A Study Of The Analgesic (Pain-Relief) Effects Of Tanezumab In Adult Patients With Diabetic Peripheral Neuropathy

Participant rated their DPN pain using 11-point NRS with score ranging from 0 (no pain) to 10 (worst possible pain) during past 24-hour period. Higher score indicated greater level of pain. Change: score at observation minus score at baseline.

Participant rated their DPN pain using 11-point NRS with score ranging from 0 (no pain) to 10 (worst possible pain) during past 24-hour period. Higher score indicated greater level of pain.

Participant rated their DPN pain using 11-point NRS with score ranging from 0 (no pain) to 10 (worst possible pain) during past 24-hour period. Higher score indicated greater level of pain. Change: score at observation minus score at baseline.

BPI-sf (Brief Pain Inventory-short form) is a participant-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during the 24-hour period prior to evaluation. It consists of 5 questions. Questions 1-4 measure the magnitude of pain at its worst and least (in the last 24 hours), average, and right now. Responses are provided by the participant on an 11-point numeric rating scale with anchors at 0 (No Pain) and 10 (Pain as bad as you can imagine). Question 5 consists of 7 item subsets (A to G) which measure the level of interference of pain on daily functions. Responses are given on an 11-point numeric rating scale with anchors at 0 (Does not interfere) and 10 (Completely interferes). The instrument is scored by item and by dimension, with lower scores indicating less pain or pain interference.

Participant rated questionnaire to evaluate different symptoms of neuropathic pain (burning [superficial] spontaneous pain, pressing [deep] spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dyesthesia [P/D]) during past 24-hour period and included 10 descriptors quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) and 2 temporal items assessing duration of spontaneous ongoing and paroxysmal pain. Questionnaire generated a score in each of the relevant dimensions and a total score of 0-100. Higher score indicated a greater intensity of pain.

BPI-sf (Brief Pain Inventory-short form) is a participant-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during the 24-hour period prior to evaluation. It consisted of 5 questions. Questions 1-4 measure the magnitude of pain at its worst and least (in the last 24 hours), average, and right now. Responses were provided by the participant on an 11-point numeric rating scale with anchors at 0 (No Pain) and 10 (Pain as bad as you can imagine). Question 5 consisted of 7 item subsets (A to G) as being pain interference with general activity; mood; walking ability; normal work (outside home and housework); relations with other people; sleep and enjoyment of life. Responses were given on an 11-point numeric rating scale with anchors at 0 (Does not interfere) and 10 (Completely interferes). The instrument was scored by item and by dimension, with lower scores indicated less pain or pain interference.

The PGA is a global evaluation that utilizes a 5-point Likert scale with a score of 1 being the best (very good: Asymptomatic and no limitation of normal activities) and a score of 5 being the worst (very poor: Very severe symptoms which are intolerable and inability to carry out all normal activities).

The PGA is a global evaluation that utilizes a 5-point Likert scale with a score of 1 being the best (very good: Asymptomatic and no limitation of normal activities) and a score of 5 being the worst (very poor: Very severe symptoms which are intolerable and inability to carry out all normal activities).

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression; 1 indicates better health state (no problems); 3 indicates worst health state (extreme problems). Scoring formula developed by Euro Quality of life group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicated a better health state.

Participants who did not experience adequate pain relief for DPN pain during the treatment period took acetaminophen 3000 mg/day up to 3 days/week as rescue medication.

Participants who did not experience adequate pain relief for DPN pain during the treatment period took acetaminophen 3000 mg/day up to 3 days/week as rescue medication.

Participants who did not experience adequate pain relief for DPN pain during the treatment period took acetaminophen 3000 mg/day up to 3 days/week as rescue medication.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the 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 drug and up to 112 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Criteria:Hemoglobin(Hgb),hematocrit,red blood cell(RBC)count:less than(<)0.8*lower limit of normal(LLN), mean cell Hgb,mean corpuscular volume,mean corpuscular Hgb concentration,mean platelet volume:<0.9*LLNor>1.1*upper limit of normal(ULN),platelet:<0.5*LLN >1.75* ULN, lymphocyte,neutrophil:<0.8*LLN or>1.2*ULN,basophil, eosinophil,monocyte:>1.2*ULN;bilirubin(total, direct,)>1.5*ULN, aspartate and alanine aminotransferase,alkaline phosphatase:> 3.0*ULN;gamma GT>3.0;cholestrol,triglycerides:>1.3*ULN; total protein, albumin:<0.8*LLN or>1.2*ULN ;blood urea nitrogen,creatinine:>1.3*ULN,uric acid>1.2*ULN;sodium <0.95*LLNor>1.05*ULN,potassium,chloride,calcium,bicarbonate, magnesium:<0.9*LLN or >1.1*ULN;phosphate<0.8*LLN or>1.2*ULN;glucose <0.6*LLNor>1.5*ULN,glycosylated Hgb>1.3*ULN,creatine kinase >2.0*ULN;urine(specific gravity<1.003or>1.030;pH <4.8or>8;glucose,ketone,proteins,blood/Hgb,bilirubin,nitrite>=1;WBC, RBC≥20/HPF;hyaline cast≥1;epithelial cell>=6;bacteria >1);serum pregnancy >=1.

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 heart rate (HR). Number of participants with clinically significant abnormal ECG findings reported as adverse events were presented.

Physical examination included examination of following sites in addition to general examination: abdomen, ears, extremities, eyes, head, heart, musculoskeletal, neck, nose, skin, throat, lungs and thyroid.

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

Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative enzyme-linked immunosorbent assay (ELISA).

Neurologic examination assessed strength of groups of muscles of the head and neck, upper limbs and lower limbs, deep tendon reflexes and sensation (tactile, vibration, joint position sense and pin prick) of index fingers and great toes in order to complete the NIS. The NIS consists of 74 items (37 items assessed on the right side and 37 items assessed on the left side). Each item was rated on a scale of either 0 to 4 or 0 to 2 points, which were summed to calculate a total score. The NIS total score ranges from 0 to 244, where higher scores represent greater impairment.

The NSC (Neuropathy symptoms and change) is a standardized instrument and has been used to evaluate participants for number of symptoms of peripheral neuropathy. The NSC score included 38 (muscle weakness, Q1-19; sensation, Q20-29; and autonomic symptoms, Q30-38) symptom questions where the participants indicated experiencing the number of symptoms (to any severity). The score ranged from 0 to 38, with higher scores indicated more symptoms. The change score is the participant's comparison of the symptoms at last evaluation to the symptoms at onset. A change from baseline > 0 indicated increased neuropathy.

QST was performed on dorsum of foot and anterior thigh (at midpoint of a line from inguinal crease to midpoint of patella) to assess and quantify sensory function in lower extremity. Parameters were selected to assess small fiber function such as cooling detection threshold (mainly small diameter myelinated fibers, A delta), heat pain detection threshold (A delta and C fiber functions), and large fiber function via vibration detection threshold. normal deviate scores derived from a normal distribution of a reference population. A standard deviate score of 0 corresponds to 50th percentile of control population. Standard deviate score 1.96 corresponds to 95th percentile of normal distribution and -1.96 corresponds to 5th percentile of normal distribution. A normal deviate score indicated how many standard deviations higher (in case of positive normal deviate score) or lower (in case of negative normal deviate score) participant's value was relative to mean of reference population.

IENF density was quantified in 3 millimeter (mm) immunostained skin punch biopsies containing epidermis and superficial dermis to evaluate the amount and morphological appearance of small diameter nerve fibers, both somatic and autonomic, in sensory neuropathies. IENF density was assessed from skin biopsies taken from the distal calves and distal thigh.

Serum samples were analyzed for determining total NGF concentration. Total NGF was analyzed using a validated, sensitive and specific immunoaffinity enrichment liquid chromatography tandem mass spectrometric (IA/LC/MS/MS) method.