks 56 and 64, or at Early Termination Visits 1 and 2. Urine pregnancy tests
were performed at Baseline (Day 1, predose), and predose at Weeks 8, 16, 24, 32, 40, and 48.
Vital signs (including systolic and diastolic BP and pulse rate) were 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 were collected after the patient had been in a sitting
position for at least five minutes at each visit. In addition to sitting vital sign measurements,
orthostatic BP measurements were 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 at Early
Termination. A 12-lead ECG was performed at Screening, Weeks 16, 56, and 80, and at
Early Termination Visits 1 and 3 for determination of ECG-related eligibility and safety
monitoring.
Neurological
An AE of OH was reported for all patients meeting criteria for OH at a visit. If no apparent
medical cause was identified at the time the OH criteria were met and the patient was
symptomatic, the patient was further evaluated for the presence of sympathetic autonomic
neuropathy by a cardiologist or neurologist as soon as possible. If an apparent medical cause
was identified at the time the OH criteria were met or if the patient was asymptomatic, thepatient had a repeat assessment of OH performed at least one week, but not more than fourweeks later. If confirmed OH was present at the follow-up visit, the patient was further
evaluated for the presence of sympathetic autonomic neuropathy by a cardiologist or
neurologist as soon as possible.
Patients reporting AEs of any seriousness or severity with preferred terms of Bradycardia,
Syncope, OH, Anhidrosis, or Hypohidrosis were further evaluated for the presence of
sympathetic autonomic neuropathy by a cardiologist or neurologist as soon as possible.
Neurological examinations were performed at Screening, Baseline, and Weeks 2, 4, 8, 16, 24,
32, 40, 48, 56, 64, and 80, or at Early Termination; the NIS was completed at these time
points based on this neurological examination. Neurologic examination assessed strength ofgroups of muscles of the head and neck, upper limbs and lower limbs, deep tendon reflexes,
and sensation (tactile, vibration, joint position sense and pinprick) of index fingers and great
toes to complete the NIS.
The SAS was completed by the patient at Screening, prior to SC dosing at Week 24, and at
Weeks 56 and 80, or at Early Termination Visits 1 and 3.
A neurological evaluation was performed by a consulting neurologist if an AE suggestive of
new or worsening peripheral neuropathy or an AE of abnormal peripheral sensation wasreported as an SAE, resulted in the patient being withdrawn from the study, was ongoing at
the end of the patient’s participation in the study, or was of severe intensity. Neurologicalevaluations were also obtained if a new or worsened clinically significant abnormality on theneurologic exam was reported as an AE and met criteria listed above, or if a reported

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non-neuropathic neurological AE (eg, stroke, seizure) was considered medically important by
the Investigator.
Musculoskeletal and Joint-Related
Each patient underwent a musculoskeletal physical examination at Screening, Baseline,
Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64, and 80, or Early Termination. A thoroughmusculoskeletal history was collected at Screening wherein the Investigator inquired about
current and past history of OA, ligament tear or rupture, joint surgeries (including
arthroscopic procedures), fractures, gout, osteoporosis or osteopenia, join injuries, or otherconditions. At each subsequent visit, the Investigator conducted a thorough musculoskeletal
physical examination of all major joints. This examination evaluated the joints for swelling,
redness, tenderness, deformity, osteophytes or nodes, crepitus, and pain on motion. Findings
were documented on the appropriate case report form. Information was also collected on any
patient-reported joint symptoms including pain, stiffness, and swelling. Any clinicallysignificant change in symptoms or the examination was reported as an AE.
Radiographic assessments (X-rays) of the hips, knees and shoulders were obtained at
Screening, Weeks 24, 56, and 80, or at Early Termination Visits 1 and 3.
A central radiology reader reviewed the X-ray images for assessment of eligibility. During
the study, the Central Reader reviewed X-ray images for continued radiologic eligibility andfor diagnosis of joint conditions that would warrant further evaluation by the Adjudication
Committee.
For patients who were identified with a possible or probable joint event (ie, Rapidly
progressive OA, Subchondral insufficiency fracture, Primary osteonecrosis, or Pathologicalfracture) and patients undergoing TJR for any reason, all images and other source
documentation were provided to the blinded Tanezumab Adjudication Committee for review
and adjudication of the event. The Adjudication Committee’s assessment of the event
represented the final classification of the event.
Immunogenicity
Blood samples for the assessment of ADA (anti-tanezumab antibodies) were collected atBaseline (Day 1; predose) and Weeks 8 (predose), 16 (predose), 32 (predose), 48 (predose),56, 64, and 80. If patients terminated prior to Week 56, ADA was determined at
approximately 8, 16, and 24 weeks after the last dose of SC study medication was
administered or at Early Termination.
Adverse Event Reporting
For SAEs, the active reporting period to Pfizer or its designated representative began fromthe time that the patient provided informed consent, which was obtained prior to the patient’s
participation in the study (ie, prior to undergoing any study-related procedure and/or
receiving study medication) through the end of the Safety Follow-up Period or through and

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CLINICAL STUDY REPORT SYNOPSIS
including 112 calendar days after the patient’s last administration of the SC study
medication, if the patient refused the protocol-defined Follow-up Period.
STATISTICAL METHODS
A minimum sample size of approximately 130 patients per treatment group was needed forthe safety evaluation. The total sample size was planned to be approximately 390 patients.
The primary objective of this study was to evaluate safety; the sample size was calculated toobtain approximately 100 Japanese CLBP patients per group (ie, 80 to 100 patients pergroup) with one year’s exposure of tanezumab.
NOTE: The planned sample size was reduced in Protocol Amendment 2. Considering
study feasibility, the number of patients with one-year exposure and the capability ofsafety evaluation with the data from this study, the target sample size was changed toapproximately 200 (170-220) patients. Additionally, from the safety perspective, it was
acceptable to randomize more than 220 patients.
When approximately 170 patients were enrolled in this study, AEs related to abnormal
peripheral sensation and decreased sympathetic function were expected to occur in several
patients so neurological safety could be evaluated with high probability in Japanese patients.
Analysis of the Primary (Safety) Endpoints
AEs, concomitant medications, laboratory safety tests, physical and neurologicalexaminations, vital signs, ECG, and ADA were collected for each patient. Standard safety
reporting tables summarized and listed the safety data.
AEs of Syncope, Bradycardia, OH, Anhidrosis, and Hypohidrosis were designated as AEs ofinterest that were reviewed by the unblinded External Data Monitoring Committee (E-DMC).
A three-tier AE reporting approach was used. A pre-specified composite AE of potential
sympathetic dysfunction (Syncope, Bradycardia, OH, Anhidrosis, and Hypohidrosis) was
considered clinically important and classified as a Tier 1 AE. Tier 2 AEs were those with afrequency of ≥3% in any treatment group. Tier 3 AEs were those not in Tier 1 or Tier 2. AEs
within Tier 1 and Tier 2 were summarized using risk differences between each tanezumab
group and celecoxib, together with 95% confidence interval (CI), using exact methods. There
was no multiplicity adjustment for these significance tests.
Analysis of Secondary (Efficacy) Endpoints
All efficacy analyses used the Intent-to-Treat (ITT) analysis set. If not otherwise specified,
the observed data (no imputation for missing data) were summarized.
The descriptive statistics n, mean, median, standard deviation (SD), minimum (min),maximum (max), and 95% CI were used to summarize the endpoints. The analysis forchange from Baseline of average LBPI used a mixed model analysis of covariance
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CLINICAL STUDY REPORT SYNOPSIS(ANCOVA) with a fixed effect of treatment group, Baseline average LBPI as a covariate,and study site as a random effect. The analysis for change from Baseline of RMDQ used amixed model ANCOVA with a fixed effect of treatment group, Baseline score, and Baseline
average LBPI as covariates, and study site as a random effect. Change from Baseline at eachtime point was estimated using LS means with SE and 95% CI. Estimates of treatment
differences between each tanezumab treatment group versus celecoxib group was done using
least squares (LS) means with standard error (SE) and 95% CI. P-values were not shown.
Missing LBPI, RMDQ, PG, and BPI-sf data were handled using a multiple imputation
approach, with imputation dependent on the reason for missing data. Data missing due totreatment discontinuation due to death, AEs, insufficient clinical response, or patient's
meeting protocol-specified pain criteria for discontinuation; used a multiple imputation
version of a baseline observation carried forward (BOCF) single imputation method.
Multiple imputations were created by sampling from a normal distribution based on thepatient’s Baseline score and the SD (over all treatment groups) of the observed efficacy dataat the timepoint over all ITT patients. Data missing due to other reasons used a multiple
imputation version of a last observation carried forward (LOCF) single imputation method.
Multiple imputations were created by sampling from a normal distribution based on thepatient’s last score and the SD (over all treatment groups) of the observed efficacy data at the
timepoint over all ITT patients.
Analysis of Pharmacokinetic Data
Pharmacokinetic data were reported as follows:A listing of all plasma tanezumab concentrations sorted by patient, active treatmentgroup, and nominal time post dose. The listing of concentrations includes 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.

Pharmacodynamic Analysis
Serum samples were run in the bioanalytical assays for the assessment of NGF and themeasurements were summarized in the following tables and figures:A listing of individual NGF concentrations sorted by patient, active treatment group, andtime postdose.

Descriptive statistics of NGF concentrations based on time postdose for each treatmentgroup.

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Box plots of NGF over time postdose for each treatment group.

RESULTS
Patient Disposition and Demography
Of 409 patients screened for entry the study, 277 patients were randomized to double-blind
treatment and received study medication according to assigned treatment.
A summary of disposition events is shown in Table S2. Slightly more than half (53.4%) of all
patients completed the Treatment Phase of the study; more patients in the tanezumab 5 mg
treatment group (67.4%) than in the tanezumab 10 mg treatment group (46.2%) or thecelecoxib treatment group (46.7%) completed the Treatment Phase. The most frequent reason
for discontinuation during the Treatment Phase in any treatment group was due to meeting
protocol-specified pain criteria for discontinuation; more patients discontinued for this reason
in the tanezumab 10 mg treatment group (37.6%) and the celecoxib treatment group (38.0%)
than in the tanezumab 5 mg treatment group (27.2%). The majority of patients (92.8%)
completed the study; an approximately equal proportion of patients in the tanezumab 5 mg
treatment group (95.7%) and the celecoxib treatment group (94.6%), and a smaller
proportion in the tanezumab 10 mg treatment group (88.2%).
One patient entered the substudy.

Table S2. Data Set Analyzed
Tanezumab 5 mg
(N=92)

Tanezumab 10 mg(N=93)

Celecoxib(N=92)

Total(N=277)

n (%)

n (%)

n (%)

n (%)

Randomized

92 (100.0)

93 (100.0)

92 (100.0)

277 (100.0)

TreatedScreened: 409
Screen Failure: 130
Other Screened but not Randomized: 2

92 (100.0)

93 (100.0)

92 (100.0)

277 (100.0)

Not Treated

0

0

0

0

ITT Population

92 (100.0)

93 (100.0)

92 (100.0)

277 (100.0)

Safety Population

92 (100.0)

93 (100.0)

92 (100.0)

277 (100.0)0

1 (1.1)0

1 (0.4)Completed study

88 (95.7)

82 (88.2)

87 (94.6)

257 (92.8)

Discontinued study

4 (4.3)

11 (11.8)

5 (5.4)20 (7.2)

TJR (Total Joint Replacement) Subset
Population

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Table S2. Data Set Analyzed
Tanezumab 5 mg
(N=92)

Tanezumab 10 mg(N=93)

Celecoxib(N=92)

Total(N=277)

n (%)

n (%)

n (%)

n (%)

62 (67.4)

43 (46.2)

43 (46.7)

148 (53.4)

61 (66.3)

42 (45.2)

43 (46.7)

146 (52.7)

Number of subjects[1]Completed Treatment Phase
Completed Safety Follow-Up

1 (1.1)1 (1.1)0

2 (0.7)

Discontinued Treatment Phase

Discontinued Safety Follow-Up

30 (32.6)

50 (53.8)

49 (53.3)

129 (46.6)

Completed Safety Follow-Up

27 (29.3)

40 (43.0)

44 (47.8)

111 (40.1)

Discontinued Safety Follow-Up

2 (2.2)4 (4.3)2 (2.2)8 (2.9)Did not enter Safety Follow-Up

1 (1.1)6 (6.5)3 (3.3)10 (3.6)0

1 (1.1)0

1 (0.4)Entered into Sub-Study

N is Number of Subjects Randomized. Percentages are based on the number of subjects Randomized.
[1]Subjects in Safety Population.
Not treated is subjects who received no SC study medication.
Safety population consists of all subjects treated with Tanezumab or Placebo SC. ITT population consists of all
randomized subjects who received at least one dose of
Tanezumab or Placebo SC.
"Other Screened but not Randomized" displays subjects who were screened but not randomized for a reason not related toa specific eligibility criterion.

CCI

Demographic characteristics were similar across the treatment groups. The mean age and age
range were similar across treatment groups which were overall balanced within each age
category. There were more male than female patients in the tanezumab 5 mg treatment group(59.8% male) and the celecoxib treatment group (58.7% male), while the tanezumab 10 mg
treatment group (52.7% male) was more balanced. All patients were randomized at sites inJapan and all patients were Asian (Japanese). The mean height, weight, and BMI weresimilar across treatment groups. Over 90% of patients across treatment groups had not been
diagnosed with diabetes mellitus.
Inclusion criteria required that patients have experienced some benefit from their current
stable dose regimen of oral therapy of NSAID (celecoxib, loxoprofen, or meloxicam). These
were the prior drug treatments for CLBP identified as meeting inclusion criteria and may notinclude all prior medications for CLBP. There was no limit on the recall period for theseprior treatments for CLBP. Of these protocol-qualifying drugs, across all treatment groups,
celecoxib was the most frequently used drug treatment prior to study entry, followed byloxoprofen; meloxicam was used by 2 patients overall.
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The mean duration since diagnosis of LBP ranged from 7.7 to 9.1 years across treatmentgroups. Baseline disease characteristics such as average LBPI score, mean RMDQ Total
Score, PGA-LBP, and BPI-sf scores were similar across the treatment groups. The Quebec
Task Force Classification was similar across treatment groups, with most patients in Quebec
Task Force Category 1 (pain without radiation) at Baseline. In the painDetect evaluation,
most patients did not have a neuropathic component of their CLBP (painDetect score ≤12).
The tanezumab 5 mg treatment group had a higher proportion of patients in the painDetect≥19 category (neuropathic component is likely) and a smaller proportion in the 13 to 18(neuropathic component uncertain) category compared to the other treatment groups, while
the tanezumab 10 mg treatment group had a higher proportion of patients in the 13 to 18
category and a smaller proportion in the ≥19 category compared to the other treatmentgroups.
The proportion of patients assessed as having pain due to degenerative disc disease was
34.8%-43.0%. CLBP due to degenerative joint disease/OA was assessed in 11.8%-18.5% of
patients across treatment groups. The remainder of patients (39.1%-51.1%) had pain due to
Other/Injury/Muscle strain.
Efficacy Results
The study was not designed or powered to detect treatment differences between thetanezumab and celecoxib treatment groups; there were no formal hypotheses to be tested forthe efficacy endpoints.
Primary Efficacy Analysis
The primary endpoints in this study were safety; refer to the Safety Results section.
Secondary Efficacy Analysis
Starting at Week 4 in the tanezumab 5 mg treatment group and at Week 1 in thetanezumab 10 mg treatment group and continuing through Week 64, patients in thetanezumab treatment groups showed a larger change from Baseline in the mean LBPI
score (decrease = improvement) than those in the celecoxib treatment group (ObservedData). The tanezumab 5 mg treatment group showed larger LS mean changes fromBaseline in the mean LBPI score than those in the tanezumab 10 mg treatment groupfrom Week 16 though Week 56 and the celecoxib treatment group starting at Week 4through Week 56. The tanezumab 10 mg treatment group showed a larger LS meanchange from Baseline in the mean LBPI score than the celecoxib treatment group startingat Week 2 through Week 48; at Week 56 the LS mean change from Baseline in patientsin the tanezumab 10 mg treatment group was similar to those in the celecoxib treatmentgroup (Multiple Imputation).

Starting at Week 2 and continuing through Week 56, patients in the tanezumab treatmentgroups, except at Week 24 in the tanezumab 5 mg treatment group, showed a largerchange from Baseline in the mean RMDQ score (decrease=improvement) than those in
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the celecoxib treatment group (Observed Data). Patients in the tanezumab 5 mg treatmentgroup showed a larger decrease in the LS mean change from Baseline in the RMDQ
score than those in the tanezumab 10 mg treatment group at Week 32 through Week 56.
The LS mean change from Baseline (decrease = improvement) in patients in thetanezumab 5 mg treatment group was larger than those in the celecoxib treatment groupat Weeks 2 and 4, and at Week 24 through Week 56; at Weeks 8 and 16, the LS meanchange from Baseline between the tanezumab 5 mg treatment group and the celecoxib
treatment group was similar. Patients in the tanezumab 10 mg treatment group showed alarger LS mean change (decrease) from Baseline in the RMDQ score than those in thecelecoxib treatment group starting at Week 2 through Week 24; starting at Week 32 andcontinuing through Week 56, the LS mean change from Baseline in patients in thetanezumab 10 mg treatment group was similar to those in the celecoxib treatment group(Multiple Imputation).
Starting at Week 2 and continuing through Week 56 patients in the tanezumab 5 mg
treatment group showed a larger change from Baseline in the mean PGA-LBP score(decrease = improvement) compared to patients in the celecoxib treatment group. Startingat Week 2 and continuing through Week 8, and at Weeks 24 and 32, patients in thetanezumab 10 mg treatment group showed a larger decrease from Baseline in the mean
PGA-LBP compared to patients in the celecoxib treatment group (Observed Data). At
Week 16 and Week 56, patients in the tanezumab 5 mg treatment group showed a larger
decrease from Baseline in the mean PGA-LBP score than those in the tanezumab 10 mg
treatment group and the celecoxib treatment group; the mean PGA-LBP scores forpatients in the tanezumab 10 mg treatment group were similar to those for patients in thecelecoxib treatment group (Multiple Imputation).



At Week 16, there was a higher percentage of patients in the tanezumab 5 mg treatmentgroup than in the celecoxib treatment group with a cumulative reduction from Baselinein the average LBPI score of >0% to ≥80%; in the tanezumab 10 mg treatment group, ahigher percentage of patients showed a cumulative ≥60% to ≥80% reduction fromBaseline in the average LBPI score than in the celecoxib treatment group (Mixed
BOCF/LOCF).
At Week 24, there was a higher percentage of patients in the tanezumab 5 mg treatmentgroup with >0% to ≥50% cumulative reduction from Baseline in the average LBPI
score than in the tanezumab 10 mg treatment group and a >0% to ≥90% cumulative
reduction from Baseline in the average LBPI score than in the celecoxib treatment group;in the tanezumab 10 mg treatment group, a higher percentage of patients showed a ≥50%
to ≥80% cumulative reduction from Baseline in the average LBPI score than in thecelecoxib treatment group (Mixed BOCF/LOCF).
At Week 56, there was a higher percentage of patients in the tanezumab 5 mg treatmentgroup with a >0% to ≥90% cumulative reduction from Baseline in the average LBPI
score than in the tanezumab 10 mg treatment group and the celecoxib treatment group.
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Only at the ≥70% response level was there a higher percentage of patients in thetanezumab 10 mg treatment group than in the celecoxib treatment group showing acumulative reduction from Baseline in the average LBPI score; at all other response
levels, percentage of patients in the tanezumab 10 mg treatment group was similar to thatin the celecoxib treatment group.
Treatment with tanezumab 5 mg was associated with a higher percentage of responders
with a reduction from Baseline in the weekly average LBPI score compared totanezumab 10 mg treatment at the ≥30% and ≥50% levels at each timepoint measured(Weeks 16, 24, 40, and 56), for a ≥70% reduction from Baseline at Weeks 40 and 56, andfor a ≥90% reduction from Baseline at Week 56. Treatment with tanezumab 5 mg was
associated with a higher percentage of responders compared to celecoxib treatment for all
response levels (≥30%, ≥50%, ≥70%, ≥90% reduction from Baseline) at each timepoint
measured, except for a ≥90% reduction from Baseline at Week 16. Treatment withtanezumab 10 mg was associated with a higher percentage of responders compared tocelecoxib treatment for a ≥50% reduction from Baseline at Weeks 24 and 40; for a ≥70%
reduction from Baseline at Weeks 16, 24, 40, and 56; and for a ≥90% reduction fromBaseline at Week 40.
Overall, the percentage of responders with a reduction from Baseline in the weekly
average LBPI score in the tanezumab treatment groups was either comparable to or
greater than those in the celecoxib treatment group, with the exception of patients with a≥30% reduction from Baseline in the tanezumab 10 mg treatment group compared to thecelecoxib treatment group.



For the change from Baseline in the BPI-sf scores, in the BPI-sf Worst Pain score andBPI-sf Average Pain score, there was a decrease from Baseline (decrease = improvement)in all treatment groups at all weeks. The mean decrease from Baseline in both the BPI-sf
Worst Pain score and BPI-sf Average Pain score was greater in patients in bothtanezumab treatment groups than in patients in the celecoxib treatment group from
Week 2 to Week 56 (Observed Data). At Week 16 and Week 56 (Multiple Imputation),patients in the tanezumab 5 mg treatment group showed greater mean decreases fromBaseline in BPI-sf Worst Pain and Average Pain than patients in the celecoxib treatmentgroup. Patients in the tanezumab 10 mg treatment group showed greater mean decreases
from Baseline in BPI-sf Worst Pain and Average Pain than patients in the celecoxib
treatment group at Week 16; at Week 56, the values for patients in the tanezumab 10 mg
treatment group were similar to those in patients in the celecoxib treatment group.


For the BPI-sf Pain Interference Index, patients in the tanezumab treatment groups
showed a larger mean decrease from Baseline than those in the celecoxib treatmentgroup at all weeks from Week 2 to Week 64, except for the tanezumab 10 mg
treatment group at Weeks 16 and 40 (Observed Data). At Weeks 16 and 56 (Multiple
Imputation), patients in the tanezumab 5 mg treatment group showed a larger mean
decrease from Baseline in the BPI-sf Pain Interference Index than patients in the
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tanezumab 10 mg treatment group and the celecoxib treatment group; the results forpatients in the tanezumab 10 mg treatment group were similar to those for patients inthe celecoxib treatment group.



For the BPI-sf score of Pain Interference with General Activity, patients in thetanezumab treatment groups showed larger mean decreases from Baseline thanpatients in the celecoxib treatment group at all time points from Week 2 though Week
64 (Observed Data); at Weeks 16 and 56 (Multiple Imputation), the mean decrease
from Baseline in patients in the tanezumab treatment groups was larger than inpatients in the celecoxib treatment group.



For the BPI-sf score of Pain Interference with Walking Ability, the mean decrease
from Baseline in patients in the tanezumab 5 mg treatment group was larger than inpatients in the celecoxib treatment group at all timepoints from Week 2 through Week
56; the mean decrease from Baseline in patients in the tanezumab 10 mg treatmentgroup was larger than in patients in the celecoxib treatment group from Week 2
through Week 24 (Observed Data). At Weeks 16 and 56 (Multiple Imputation), themean decrease from Baseline in patients in the tanezumab 5 mg treatment group waslarger than in patients in the celecoxib treatment group; the results for patients in thetanezumab 10 mg treatment group were similar to those for patients in the celecoxib
treatment group.



For the BPI-sf score of Pain Interference with Sleep, patients in the tanezumab
treatment groups showed a larger mean decrease from Baseline compared to patientsin the celecoxib treatment group at all time points from Week 2 though Week 64,
except for the tanezumab 10 mg treatment group at Week 40 (Observed Data). At
Weeks 16 and 56 (Multiple Imputation), the mean decrease from Baseline in patientsin the tanezumab treatment groups was larger than in patients in the celecoxib
treatment group.



For the BPI-sf score of Pain Interference with Normal Work, patients in thetanezumab treatment groups showed larger decreases from Baseline compared topatients in the celecoxib treatment group at all time points from Week 2 though Week
56, except for the tanezumab 5 mg treatment group at Week 2 and the tanezumab 10
mg treatment group at Weeks 4, 40, and 56 (Observed Data). At Weeks 16 and 56(Multiple Imputation), the mean decrease from Baseline in patients in the tanezumab
5 mg treatment group was larger than in patients in the celecoxib treatment group; theresults for patients in the tanezumab 10 mg treatment group were similar to those forpatients in the celecoxib treatment group.

Analysis of the CLBP Responder Index (composite endpoint of average LBPI score,
PGA-LBP, and RMDQ score) showed higher proportions of responders in the tanezumab
5 mg treatment group than in the tanezumab 10 mg treatment group and the celecoxib
treatment group at each week analyzed. At all weeks (Weeks 16, 24, 40, and 56), the
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proportion of responders was similar between the tanezumab 10 mg treatment group andthe celecoxib treatment group (Mixed BOCF/LOCF).
The proportion of patients showing a ≥2-point reduction from Baseline in the
PGA-LBP was larger in the tanezumab 5 mg treatment group than in the tanezumab 10
mg treatment group and the celecoxib treatment group at all timepoints (Weeks 16, 24, 40
and 56). The proportion of patients showing a ≥2-point reduction from Baseline in the
PGA-LBP was larger in the tanezumab 10 mg treatment group than in the celecoxib
treatment group at Weeks 24 and 40 (Mixed BOCF/LOCF).

For each of the Euro Quality of Life Health State Profile Dimensions (Mobility, SelfCare, Usual Activities, Pain/Discomfort, and Anxiety/Depression), as well as for theIndex Value, the mean values across treatment groups showed similar improvement fromBaseline at Week 16 and Week 56.



WPAI:LBP change from Baseline: At Weeks 16 and 56, mean decreases from Baseline(decrease = improvement) were observed for all WPAI:LBP measures, across alltreatment groups. Patients in the tanezumab 5 mg treatment group showed a larger mean
decrease from Baseline than those in the celecoxib treatment group in all measures at
Weeks 16, 56, and 64, except for Percent Work Time Missed at Week 16, and Percent
Impairment While Working at Week 64. Patients in the tanezumab 10 mg treatmentgroup showed larger mean decreases from Baseline than those in the celecoxib treatmentgroup for Percent Work Time Missed at Weeks 16, 56, and 64; in Percent Impairment
While Working and in Percent Overall Work Impairment at Weeks 56 and 64. The mean
decrease from Baseline for Percent Activity Impairment was similar between patients inthe tanezumab 10 mg treatment group and the celecoxib treatment group at Weeks 16, 56,
and 64.

During the Treatment Period (ie, up to Week 56), the proportion of patients who
discontinued treatment due to insufficient clinical response and the patient’s meetingthe protocol-specified pain criteria were similar in the tanezumab 10 mg treatment group(39 [41.9%]) and the celecoxib treatment group (36 [39.1%]); the tanezumab 5 mg
treatment group (26 [28.3%]) had the lowest number of patients who discontinued forthese reasons. For each comparison of a tanezumab treatment group versus the celecoxib
treatment group, however, the 95% CI includes 0, so the difference between treatmentgroups in number of patients discontinuing is not significant. Four (4 [4.3%]) patients inthe tanezumab 10 mg treatment group and one (1 [1.1%]) patient each in the tanezumab 5
mg treatment group and the celecoxib treatment group discontinued due to insufficient
clinical response.



At Baseline, the incidence of rescue medication use per week ranged from 31.2% to39.1% across treatment groups and decreased in all treatment groups up to Week 16, to16.3% to 28.3%. The incidence of use of rescue medication was lower in the tanezumab 5
mg treatment group than in the celecoxib treatment group at Weeks 12, 16, 32, 40, and
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56; at other weeks, the incidence of use of rescue medication in the tanezumab 5 mg
treatment group was similar to or higher than that in the celecoxib treatment group. The
incidence of use of rescue medication was lower in the tanezumab 10 mg treatment groupthan in the celecoxib treatment group from Week 1 through Week 32 and at Week 56; at
Weeks 40 and 48, the incidence of use of rescue medication in the tanezumab 10 mg
treatment group was similar to that in the celecoxib treatment group (LOCF).
The mean number of days of rescue medication use per week at Baseline ranged from
0.9 to 1.3 days and decreased at Week 16 to 0.5 to 0.7 days per week across the treatmentgroups. Up to Week 16, the number of days of rescue medication use across all treatmentgroups was small, mostly less than 1 day per week; from Week 24 through Week 56, thenumber of days of rescue medication use across all treatment groups ranged from 1.2 to
1.6 days per week. The mean number of days of rescue medication use was lower in thetanezumab treatment groups than in the celecoxib treatment group at all weeks from
Week 1 though Week 56, except for Week 2 in the tanezumab 10 mg treatment group andWeeks 2 and 4 in the tanezumab 5 mg treatment group (LOCF).
At Baseline, the use of rescue medication per week was less in patients in thetanezumab 10 mg treatment group (731 mg) compared to patients in the tanezumab 5 mg
treatment group (1238 mg) or the celecoxib treatment group (1257 mg). Starting at Week
1 through Week 16, the mean amount of rescue medication used by patients in thetanezumab 5 mg treatment group and patients in the celecoxib treatment group was
similar, except at Week 2 where rescue medication use in the tanezumab 5 mg treatmentgroup was higher than in the celecoxib treatment group. Starting at Week 1 throughWeek 16, the mean amount of rescue medication used was lower in patients in thetanezumab 10 mg treatment group than in patients in the celecoxib treatment group(LOCF).



Treatment Satisfaction Measures: At Week 16 and Week 56, most patients in alltreatment groups said that they were ‘Very Satisfied’, ‘Satisfied’, or "Somewhat Satisfied'with the ability of the study medication to prevent/treat their condition and the way thestudy medication relieved their symptoms. Over 93% of patients in all treatment groups
reported at Weeks 16 and 56 that they experienced no side effects from the study
medication.

In general, most of patients in all treatment groups expressed a preference for the study
drug received compared to previous treatment, and a willingness to use the study
medication received for low back pain, in each mPRTI endpoint at Weeks 16 and 56.

Pharmacokinetic Results
The mean tanezumab plasma concentrations were higher in the tanezumab 10 mg treatmentgroup than the tanezumab 5 mg treatment group at all nominal sampling times (Week 2 to
Week 56) in a dose-proportional manner. By Week 64, 16 weeks after the seventh dose of
study medication, the mean tanezumab plasma concentrations were 5.7% and 14.9% of the
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mean Week 48 trough concentrations for the tanezumab 5 mg and tanezumab 10 mg
treatment groups, respectively.
Pharmacodynamic Results
Blood samples were analyzed for the determination of serum concentration of soluble p75,
total NGF, and proNGF.
Mean and median serum soluble p75 concentrations were comparable at all time points for
all treatment groups, suggesting the presence of tanezumab does not affect levels of
circulating soluble p75.
Mean serum total NGF concentrations were comparable at Baseline across treatment groups
and increased with tanezumab dosing. Mean total NGF trough concentrations were higher inthe tanezumab 10 mg treatment group compared with the tanezumab 5 mg treatment group at
all time points. Mean serum proNGF was comparable across treatment groups at all nominal
sampling times.
Safety Results
At least one treatment-emergent AE was experienced by 58 (63.0%), 51 (54.8%), and62 (67.4%) patients in the tanezumab 5 mg treatment group, the tanezumab 10 mg treatmentgroup, and the celecoxib treatment group, respectively; 4 (4.3%), 9 (9.7%), and 2 (2.2%)
patients in the tanezumab 5 mg treatment group, the tanezumab 10 mg treatment group, andthe celecoxib treatment group, respectively, experienced at least one treatment-emergent
SAE (Table S3). Most treatment-emergent AEs were mild or moderate in severity.
There were 3 (3.3%), 5 (5.4%), and 4 (4.3%) patients in the tanezumab 5 mg treatmentgroup, the tanezumab 10 mg treatment group, and the celecoxib treatment group,
respectively, that discontinued study medication due to AEs. Most patients continued in the
study after discontinuation of study medication due to AEs. Few patients had a dose
reduction or temporary discontinuation during the study (Table S3). Most treatmentemergent AEs were considered by the Investigator not to be related to study medication.

Table S3. Treatment-Emergent Adverse Events (All-Causality) During theTreatment PeriodTanezumab 5 mg Tanezumab 10 mg

Celecoxib

Number (%) of Subjects

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

92

93

92

Number of adverse events

155

110

123

Subjects with adverse events

58 (63.0)

51 (54.8)

62 (67.4)

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Table S3. Treatment-Emergent Adverse Events (All-Causality) During theTreatment PeriodTanezumab 5 mg Tanezumab 10 mg

Celecoxib

Number (%) of Subjects

n (%)

n (%)

n (%)

Subjects with serious adverse events

4 (4.3)9 (9.7)2 (2.2)

Subjects with severe adverse events

3 (3.3)2 (2.2)

1 (1.1)

Subjects discontinued study drug due to adverse event

3 (3.3)5 (5.4)4 (4.3)

Subjects discontinued from study due to adverse event (a)1 (1.1)1 (1.1)0

Subjects discontinued study drug due to adverse event andcontinued Study (b)2 (2.2)4 (4.3)4 (4.3)

Subjects with dose reduced or temporary discontinuation due toadverse events

2 (2.2)

1 (1.1)0

Includes treatment-emergent events that begin up to the week 56 (end of treatment) visit date for subjects who completed
the treatment period or up
to the withdrawal from treatment date for subjects who withdrew early from the treatment period.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study(b) Subjects who have an AE record that indicates that action taken with study treatment was drug withdrawn but AE did
not cause the subject
to be discontinued from study
MedDRA v22.0 coding dictionary applied.

CCI

During the 24-week Safety Follow-up Period and Early Termination Follow-up Period, ahigher percentage of patients in the tanezumab 5 mg treatment group (47.3%) reported AEs
than those in the tanezumab 10 mg treatment group (40.2%) or the celecoxib treatment group(40.4%). During this period, few SAEs were reported in all treatment groups (Table S4).

Table S4. Treatment-Emergent Adverse Events (All-Causality) During the Followup PeriodTanezumab 5 mg Tanezumab 10 mg

Celecoxib

Number (%) of Subjects

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

91

87

89

Number of adverse events

85

53

62

Subjects with adverse events

43 (47.3)

35 (40.2)

36 (40.4)

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Table S4. Treatment-Emergent Adverse Events (All-Causality) During the Followup PeriodTanezumab 5 mg Tanezumab 10 mg

Celecoxib

Number (%) of Subjects

n (%)

n (%)

n (%)

Subjects with serious adverse events

5 (5.5)2 (2.3)2 (2.2)

Subjects with severe adverse events00

1 (1.1)

Subjects discontinued study drug due to adverse event

0

0

0

Subjects discontinued from study due to adverse event (a)

0

0

0

Subjects discontinued study drug due to adverse event andcontinued Study (b)

0

0

0

Subjects with dose reduced or temporary discontinuation due toadverse events

0

0

0

Includes treatment-emergent events that begin after the week 56 (end of treatment) visit date for subjects who completed
the treatment period
or after the withdrawal from treatment date for subjects who withdrew early from the treatment period.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study(b) Subjects who have an AE record that indicates that action taken with study treatment was drug withdrawn but AE did
not cause the Subject to bediscontinued from study
MedDRA v22.0 coding dictionary applied.

CCI

Of the treatment-emergent AEs that occurred most frequently (≥2% in any treatment group)
during the Treatment Period (Table S5), Nasopharyngitis, Fall, Arthralgia, Contusion,
Hypoaesthesia, and Back pain were the most commonly reported AEs in one or both of thetanezumab treatment groups, and were mostly reported in a similar number of patientscompared to the celecoxib treatment group; the exception was Nasopharyngitis which wasreported in more patients in the tanezumab treatment groups.

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CLINICAL STUDY REPORT SYNOPSIS
Table S5. Incidence of Treatment-Emergent Adverse Events Occurring in ≥2%
Patients During the Treatment Period by Descending Frequency (AllCausality)
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=92)

Tanezumab 10 mg(N=93)

Celecoxib(N=92)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Nasopharyngitis

14 (15.2)

13 (14.0)

6 (6.5)Back pain

4 (4.3)5 (5.4)4 (4.3)

Contusion

3 (3.3)4 (4.3)2 (2.2)Fall

6 (6.5)4 (4.3)3 (3.3)Arthralgia

5 (5.4)3 (3.2)6 (6.5)

Headache

2 (2.2)3 (3.2)2 (2.2)

Intervertebral disc protrusion

2 (2.2)3 (3.2)3 (3.3)

Carpal tunnel syndrome

1 (1.1)2 (2.2)0

Dental caries

2 (2.2)2 (2.2)2 (2.2)Dysmenorrhoea

1 (1.1)2 (2.2)0Eczema0

2 (2.2)0

Hypoaesthesia

5 (5.4)2 (2.2)3 (3.3)

Influenza

1 (1.1)2 (2.2)2 (2.2)

Musculoskeletal stiffness

1 (1.1)2 (2.2)2 (2.2)

Orthostatic hypotension0

2 (2.2)

1 (1.1)

Rotator cuff syndrome0

2 (2.2)0

Sudden hearing loss

0

2 (2.2)0

Diarrhoea

1 (1.1)1 (1.1)3 (3.3)Dizziness

2 (2.2)

1 (1.1)2 (2.2)

Epicondylitis

01 (1.1)2 (2.2)

Gastroenteritis

1 (1.1)1 (1.1)3 (3.3)

Ligament sprain

2 (2.2)

1 (1.1)2 (2.2)

Muscle spasms

2 (2.2)

1 (1.1)0

Myalgia

3 (3.3)

1 (1.1)1 (1.1)Pain in extremity

3 (3.3)

1 (1.1)3 (3.3)

Pharyngitis

2 (2.2)

1 (1.1)1 (1.1)Pyrexia

2 (2.2)

1 (1.1)4 (4.3)Tendon rupture

2 (2.2)

1 (1.1)0

Tendonitis0

1 (1.1)2 (2.2)Arthropod sting

2 (2.2)00Asthma2 (2.2)00Bradycardia

2 (2.2)0

1 (1.1)

Cervical radiculopathy

2 (2.2)

0

0

Cough

2 (2.2)0

0

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CLINICAL STUDY REPORT SYNOPSIS
Table S5. Incidence of Treatment-Emergent Adverse Events Occurring in ≥2%
Patients During the Treatment Period by Descending Frequency (AllCausality)
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=92)

Tanezumab 10 mg(N=93)

Celecoxib(N=92)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Dyslipidaemia

2 (2.2)00

Dysuria

2 (2.2)00

Fatigue

2 (2.2)0

1 (1.1)Hypertension

2 (2.2)0

3 (3.3)Hyperventilation

00

2 (2.2)

Joint effusion

2 (2.2)00Meniscus injury

2 (2.2)00

Muscle strain00

2 (2.2)

Musculoskeletal pain

3 (3.3)0

3 (3.3)

Palpitations

00

2 (2.2)

Periarthritis

2 (2.2)00Pneumonia

3 (3.3)0

1 (1.1)Rash

2 (2.2)0

1 (1.1)

Rhinitis allergic

2 (2.2)00Somnolence

1 (1.1)0

2 (2.2)

Stomatitis

2 (2.2)

0

0

0

0

2 (2.2)Upper respiratory tract inflammation

Includes treatment-emergent events that begin up to the week 56 (end of treatment) visit date for subjects who completed
the treatment period or up to thewithdrawal from treatment date for subjects who withdrew early from the treatment period.
Subjects are only counted once per treatment per event.
Adverse events are shown by descending frequency by the highest tanezumab dose.
MedDRA v22.0 coding dictionary applied.

CCI

Nasopharyngitis was the most frequently reported AE across treatment groups during the
24-week Safety Follow-up or Early Termination Follow-up Period, and it was reported withsimilar frequency across treatment groups. Arthralgia and Periarthritis were reported in morepatients in the tanezumab treatment groups than in the celecoxib treatment group, and Backpain was reported in more patients in the celecoxib treatment group than in the tanezumab
treatment groups. Other AEs were reported in too few patients to draw conclusions(Table S6).

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CLINICAL STUDY REPORT SYNOPSIS

Table S6. Incidence of Treatment-Emergent Adverse Events During the Safety
Follow-up Period (All Causalities) - Safety Population
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=91)

Tanezumab 10 mg(N=87)

Celecoxib(N=89)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Nasopharyngitis

8 (8.8)8 (9.2)8 (9.0)0

3 (3.4)0Constipation03 (3.4)

1 (1.1)

Arthralgia

6 (6.6)2 (2.3)

1 (1.1)

Back pain

3 (3.3)2 (2.3)5 (5.6)Fall

1 (1.1)2 (2.3)2 (2.2)

Ligament sprain

1 (1.1)2 (2.3)2 (2.2)

Tenosynovitis

0

2 (2.3)2 (2.2)Atrioventricular block0

1 (1.1)0

Bronchitis01 (1.1)0

Cellulitis

01 (1.1)0

Conjunctivitis allergic01 (1.1)0

Arthritis

Contusion

2 (2.2)

1 (1.1)1 (1.1)

Dyslipidaemia

01 (1.1)0

Eczema0

1 (1.1)0

Haemangioma0

1 (1.1)0

2 (2.2)

1 (1.1)2 (2.2)

Hepatic function abnormal0

1 (1.1)0

Hordeolum01 (1.1)0Hyperlipidaemia

01 (1.1)0

Hypoaesthesia

1 (1.1)1 (1.1)2 (2.2)

Hypotension0

1 (1.1)0

Influenza0

1 (1.1)0

Insomnia

Headache1 (1.1)1 (1.1)1 (1.1)

Liver function test abnormal0

1 (1.1)0

Musculoskeletal pain0

1 (1.1)1 (1.1)

Oesophageal carcinoma01 (1.1)0

Osteoarthritis0

1 (1.1)

0

Pain in extremity

2 (2.2)

1 (1.1)1 (1.1)

Periarthritis

4 (4.4)

1 (1.1)0

Procedural pain0

1 (1.1)0

Pyrexia0

1 (1.1)1 (1.1)

Road traffic accident0

1 (1.1)0

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CLINICAL STUDY REPORT SYNOPSIS

Table S6. Incidence of Treatment-Emergent Adverse Events During the Safety
Follow-up Period (All Causalities) - Safety Population
Number of Subjects Evaluable for AEs
Number (%) of Subjects:
by Preferred Term

Sinusitis
SomnolenceTanezumab 5 mg
(N=91)

Tanezumab 10 mg(N=87)

Celecoxib(N=89)

n (%)

n (%)

n (%)

0

1 (1.1)0

1 (1.1)1 (1.1)0

Syncope01 (1.1)0

Tonsillitis

01 (1.1)0

Abdominal discomfort

00

1 (1.1)

Abdominal pain upper

1 (1.1)0

1 (1.1)

Actinic keratosis

1 (1.1)00Anastomotic ulcer

1 (1.1)00Arthropathy

1 (1.1)00Basedow's disease

1 (1.1)0

0

Blood creatine phosphokinase increased

2 (2.2)00Bone neoplasm

1 (1.1)00

Bradycardia

00

1 (1.1)

Calcinosis

1 (1.1)00

Cardiac failure

1 (1.1)00Chalazion

1 (1.1)

0

0

0

0

1 (1.1)Chronic kidney disease

1 (1.1)00Decreased appetite

1 (1.1)0

1 (1.1)

Dental caries

1 (1.1)00Dental cyst

00

1 (1.1)

Depression00

1 (1.1)Diabetes mellitus

00

1 (1.1)

Diarrhoea

1 (1.1)0

0

Dizziness

00

2 (2.2)

Dizziness postural00

1 (1.1)

Dry skin00

1 (1.1)

Epicondylitis

2 (2.2)00Extrasystoles

00

1 (1.1)

Femoroacetabular impingement00

1 (1.1)

Gallbladder polyp00

1 (1.1)

Gastritis

1 (1.1)0

0

Gastroenteritis

1 (1.1)00Haemorrhoids

1 (1.1)0

0

Hand fracture

1 (1.1)00Chondrocalcinosis pyrophosphate

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CLINICAL STUDY REPORT SYNOPSIS

Table S6. Incidence of Treatment-Emergent Adverse Events During the Safety
Follow-up Period (All Causalities) - Safety Population
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=91)

Tanezumab 10 mg(N=87)

Celecoxib(N=89)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Hyperkeratosis

1 (1.1)00Hypertension00

1 (1.1)Hyperuricaemia

00

1 (1.1)

Hypogeusia

1 (1.1)

0

0

Joint effusion

2 (2.2)00Large intestine polyp1 (1.1)00Limb discomfort

1 (1.1)00

Lipoma1 (1.1)0

0

Malaise1 (1.1)0

0

Musculoskeletal stiffness

1 (1.1)00Nail injury

1 (1.1)0

0

Nausea1 (1.1)0

1 (1.1)

Neck pain

1 (1.1)00Nephrolithiasis

00

1 (1.1)

Oropharyngeal pain

1 (1.1)00Orthostatic hypotension

1 (1.1)00Osteonecrosis

1 (1.1)00Pruritus

1 (1.1)00

Pseudomonas infection

00

1 (1.1)

Pyelonephritis acute

1 (1.1)00

Rapidly progressive osteoarthritis

1 (1.1)

0

0

Rash

1 (1.1)0

2 (2.2)

Renal abscess

1 (1.1)00Renal neoplasm

00

1 (1.1)

Rhinorrhoea

1 (1.1)00Rotator cuff syndrome

1 (1.1)0

1 (1.1)

Sciatica

00

1 (1.1)Sinus tachycardia

00

1 (1.1)Skin abrasion00

1 (1.1)

Spinal compression fracture00

1 (1.1)

Temporomandibular joint syndrome

1 (1.1)00

Tendonitis

2 (2.2)00Tinnitus

1 (1.1)00Toothache

1 (1.1)0

0Trigeminal neuralgia

1 (1.1)

0

0

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS

Table S6. Incidence of Treatment-Emergent Adverse Events During the Safety
Follow-up Period (All Causalities) - Safety Population
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=91)

Tanezumab 10 mg(N=87)

Celecoxib(N=89)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Trigger finger

1 (1.1)00

Ureterolithiasis

1 (1.1)0

1 (1.1)00

2 (2.2)

Vision blurred

1 (1.1)00White blood cell count increased

1 (1.1)

0

0

0

0

1 (1.1)

Urticaria

Wound complication

Includes treatment-emergent events that begin after the week 56 (end of treatment) visit date for subjects who completed
the treatment period orafter the withdrawal from treatment date for subjects who withdrew early from the treatment period.
Subjects are only counted once per treatment per event.
Adverse events are shown by descending frequency by the highest tanezumab dose.
MedDRA v22.0 coding dictionary applied.

CCI

Treatment-Related Adverse Events: During the Treatment Period, at least one
treatment-related AE was experienced by 10 (10.9%), 6 (6.5%) and 12 (13.0%) patientsin the tanezumab 5 mg treatment group, the tanezumab 10 mg treatment group, and thecelecoxib treatment group, respectively; 1 (1.1%) patient, in the tanezumab 10 mg
treatment group, experienced a treatment-related SAE.



Severe Adverse Events: The only treatment-related severe AE during the Treatment
Period was Osteonecrosis, reported in one patient in the tanezumab 10 mg treatmentgroup (which was adjudicated to a diagnosis of Rapidly progressive OA type 2); this was
also an SAE. Study medication was withdrawn, the patient had a TJR, recovered, andtransitioned to the substudy.



Injection Site Reactions: Injection site reactions were reported in one patient, in thetanezumab 5 mg treatment group. This patient had injection site discoloration andinjection site pruritus when study medication was administered on study Day 1 and 61,
and injection site pruritus on study day 117; all reactions were mild in severity. These
events were considered by the Investigator to be related to study medication. The patientalso received study medication on study days 167, 229, 282, and 334 with no additional
injection site reactions reported.

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS

Potential Hypersensitivity Adverse Events: Overall few potential hypersensitivity
adverse events were reported during the study: eight AEs in 6 (6.5%) patients in thetanezumab 5 mg treatment group, and six AEs in 4 (4.3%) patients in the tanezumab 10
mg treatment group. All potential hypersensitivity AEs were mild in severity and none
were considered by the Investigator to be related to study medication.

Tier 1 Adverse Events: A pre-specified composite of AEs of potential sympathetic
dysfunction (Syncope, Bradycardia, Orthostatic hypertension, Anhidrosis, andHypohidrosis) was considered clinically important and classified as a Tier 1 AE in the
product’s Safety Review Plan. AEs within the Tier 1 composite were infrequently
reported with a similar incidence across treatment groups. The composite Tier 1 AE
incidence was the same (2.2%) across all treatment groups

Tier 2 Adverse Events: Tier 2 AEs were defined as AEs occurring in ≥3% of patients inany treatment group; the frequency of occurrence in each tanezumab treatment group wascompared to celecoxib, with 95% CIs provided to help gauge the precision of theestimates for risk difference. There were no differences in the frequency of occurrence ofTier 2 AEs (all 95 % CIs included 0) in either tanezumab treatment group compared tothe celecoxib treatment group

Deaths: No patients died during the study.

Serious Adverse Events: During the Treatment Period, SAEs were infrequently reported
in all treatment groups; the only SAE that occurred in more than one patient in atreatment group was Rotator cuff syndrome, which occurred in two patients in thetanezumab 10 mg treatment group. Of the 15 SAEs, one was considered by theInvestigator to be related to study medication: Osteonecrosis (left femoral head), severe
in intensity, in the tanezumab 10 mg treatment group (which was adjudicated to adiagnosis of Rapidly progressive OA type 2).
During the 24-week Safety Follow-up or Early Termination Follow-up Periods, ninepatients had SAEs: 5 (5.5%) in the tanezumab 5 mg treatment group, 2 (2.3%) in thetanezumab 10 mg treatment group, and 2 (2.2%) in the celecoxib treatment group. No
individual preferred term was reported in more than one patient. Of the nine SAEs, one,
Rapidly progressive OA (right knee), moderate in severity, in the tanezumab 5 mg
treatment group, was considered by the Investigator to be related to study medication.

Adverse Events of Abnormal Peripheral Sensation: The most frequently reported AEof abnormal peripheral sensation during the Treatment Period was Hypoesthesia, reported
in 5 (5.4%) patients in the tanezumab 5 mg treatment group, 2 (2.2%) patients in thetanezumab 10 mg treatment group, and 3 (3.3%) patients in the celecoxib treatmentgroup. All AEs of abnormal peripheral sensation during the Treatment Period were mild
in severity, except for a single event of Sciatica in a patient in the celecoxib treatmentgroup, which was moderate in severity.
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CLINICAL STUDY REPORT SYNOPSIS

Peripheral Neurological Consultation: Three patients each in the tanezumab 5 mg
treatment group and the celecoxib treatment group had AEs of abnormal peripheral
sensation that met criteria for requiring a neurologic consultation; no patient in thetanezumab 10 mg treatment group had an AE of abnormal peripheral sensation that met
criteria for requiring a neurologic consultation. Clinical data, including consultation datawhen available, were reviewed by an external neurology expert for all patients who had
at least one event requiring consultation. The most frequent expert primary diagnoses
were mononeuropathy and radiculopathy; there was no dose-dependence in theoccurrence. Mononeuropathy (Carpal tunnel syndrome [CTS]) was diagnosed in twopatients in the tanezumab 5 mg treatment group; in both cases the diagnosis was
definitive, new, and the presentation was sensory. In one patient, the CTS was bilateraland in the other patient, it was on the right side. Radiculopathy was diagnosed in one
patient in the tanezumab 5 mg treatment group (possible, cervical, new, sensory, rightsided) and in two patients in the celecoxib treatment group (both: probable, lumbosacral,pre-existing, sensory, left-sided). Polyneuropathy was diagnosed in one patient, in thecelecoxib treatment group (possible, length-dependent, new, sensory, bilateral).



Adverse Events of Possible Decreased Sympathetic Function: AEs indicative of
possible decreased sympathetic function were reported infrequently in all treatmentgroups with no individual AE being reported in more than two patients in the tanezumab
treatment groups. All AEs of possible decreased sympathetic function were mild, except
for one event of Diarrhea in the celecoxib treatment group which was moderate inseverityConsultations for Adverse Events of Possible Decreased Sympathetic Function: The
only key AEs meeting criteria for consultation were OH, Bradycardia and Syncope. No
patient was reported to have Anhidrosis or Hypohidrosis. Consultations were obtained forall patients who met the criteria for a consultation. Sympathetic neuropathy was notconfirmed for any of the patients who had a consultation, as determined by theInvestigator after a review of clinical data including available consultation material.



Neuropathy Impairment Score: The conclusion from the neurological examination forover 97% of patients across all treatment groups was that there was no new or worsened
neurological examination abnormality at the last assessment. Less than 2% of patients inany treatment group had a new or worsened neurological examination abnormality thatwas considered by the Investigator to be clinically significant.



Adjudication: The adjudicated outcomes of the six potential joint safety events analyzed
by the Adjudication Committee were Rapidly progressive OA type 1 (right/left knee, onepatient [2 events]) and Other: Pre-existing Subchondral insufficiency fracture, in thetanezumab 5 mg treatment group; Rapidly progressive OA type 2 (SAE of Osteonecrosis)
and Subchondral insufficiency fracture, in the tanezumab 10 mg treatment group; andOther: Pre-existing arthroplasty, in the celecoxib treatment group. Primary osteonecrosis
and Pathological fracture were not adjudicated outcomes in this study.
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CLINICAL STUDY REPORT SYNOPSIS
One patient, in the tanezumab 5 mg treatment group, had two joint safety events
adjudicated as Rapidly progressive OA type 1, one in each knee. The joints hadradiographic evidence of OA on the Screening X-ray (KL grade 1 or 2); the patient did
not have a TJR. One patient, in the tanezumab 10 mg treatment group, had a joint safety
event adjudicated as Rapidly progressive OA type 2. The affected joint was a hip that hadradiographic evidence of OA on the Screening X-ray (KL grade 1); the patient had a TJR.
One patient, in the tanezumab 10 mg treatment group, had an adjudicated outcome ofSubchondral insufficiency fracture; the affected joint was a knee that had a KL grade of 2
on the Screening X-ray. One patient, in the tanezumab 5 mg treatment group, had an
adjudicated outcome of Other: Pre-existing Subchondral insufficiency fracture; theaffected joint was a knee that had a KL grade of 1 on the Screening X-ray. One patient, inthe celecoxib treatment group, had an adjudicated outcome of Other: pre-existingarthroplasty; the affected joint was a knee that had a KL grade N/A on the screening Xray.


Total Joint Replacements: One patient, in the tanezumab 10 mg treatment group, who
had an adjudicated outcome of Rapidly progressive OA type 2, had a hip TJR during thestudy. The patient agreed to participate in the TJR substudy.

Laboratory Parameters: The incidence of patients with normal Baseline who had
post-Baseline laboratory test abnormalities that met the pre-specified threshold forchange from Baseline was low, mostly affected one or two patients within a treatmentgroup and was mostly evenly distributed across treatment groups. Laboratory
abnormalities considered clinically significant by the Investigator post-Baseline were to
be reported as AEs. All laboratory abnormalities reported as AEs in the Treatment Period
were reported in one patient each.



Vital Signs: Categorical changes from Baseline to the last post-Baseline value in sitting
BP during the Treatment Period (ie, up to Week 56) were mostly similar across treatmentgroups for systolic and diastolic BP, except for the sitting systolic and diastolic BP of >0
to <10, where a higher proportion of the celecoxib treatment group showed a change
compared to the tanezumab 5 mg treatment group and tanezumab 10 mg treatment group.
Overall, there was no dose-dependency in the differences between treatment groups.
Categorical changes in sitting systolic and diastolic BP with a maximum increase fromBaseline were mostly similar across the treatment groups, except for the increase insitting systolic BP of >10 to 20 and sitting diastolic BP of >0 to 10, where a higher
proportion of the tanezumab 5 mg treatment group showed an increase compared to thetanezumab 10 mg treatment group and celecoxib treatment group. Overall, there was nodose-dependency in the differences between treatment groups. Categorical changes insitting systolic and diastolic BP with a maximum decrease from Baseline were mostly
similar across the treatment groups. Overall, there was no dose-dependency in the
differences between treatment groups.

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CLINICAL STUDY REPORT SYNOPSIS
AEs associated with abnormal vital signs during the Treatment Period were infrequently
observed across treatment groups.


ECG: One patient, in the tanezumab 10 mg treatment group, had a QTc corrected using
Bazett's formula (QTcB)/QTc corrected using Fridericia's formula (QTcF) value ≥500
msec at any point during the study. This patient had a QTcB and QTcF value ≥500 msec
at Screening. The maximum changes in all ECG parameters up to the End of Study weresimilar across treatment groups.



Immunogenicity: Treatment-emergent (TE) ADA status (ie, TE ADA+ or TE ADA-) did
not appear to influence the proportion of patients identified as responders (ie, patientswith a reduction from Baseline in average LBPI score of ≥30% at Week 16) in thetanezumab treatment groups. The overall percent incidence of AEs in the combined TE
ADA+ tanezumab treatment group was comparable to the corresponding TE ADAcombined tanezumab treatment group.

CONCLUSIONSThe primary objective of this study was to evaluate the long-term safety of treatment withtanezumab. Although the study was not powered nor designed to detect treatment differencesin efficacy,Patients treated with tanezumab 5 mg had a greater mean change from Baseline in the
LBPI score and PGA-LBP compared with patients treated with celecoxib at Week 16
and 56. Patients treated with tanezumab 5 mg had a greater mean change fromBaseline in the RMDQ score than patients treated with celecoxib at Week 56, but not
at Week 16.

Patients treated with tanezumab 10 mg had a greater mean change from Baseline in
the LBPI and RMDQ scores compared to patients treated with celecoxib at Week 16;
results for tanezumab 10 mg and celecoxib treatment were similar for the LBPI andRMDQ scores at Week 56 and for the PGA-LBP at Weeks 16 and 56.

Tanezumab treatment was generally safe and well-tolerated in Japanese patients with
CLBP in this study. The adverse event data were generally consistent with previous
tanezumab CLBP studies and no new safety signals were identified.



Three patients contributed to the composite joint safety endpoint: one patient in thetanezumab 5 mg treatment group with an adjudicated diagnosis of Rapidly
progressive OA type 1; in the tanezumab 10 mg treatment group, one patient each had
an adjudicated diagnosis of Rapidly progressive OA type 2 and Subchondral
insufficiency fracture. The patient with Rapidly progressive OA type 2 had a TJR.



The adverse event data related to abnormal peripheral sensation were consistent withprevious studies and the incidence of these adverse events was higher in the
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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS
tanezumab 5 mg treatment group than in the tanezumab 10 mg treatment group andthe celecoxib treatment group.


There was no evidence of an effect of tanezumab on sympathetic nervous system
function.



There was no evidence of an effect of tanezumab on safety related to vital signs, ECG
measures, or safety laboratory tests.



The immunogenicity results do not provide any evidence that the presence oftreatment-emergent ADA affects the safety or efficacy profile of tanezumab.

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