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

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness and safety of the investigational drug, tanezumab, in adult patients with painful diabetic peripheral neuropathy.

Detailed Description
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This study was terminated on 18 November 2010 following a US FDA clinical hold for the tanezumab diabetic peripheral neuropathy clinical study which halted dosing and enrollment of patients on 19 July 2010 for potential safety issues.

Official Title
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A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER, PARALLEL GROUP, PROOF OF CONCEPT STUDY OF THE ANALGESIC EFFECTS OF TANEZUMAB IN ADULT PATIENTS WITH DIABETIC PERIPHERAL NEUROPATHY

Conditions
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Diabetic Peripheral Neuropathy

Intervention / Treatment
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* Biological: Tanezumab
* Biological: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of diabetes mellitus (high blood sugar) with HbA1c levels of ≤11% at Screening, and on a stable anti-diabetic medication regimen for the 30 days prior to randomization. Diagnosis of diabetic peripheral neuropathy pain in the legs or feet with decreased sensation in the feet or decreased/absent ankle jerk/ reflexes. Presence of ongoing pain due to diabetic peripheral neuropathy for at least 3 months. A pain score of greater than or equal to (≥) 4 for from diabetic peripheral neuropathy on the Numerical Rating Scale (NRS), a 11-point scale with 0 meaning no pain and 10 meaning worst pain at Screening. Be willing to stop all pain medications for diabetic peripheral neuropathy except for the limited use of acetaminophen (Tylenol) or ibuprofen-like (Motrin) medications between Screening and Baseline and not use prohibited pain medications throughout the duration of the study except as permitted by the study guidelines. Exclusion Criteria: Painful neuropathies other than diabetic peripheral neuropathy. Other types of diabetic neuropathies. Patients with a past history of carpal tunnel syndrome (CTS) with signs or symptoms of CTS in the one year prior to Screening are not eligible for participation. Patients with fibromyalgia, regional pain caused by lumbar or cervical compression with radiculopathy or other moderate to severe pain. Patients with a present (current) history of sciatica are not eligible for participation. The presence of pain conditions that cannot be distinguished from diabetic peripheral neuropathy such as peripheral vascular disease. Amputations dues to diabetes. Patient with any clinically significant medical condition or laboratory abnormalities. History, diagnosis, or signs and symptoms of clinically significant neurological diseases (such as Alzheimer's disease, head trauma, epilepsy or stroke). History, diagnosis, or signs and symptoms of clinically significant psychiatric diseases (such as bipoar disorder or schizophrenia). History of known alcohol, analgesic or drug abuse within 2 years of Screening. Pregnant women, lactating mothers, women suspected of being pregnant, and women who wish to be pregnant during the course of clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tanezumab<br> | Biological: Tanezumab<br>* 20 mg subcutaneous injection every 8 weeks x 2 doses (at Baseline and week 8)<br>* Other names: PF-04383119;|
| Placebo Comparator: Placebo<br> | Biological: placebo<br>* Placebo to match tanezumab 20 mg subcutaneous injection every 8 weeks x 2 doses (at Baseline and week 8)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Diabetic Peripheral Neuropathy (DPN) Pain Score at Week 16 | Participants assessed their DPN pain during the past 24 hours using 11-point Numeric Rating Scale (NRS) with score range of 0 (no pain) to 10 ( worst possible pain). Baseline score was calculated as the mean of the average pain scores over the 3 days in the initial pain assessment period. The Week 16 value was the average DPN Pain score calculated for the 7 days prior to and including Day 113 (Week 16). | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Diabetic Peripheral Neuropathy (DPN) Pain Score at Week 1, 2, 4, 6, 8, and 12 | 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. | Baseline, Week 1, 2, 4, 6, 8, 12 | 
| Number of Participants With Cumulative Reduction From Baseline in Average Diabetic Peripheral Neuropathy (DPN) Pain Score at Week 16 | 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. | Week 16 | 
| Number of Participants With at Least 30 Percent (%), 50%, 70% and 90% Reduction From Baseline in Average DPN Pain Score: Last Observation Carried Forward (LOCF) | 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. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Worst and Average Pain Score at Week 8 and 16 | 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. | Baseline, Week 8, 16 | 
| Change From Baseline in Neuropathic Pain Symptom Inventory (NPSI) Total Score at Week 8 and 16: Last Observation Carried Forward (LOCF) | 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. | Baseline, Week 8, 16 | 
| Change From Baseline in BPI-sf Pain Interference Index and Pain Interference Score for General Activity, Walking Ability, Sleep and Normal Work at Week 8 and Week 16 | 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. | Baseline, Week 8, 16 | 
| Change From Baseline in Patient's Global Assessment (PGA) of Diabetic Peripheral Neuropathy (DPN) at Week 4, 8, 12 and 16 | 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). | Baseline, Week 4, 8, 12, 16 | 
| Number of Participants With Improvement of at Least 2 Points in Patient's Global Assessment (PGA) of Diabetic Peripheral Neuropathy | 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). | Week 4, 8, 12, 16 | 
| Change From Baseline in Euro Quality of Life (EQ-5D)- Health State Profile Utility at Week 16 | 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. | Baseline, Week 16 | 
| Time to Discontinuation Due to Lack of Efficacy |  | Baseline up to Week 16 | 
| Number of Participants Who Used 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. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Days Per Week of Rescue Medication Usage | 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. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Amount of Rescue Medication Taken | 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. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to 112 days after last dose of study treatment (up to 169 days) | 
| Number of Participants With Clinically Significant Laboratory Values | 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. | Baseline up to Week 24 | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 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. | Baseline up to Week 24 | 
| Number of Participants With Clinically Significant Change From Baseline Physical Examination | 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. | Baseline up to Week 24 | 
| Number of Participants With Clinically Significant Vital Signs Abnormalities | 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. | Baseline up to Week 24 | 
| Number of Participants With Anti Drug Antibody (ADA) for Tanezumab | 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). | Baseline, Week 8, 16, 24 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Weeks 2, 4, 8, 12, 16 and 24: Last Observation Carried Forward (LOCF) | 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. | Baseline, Weeks 2, 4, 8, 12, 16 and 24 | 
| Change From Baseline Neuropathy Symptoms and Change (NSC) Score at Week 16: Last Observation Carried Forward (LOCF) | 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. | Baseline, Week 16 | 
| Change From Baseline in Quantitative Sensory Testing (QST) at Week 16 | 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. | Baseline, Week 16 | 
| Change From Baseline in the Average Density of Protein Gene Product (PGP) 9.5-Positive Intraepidermal Nerve Fiber (IENF) at Week 16: LOCF | 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. | Baseline, Week 16 | 
| Plasma Tanezumab Concentration |  | Baseline(Day 1), Week 2, 4, 8, 12, 16, 24 | 
| Serum Nerve Growth Factor (NGF) | 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. | Day 1, Week 8, 16, 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetic peripheral neuropathy, tanezumab, diabetic neuropathies, diabetic polyneuropathy, diabetic neuropathy painful