Long-Term Study Of The Safety Of Tanezumab In Arthritis Patients

5NC(nd)+HRdb(nd)composite score included 5 Nerve Conduction Studies(NCS)attributes(peroneal motor nerve distal latency \[MNDL\],peroneal nerve compound muscle action potential\[CMAP\],peroneal motor nerve conduction velocity\[MNCV\],tibial MNDL,sural sensory nerve action potential amplitude \[SNAP\])and HRdb value. Values of attributes scored as percentile(calculated from distribution of normal values corresponding to participant's baseline demographic characteristics),then expressed as normal deviate(nd)score based on standard normal distribution.Score \>0=worse response,less than(\<)0=better response compared to normal matched population.Score change\>0=worsening,\<0=improvement compared to baseline.2 neurological visits(NVs) were conducted both at baseline and Week 24. NCS measurements were collected once at each NV.HRdb measurements were collected twice and highest nd score was selected at each NV. Mean of selected measurements at each NV was calculated to obtain Baseline and Week 24 values.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: Intent-to-treat (ITT) analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using last observation carried forward (LOCF) method.

NIS-LL:assess muscle weakness, reflexes, sensation;scored separately for left, right limbs. Components of muscle weakness (hip and knee flexion,hip and knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors) scored on scale 0(normal) to 4(paralysis),higher score=greater weakness. Components of reflexes(quadriceps femoris,triceps surae);sensation (touch pressure,pin-prick,vibration,joint position) scored 0=normal,1=decreased, or 2=absent. NIS-LL score: sum of scores of NIS items 17-24, 28-29 and 34-37. Total possible NIS-LL score range 0-88,high score=more impairment.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

NIS: 74 items, assess muscle weakness, reflexes and sensation; scored separately for left, right limbs (37 items for each side). Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS score range 0-244, higher score=greater impairment.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

NSC score is the number of the 38 symptom questions where the participants indicated experiencing the symptom to any severity. Total score range: 0 to 38 where higher score indicated more symptoms.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

SF-36v2 is a self-administered questionnaire evaluating 8 aspects/domains of functional health and wellbeing: physical function, role physical, bodily pain, vitality, general health, social function, role emotional and mental health. The total score for each domain is scaled 0-100 (100 = highest level of functioning). Change from baseline \>0 indicates an improvement.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

SF-36v2 is a self-administered questionnaire evaluating 8 aspects/domains of functional health and wellbeing: physical function, role physical, bodily pain, vitality, general health, social function, role emotional and mental health. Total score for each aspect were scaled 0-100 (100=highest level of functioning). For obtaining physical and mental component scores, z-score for each scale = (observed score -mean score for general 1990 United States \[US\] population)/corresponding standard deviation. The 2 component scores were obtained by multiplying each aspect z-score by physical or mental factor score coefficient (1990 general US population) and summing the eight products. Component scores indicated how many standard deviations higher (in case of positive z-score \[better functioning\])/lower (in case of negative z-score \[worse functioning\]) participant's value was relative to the mean of the reference population. Change from baseline \>0 indicates an improvement.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

5NC (nd) score included five NCS attributes: peroneal MNDL, CMAP, MNCV; tibial MNDL; sural SNAP. Values of attributes scored as percentiles (calculated from distribution of normal values corresponding to participant's baseline demographic characteristics), then expressed as nd score based on standard normal distribution. For CMAP, MNCV, SNAP: score \<0 indicated worse and \>0 indicated better response; for peroneal,tibial MNDL: score \>0 indicated worse and \<0 indicated better response, as compared to normal matched population. For CMAP, MNCV, SNAP: score change \<0 indicated worsening and \>0 indicated improvement; for peroneal,tibial MNDL: score change \>0 indicated worsening and \<0 indicated improvement, as compared to baseline. Total score calculated as sum of each NCS attribute. Total score \>0 indicated worse and \<0 indicated better response as compared to normal matched population. Total score change \>0 indicated worsening and \<0 indicated improvement as compared to baseline.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method. 'Number Analyzed' signifies participants evaluated at specific time point for each arm group, respectively.

HRdb test was used to evaluate the effect of treatment on autonomic function. Participant took a series of 8 deep breaths and average heart rate difference was measured and compared to normative data. R-R (time between two consecutive R waves in the electrocardiogram) response to deep breathing was reported as normal deviates. Score \<0 indicated worse response and \>0 indicated better response as compared to normal matched population. Score change \<0 indicated worsening and \>0 indicated improvement as compared to baseline. 2 neurological visits (NVs) were conducted both at baseline and Week 24. Measurements were collected twice and highest nd score was selected at each NV. Mean of the selected measurements was calculated to obtain Baseline and Week 24 values.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

IENF density was quantified in 3 millimeter (mm) immunostained (PGP 9.5 immunohistochemical staining) skin punch biopsies taken from the distal end of the leg, 10 centimeter (cm) above the lateral malleolus, within the territory of the sural nerve, containing epidermis and superficial dermis to evaluate amount of small diameter nerve fibers. Skin biopsies were taken from normal appearing skin and skin having local scar, signs of trauma, ulceration, or active dermatologic process were avoided.

Time frame: A4091026: Baseline, A4091040: Week 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

PGA: Participants answered the following question: Considering all the ways your osteoarthritis in your knee or hip affects you, how are you doing today? Participants rated their condition using a 5-point Likert scale. Score range: 1 to 5. 1: Very Good (asymptomatic and no limitation of normal activities); 2: Good (mild symptoms and no limitation of normal activities); 3: Fair (moderate symptoms and limitation of some normal activites); 4: Poor (severe symptoms and inability to carry out most normal activities); 5: Very Poor (very severe symptoms which are intolerable and inability to carry out all normal activities).

Time frame: A4091026: Baseline, A4091040: Week 8, 16, 24, 32

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method. Results were not reported at Week 32 as none of the participants were evaluable for this measure at Week 32.

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 to 10, where higher score indicates worse response. Change from baseline \<0 indicates an improvement.

Time frame: A4091026: Baseline, A4091040: Week 8, 16, 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

WOMAC Index: 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 the index hip or index knee. Each question was assessed on Numeric Rating Scale (NRS) as 0(none) to 10(extreme).Total possible domain score was calculated as the mean of the score for each domain questions. Score range:0-10,high scores=high pain/stiffness/difficulty in physical activity.

Time frame: A4091026: Baseline, A4091040: Week 8, 16, 24, 32

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method. Results were not reported at Week 32 as none of the participants were evaluable for this measure at Week 32.

The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index joint (knee or hip) during the past 48 hours. It is calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 to 10, where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain.

Time frame: Week 8, 16, 24, 32

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

PGA: Participants answered the following question: Considering all the ways your osteoarthritis in your knee or hip affects you, how are you doing today? Participants rated their condition using a 5-point Likert scale. Score range: 1 to 5. 1: Very Good (asymptomatic and no limitation of normal activities); 2: Good (mild symptoms and no limitation of normal activities); 3: Fair (moderate symptoms and limitation of some normal activites); 4: Poor (severe symptoms and inability to carry out most normal activities); 5: Very Poor (very severe symptoms which are intolerable and inability to carry out all normal activities).

Time frame: Week 8, 16, 24, 32

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.

OMERACT-OARSI response: \>=50 percent (%) improvement from A4091026 (NCT00863772) baseline and absolute change from A4091026 (NCT00863772) baseline of \>=2 units at week of interest in WOMAC pain or physical function subscales, or at least 2 of the following 3 being true: \>=20% improvement from A4091026 (NCT00863772) baseline and absolute change from A4091026 (NCT00863772) baseline of \>=1 unit at week of interest in 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: Week 8, 16, 24

Population: ITT analysis set included all participants who received at least 1 dose of intravenous study medication during this study A4091040. Missing values were imputed using LOCF method.