Full Clinical Study Report
Protocol A4091059

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Tanezumab
Clinical Study Report Synopsis: Protocol A4091059
Protocol Title: A Phase 3, Randomized, Double Blind, Placebo and Active-Controlled,
Multicenter, Parallel-Group Study of the Analgesic Efficacy and Safety of Tanezumab in
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 191 sites randomized patients in this study. The study was
conducted at 245 sites in the United States (US), Canada, France, Spain, Sweden, Denmark,
Hungary, Japan, and the Republic of Korea. Two patients were screened in Denmark;however, none were randomized.
Publications Based on the Study: None
Study Initiation and Completion Dates:
Study Initiation Date: 18 August 2015
Primary Completion Date: 17 October 2017
Study Completion Date: 20 December 2018
Report Date: 26 July 2019
Previous Report Date(s): Not applicable.
Phase of Development: Phase 3
Study Objective(s):Primary ObjectiveDemonstrate superior analgesic efficacy of tanezumab 10 mg and 5 mg administeredsubcutaneously (SC) every 8 weeks compared to placebo at Week 16.

Secondary Objectives

Evaluate the long-term safety of tanezumab 10 mg and 5 mg SC administered every
8 weeks (7 administrations);

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CLINICAL STUDY REPORT SYNOPSIS

Estimate the long-term analgesic efficacy of tanezumab 10 mg and 5 mg SC administered
every 8 weeks (7 administrations) up to Week 56;Compare the analgesic efficacy of tanezumab 10 mg SC administered every 8 weeks
relative to an active comparator (oral tramadol prolonged release [PR]) at Week 16.

METHODS
Study Design:This was a randomized, double-blind, placebo- and active-controlled, multicenter,
parallel-group Phase 3 study of the efficacy and safety of tanezumab when administered SC
for up to 56 weeks in patients with chronic low back pain (CLBP). Approximately
1800 patients were planned to be randomized in a 2:2:2:3 ratio to one of four treatmentgroups:

Placebo administered SC at an 8-week interval plus placebo matching tramadol PR up to
Week 16 (approximately 400 patients). At the Week 16 visit, patients in this group who
met the efficacy responder criteria were switched in a blinded fashion in a 1:1 ratio toeither tanezumab 5 mg or 10 mg administered SC at an 8-week interval plus placebo
matching tramadol PR to Week 56;

Tanezumab 5 mg SC administered at an 8-week interval plus placebo matching tramadol
PR to Week 56 (approximately 400 patients);Tanezumab 10 mg SC administered at an 8-week interval plus placebo matchingtramadol PR to Week 56 (approximately 400 patients);

Oral tramadol PR plus placebo administered SC at an 8-week interval to Week 56(approximately 600 patients).

The total study duration consisted of three periods: Screening (up to a maximum of 37 days,
including a Washout Period [2-32 days] and an Initial Pain Assessment Period [IPAP],
five days prior to randomization/baseline), a Double-blind Treatment Period (including the
16-week Primary Efficacy Phase and a 40-Week Long Term Safety and Efficacy Phase), anda Follow-up Period (24 weeks). The post-randomization study duration (ie, Double-blind
Treatment Period and Follow-up Period) was approximately 80 weeks.
Patients who underwent total knee, hip, or shoulder joint replacement surgery during thestudy (ie, during the Treatment Period or the Follow-up Period) were discontinued fromstudy treatment and were followed for 24 weeks after the procedure as part of a substudy,
provided the patient met protocol criteria and provided consent. Patients who had other types
of joint replacement surgery or arthroplasty during the study were discontinued fromtreatment and completed the Safety Follow-up Period.

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After obtaining informed consent at Screening, the Investigator evaluated the patient basedon the Screening inclusion/exclusion criteria. The Screening Period included thediscontinuation and washout of all prohibited pain medications, X-rays to confirm thepatient’s radiographic eligibility for the study, and the IPAP. Patients who did not require a
washout of prohibited pain medications could have started the IPAP the day after X-ray
confirmation of radiographic eligibility was received from the Central Reader.
Patients who met eligibility criteria at the Screening visit were instructed in the completion ofan electronic diary that utilized Interactive Response Technology (IRT). Patients recorded
Low Back Pain Intensity (LBPI) scores, joint pain scores, non-steroidal anti-inflammatory
drug (NSAID) and rescue medication usage via the IRT. During the Screening Period, allpatients underwent X-rays of the hips, knees, and shoulders. Other major joints exhibiting
signs or symptoms suggestive of osteoarthritis (OA) were also imaged. At Screening,
patients also provided a pain score (scored with an 11-point numerical rating scale [NRS])
for knees, hips, and shoulders, and any other major joint for which a radiograph was
obtained.
Patients who were eligible at the Randomization/Baseline Visit (Day 1) were randomized to
one of the four treatment groups.
Administration of SC study medication (placebo, tanezumab 5 mg, or tanezumab 10 mg)
occurred at Baseline and Week 8. Assuming a sufficient treatment response wasdemonstrated at Week 16, additional administration of SC study medication occurred at
Weeks 16, 24, 32, 40, and 48. Patients were observed for adverse events including signs andsymptoms of hypersensitivity in the clinic for a minimum of one hour after eachadministration of SC study medication.
At the Week 16 visit, patients must have had at least a 30% reduction in average LBPI(aLBPI) score relative to Baseline and at least a 15% reduction in aLBPI score relative toBaseline at any week from Week 1 to Week 15 in order to continue study treatment to
Week 32. At the Week 32 visit, patients must have had at least a 30% reduction in aLBPIscore relative to Baseline in order to continue study treatment to Week 56. Patients who did
not meet these response criteria were discontinued from the Double-blind Treatment Period
and entered the Early Termination Follow-up Period.
Each treatment group received tramadol PR or matching placebo tablets to maintain blindingof the active oral study medication. Patients randomized to tramadol PR at Baseline werestarted on a tramadol PR dose of 100 mg once a day (QD). During the first four weeks of the
Double-blind Treatment Period (Baseline to Week 4), the tramadol PR dose could be
adjusted as necessary every five to seven days by 100 mg increments depending on pain
relief or tolerability, up to a maximum dose of tramadol PR 300 mg QD. In order to maintainthe blind, patients receiving matching placebo were also allowed to titrate their dose.
Patients were contacted by telephone at Weeks 1 and 3 to evaluate pain relief and tolerabilityof the oral study medication and to receive counsel regarding dose adjustment, and a clinic
visit occurred at Week 2. After the Week 4 visit, the dose of tramadol PR (or matching
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placebo) was held constant until the Week 56 visit. Note: For patients participating inEurope, following the completion of the Week 16 visit through the Week 56 visit, the dose oftramadol PR or oral placebo could be decreased to a minimum of 100 mg per day, if
clinically indicated. If the dose of tramadol PR or oral placebo was reduced, it could later be
re-escalated for reasons of inadequate pain control to a maximum of the previous
individually titrated dose.
Oral study medication and rescue medication were dispensed at every clinic visit beginningat Baseline and concluding with the Week 48 visit. Oral tramadol PR or matching placebo
was self-administered by patients on a daily basis from Baseline through Week 56.
At the Week 16 visit, presuming a treatment response was demonstrated, patients randomized
to the placebo treatment arm were switched in a blinded manner to tanezumab SC treatment.
These patients were switched in a 1:1 ratio to tanezumab 5 mg or tanezumab 10 mg SC plus
matching placebo and received the first administration of SC tanezumab at Week 16.
The Primary Efficacy Phase comprised the time from Baseline to Week 16. The primary
efficacy endpoint, aLBPI score, was collected daily via IRT from Baseline to Week 16.
Rescue medication use was recorded daily and NSAID use and joint pain assessments wererecorded once a week via the IRT. Secondary efficacy and safety assessments were collected
at Weeks 2, 4, 8, and 16. During the Primary Efficacy Phase, all concomitant medications
for the treatment of CLBP were prohibited with the exception of rescue medication(acetaminophen/paracetamol) and study medication. During the Primary Efficacy Phase,patients were permitted to continue with stable non-pharmacologic treatments (eg, massage,
physical therapy) for CLBP, but were prohibited from beginning new non-pharmacologicaltreatments until after Week 16.
The Long Term Safety and Efficacy Phase began after the Week 16 visit and continued until
Week 56. The aLBPI score, rescue medication use, NSAID use, and joint pain assessments
were collected once a week via IRT, and safety and secondary efficacy assessments werecollected at study visits at Weeks 24, 32, 40, 48, and 56. In addition, patients were contacted
by telephone at Weeks 20, 28, 36, 44, and 52 to assess compliance and collect adverse
events, concomitant drug, and concomitant non-drug information. Starting at Week 16, atthe discretion of the Investigator, patients could have started certain permitted medications
and non-pharmacological therapies for the treatment of low back pain. X-rays of the hips,
knees, and shoulders, as well as any additional joint that was imaged at Screening or
identified as at risk during the study, were obtained for all patients at Weeks 24 and 56 andsent to the Central Reader for review. Confirmation by the Central Reader of the continuing
radiographic eligibility of the patient must have been received at Week 24 prior toadministration of the Week 24 SC study medication.
Patients who completed the Week 56 visit were considered to have completed the
Double-blind Treatment Period and entered the 24-week Safety Follow-up period. Patients
who completed the Double-blind Treatment period and entered the 24-week Safety
Follow-up Period and completed the Week 80 visit were considered to have completed the
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study. Patients who discontinued study treatment prior to completing the Week 56 visit were
not considered to have completed the Double-blind Treatment Period. Patients who did notcomplete the Double-blind Treatment Period but who entered and completed the 24-week
Early-termination Follow-up Period were considered to have completed the study while thosepatients who did not complete the 24-week Early-termination Follow-up Period were notconsidered to have completed the study.
With the completion of the Week 56 visit, patients began the 24-week Follow-up Period andwere asked to return to the clinic for two additional study visits.
At Week 64 or up to 16 weeks after the last dose of SC study medication, efficacy
assessments, adverse event, and concomitant medication information was collected andstandard of care medication was initiated if determined appropriate by the Investigator.
Between the clinic visits in the Follow-up Period, patients were contacted by telephone at
Weeks 60, 68, 72, and 76 to collect adverse event, concomitant drug, and concomitant
non-drug information. The aLBPI score was collected once a week (using a 24-hour recall
period) through the Week 64 visit via IRT. Patients continued to report new or increased
joint pain, acetaminophen, and NSAID use on a weekly basis via IRT through Week 80. As
in the Double-blind Treatment Period, patients with severe, persistent joint pain had moredetailed evaluations to investigate the pain. At the end of the 24-week Follow-up Period,
patients returned for a final study visit at Week 80 (End of Study). At that visit, all End of
Study procedures were completed including X-rays of the hips, knees, and shoulders, as wellas any additional joint that was imaged at Screening or identified as at risk during the study.
The window for the Week 80 X-rays was 30 days of the nominal time of the visit but was tobe obtained as close as possible to the Week 80 visit, and preferably no more than 14 days
after the Week 80 visit.
Patients who discontinued treatment prior to Week 56, whether at their request or at thedecision of the Investigator, were required to undergo 24 weeks of follow-up (Early
Termination Follow-up Period). The 24 weeks of follow-up were obtained throughthree clinic visits and monthly phone calls to yield 24 weeks of post-treatment follow-up. In
addition, patients were asked about the presence and severity of joint pain (hips, knees, andshoulders), rescue medication use, and NSAID use once per week via IRT through the end of
the Early Termination 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) were performed as soon as possible after the decision towithdraw from the study was made, provided at least 30 days had passed since the previous
X-rays were taken. The remainder of efficacy and safety assessments were performed at thefirst scheduled visit, which was eight weeks following the last dose of study medication.
Two additional clinic visits were also scheduled. The second visit occurred at Week 64 or up
to approximately 16 weeks after the patient’s last dose of SC study medication to collectsafety and efficacy data. Once this visit and final efficacy assessments were conducted,
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standard of care treatment was offered to patients for the remaining eight weeks of the Early
Termination Follow-up Period.
The third and final clinic visit occurred approximately 24 weeks following the last dose of
SC study medication. At this visit, repeated X-rays of the hips, knees, and shoulders (andany other major joint imaged at Screening or identified as at risk during the study) were
performed, provided at least 30 days had elapsed since the previous set of X-rays were taken.
The window for obtaining end of study X-rays was 30 days before or 14 days after thenominal time of the visit.
Telephone contact was made with patients who withdrew early from treatment at
approximately 12 and 20 weeks following the last dose of SC study medication.
If a patient refused to complete the Early Termination Follow-up Period, or chose to
discontinue during that time, a complete early termination visit was performed.
Diagnosis and Main Criteria for InclusionMale or female of any race, 18 years of age; willing and able to provide informed
consent.

Presented with duration of CLBP of 3 months.

Primary location of low back pain must have been between the 12th thoracic vertebra andthe 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.



Documented history of previous inadequate treatment response (ie, the agent did notprovide sufficient pain relief while on the maximum tolerated dose of the therapy or thepatient was unable to take the agent due to contraindication or inability to tolerate) to atleast three different categories of agents commonly and generally considered effective forthe treatment of CLBP. If a patient had been treated with two or more agentssimultaneously but continued to have inadequate pain relief, the pain was consideredunresponsive to all of the agents taken.



LBPI score of ≥5 at Screening.

Completed at least four daily pain diaries during the five days prior to the day ofRandomization, with an aLBPI score of ≥5.

Patient’s Global Assessment (PGA) of Low Back Pain must have been “fair,” “poor,” or“very poor” at Baseline.

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Patients must have been willing to discontinue all pain medications for CLBP except
rescue medication and study medication and not use prohibited pain medications
throughout the duration of the study except as permitted per Protocol.

Diagnosis and Main Criteria for ExclusionBody Mass Index of ≥45 kg/m2.

Diagnosis of 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.


Patients who had Kellgren Lawrence (KL) grade ≥2 radiographic evidence of hip OA
were excluded;

Patients who had KL grade ≥3 radiographic evidence of knee OA were excluded;

Patients who had KL grade 2 radiographic evidence of knee OA but who did notmeet 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). Patients with trauma occurring >6 months prior to Screening were
eligible to be considered for entry into the study.



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 associatedwith CLBP.

History of disease that may involve the spine, including inflammatory joint diseases suchas seronegative spondyloarthropathy (eg, ankylosing spondylitis), rheumatoid arthritis(RA), infections, or tumors of the spinal cord, or Paget’s disease of the spine, 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, RA), systemic metabolic bone disease (eg, pseudogout, Paget’s disease,metastatic calcifications); large cystic lesions, primary or metastatic tumor lesions; orstress or traumatic fracture.
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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 3) subchondral
insufficiency fractures 4) spontaneous osteonecrosis of the knee 5) osteonecrosis6) 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.



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



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 is contraindicated (refer to product labeling).



History of intolerance or hypersensitivity to tramadol or any of its excipients or existenceof a medical condition or use of concomitant medication for which the use of tramadol iscontraindicated (refer to product labeling).



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



Signs and symptoms of clinically significant cardiac disease.

Patients who had evidence of orthostatic hypotension (OH) based upon replicate
orthostatic blood pressure (BP) measurements.

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 would
preclude completion of required study activities.



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



History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder.

Randomization Criteria

Patient must have completed appropriate washout of analgesics.

Patient must have entered at least four LBPI scores on the daily pain diary in thefive days prior to the Baseline (Day 1) visit.
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Patient must have abstained from taking rescue medication (acetaminophen/paracetamol)
within the 24 hours that preceded dosing.



Patients must have met the Baseline LBPI score and PGA of Low Back Pain 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 5 mg, tanezumab 10 mg, and placebo for tanezumab were each presented as asterile solution for SC administration, in a glass pre-filled syringe (PFS; Table S1). Eachtanezumab PFS contained a sufficient amount of tanezumab to provide the intended dose of
drug at a concentration of 5 mg/mL or 10 mg/mL.
Each PFS was packaged in an individual carton and had a unique container number.
Tramadol PR was provided as a tablet containing tramadol 100 mg, tramadol 200 mg, andtramadol 300 mg with a PR formulation. The bottles used for the titration period contained
60 tablets of tramadol 100 mg. The bottles for the treatment period contained 72 tablets oftramadol 100 mg, 200 mg, or 300 mg. Each bottle had a unique container number.
The placebo for tramadol PR was provided as tablets manufactured by a Pfizer designee tomatch the active tramadol PR 100 mg, tramadol PR 200 mg, and tramadol PR 300 mg,
respectively. The bottles used for the titration period contained 60 tablets of placebo fortramadol 100 mg. The bottles for the treatment period contained 72 tablets of placebo fortramadol 100 mg, 200 mg, or 300 mg. Each bottle had a unique container number.

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Table S1. Investigational Product Description
Investigational
Product Description
PF-04383119 Solution
for Injection, 5 mg/mL

Vendor Lot
Number
M76807
L50447

PF-04383119 Solution
for Injection, 10 mg/mL

N09941
L52539Placebo for
PF-04383119 Solution
for Injection
Tramadol HCl PR,
100 mg

L39168Tramadol HCl PR,
200 mgTramadol HCl PR,
300 mgPlacebo forTramadol HCl PR
100 mgPlacebo forTramadol HCl PR
200 mgPlacebo forTramadol HCl PR
300 mg139705B
143759A
147888A
149290B
145700A
141648G
135509E
148661A
157289A
135510E
141632D
146699D
152517Z
169615A
B13143
B12291
B15115
B16005
B12292
B13144B15116
B16006
B12293
B13145B15117
B16007B17029Pfizer Lot Number

Strength/Potency

Dosage Form

16-000831
15-002258
15-002259
16-001924
15-002260
15-002261
15-002262
15-002263

5 mg/mL

Pre-filled
Syringe

10 mg/mL

Pre-filled
Syringe

0 mg/mL

Pre-filled
Syringe14-001196
15-002127
15-004884
16-000960
15-003171
15-002128
14-001049
15-004885
16-000961
14-000059
15-002129
15-004886
16-000962
17-001613
13-110345
12-005704
15-004149
16-000640
12-005705
13-110346
15-004150
16-000664
12-005830
13-110574
15-004151
16-000665
17-001433

100 mgTablet

200 mgTablet

300 mgTablet0 mg

Tablet0 mg

Tablet0 mg

TabletPFIZER CONFIDENTIAL
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EFFICACY EVALUATIONSQuestionnaires for primary and secondary efficacy parameters were completed by thepatients at the site via IRT (electronic tablets), or at home via electronic diaries.
Questionnaires at the site were completed prior to dosing on dosing days.
Primary Efficacy Evaluation
The primary efficacy endpoint was the change from Baseline to Week 16 in the daily aLBPIscore as measured by an 11-point numerical rating scale (NRS) for tanezumab versus
placebo.
Key Secondary Efficacy Evaluation
The key secondary efficacy endpoints were the change from Baseline to Week 16 in the
Roland Morris Disability Questionnaire (RMDQ) for tanezumab versus placebo, the response
as defined by a ≥50% reduction from Baseline in daily aLBPI score derived from the patient
diary at Week 16 for tanezumab versus placebo, and the change from Baseline to Week 2 inaLBPI score for tanezumab versus placebo.
Secondary Efficacy Evaluation
Secondary efficacy endpoints included change from Baseline to Weeks 2, 4, 8, 12, 24, 32, 40,
48, 56, and 64 in aLBPI score; change from Baseline to Weeks 2, 4, 8, 16 (for tanezumab vstramadol) 24, 32, 40, 48, 56, 64 and 80 in RMDQ total score; change from Baseline to
Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, and 64 in PGA of Low Back Pain; cumulative
distribution of percent change from Baseline in aLBPI score to Weeks 16, 24, and 56(endpoint for summary only); response as defined by a 30%, 50%, 70% and a 90%
reduction from Baseline in daily aLBPI score derived from the patient diary at Weeks 2, 4, 8,
12, 16, 24, 32, 40, 48, 56, and 64; response as defined by a 30%, 50%, 70% and a 90%
reduction from Baseline in the RMDQ score at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and80; cumulative distribution of percent change from Baseline in RMDQ score to Weeks 16,
24, and 56 (endpoint for summary only); CLBP Responder Index analysis (composite
endpoint of aLBPI score, PGA of Low Back Pain, and RMDQ total score at Weeks 2, 4, 8
16, 24, 32, 40, 48 and 56); improvement of 2 points in PGA of Low Back Pain at Weeks 2,
4, 8, 16, 24, 32, 40, 48, 56, and 64; and incidence of and time to discontinuation due to lackof efficacy.
Secondary patient-reported outcome endpoints included change from Baseline to Weeks 2, 4,
8, 16, 24, 32, 40, 48, 56, and 64 in the Brief Pain Inventory short form (BPI-sf) scores; Work
Productivity and Activity Impairment Questionnaire:Low Back Pain (WPAI:LBP) scoreschange from Baseline to Weeks 16, 56, and 64; Euro Quality of Life-5 Dimension-5 Level(EQ-5D-5L) dimensions and overall health utility score at Baseline, Weeks 8, 16, 24, 40, 56,
and 64; Treatment Satisfaction Questionnaire for Medication v.II (TSQM) score at Weeks 16
and 56; Patient-Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and56; and Health Care Resource Utilization at Baseline, and Weeks 64, and 80.
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Rescue medication was measured by the incidence and number of days of usage during
Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and Week 64 and the amount taken (mg) during
Weeks 2, 4, 8, 12 and 16.
Pharmacokinetic and Pharmacodynamic Evaluations:Pharmacokinetic Evaluations
Tanezumab concentrations were measured to support the development of an SC
administration population pharmacokinetic (PK) model that allows for the prediction of thetanezumab concentration over time in individuals. In addition, tanezumab concentrations
were measured to inform the immunogenicity profile of tanezumab.
Pharmacokinetic SamplingBlood samples for the assessment of the PK of tanezumab were collected at Baseline (Day 1;
predose) and at Weeks 2 and 4 (in approximately 30% of patients randomized at selectedsites), Week 8 (predose), Week 16 (predose), Week 32 (predose), Week 48 (predose),
Week 56, and Week 64.
Pharmacodynamic Evaluations
Blood samples were collected for the assessment of soluble p75, total nerve growth factor(NGF), and proNGF. In addition, blood and urine samples were collected for the assessmentof biomarkers.
Pharmacodynamic SamplingBlood samples for the assessment of NGF (total NGF and proNGF) and soluble p75 werecollected at Baseline (Day 1; predose), at Weeks 2 and 4 (in approximately 30% of patientsrandomized at selected sites), Week 8 (predose), Week 48 (predose), and at Weeks 56 and64 (or at Early Termination). Blood and 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, safety laboratory
testing (chemistry and hematology), sitting vital signs, 12-lead ECG, orthostatic(supine/standing) BP, Survey of Autonomic Symptoms (SAS) scores, joint safety
adjudication outcomes, total joint replacements (TJRs), neurologic examination (using the
Neuropathy Impairment Score [NIS]), anti-drug antibodies (ADA), and physicalexaminations.
Safety Assessments
Adverse events, 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).
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For female patients of childbearing potential, serum pregnancy tests were conducted at
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, and at Weeks 56,
64, and 80, or Early Termination. Vital signs were collected after the patient had been sitting
for at least 5 minutes. 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.
NeurologicalAn adverse event of OH was reported for all patients meeting criteria for OH at a visit. If noapparent 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, the patient had a repeat assessment of OH performed at least one week, but
not more than four weeks, later. If confirmed OH was present at the follow-up visit, thepatient was further evaluated for the presence of sympathetic autonomic neuropathy by a
cardiologist or neurologist as soon as possible.
Patients reporting adverse events of any seriousness or severity with preferred terms of
Bradycardia, Syncope, OH, Anhidrosis, or Hypohidrosis were further evaluated for thepresence 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) and 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 adverse event
suggestive of new or worsening peripheral neuropathy or an adverse event of abnormal
peripheral sensation was reported as an SAE, resulted in the patient being withdrawn fromthe study, was ongoing at the end of the patient’s participation in the study, or was of severe
intensity. Neurological evaluations were also obtained if a new or worsened clinicallysignificant abnormality on the neurologic exam was reported as an adverse event and met
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criteria listed above, or if a reported non-neuropathic neurological adverse event (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 adverse event.
Radiographic assessments (X-rays) of the hips, knees and shoulders were obtained at
Screening, Weeks 24, 56 and 80 (or at Early Termination Visit 1 and 3).
A central radiology reader reviewed the radiology images for assessment of eligibility.
During the study, the Central Reader reviewed radiology images for continued radiologic
eligibility and for 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 SC dose 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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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 400 patients per treatment group was needed toprovide at least 80% power to achieve statistical significance (at the 5% 2-sided level) bothfor comparisons of tanezumab 10 mg and 5 mg versus placebo, as well as the comparison oftanezumab 10 mg versus the active comparator in the primary endpoint. Since placebo
patients who reached Week 16 response criteria were switched to tanezumab treatment only,
in order to balance patient exposure during the safety phase of the trial (post-Week 16), thenumber of patients randomized at Baseline to the active comparator group was increased toapproximately 600. The total sample size was therefore planned to be approximately
1800 patients.
Analysis of the Primary Endpoint
The primary efficacy endpoint was change from Baseline to Week 16 in aLBPI score for thecomparison of tanezumab versus placebo in the Intent-to-Treat (ITT) analysis set, which
consisted of all randomized patients who received at least one dose of SC study medication(either tanezumab or placebo SC). The analysis for the primary endpoint used analysis ofcovariance (ANCOVA) with covariates of Baseline aLBPI score, treatment group, and studysite as a random effect. Testing of the primary endpoint followed the graphical approach ofgate-keeping strategy. This approach controls the family-wise type I error rate of 5% (twosided).
Analysis of Key Secondary Endpoints
The analysis of the key secondary endpoint of change from Baseline to Week 16 in RMDQ
for tanezumab versus placebo used the ANCOVA model described for the primary endpoint
analysis with covariates of Baseline RMDQ score, Baseline aLBPI score, treatment group,and study site as a random variable.
The analysis of response as defined by a ≥50% reduction from Baseline in daily aLBPI scoreat Week 16 for tanezumab versus placebo used logistic regression with Baseline aLBPI scoreas a covariate.
The analysis of the change from Baseline to Week 2 in the daily aLBPI score for tanezumab
versus placebo used the ANCOVA model described for the primary efficacy analysis withcovariates of Baseline aLBPI score, treatment, and study site as a random effect.
Analysis of Secondary Endpoints
Secondary endpoints examined the change from Baseline to additional timepoints prior to
Week 16 in LBPI score (ie, Weeks 2, 4, 8 and 12), using the multiple imputation for missing
data procedure and analysis described above for the comparisons of tanezumab versus
placebo and tramadol. The same analyses were undertaken for the change from Baseline to
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Weeks 24, 32, 40, 48, and 56 in aLBPI for the comparisons of tanezumab versus tramadol
only.
Other secondary endpoints included the RMDQ total score, the PGA of Low Back Pain, andthe 7 BPI-sf measures. The analysis of these endpoints, as change from Baseline to Weeks 2,
4, 8, and 16 (for tanezumab versus placebo and tramadol comparisons) and to Weeks 24, 32,
40, 48, and 56 (for tanezumab versus tramadol comparisons) used the same ANCOVA
analysis as for the primary endpoint.
Patient response endpoints of improvement in the aLBPI score and the RMDQ score of ≥30,
50, 70 and 90%, improvement in the PGA of Low Back Pain ≥2 points and the CLBP
Responder Index were analyzed at Weeks 2, 4, 8, 12 (aLBPI response only) and 16 (fortanezumab versus placebo and tramadol comparisons) and to Weeks 24, 32, 40, 48 and
56 (for tanezumab versus tramadol comparisons) using logistic regression for binary data.
The model for the analysis of the responders based on aLBPI score and CLBP Responder
Index included model terms for Baseline aLBPI score and treatment group. The model forthe analysis of the PGA of Low Back Pain responders included the Baseline PGA score,
Baseline aLBPI score and treatment group. These analyses were performed using a mixed
baseline observation carried forward (BOCF)/last observation carried forward (LOCF)
imputation approach. In this analysis BOCF imputation (ie, a patient would be a
non-responder) was used for missing data due to discontinuation for reasons of lack ofefficacy, adverse event, or death up to the timepoint of interest, and LOCF imputation wasused for missing data for any other reason.
Analysis of Pharmacokinetic Data
Pharmacokinetic data was 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 timepost-dose for each treatment group.

Boxplots of tanezumab plasma trough concentrations at the nominal times
for the tanezumab treatment groups.

RESULTS
Patient Disposition and Demography:
Of 6518 patients screened for the study, 1832 patients were randomized.
The majority of patients completed treatment up to Week 16 (77.8%). At the Week 16 visit,patients treated with placebo who met the Week 16 efficacy response criteria were eligible tocontinue in treatment and were switched to either tanezumab 5 mg or tanezumab 10 mg
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treatment for the remainder of the study. Of the 407 patients in the placebo treatment group,
99 patients were randomized at Week 16 to receive tanezumab 5 mg, and 95 patients wererandomized at Week 16 to receive tanezumab 10 mg (Table S2).
Of the 1832 patients who were randomized, a total of 631 patients (34.4%) completed theTreatment Period (ie, up to Week 56) and of those, most (586 patients [92.9%]) completed
the Safety Follow-up Period (Table S2). Of those who discontinued from the Treatment
Period (1194 patients [65.2%]), fewer than half completed the Safety Follow-up Period(595 patients [49.8%]).
Overall, the proportion of patients who completed the Treatment Period was greater forpatients treated with tanezumab (34.4% and 39.0% for tanezumab 5 mg and 10 mg,
respectively) than for patients who started with placebo treatment (30.5% and 31.4% for theplacebo  tanezumab 5 mg and placebo  tanezumab 10 mg treatment groups, respectively;
Table S2). In general, the proportion of patients who completed the Treatment Period was
similar in the placebo treatment groups, the tanezumab 5 mg treatment group, and thetramadol PR treatment group, ranging from 30.5% to 34.4%. The incidence of patientscompleting the Treatment Period in the tanezumab 10 mg treatment group (39.0%) was
higher than in the other treatment groups (Table S2).

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Table S2. Subject Disposition
Placebo -> Tanezumab 5
mg(N=203)

Placebo -> Tanezumab 10
mg(N=204)

Tanezumab 5 mg
(N=407)

Tanezumab 10 mg(N=408)Tramadol(N=610)Total(N=1832)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Randomized

203 (100.0)

204 (100.0)

407 (100.0)

408 (100.0)

610 (100.0)

1832 (100.0)

Treated202 (99.5)

204 (100.0)

407 (100.0)

407 (99.8)

605 (99.2)

1825 (99.6)

Screened: 6518
Screen Failure: 4557
Other Screened but not Randomized: 129

Not Treated

1 (0.5)00

1 (0.2)5 (0.8)7 (0.4)Treated at Week 16

99 (48.8)

95 (46.6)

236 (58.0)

242 (59.3)

307 (50.3)

979 (53.4)

ITT Population

202 (99.5)

204 (100.0)

407 (100.0)

407 (99.8)

605 (99.2)

1825 (99.6)

Per-Protocol Population

148 (72.9)

170 (83.3)

335 (82.3)

327 (80.1)

492 (80.7)

1472 (80.3)

Safety Population

205 (101.0)

204 (100.0)

407 (100.0)

407 (99.8)

602 (98.7)

1825 (99.6)

Completed study

130 (64.0)

134 (65.7)

267 (65.6)

271 (66.4)

379 (62.1)

1181 (64.5)

Discontinued study

75 (36.9)

70 (34.3)

140 (34.4)

136 (33.3)

223 (36.6)

644 (35.2)

Number of subjects[1]Completed Treatment Phase

62 (30.5)64 (31.4)

140 (34.4)

159 (39.0)

206 (33.8)

631 (34.4)

Completed Safety Follow-Up

61 (30.0)57 (27.9)

132 (32.4)

145 (35.5)

191 (31.3)

586 (32.0)

Discontinued Safety Follow-Up

1 (0.5)7 (3.4)8 (2.0)13 (3.2)

12 (2.0)41 (2.2)

Did not enter Safety Follow-Up

0

0

0

1 (0.2)3 (0.5)4 (0.2)

Discontinued Treatment Phase143 (70.4)

140 (68.6)

267 (65.6)

248 (60.8)

396 (64.9)

1194 (65.2)

Completed Safety Follow-Up

69 (34.0)

77 (37.7)

135 (33.2)

126 (30.9)

188 (30.8)595 (32.5)

Discontinued Safety Follow-Up

43 (21.2)

32 (15.7)

76 (18.7)

59 (14.5)

133 (21.8)

343 (18.7)

Did not enter Safety Follow-Up

31 (15.3)

31 (15.2)

56 (13.8)

63 (15.4)

75 (12.3)

256 (14.0)

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Table S2. Subject Disposition
Placebo -> Tanezumab 5
mg(N=203)

Placebo -> Tanezumab 10
mg(N=204)

Tanezumab 5 mg
(N=407)

Tanezumab 10 mg(N=408)Tramadol(N=610)Total(N=1832)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

Entered into Sub-Study03 (1.5)0

1 (0.2)04 (0.2)

Rollover to Study A4091064

0

0

0

0

0

0

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 Tanezumabor Placebo SC.
"Other Screened but not Randomized" displays subjects who were screened but not randomized for a reason not related to a specific eligibility criterion.
One (1) subject randomized to Placebo, 1 subject randomized to Tanezumab 10 mg, and 5 subjects randomized to Tramadol were not treated because the subjects were discovered
violating inclusion/exclusion criteria after randomization.
Three (3) subjects who were randomized to Tramadol but did not receive Tramadol.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:16) Source Data: Listing 16.2.1.1 Output File: ./nda1/A4091059/adsl_s002_chk_i Date of Generation: 20FEB2019(18:31)
Table 14.1.1.1.2.i is for Pfizer internal use.

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The proportion of patients who discontinued treatment up to Week 16 was lower in thetanezumab 10 mg treatment group (17.0%) than all other treatment groups (22.0% to 25.7%).
The proportion of patients who discontinued treatment during the Treatment Period (ie, up to
Week 56) was lower in the tanezumab 10 mg treatment group (60.9%) than all othertreatment groups (65.6% to 69.8%).
The most frequent reasons for discontinuation from treatment across treatment groups were“Patient meets protocol-specified pain criteria for discontinuation” (16.0% to 19.6%),“Other” (12.1% to 17.0%), and “Insufficient clinical response” (10.1% to 20.1%). The
incidence of treatment discontinuation due to “Insufficient clinical response” and “Patient
meets protocol-specified pain criteria for discontinuation” was highest in patients who
received placebo up to Week 16 (12.2% and 20.1% due to “Insufficient clinical response” forthe placebo  tanezumab 5 mg and placebo  tanezumab 10 mg treatment groups,
respectively, and 19.5% and 19.6% due to “Patient meets protocol-specified pain criteria for
discontinuation” for the placebo  tanezumab 5 mg and placebo  tanezumab 10 mg
treatment groups, respectively). The incidence of patients discontinuing from treatment due
to adverse events was highest with tramadol PR treatment (11.0%).
The most frequent reasons for discontinuation from the study were “Withdrawal by subject”
and “Other”. There were no apparent treatment- or dose-related trends in discontinuationfrom the study.
Demographic characteristics were similar across the treatment groups. Across treatmentgroups, there were more female patients than male patients. The majority of patients in alltreatment groups were white, with the mean age ranging from 48.4 to 49.1 years. Mean age
and range were similar across gender and treatment groups which were overall balanced
within each age category. Overall racial groups were well balanced across the treatmentgroups, with slightly fewer Asian patients in the tanezumab 10 mg treatment group (6.9%)
compared with the other groups (9.3% to 10.8%).
Inadequate pain relief was the primary reason for treatment failure with acetaminophen or
low-dose NSAIDs, prescription NSAIDs or coxibs, and opioids. Intolerability was also
reported as a reason for treatment failure by substantial numbers of patients for opioids(>18% of patients across treatment groups).
With the exception of one patient, all patients had data regarding the duration of the primary
diagnosis of low back pain at baseline. The mean duration since first diagnosis of CLBP was
similar across the treatment groups.
In general, Baseline disease characteristics such as aLBPI score, RMDQ score, PGA of Low
Back Pain, and BPI-sf scores were similar across the treatment groups. The mean aLBPI atBaseline was greater than seven in all treatment groups. The Quebec Task ForceClassification was similar across treatment groups, with the majority of patients in Quebec
Task Force Category 1 (pain without radiation) at Baseline.

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The majority of patients did not have a neuropathic component (painDetect score ≤12) of
their CLBP per the painDetect questionnaire. The proportion of patients in the 13 to
18 category (neuropathic component uncertain) was similar across the treatment groups at
Baseline. The tanezumab 10 mg treatment group had a higher proportion of patients in the≤12 category and a lower proportion of patients in the ≥19 category (neuropathic component
is likely) compared to the other treatment groups, while the placebo treatment group had alower proportion of patients in the ≤12 category and a higher proportion of patients in the≥19 category compared to the other treatment groups.
Approximately one third of patients were assessed as having pain due to degenerative discdisease, and approximately one third of patients were assessed as having pain due toinjury/muscular strain. Approximately 25% of patients were assessed as having CLBP due todegenerative joint disease/OA. The remainder (9.3% to 15.5%) was in the other category(unknown or multiple causes).
Efficacy Results
The primary objective of the study was met for tanezumab 10 mg, applying the gate-keeping
strategy. Tanezumab 10 mg treatment resulted in significant improvement (reduction)compared to placebo treatment in the primary efficacy endpoint, change from Baseline to
Week 16 in the aLBPI score. Further hypothesis testing for the key secondary endpoints was
performed for tanezumab 10 mg versus placebo.
Treatment with tanezumab 10 mg resulted in significant improvements in all three key
secondary efficacy endpoints compared to placebo (change from Baseline to Week 16 in
RMDQ score, the proportion of patients with a ≥50% reduction in aLBPI score fromBaseline to Week 16, change from Baseline to Week 2 in aLBPI score), applying thegate-keeping strategy.
Focusing on nominal (unadjusted) p-values, tanezumab 10 mg treatment resulted insignificant improvement from Baseline in the aLBPI score compared to placebo treatment at
Week 1 through Week 12 (p-values <0.05, with no multiplicity correction). Tanezumab
10 mg treatment resulted in significant improvement from Baseline in the RMDQ scorecompared to placebo treatment at Weeks 2, 4, and 8 (p-values <0.05, with no multiplicity
correction).
The primary objective of the study was not met for tanezumab 5 mg, applying thegate-keeping strategy. For tanezumab 5 mg, no significant improvement in aLBPI score wasdemonstrated compared to placebo treatment at Week 16. As the primary objective fortanezumab 5 mg was not met, further hypothesis testing for the key secondary endpoints
could not be performed for tanezumab 5 mg versus placebo.
Outside the framework of the gate-keeping strategy, treatment with tanezumab 5 mg resulted
in numerical improvement in RMDQ score at Week 16 (p=0.0035), the proportion of patients

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with a ≥50% reduction in aLBPI score at Week 16 (p=0.0846), and aLBPI score at Week 2(p=0.0015).
Focusing on nominal (unadjusted) p-values, tanezumab 5 mg treatment resulted in significant
improvement from Baseline in the aLBPI score compared to placebo treatment at Week 1
through Week 12 (p-values <0.05, with no multiplicity correction). Tanezumab 5 mg
treatment resulted in significant improvement from Baseline in the RMDQ score compared toplacebo treatment at Weeks 2, 4, and 8 (p-values <0.05, with no multiplicity correction).
Treatment with tramadol PR did not result in significant improvements in any of the primaryor key secondary efficacy endpoints compared to placebo (p-values ≥0.05, with nomultiplicity correction).
Primary Efficacy Analysis
The primary efficacy endpoint was the change from Baseline in the aLBPI score at Week 16
for tanezumab versus placebo. The testing of significance for this endpoint used agate-keeping strategy, with a multiple imputation method for missing data.
Using the gate-keeping strategy, treatment with tanezumab 10 mg resulted in significant
improvement (reduction) in the aLBPI score from Baseline compared to placebo treatment
and met the primary objective of the study (Table S3). Tanezumab 5 mg resulted innumerical improvement compared to placebo treatment; however, the treatment difference
did not reach significance. The improvement with tramadol PR was modest, and thetreatment difference compared to placebo was not significant. The incremental
improvements from Baseline to Week 16 for tanezumab 10 mg and tanezumab 5 mg
treatments compared to tramadol PR were modest and not significant.

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Table S3. Analysis of Primary Efficacy Endpoint - Change from Baseline to Week 16(Intent-to-Treat, Multiple Imputation)
Placebo(N=406)

Tanezumab 5 mg
(N=407)

Tanezumab 10 mg(N=407)

Tramadol(N=605)-2.68 (0.15)(-2.97,-2.40)-2.98 (0.14)(-3.26,-2.70)-3.08 (0.14)(-3.36,-2.81)-2.81 (0.12)(-3.04,-2.57)

Versus Placebo
LS Mean Difference (SE)
95% CI for LS Mean Difference
p-value-0.30 (0.19)(-0.66,0.07)
0.1117-0.40 (0.18)(-0.76,-0.04)
0.0281-0.12 (0.17)(-0.46,0.21)
0.4620Versus Tramadol
LS Mean Difference (SE)
95% CI for LS Mean Difference
p-value-0.17 (0.17)(-0.50,0.16)
0.3118-0.28 (0.17)(-0.60,0.05)
0.0958LS Mean (SE)
95% CI for LS Mean

A change from baseline < 0 is an improvement.
Multiple imputation method is applied for missing data, with imputation dependent on reason for missing data.
ANCOVA model for imputed datasets includes treatment as a fixed effect, and baseline average LBPI as a covariate, andstudy site as a random effect.
Results are taken from a combined analysis of the individual imputed dataset ANCOVA results.
PFIZER CONFIDENTIAL SDTM Creation: 29JAN2019 (12:20) Source Data: Listing 16.2.6.1 Output File:./nda1/A4091059/adnr_infr_chg_ancova_mi_p1_i Date of Generation: 08JUL2019 (15:26)
Table 14.2.1.3.1.i is for Pfizer internal use.

Key Secondary Efficacy Analysis
Change from Baseline to Week 16 in the RMDQ score: Tanezumab 10 mg treatment
resulted in a significant improvement compared to placebo treatment. As the primaryobjective (tanezumab superiority compared to placebo for aLBPI score) was not met for
tanezumab 5 mg, per the gate-keeping strategy, further hypothesis testing for the key
secondary endpoints could not be performed for tanezumab 5 mg versus placebo.
Tanezumab 5 mg treatment resulted in a numerical improvement in RMDQ scorecompared to placebo treatment (p=0.0035; with no multiplicity correction). Bothtanezumab treatments resulted in significant improvements compared to tramadol PR
treatment (with no multiplicity correction). No significant improvement was observed
for treatment with tramadol PR versus placebo treatment (with no multiplicity
correction).

Proportion of Patients with 50% Reduction in Average LBPI Score from Baseline
to Week 16: Treatment with tanezumab 10 mg was associated with a significant increasein the proportion of patients with a 50% or greater reduction from Baseline in aLBPIscore compared with placebo treatment at Week 16 (p=0.0101). As the primary objective(superiority of tanezumab compared to placebo for aLBPI score) was not met for
tanezumab 5 mg, per the gate-keeping strategy, further hypothesis testing for key
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secondary endpoints could not be performed for tanezumab 5 mg versus placebo.
Tanezumab 5 mg resulted in a numerical improvement in the proportion of patients witha 50% or greater reduction from Baseline in aLBPI score compared to placebo treatment
at Week 16 (p=0.0846, with no multiplicity correction). No significant difference wasobserved for either tanezumab treatment versus tramadol PR or for tramadol PR versus
placebo.


Change from Baseline to Week 2 in Average LBPI Score: Tanezumab 10 mg
treatment resulted in a significant improvement compared to placebo treatment, which
demonstrated an early onset of effect by tanezumab 10 mg at Week 2. As the primaryobjective (superiority of tanezumab compared to placebo for aLBPI score) was not met
for tanezumab 5 mg, per the gate-keeping strategy, further hypothesis testing for key
secondary endpoints could not be performed for tanezumab 5 mg versus placebo.
Tanezumab 5 mg resulted in a numerical improvement in aLBPI score at Week 2
compared to placebo (p=0.0015; with no multiplicity correction). Treatment withtanezumab 10 mg resulted in a significant improvement compared to tramadol PR
treatment at Week 2 (with no multiplicity correction). No significant difference wasobserved for tramadol PR treatment versus placebo treatment.

Secondary Efficacy Analysis
Tanezumab 5 mg and 10 mg treatments resulted in significant improvement in the aLBPIscore from Baseline compared to placebo treatment at Weeks 1, 2, 4, 8 and 12.
Tramadol PR treatment resulted in significant improvement in aLBPI score compared toplacebo treatment at Weeks 1 and 8. From Weeks 24 to 56, tanezumab 10 mg treatment
resulted in a numerical reduction in aLBPI score from Baseline compared to tramadol PR
treatment, but the difference was not significant at any of the time points. The reduction
in aLBPI score from Baseline for tanezumab 5 mg treatment was similar to tanezumab
10 mg treatment from Weeks 24 to 56, and treatment differences compared totramadol PR treatment were not significant.



Tanezumab 5 and 10 mg treatments resulted in significant improvement (reduction) in
RMDQ score compared to placebo treatment at Weeks 2, 4, and 8. Significant
reductions in RMDQ score versus tramadol PR treatment were observed for tanezumab
10 mg at Weeks 2, 4, and 8 and for tanezumab 5 mg at Weeks 4 and 8. From Week 24 to
Week 56, treatment with tanezumab 10 mg resulted in numerical improvement in RMDQ
score compared to tramadol PR, but the differences were not significant, except at
Week 24. Treatment with tanezumab 5 mg also resulted in numerical reductions in
RMDQ score compared to tramadol PR treatment; however, the reductions were smaller
than those observed for tanezumab 10 mg treatment. No significant differences wereobserved compared to tramadol PR treatment at Week 56.

Tanezumab 10 mg treatment resulted in significant improvement in PGA scorecompared to placebo at Week 16 and all interim time points (Weeks 2, 4, and 8). For
tanezumab 5 mg treatment, significant improvements compared to placebo were detected
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at Weeks 4 and 8. For the tramadol PR treatment group, there were no significant
differences compared to placebo treatment at any time point assessed. For thecomparison to the tramadol PR, tanezumab 10 mg treatment resulted in significant
improvement in PGA score at Week 16 and all interim time points (Weeks 2, 4, and 8).
For the tanezumab 5 mg treatment group, significant improvements compared totramadol PR were detected at Weeks 4 and 16. From Week 24 to Week 56, no
significant differences in PGA score were observed for either tanezumab treatmentcompared to tramadol PR.


Analysis of the CLBP Responder Index showed higher proportions of responders in thetanezumab treatment groups than in the placebo and tramadol PR treatment groups ateach week analyzed. Treatment differences with tanezumab 5 mg and 10 mg versus
placebo were significant at Weeks 2, 4, 8, and 16 (p<0.0001 to p=0.0179). The treatment
differences with tramadol PR versus placebo were significant at Weeks 2, 4, and 8(p=0.0033 to p=0.0300). Treatment differences with tanezumab 10 mg versus
tramadol PR were significant at Weeks 2, 4, 8, and 16 (p=0.0005 to p=0.0100). The
treatment differences with tanezumab 5 mg versus tramadol PR were significant at
Weeks 4, 16, and 24 (p=0.0179 to p=0.0296).

Reduction in the Average LBPI Score of 30%, ≥50%, ≥70%, and ≥90%: Overall,tanezumab 5 and 10 mg treatments were associated with numerical increases in the
proportion of responders in aLBPI score at all levels at all weeks compared to placebo(except Week 1, ≥70%), and the proportions of responders at these doses werecomparable or greater than those for the tramadol PR treatment groups.



Reduction in the RMDQ Score of 30%, ≥50%, ≥70%, and ≥90%: Overall,tanezumab 5 mg and 10 mg treatments were associated with numerical increases in the
proportion of responders in RMDQ score at all levels at all weeks compared to placebo
treatment, and the proportions of responders at these doses were comparable or greaterthan those for tramadol PR treatment.

Treatment with tanezumab 10 mg was associated with a significant increase in the
proportion of patients reporting a ≥2 point reduction from Baseline in PGA scorecompared to placebo treatment at Weeks 2, 4, 8, and 16. Significant differences wereobserved for tanezumab 5 mg treatment compared to placebo treatment at Weeks 4 and 8.
Significant differences compared to tramadol PR treatment were observed withtanezumab 10 mg treatment at Weeks 2, 4, and 16 and with tanezumab 5 mg treatment at
Weeks 4, 16, 24, 32, and 40. No significant difference compared to placebo treatment
was observed with tramadol PR treatment.

For both the change from Baseline in BPI-sf worst and average pain scores, there wasan improvement (reduction) from Baseline in all treatment groups at all weeks. For the
BPI-sf pain interference index, there was a numerical improvement in all treatmentgroups at Week 16. Tanezumab 5 mg and 10 mg treatments resulted in significant
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improvements in the pain interference index compared to placebo treatment at Weeks 2,
4, 8, and 16. Significant improvements in the BPI-sf pain interference index compared totramadol PR treatment were observed with tanezumab 5 mg treatment at Weeks 2 and 4(p=0.0160 and p=0.0209) and with tanezumab 10 mg treatment at Weeks 2, 4, 8, and 16(p=0.0003 to p=0.0121). Treatment with tramadol PR was not statistically different fromplacebo treatment at any week analyzed. Tanezumab 5 mg and 10 mg treatments resulted
in numerical improvements in BPI-sf pain interference index compared to tramadol PR
treatment, but the differences were not significant at any week beyond Week 16.


At Weeks 16 and 56, decreases from Baseline were observed for all WPAI:LBP
measures, across all treatment groups. No significant differences were observed for thechange from Baseline in percent work time missed between tanezumab treatment groups
and the placebo or tramadol PR treatment groups. Significant improvements in percent
impairment while working and percent overall work impairment were observed at
Week 16 for the tanezumab 10 mg treatment group compared to placebo (p=0.0477 and
p=0.0289, respectively); no significant differences were observed for the tanezumab 5 mg
treatment group compared to placebo or the tanezumab treatment groups compared totramadol PR. A significant improvement in activity impairment was observed for thetanezumab 5 mg and 10 mg treatment groups compared to placebo (p=0.0157 and
p=0.0159, respectively) at Week 16. No significant treatment difference was observed
for the tanezumab treatments compared to tramadol PR at Week 16 or Week 56.

During the first 16 weeks, a significantly larger proportion of patients treated withplacebo (14.0%) discontinued due to insufficient clinical response than patients treatedwith tanezumab 5 mg (7.4%), tanezumab 10 mg (8.6%), or tramadol PR (8.3%). During
the Treatment Period (ie, up to Week 56), the proportion of patients who discontinued
treatment due to insufficient clinical response was highest in the treatment groups thatbegan the study on placebo and switched to tanezumab at Week 16 (12.4% and 20.1% for
the placebo  tanezumab 5 mg and placebo  tanezumab 10 mg treatment groups,
respectively), followed by the tanezumab 10 mg (11.3%), tramadol PR (10.7%), andtanezumab 5 mg treatment groups (10.1%). There was no significant difference in theincidence of treatment discontinuation due to insufficient clinical response for thetanezumab treatment groups compared with the tramadol PR treatment group.

The mean number of days of rescue medication use per week at Week 16 was similar
across the treatment groups, ranging from 0.7 to 0.9 days. There was no significant
difference in the number of days of rescue medication use per week at Week 16 for thetanezumab treatment groups versus placebo or tramadol PR treatment groups. There wasno significant difference in the number of days of rescue medication use per week at
Week 56 for the tanezumab treatment groups versus the tramadol PR treatment group.



The incidence of rescue medication use per week was highest at Baseline (during thefive days prior to the start of treatment; 71.7% to 76.2%) and decreased in all treatmentgroups up to Week 16 (29.0% to 31.4%). Overall, the incidence of rescue medication use
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by week was similar across treatment groups. No significant differences in the incidenceof rescue medication use were observed at any time point between the tanezumab
treatment groups and the placebo or tramadol PR treatment groups.


The mean amount of rescue medication used by patients at Week 16 was similar acrossthe treatment groups, ranging from 829 to 944 mg. There was no significant difference inthe amount of rescue medication used at Week 16 for tanezumab treatment groups versus
placebo or tramadol PR treatment groups.



In general, patients in all treatment groups expressed improvement in each TSQM
endpoint between Week 16 and Week 56.

Treatment with tanezumab 5 mg and 10 mg resulted in significant improvements in
mPRTI (preference for the study drug received to previous treatment) at Week 16
compared to placebo treatment (p=0.0333 and p=0.0244). Similarly, treatment withtanezumab 5 mg and 10 mg resulted in significant improvements in mPRTI (willingness
to use the study drug received for low back pain) at Week 16 compared to placebo
treatment (p=0.0045 and p=0.0099). No significant improvements in mPRTI wereobserved for tanezumab treatments versus tramadol PR treatment at Week 16 or
Week 56.

Pharmacokinetic and Pharmacodynamic Results:
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) by a proportion similar to the increase in dose. By Week 64, 16 weeks after theseventh dose of study medication, the mean tanezumab plasma concentrations were low,
consistent with elimination of tanezumab from the body over five half-lives postdose.
Tanezumab plasma concentrations in patients who were administered tanezumab after
receiving placebo treatment for the first 16 weeks (placebo  tanezumab 5 mg andplacebo  tanezumab 10 mg treatment groups) were similar to the tanezumab treatmentgroups wherein patients started and finished on tanezumab, with the exception of nominal
sampling time Week 48. Plasma tanezumab concentrations at this nominal sampling time
were lower in the placebo  tanezumab treatment groups in contrast to what was reported
for patients starting on tanezumab. This is a consequence of the Week 48 nominal samplingtime point occurring 16 weeks after the last dose for patients who first received tanezumab at
Study Week 16, compared to eight weeks for those patients randomized to tanezumab for theduration of the trial.
Pharmacodynamic Results
Mean and median soluble p75 plasma trough concentrations were comparable at all time
points for all treatment groups.
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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 groupby approximately 28% at Week 8 (eight weeks after the first dose). Similarly, at Week 48,
just prior to the seventh and last dose, mean total NGF trough concentrations were higher inthe tanezumab 10 mg treatment group by approximately 37%. At Week 56, eight weeks after
the last dose, mean total NGF trough concentrations were similar to the Week 48
observations with mean total NGF trough concentrations higher in the tanezumab 10 mg
compared to the tanezumab 5 mg treatment group by approximately 42%. At Week 64,
mean total NGF concentrations had declined in both the 10 mg and 5 mg tanezumab
treatment groups and were approximately 53% and 32% of the Week 56 values, respectively.
Mean proNGF was comparable across treatment groups at all nominal sampling times.
Safety Results
The incidence of adverse events reported up to Week 16 was higher in the tramadol PR
treatment group (Table S4). The incidence of SAEs during this period was low acrosstreatment groups, with fewer patients reporting SAEs in the placebo treatment groupcompared with the tanezumab and tramadol PR treatment groups. The incidence of treatment
discontinuation due to an adverse event was low in all treatment groups, but highest in thetramadol PR treatment group (8.5%).

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Table S4. Treatment-Emergent Adverse Events Up to Week 16 (All Causalities) Safety Population
PlaceboTanezumab 5 mg Tanezumab 10 mg

TramadolNumber (%) of Subjects

n (%)

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

409

407

407

602

Number of adverse events

407

366

394

812

Subjects with adverse events

189 (46.2)

191 (46.9)

211 (51.8)

339 (56.3)

Subjects with serious adverse events

4 (1.0)6 (1.5)7 (1.7)10 (1.7)

Subjects with severe adverse events

16 (3.9)8 (2.0)9 (2.2)16 (2.7)

Subjects discontinued study drug due to adverse event

16 (3.9)

18 (4.4)

19 (4.7)

51 (8.5)

Subjects discontinued from study due to adverse event(a)4 (1.0)4 (1.0)4 (1.0)12 (2.0)

Subjects discontinued study drug due to adverse eventand continued Study (b)13 (3.2)

14 (3.4)

16 (3.9)40 (6.6)

Subjects with dose reduced or temporary
discontinuation due to adverse events

10 (2.4)

10 (2.5)

12 (2.9)45 (7.5)

Includes treatment-emergent events that begin up to the week 16 dosing visit date for subjects who completed the Week 16
dosing visit, or up to the withdrawal from treatment date for subjects who withdrew before the Week 16 dosing visit. Any
events started on the Week 16 dosing date are not included.
For 2 subjects who missed the Week 16 dose, treatment-emergent events that begin up to the Week 24 dosing visit(exclusive) are included.
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 Adverse Event record that indicates that the Adverse Event caused the subject to be discontinued
from the study(b) Subjects who have an Adverse Event record that indicates that action taken with study treatment was drug withdrawn but
Adverse Event did not cause the subject to be discontinued from study
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:55) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091059/adae_s020_tp1_i Date of Generation: 19FEB2019 (15:24)
Table 14.3.1.2.1.1.i is for Pfizer internal use.

The incidence of adverse events reported during the Treatment Period (ie, up to Week 56)
was highest in the tramadol PR (65.4%) and tanezumab 10 mg (63.7%) groups and lowest in
the tanezumab 5 mg treatment group (58.3%; Table S5). The incidence of SAEs during theTreatment Period was lowest in the tanezumab 5 mg treatment group (2.2%) and highest in
the tanezumab 10 mg treatment group (4.6%). There were patients in all treatment groups
who discontinued treatment during this period due to an adverse event, with the greatest
incidence in the tramadol PR group (10.5%) and lowest in the tanezumab 5 mg treatmentgroup (6.7%).

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Table S5. Treatment-Emergent Adverse Events During the Treatment Period (All
Causalities) - Safety Population
Tanezumab 5 mg

Tanezumab 10 mg

TramadolNumber (%) of Subjects

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

506

502

602

Number of adverse events

815

894

1197

Subjects with adverse events

295 (58.3)

320 (63.7)

394 (65.4)

Subjects with serious adverse events

11 (2.2)

23 (4.6)

19 (3.2)

Subjects with severe adverse events

12 (2.4)

24 (4.8)

26 (4.3)

Subjects discontinued study drug due to adverse event

34 (6.7)

37 (7.4)

63 (10.5)

Subjects discontinued from study due to adverse event (a)5 (1.0)10 (2.0)

15 (2.5)

Subjects discontinued study drug due to adverse event andcontinued Study (b)29 (5.7)

29 (5.8)

50 (8.3)

Subjects with dose reduced or temporary discontinuation due
to adverse events

17 (3.4)

19 (3.8)

52 (8.6)

Includes treatment-emergent events that begin up to the week 56 visit 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 ofAdverse 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 Adverse Event record that indicates that the Adverse Event caused the subject to be discontinued
from the study(b) Subjects who have an Adverse Event record that indicates that action taken with study treatment was drug withdrawn but
Adverse Event did not cause the subject to be discontinued from study
Patients who were randomized to Tanezumab 5 mg (or 10 mg) and patients who were randomized to Placebo and received
Tanezumab 5 mg (or 10 mg) at Week 16 are included in the Tanezumab 5 mg (or 10 mg) group.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:55) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091059/adae_s020_tp3g_i Date of Generation: 21FEB2019 (14:09)
Table 14.3.1.2.1.3.i is for Pfizer internal use.

During the 24-week Safety Follow-up or Early Termination Follow-up Periods, a similar
proportion of patients in the placebo, tanezumab 10 mg, and tramadol PR treatment groups
reported adverse events (Table S6); a higher proportion of patients reported adverse events inthe tanezumab 5 mg treatment group (33.5%). The incidence of SAEs during this period waslow, ranging from 1.1% to 3.7% across all treatment groups.

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Table S6. Treatment-Emergent Adverse Events During the Safety Follow-up Period
and the Early Termination Follow-up Period (All Causalities) - Safety
Population
PlaceboTanezumab 5 mg Tanezumab 10 mg

TramadolNumber (%) of Subjects

n (%)

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

166

442

433

524

Number of adverse events

83

304

260

258

Subjects with adverse events46 (27.7)

148 (33.5)

136 (31.4)

146 (27.9)

Subjects with serious adverse events

3 (1.8)11 (2.5)

16 (3.7)

6 (1.1)

Subjects with severe adverse events

3 (1.8)11 (2.5)

13 (3.0)

13 (2.5)

Subjects discontinued study drug due to adverse event

1 (0.6)5 (1.1)05 (1.0)Subjects discontinued from study due to adverse event(a)1 (0.6)

1 (0.2)1 (0.2)3 (0.6)

Subjects discontinued study drug due to adverse eventand continued Study (b)04 (0.9)03 (0.6)

1 (0.6)00

1 (0.2)

Subjects with dose reduced or temporary
discontinuation due to adverse events

Includes treatment-emergent events that begin after the week 56 visit for subjects who completed the treatment period orafter 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 Adverse Event record that indicates that the Adverse Event caused the subject to be discontinued
from the study(b) Subjects who have an Adverse Event record that indicates that action taken with study treatment was drug withdrawn but
Adverse Event did not cause the Subject to be discontinued from Study
Placebo group represents subjects who received only Placebo in the treatment period. Patients who were randomized toPlacebo ->tanezumab 5 mg (or 10 mg) and received Tanezumab 5 mg (or 10 mg) at Week 16 are included in the Tanezumab
5 mg (or 10 mg) group.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:55) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091059/adae_s020_fup_i Date of Generation: 19FEB2019 (15:47)
Table 14.3.1.2.1.4.i is for Pfizer internal use.

Treatment-emergent adverse events occurring at a greater frequency (≥1% difference
between treatment groups) in the tanezumab 5 mg treatment group versus the placebo
treatment group included Headache, Hypoaesthesia, and Pruritis (Table S7).
Treatment-emergent adverse events occurring at a greater frequency (≥1% difference
between treatment groups) in the tanezumab 10 mg treatment group versus the placebo
treatment group included Headache, Upper respiratory tract infection, Nasopharyngitis,
Paraesthesia, and Hypoaesthesia.

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Table S7. Incidence of Treatment-Emergent Adverse Events Up to Week 16 in ≥2%subjects by Descending Frequency (All Causalities) - Safety Population
Number of Subjects Evaluable for AEs

Placebo(N=409)Tanezumab 5 mg
(N=407)

Tanezumab 10 mg(N=407)

Tramadol(N=602)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

n (%)

Arthralgia

28 (6.8)

21 (5.2)

28 (6.9)

38 (6.3)

Headache16 (3.9)24 (5.9)23 (5.7)

38 (6.3)

Upper respiratory tract infection

10 (2.4)

11 (2.7)

16 (3.9)

18 (3.0)

Nasopharyngitis

10 (2.4)

12 (2.9)

14 (3.4)

13 (2.2)

Paraesthesia

4 (1.0)6 (1.5)

13 (3.2)

9 (1.5)

Musculoskeletal pain

15 (3.7)

6 (1.5)10 (2.5)

19 (3.2)

Nausea7 (1.7)6 (1.5)10 (2.5)

68 (11.3)

Back pain

14 (3.4)

15 (3.7)

9 (2.2)15 (2.5)

Hypoaesthesia

3 (0.7)8 (2.0)8 (2.0)5 (0.8)Pain in extremity

8 (2.0)5 (1.2)8 (2.0)7 (1.2)

Dizziness

5 (1.2)6 (1.5)7 (1.7)31 (5.1)

Constipation

6 (1.5)5 (1.2)6 (1.5)45 (7.5)Fall

7 (1.7)8 (2.0)6 (1.5)7 (1.2)

Neck pain

8 (2.0)5 (1.2)6 (1.5)8 (1.3)

Dry mouth

6 (1.5)3 (0.7)5 (1.2)17 (2.8)

Fatigue

3 (0.7)3 (0.7)5 (1.2)16 (2.7)

Sinusitis

5 (1.2)8 (2.0)5 (1.2)10 (1.7)

Somnolence

8 (2.0)3 (0.7)4 (1.0)33 (5.5)

Pruritus

2 (0.5)6 (1.5)2 (0.5)15 (2.5)

Vomiting

7 (1.7)1 (0.2)1 (0.2)23 (3.8)

Includes treatment-emergent events that begin up to the week 16 dosing visit date for subjects who completed the Week 16
dosing visit, or up to the withdrawal from treatment date for subjects who withdrew before the Week 16 dosing visit. Any
events started on the Week 16 dosing date are not included.
Subjects are only counted once per treatment per event.
Adverse events are shown by descending frequency by the highest tanezumab dose.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:55) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091059_IMMU_CUTOFF/adae_s180_tp1_i Date of Generation: 08MAR2019 (11:21)
Table 14.3.1.2.2.6.i is for Pfizer internal use.

Arthralgia and Headache were the most commonly reported adverse events during theTreatment Period (ie, up to Week 56) in the tanezumab treatment groups and were reported ata similar frequency across both treatment groups. Nausea was the most commonly reported
adverse event in the tramadol PR group (Table S8) and was reported less frequently in thetanezumab treatment groups. Treatment-emergent adverse events occurring at a greater
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frequency (≥1% difference between treatment groups) in the tanezumab 5 mg versus thetramadol PR treatment groups included Back pain, Hypoaesthesia, Bronchitis, Fall, Muscle
spasms, and Contusion. Treatment-emergent adverse events occurring at a greater frequency(≥1% difference between treatment groups) in the tanezumab 10 mg treatment group versus
the tramadol PR treatment group included Arthralgia, Upper respiratory tract infection,
Paraesthesia, Pain in extremity, Hypoaesthesia, Bronchitis, Bradycardia, Muscle spasms,
Toothache.
Table S8. Incidence of Treatment-Emergent Adverse Events During the Treatment
Period in ≥2% subjects by Descending Frequency (All Causalities) - Safety
Population
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=506)

Tanezumab 10 mg(N=502)

Tramadol(N=602)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Arthralgia

46 (9.1)

53 (10.6)

54 (9.0)

Headache35 (6.9)33 (6.6)

45 (7.5)

Nasopharyngitis

23 (4.5)

31 (6.2)

35 (5.8)

Upper respiratory tract infection

22 (4.3)

31 (6.2)

26 (4.3)

Musculoskeletal pain

18 (3.6)

24 (4.8)

29 (4.8)

Back pain

27 (5.3)

21 (4.2)

23 (3.8)

Paraesthesia

13 (2.6)

21 (4.2)

14 (2.3)

Pain in extremity

11 (2.2)

20 (4.0)

14 (2.3)

Hypoaesthesia

15 (3.0)

19 (3.8)

7 (1.2)

Nausea11 (2.2)

15 (3.0)75 (12.5)

Bronchitis

14 (2.8)

12 (2.4)

8 (1.3)Fall

21 (4.2)

11 (2.2)

17 (2.8)

Bradycardia

5 (1.0)10 (2.0)

4 (0.7)

Dizziness

11 (2.2)

10 (2.0)41 (6.8)

Muscle spasms

12 (2.4)

10 (2.0)5 (0.8)Sinusitis

18 (3.6)

10 (2.0)

17 (2.8)

Toothache

8 (1.6)

10 (2.0)

4 (0.7)

Constipation

7 (1.4)9 (1.8)49 (8.1)

Diarrhoea

7 (1.4)9 (1.8)12 (2.0)

Influenza

10 (2.0)

9 (1.8)13 (2.2)

Neck pain

7 (1.4)8 (1.6)

12 (2.0)

Fatigue

4 (0.8)7 (1.4)18 (3.0)

Somnolence

4 (0.8)7 (1.4)33 (5.5)

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Table S8. Incidence of Treatment-Emergent Adverse Events During the Treatment
Period in ≥2% subjects by Descending Frequency (All Causalities) - Safety
Population
Number of Subjects Evaluable for AEs

Tanezumab 5 mg
(N=506)

Tanezumab 10 mg(N=502)

Tramadol(N=602)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

Contusion

11 (2.2)

6 (1.2)6 (1.0)Dry mouth

5 (1.0)6 (1.2)19 (3.2)

Gastroenteritis

10 (2.0)

6 (1.2)9 (1.5)

Vomiting

2 (0.4)5 (1.0)25 (4.2)

Pruritus

6 (1.2)4 (0.8)16 (2.7)

Includes treatment-emergent events that begin up to the week 56 visit for subjects who completed the treatment period or up
to 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.
Patients who were randomized to Tanezumab 5 mg (or 10 mg) and patients who were randomized to Placebo and received
Tanezumab 5 mg (or 10 mg) at Week 16 are included in the Tanezumab 5 mg (or 10 mg) group.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:55) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091059/adae_s180_tp3g_i Date of Generation: 19FEB2019 (16:20)
Table 14.3.1.2.2.8.i is for Pfizer internal use.

Arthralgia was the most frequently reported adverse event during the 24-week Safety
Follow-up or the Early Termination Follow-up Periods across treatment groups, and it wasreported with higher frequency in the tanezumab treatment groups than in the tramadol PR
and placebo treatment groups (Table S9). Back pain, Musculoskeletal pain, andNasopharyngitis were also reported with greater frequency in the tanezumab 5 mg treatmentgroup than the other treatment groups.

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Table S9. Incidence of Treatment-Emergent Adverse Events During the Safety
Follow-Up Period and the Early Termination Follow-Up Period in ≥2%subjects by Descending Frequency (All Causalities) - Safety Population
Number of Subjects Evaluable for AEs

Placebo(N=166)

Tanezumab 5 mg
(N=442)

Tanezumab 10 mg(N=433)

Tramadol(N=524)

Number (%) of Subjects:
by Preferred Term

n (%)

n (%)

n (%)

n (%)

Arthralgia

6 (3.6)27 (6.1)

27 (6.2)

15 (2.9)

Back pain

4 (2.4)17 (3.8)

12 (2.8)

11 (2.1)

Musculoskeletal pain

3 (1.8)19 (4.3)

5 (1.2)3 (0.6)

Pain in extremity09 (2.0)5 (1.2)1 (0.2)

Nasopharyngitis

3 (1.8)10 (2.3)

3 (0.7)5 (1.0)Bronchitis

5 (3.0)3 (0.7)2 (0.5)5 (1.0)Includes treatment-emergent events that begin after the week 56 visit 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.
Placebo group represents subjects who received only Placebo in the treatment period. Patients who were randomized toPlacebo ->tanezumab 5 mg (or 10 mg) and received Tanezumab 5 mg (or 10 mg) at Week 16 are included to in the
Tanezumab 5 mg (or 10 mg) group.
MedDRA v21.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 26JAN2019 (01:55) Source Data: Listing 16.2.7.1 Output File:./nda1/A4091059/adae_s180_fup_i Date of Generation: 19FEB2019 (16:21)
Table 14.3.1.2.2.9.i is for Pfizer internal use.



Treatment-Related Adverse Events: Up to Week 16, the overall incidence oftreatment-related adverse events was similar across the placebo and tanezumab treatmentgroups (15.9% in the placebo treatment group, 17.9% in the tanezumab 5 mg treatmentgroup, and 19.7% in the tanezumab 10 mg treatment group) and higher in thetramadol PR treatment group (30.2%). Treatment-related adverse events occurring at agreater frequency (≥1% difference between treatment groups) in the tanezumab 10 mg
versus the placebo treatment group included Fatigue, Arthralgia, Dizziness, Headache,and Paraesthesia. Arthralgia, Paraesthesia, Headache, and Nausea were the mostcommonly reported treatment-related adverse events during the Treatment Period (ie, up
to Week 56) in the tanezumab treatment groups. Nausea, Constipation, and Dizzinesswere the most commonly reported treatment-related adverse events in the tramadol PR
treatment group. Arthralgia was the only treatment-emergent adverse event occurring at
a greater frequency (≥1% difference between treatment groups) in the tanezumab 5 mg
treatment group versus the tramadol PR treatment group. Treatment-emergent adverse
events occurring at a greater frequency (≥1% difference between treatment groups) in thetanezumab 10 mg treatment group versus the tramadol PR treatment group included
Arthralgia and Paraesthesia.
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Severe Adverse Events: Severe adverse events were infrequently reported during theTreatment Period (ie, up to Week 56) across treatment groups. The most commonly
reported all-causality severe adverse events during the Treatment Period were Back pain
(four patients [0.8%]) in the tanezumab 5 mg treatment group, Rapidly progressive OA(three patients [0.6%]) in the tanezumab 10 mg treatment group, and Dizziness(three patients [0.5%]) in the tramadol PR treatment group.

Injection Site Reactions: Injection site reactions were infrequently reported acrosstreatment groups during the Treatment Period (ie, up to Week 56). All injection site
reactions were mild in severity except for one moderate adverse event of Injection site
pain in a patient who received placebo SC in the tramadol PR treatment group. One
patient who received tanezumab 5 mg had two adverse events, Injection site rash andInjection site reaction, which were both mild in severity. The patient permanently
discontinued study treatment due to the adverse event of Injection site rash. No otherinjection site reaction resulted in permanent discontinuation.

Potential Hypersensitivity Adverse Events: Overall, few potential hypersensitivity
adverse events were reported during the study. All potential hypersensitivity adverse
events were mild or moderate in severity, except for one adverse event of Drughypersensitivity in a patient in the tramadol PR group which was severe and serious.



Tier 1 Adverse Events: Up to Week 16, the overall incidence of Tier 1 adverse events(a pre-specified composite of adverse events of potential sympathetic dysfunction[Syncope, Bradycardia, OH, Anhidrosis, and Hypohidrosis] considered clinicallyimportant) was low and there was no significant difference in the frequencies ofoccurrence when comparing either of the tanezumab treatment groups or the tramadol PR
treatment group to the placebo treatment group. During the entire Treatment Period (ie,up to Week 56), the overall incidence of this composite event was also low (nine patients[1.8%] in the tanezumab 5 mg treatment group, 12 patients [2.4%] in the tanezumab
10 mg treatment group, and nine patients [1.5%] in the tramadol PR treatment group). As
observed up to Week 16, there were no significant differences in the frequency ofoccurrence of this composite event in either tanezumab treatment group versus thetramadol PR treatment group.



Tier 2 Adverse Events: Tier 2 adverse events were defined as non-Tier 1 adverse eventsoccurring in ≥3% of patients in any treatment group. Up to Week 16, Paraesthesia
occurred more frequently (confidence interval [CI] did not include zero) in the tanezumab
10 mg treatment group than in the placebo treatment group. There were no differences in
the frequency of occurrence of events in the tanezumab 5 mg treatment group versus theplacebo treatment group. During the Treatment Period (ie, up to Week 56),
Hypoaesthesia occurred more frequently (CI did not include zero) in the tanezumab 10
mg treatment group than in the tramadol PR treatment group.

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Deaths: A total of seven patients died during the study; one patient following placebo
treatment (Cardiac failure), three patients following tanezumab 5 mg treatment(Aneurysm, Aneurysm ruptured, and Myocardial infarction; Toxicity to various agents;
and Influenza), two patients following tanezumab 10 mg treatment (Toxicity to various
agents and Road traffic accident), and one patient following tramadol PR treatment(Aspiration and Pneumonia). None of the SAEs resulting in death were consideredrelated to study treatment.



Serious Adverse Events: Over the course of the entire study, a greater proportion ofpatients reported treatment emergent SAEs in the tanezumab 10 mg treatment group(37 patients [7.4%]) than in the placebo treatment group (seven patients [3.3%]), thetanezumab 5 mg treatment group (21 patients [4.2%]), or the tramadol PR group(25 patients [4.2%]). The incidence of SAEs up to Week 16 was similar across treatmentgroups. No single preferred term was reported by more than one patient in any treatmentgroup. During the entire Treatment Period (ie, up to Week 56), the incidence of SAEs
was higher in the tanezumab 10 mg treatment group (4.6%) than in the other treatmentgroups (3.2% in the tramadol PR treatment group and 2.2% in the tanezumab 5 mg
treatment group). The system organ class, Musculoskeletal and connective tissue
disorders, was the only system organ class with more (≥1% difference between groups)
SAEs for the tanezumab 10 mg treatment group than the tramadol PR treatment group.
In general, each SAE occurred in only one patient per treatment group, with the exceptionof Vertigo, which occurred in two patients in the tramadol PR treatment group and
Rapidly progressive OA which occurred in four patients in the tanezumab 10 mg
treatment group.

Adverse Events of Abnormal Peripheral Sensation: Adverse events of abnormal
peripheral sensation occurring up to Week 16 at a greater frequency (≥1% difference
between treatment groups) in the tanezumab 10 mg treatment group versus the placebo
treatment group included Burning sensation, Carpal tunnel syndrome, Hypoaesthesia, andParaesthesia. For tanezumab 5 mg, only Hypoaesthesia occurred at a greater frequency(≥1% difference between treatment groups) versus the placebo treatment group. The
same adverse events occurred at a higher incidence (≥1% difference) in the tanezumab
treatment groups versus the tramadol PR treatment group during the entire Treatment
Period (ie, up to Week 56). All adverse events of abnormal peripheral sensation
occurring up to Week 16 were mild or moderate in severity.



Peripheral Neurological Consultations: More patients in the tanezumab 5 and 10 mg
treatment groups had adverse events of abnormal peripheral sensation that met criteria forrequiring a neurologic consult than the placebo and tramadol PR treatment groups.
Clinical data, including consultation data when available, were reviewed by an external
neurology expert for all patients who had at least one event requiring consult. The mostfrequent (occurring in ≥1% in any one treatment group) expert primary diagnoses were
Mononeuropathy and Radiculopathy, and these occurred at a greater frequency in thetanezumab treatment groups versus the placebo and tramadol PR treatment groups.
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Adverse Events Potentially Indicative of Decreased Sympathetic Function: The
proportion of patients reporting adverse events potentially indicative of decreased
sympathetic function up to Week 16 was similar across the placebo and tanezumab
treatment groups and higher in the tramadol PR treatment group. This is due to theincreased incidence of Nausea and Vomiting in the tramadol PR treatment group versus
all other treatment groups. No individual adverse event potentially indicative ofdecreased sympathetic function occurred at a greater frequency (≥1%) in the tanezumab
treatment groups relative to the placebo or tramadol PR treatment groups. Severe adverse
events potentially indicative of decreased sympathetic function occurred in one patient(Presyncope) in the placebo treatment group and two patients (Nausea and Vomiting) in
the tramadol PR treatment group. During the Treatment Period (ie, up to Week 56), theincidence of adverse events potentially indicative of decreased sympathetic function was
similar in the tanezumab groups, and was highest in the tramadol PR treatment group,
due to the increased incidence of Nausea and Vomiting. Bradycardia, in the tanezumab
10 mg treatment group, was the only adverse event potentially indicative of decreased
sympathetic function reported at a greater frequency (≥1% difference) for a tanezumab
treatment group versus the tramadol PR treatment group. As with events observed up to
Week 16, few of these were considered severe and all were reported by patients in thetramadol PR treatment group: two patients (0.3%) reported Nausea, one patient (0.2%)
reported Respiratory failure, and one patient (0.2%) reported Vomiting.

Consultations for Adverse Events Potentially Indicative of Decreased Sympathetic
Function: The only key adverse events meeting criteria for consultation were
Bradycardia and Syncope, and each occurred with similar frequency across treatmentgroups. No patient was reported to have Anhidrosis or Hypohidrosis. Consults wereobtained in the majority of patients who met criteria for a consult. Sympathetic
neuropathy was not confirmed for any of the patients who had a consultation, as
determined by the Investigator after a review of clinical data, including available
consultation material.



Neuropathy Impairment Score: The conclusion from the neurological examination forover 95% of patients in each treatment group was no new or worsened neurologicalexamination abnormality. Less than 1% of patients in any treatment group had a new orworsened neurological examination abnormality that was considered by the Investigatorto be clinically significant.



Adjudication: A total of 30 patients had 34 events that met criteria for adjudication.
These included all TJRs, possible or probable joint safety events as identified on X-ray ormagnetic resonance imaging by the Central Reader based on the tanezumab program
imaging charter, and Investigator-reported joint safety events. The treatment group withthe highest number of patients with events requiring adjudication was the tanezumab
10 mg treatment group (17 patients [3.4%]), followed by the tanezumab 5 mg treatmentgroup (nine patients [1.8%]), and the tramadol PR treatment group (four patients [0.7%]).
Four of the patients in the tanezumab 10 mg treatment group and two of the patients in
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the tanezumab 5 mg treatment group initially received placebo and were switched toactive tanezumab treatment at Week 16; the events requiring adjudication occurred after
Week 16 for all these patients, with the exception of one patient. No events requiring
adjudication occurred in the placebo treatment group. Most of the joints adjudicatedwithin each tanezumab treatment group were adjudicated as Rapidly progressive OA by
the Adjudication Committee, and most of the joints adjudicated within the tramadol PR
treatment group were Other joint outcome. Of the seven patients who had TJRs,
two patients had an adjudication outcome of Rapidly progressive OA type 1, two patients
had an adjudication outcome of Rapidly progressive OA type 2, and one patient had an
adjudication outcome of Subchondral insufficiency fracture. For the remaining
two patients who had a TJR, their adjudication outcome was Other (meniscal tear andtrauma).


Total Joint Replacements: A total of seven patients had one TJR during the study, allin the tanezumab 10 mg treatment group. No patient had more than one TJR during thestudy. Three of the seven patients had their TJR during the Treatment Period (ie, up to
Week 56), two of whom initially received placebo treatment and were then switched totanezumab 10 mg treatment at Week 16; both of these patients had their TJRs after
receiving tanezumab treatment. Two patients had their TJR after completing theTreatment Period and after the Safety Follow-up Period, and two patients had their TJR
during the Safety Follow-up Period after discontinuing the Treatment Period. All TJRs
were associated with an adverse event (ie, not elective). One of the seven patients had aprevious TJR (hip joint). All seven TJRs were adjudicated: five were adjudicated ascomposite joint endpoints and two were adjudicated as Other. Of the four knee TJRs,
two were adjudicated as Rapidly progressive OA type 1, one was adjudicated as
Subchondral insufficiency fracture, and one was adjudicated as Other (meniscal tear).
The four patients who had a TJR in the knee during the study had radiographic evidenceof OA on the Screening X-ray (with KL grade 1 [n=2] and KL grade 2 [n=2]). The hip
TJR was adjudicated as Rapidly progressive OA type 2, and the patient had no evidenceof OA (KL grade 0) in the hip on the Screening X-ray. One shoulder TJR was
adjudicated as Rapidly progressive OA type 2, and the other shoulder TJR was
adjudicated as Other (trauma). KL grade was not evaluated on shoulder X-rays, butneither patient who had a TJR in the shoulder had radiographic evidence of OA on the
Screening shoulder X-rays.

Laboratory Parameters: The incidence of patients with normal Baseline who had postBaseline laboratory test abnormalities at any point during the study that met the prespecified threshold for change from Baseline was low, affected no more than 14 patients
within a treatment group, and was generally distributed evenly across treatment groups.
Laboratory abnormalities considered clinically significant by the investigator
post-Baseline were to be reported as adverse events. Laboratory abnormalities resulting
in adverse events were reported at a low frequency of one to two patients per treatmentgroup, with the exception of Blood creatine phosphokinase increased, which occurred infive patients in the tanezumab 5 mg treatment group. Three patients discontinued
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treatment due to adverse events related to laboratory abnormalities, two patients in thetanezumab 5 mg treatment group (Blood creatine phosphokinase increased and White
blood cell count increased) and one patient in the tramadol PR treatment group (Gamma
glutamyltransferase abnormal). None of these adverse events related to laboratory
abnormalities were severe.


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 generally similar acrosstreatment groups for systolic and diastolic BP. The proportion of patients with amaximum increase from Baseline of greater than 10 to 20 mmHg in sitting systolic anddiastolic BP was higher in the tanezumab and tramadol PR treatment groups than in theplacebo treatment group. The proportion of patients with a decrease or no change insitting systolic and diastolic BP was lower in the tanezumab and tramadol PR treatmentgroups than in the placebo treatment group. The proportion of patients with a maximum
decrease from Baseline of -30 to less than -20 mmHg in sitting systolic BP was higher inthe tanezumab treatment groups than in the placebo and tramadol PR treatment groups.
The proportion of patients with a maximum decrease from Baseline of lessthan -20 mmHg in sitting diastolic BP was lower in the placebo treatment group than in
all other treatment groups. The proportion of patients with a maximum decrease fromBaseline of -20 to less than -10 mmHg in sitting systolic and diastolic BP was higher inthe tanezumab 10 mg treatment group than in all other treatment groups. The proportionof patients with only an increase or no change in sitting systolic and diastolic BP waslower in the tanezumab treatment groups than in the placebo and tramadol PR treatmentgroups.
Overall, the incidence of adverse events associated with vital signs was similar acrosstreatment groups during the Treatment Period (ie, up to Week 56). Bradycardia was themost commonly reported adverse event associated with vital signs in the tanezumab
groups and it was reported with greater frequency (≥1% difference between treatmentgroups) in the tanezumab 10 mg treatment group than the tanezumab 5 mg or thetramadol PR treatment groups. Hypertension was the most commonly reported adverse
event associated with vital signs in the tramadol PR treatment group; however,Hypertension was infrequently reported in the tanezumab treatment groups.



ECG: No patient had a QTcB (QTc corrected using Bazett's formula) or QTcF (QTcF
corrected using Fridericia's formula) value ≥500 msec at any point during the study. The
maximum changes in all ECG parameters up to Week 16 and up to the end of the study
were similar across the treatment groups.
ECG abnormalities considered by the Investigator to be clinically significant and any
episode of a decrease in heart rate that met protocol criteria for Bradycardia on ECG were
to be reported as adverse events. Overall, few ECG-related adverse events were observed
during the Treatment Period (ie, up to Week 56). Bradycardia was reported in alltreatment groups, with the highest incidence in the tanezumab 10 mg treatment group.
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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 change from Baseline in aLBPI score reduction of ≥30% at Week 16) in thetanezumab treatment groups. The overall percent incidence of adverse events andinjection site reactions in the combined TE ADA+ tanezumab treatment group wascomparable to the corresponding TE ADA- combined tanezumab treatment group andthere was no association between TE ADA+ and potential hypersensitivity reactions.

CONCLUSIONS

Tanezumab 10 mg significantly improved pain and function at Week 16 versus placebo.
Treatment with tanezumab 10 mg met the primary objective (change from Baseline to
Week 16 in the aLBPI score compared to placebo).

Treatment with tanezumab 10 mg resulted in significant improvements in all three
key secondary efficacy endpoints compared to placebo (change from Baseline to
Week 16 in RMDQ score, the proportion of patients with a ≥50% reduction in aLBPIscore from Baseline to Week 16, change from Baseline to Week 2 in aLBPI score),applying the gate-keeping strategy.

Tanezumab 5 mg did not significantly improve pain at Week 16 versus placebo as it did
not meet the primary objective (change from Baseline to Week 16 in the aLBPI scorecompared to placebo). Therefore, further hypothesis testing for the three key secondary
endpoints for tanezumab 5 mg could not be performed.
Outside the framework of the gate-keeping strategy, treatment with tanezumab 5 mg
resulted in numerical improvement in the key secondary endpoints compared toplacebo (change from Baseline to Week 16 in RMDQ score [p=0.0035], theproportion of patients with a ≥50% reduction in aLBPI score from Baseline to
Week 16 [p=0.0846], change from Baseline to Week 2 in aLBPI score [p=0.0015]).



Focusing on nominal (unadjusted) p-values, tanezumab 5 mg treatment resulted insignificant improvement from Baseline in the aLBPI score compared to placebo
treatment at Week 1 through Week 12 (p-values <0.05, with no multiplicity
correction). Tanezumab 5 mg treatment resulted in significant improvement fromBaseline in the RMDQ score compared to placebo treatment at Weeks 2, 4, and 8 (pvalues <0.05, with no multiplicity correction).

Treatment with tramadol PR did not result in significant improvements in any of the
primary or key secondary efficacy endpoints compared to placebo (p-values ≥0.05, withno multiplicity correction).

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was maintained for tanezumab 5 mg and tanezumab 10 mg treatments over the 56-week
Treatment Period.



The adverse event data were generally consistent with previous tanezumab studies and no
new safety signals were identified.



The adverse event data related to abnormal peripheral sensation were consistent withprevious studies; the incidence of events was more frequent in the tanezumab treatmentgroups. As in previous studies, paraesthesia and hypoaesthesia were the most commonly
reported adverse events of abnormal peripheral sensation.


Based on blinded external neurologist's reviews of the peripheral neurologic adverse
events including neurological consult data when available, the most common
diagnoses were radiculopathy and mononeuropathy (primarily Carpal tunnel
syndrome) and overall, the results do not indicate that tanezumab treatment isassociated with a peripheral polyneuropathy.

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



Treatment with tanezumab was associated with an increased incidence of adjudicatedjoint safety events. Tanezumab 5 mg treatment had a more favorable joint safety profile
than tanezumab 10 mg treatment based on the frequency and severity of joint safety
events observed.
Composite joint safety endpoints occurred in 13 patients (2.6%) in the tanezumab
10 mg treatment group, five patients (1.0%) in the tanezumab 5 mg treatment group,
one patient (0.2%) in the tramadol PR treatment group, and no patients in the placebo
treatment group. In five of 19 patients (26.3%), the composite joint safety event was
associated with a TJR; all of these patients received tanezumab 10 mg.
Two additional patients treated with tanezumab 10 mg had a TJR.

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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