Extension Study Of Tanezumab In Osteoarthritis

Hemoglobin(Hgb),hematocrit,red blood cell(RBC):less than(\<)0.8\*lower limit of normal(LLN),MCV,MCH,MCHC\<0.9\*LLN or \>1.1\*ULN,platelet:\<0.5\*LLN or \>1.75\*upper limit of normal(ULN),white blood cell(WBC):\<0.6\*LLN or \>1.5\*ULN,lymphocyte,neutrophil,total neutrophil:\<0.8\*LLN or\>1.2\*ULN,basophil,eosinophil,monocyte:\>1.2\*ULN;total,direct bilirubin\>1.5\*ULN,aspartate aminotransferase,alanine aminotransferase,gamma-glutamyl transferase,LDH,alkaline phosphatase:\> 3.0\*ULN,total protein,albumin:\<0.8\*LLN or \>1.2\*ULN;blood urea nitrogen,creatinine:\>1.3\*ULN,uric acid\>1.2\*ULN;cholesterol,triglycerides\>1.3\*ULN;sodium \<0.95\*LLN or \>1.05\*ULN,potassium,chloride,calcium,magnesium,bicarbonate:\<0.9\*LLN or \>1.1\*ULN,phosphate\<0.8\*LLN or\>1.2\*ULN;glucose \<0.6\*LLN or \>1.5\*ULN,glycosylated Hgb \>1.3\*ULN,creatine kinase\>2.0\*ULN;urine(specific gravity \<1.003or\>1.030,pH \<4.5or\>8,glucose,ketone,protein,blood/Hgb,bilirubin,leukocyte esterase,crystals\>=1,RBC,WBC \>1.5\*ULN,epithelial cell\>=6,casts,hyaline cast\>1,bacteria\>20).

Time frame: A4091016: Day 1 up to Week 80

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783). Overall number of participants analyzed signifies those participants who were evaluable for this measure.

Following parameters were analyzed for ECG abnormality: PR interval, QRS interval, QT interval, QT interval corrected using the Fridericia's formula (QTcF), QT interval corrected using the Bazett's formula (QTcB), RR interval and VR interval. Number of participants with clinically significant abnormal ECG findings were judged by investigator and reported as adverse events were presented.

Time frame: A4091016: Baseline (Day 1) up to Week 80

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783).

AE:any untoward medical occurrence in participant who received study medication without regard to possibility of causal relationship. SAE:an AE resulting in any of following outcomes or deemed significant for any other reason:death;initial or prolonged inpatient hospitalization;life-threatening experience(immediate risk of dying);persistent or significant disability/incapacity;congenital anomaly. Treatment-emergent are events between first dose of study medication and up to 112 days after last dose that were absent before treatment in this study or that worsened relative to pretreatment state. AEs included both SAEs and all non-SAEs.

Time frame: A4091016: Baseline (Day 1) up to 112 days after last dose of study medication (up to Week 80)

Population: Intent to treat (ITT) analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783).

Participants answered: How much pain have you had going up or down the stairs? Participants responded by using a NRS of 0 to 10, where 0 = no pain and 10 = extreme pain. Higher score indicates more pain. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. 'Overall number of participants analyzed = participants who were evaluable for this measure. Number Analyzed = participants who were evaluable for this measure at given time points for each group, respectively. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96, 104 were not reported.

Participants answered: How much pain have you had when walking on a flat surface? Participants responded by using a NRS of 0 to 10, where 0 = no pain and 10 = extreme pain. Higher score indicates more pain. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. 'Overall number of participants analyzed = participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96, 104 were not reported.

NIS constitutes sum of 37 standard items of neuromuscular examination used to assess muscle strength, reflexes and sensation. Each item is scored separately for left and right sides. Components of muscle weakness (24 items) scored on a scale: 0 (normal) to 4 (paralysis), with higher score=more weakness; components of reflexes and sensation (13 items) scored on a scale: 0= normal, 1= decreased or 2= absent. Total NIS score range 0 (no impairment) to 244 (maximum impairment), higher score = more impairment. Parent study baseline value calculated as average of pre-dose measurements of participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48, 56, 64, 72

Population: ITT population. Last observation carried forward (LOCF) method was used to impute missing values. Overall number of participants analyzed signifies those participants who were evaluable for this measure. 'Number Analyzed' signifies those participants who were evaluable for this measure at given time points for each group, respectively.

Participants answered: Considering all the ways your osteoarthritis in your knee/hip affects you, how are you doing today? Participants responded by using a 5-point scale where 1 = very good and 5 = very poor. Higher scores indicate worse condition. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. 'Overall number of participants analyzed = participants who were evaluable for this measure. Number Analyzed = participants who were evaluable for this measure at given time points for each group, respectively. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96, 104 were not reported.

WOMAC: self-administered, disease-specific 24-item questionnaire which assesses clinically important, participant-relevant symptoms for pain (5 items), stiffness (2 items) and physical function (17 items) in participants with osteoarthritis of knee or hip. WOMAC average score is the mean of WOMAC pain, physical function and stiffness subscale scores and ranges from 0 (minimum difficulty) to 10 (maximum difficulty), where higher score indicates worse response. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. 'Overall number of participants analyzed = participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96, 104 were not reported.

The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee or hip joint during past 48 hours. The WOMAC pain score is calculated as mean of the scores from 5 individual questions scored on a numerical rating scale (NRS) of 0 (minimum pain) to 10 (maximum pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (minimum pain) to 10 (maximum pain), where higher scores indicate higher pain. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. Overall number of participants analyzed signifies those participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96 and 104 were not reported.

The WOMAC physical function subscale is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index knee or hip joint during past 48 hours. The WOMAC physical function score is calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (maximum difficulty), where higher scores indicate worse function. Total score range for WOMAC physical function subscale score is 0 (minimum difficulty) to 10 (maximum difficulty), where higher scores indicate worse function. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. Overall number of participants analyzed signifies those participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96 and 104 were not reported.

WOMAC stiffness subscale: questionnaire used to assess amount of stiffness experienced due to osteoarthritis in index joint during past 48 hours. The WOMAC stiffness score is calculated as mean of scores from 2 individual questions scored on NRS of 0 (minimum stiffness) to 10 (maximum stiffness), higher scores indicate higher stiffness. Total score range for WOMAC stiffness subscale score =0 (minimum stiffness) to 10 (maximum stiffness), higher scores indicate higher stiffness. Stiffness is defined as sensation of decreased ease in movement of knee/hip. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. 'Overall number of participants analyzed = participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96, 104 were not reported.

FDA approved analgesics (over-the-counter or prescription) were permitted as concomitant medications to relieve the pain of osteoarthritis. These medications included opioids, topical analgesics, NSAIDs, capsaicin products, oral/injectable corticosteroids and viscosupplementation (hyaluronan) and were prescribed at the discretion of the investigator.

Time frame: Week 1-4, 5-8, 9-16, 17-24, 25-32, 33-40, 41-48, 49-56, 57-64, 65-72, 73-80, 81-88, 89-96, 97-104, 105-112

Population: ITT population. 'Number analyzed' signifies those participants who were evaluable for this measure at given time points for each group, respectively. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 73-80, 81-88, 89-96, 97-104 and 105-112 were not reported.

Human serum anti-drug antibody (ADA) samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative enzyme-linked immunosorbent assay (ELISA). Same participant may have positive ADA result at more than 1 time point.

Time frame: A4091016: Day 1, Week 16, 24, 40, 56, 72, 80 or Early Termination (ET: anytime till Week 80)

Population: ITT population. Overall number of participants analyzed signifies those participants who were evaluable for this measure at any time point. 'Number Analyzed' signifies those participants who were evaluable for this measure at given time points for each group, respectively.

Following parameters were analyzed for examination of vital signs: body temperature, blood pressure, heart rate and respiratory rate. Number of participants with clinically significant abnormality in vital signs were judged by investigator and reported as adverse events were presented.

Time frame: A4091016: Baseline (Day 1) up to Week 80

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783).

Physical examination included examination of following sites in addition to general examination: abdomen, ears, extremities, eyes, head, heart, musculoskeletal, neck, nose, skin, throat and thyroid. Clinically significant changes were judged by investigator.

Time frame: Baseline (Day 1) up to Week 80

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783).

The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee or hip joint during past 48 hours. The WOMAC pain score is calculated as mean of the scores from 5 individual questions scored on a numerical rating scale (NRS) of 0 (minimum pain) to 10 (maximum pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (minimum pain) to 10 (maximum pain), where higher scores indicate higher pain. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 16, 24, 56, 104

Population: ITT population. LOCF method was used to impute missing values. Overall number of participants analyzed signifies those participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 104 were not reported.

United States Food and Drug Administration (FDA) approved analgesics (over-the-counter or prescription) were permitted as concomitant medications to relieve the pain of osteoarthritis. These medications included opioids, topical analgesics, non-steroidal anti inflammatory drugs (NSAIDs), capsaicin products, oral/injectable corticosteroids and viscosupplementation (hyaluronan) and were prescribed as per investigator's discretion.

Time frame: Week 1-4, 5-8, 9-16, 17-24, 25-32, 33-40, 41-48, 49-56, 57-64, 65-72, 73-80, 81-88, 89-96, 97-104, 105-112

Population: ITT population. 'Number Analyzed' signifies those participants who were evaluable for this measure at given time points for each group, respectively. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 73-80, 81-88, 89-96, 97-104 and 105-112 were not reported.

The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee or hip joint during past 48 hours. The WOMAC pain score is calculated as mean of the scores from 5 individual questions scored on a numerical rating scale (NRS) of 0 (minimum pain) to 10 (maximum pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (minimum pain) to 10 (maximum pain), where higher scores indicate higher pain. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. Overall number of participants analyzed signifies those participants who were evaluable for this measure. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96 and 104 were not reported.

Participants answered: Considering all the ways your osteoarthritis in your knee/hip affects you, how are you doing today? Participants responded by using a 5-point scale where 1 = very good and 5 = very poor. Higher scores indicated worse pain. Parent study baseline value calculated as average of pre-dose measurements of the participants from study A4091011, A4091014, A4091015 and A4091018.

Time frame: Baseline of the parent study (A4091011, A4091014, A4091015, A4091018); A4091016: Week 4, 8, 16, 24, 32, 40, 48,56, 64, 72, 80, 88, 96, 104

Population: ITT population. LOCF method was used to impute missing values. 'Overall number of participants analyzed = participants who were evaluable for this measure. Number Analyzed = participants who were evaluable for this measure at given time points for each group, respectively. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96, 104 were not reported.

OMERACT-OARSI response:\>=50 percent(%) improvement from parent study baseline and absolute change from parent study baseline of \>=2 units at given week in WOMAC pain or physical function subscale or \>=20% improvement from parent study baseline and absolute change from parent study baseline of \>=1 unit at given week in at least 2 of following 3 items: 1)WOMAC pain subscale, 2)WOMAC physical function subscale, 3)PGA of osteoarthritis (score: 1-5, higher score=more affected).WOMAC pain, physical function subscales assess amount of pain/difficulty experienced (score:0-10, higher score=higher pain/difficulty).

Time frame: A4091016: Week 4, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783). LOCF method was used to impute missing values. Efficacy results were not collected beyond Week 72 due to clinical hold. Therefore, results for Week 80, 88, 96 and 104 were not reported.

Number of participants were reported based on the maximum number of intravenous doses of either tanezumab or placebo received.

Time frame: A4091016: Baseline (Day 1) up to Week 64

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study, A4091016 (NCT00809783).