P38 Mitogen-activated Protein (Map) Kinase Inhibitor (SB-681323)Study In Patients With Neuropathic Pain

The 11 point pain intensity numerical rating scale ranged from 0 to 10, where 0 represents "No pain" and 10 represents "Maximum pain imaginable". It was used for the subjective assessment of the pain. The score ranged from 0 to 10, where 0 represented absence of symptoms and higher score indicated more severe symptoms. Current pain was the pain intensity assessments that were carried out in the unit (at Day 7 and 14 of each treatment period), were recording of the pain intensity that the participant felt at the time.

A thermode was placed on skin of participant. Temperature of block was initially set to Baseline temperature of participant's skin (32 degree Celsius [°C]). For threshold measurement, temperature of thermode was gradually increased (for warm sensation and heat pain detection thresholds) or decreased (for cold sensation and cold pain thresholds) from Baseline (32°C) at rate of 1°C per second. Ramp was stopped and temperature of thermode was returned to Baseline by participant pushing a button on a response unit when threshold was reached. It was repeated 4 (sensation thresholds) or 3 times (pain thresholds) for each modality. Threshold temperatures and average values were recorded. If thermode temperature reached 50°C (heat pain) or 0°C (cold pain) without participant responding, ramp was stopped, temperature was returned to Baseline automatically to prevent skin injury. Respective cut-off temperature was then recorded for that trial. Recorded for affected and controlled area of skin.

Allodynia is defined as increased response of neurons on painful and repetitive, stimulation or pain in response when touched. Area of static allodynia was determined using a 26 g von Frey filament. In a non-painful area, investigator repeatedly applied filament perpendicularly to skin, exerting enough pressure to make filament bend slightly, each time closer to presumed border of allodynia. When participant reported sensation becoming more unpleasant or painful, point at which filament was contacting the painful area of skin was marked with a felt tip pen by investigator. At that point, if participant's painful area was on a limb, a total of four points (each 90° apart) were drawn in order to complete mapping. If participant's painful area was irregular, or on trunk or face, a total of 8 points (45° apart) was drawn in order to complete mapping. Area of static allodynia was calculated by transferring the points to an homunculus. Points were connected to form area of allodynia.

Allodynia is defined as increased response of neurons on painful and repetitive, stimulation or pain in response to stroking lightly. Area of dynamic allodynia was determined using a one inch foam brush. In a non-painful area, investigator, exerted enough pressure to make foam brush bend slightly, would slowly move brush forward toward painful area of participant, at rate of 1 centimeter per second. When participant reported sensation becoming unpleasant or painful, point at which foam brush was contacting painful area of skin was marked with a felt tip pen by investigator. At that point, if participant's painful area was on a limb, a total of 4 points (each 90° apart) was drawn in order to complete mapping. If participant's painful area was irregular, or was in truncal or facial area, a total of 8 points (45° apart) were drawn in order to complete mapping. Area of dynamic allodynia was calculated by transferring points to an homunculus, were connected to form area of allodynia.

Allodynia is defined as increased response of neurons on painful and repetitive, stimulation. Where static allodynia was pain in response when touched and dynamic allodynia was pain in response to stroking lightly. The intensity of static and dynamic allodynia was assessed using the 11 point numeric rating scale, where 0=no pain, 10=maximum pain imaginable. The score ranged from 0 to 10, where 0 represents absence of symptoms and higher score indicates more severe symptoms.

The Global Impression of Change scale was rated by the clinician and the participant for change in overall status as perceived by the clinician and as perceived by the participant, respectively. It was rated using a 7-point numerical rating scale where 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse and 7=Very much worse. The scale ranged from 1 to 7, where 1 indicates best response and 7 indicates worst response. The assessments were done during the Visit to the unit on Day 7 and Day 14, 2 hours post-dose of each treatment period.

Any participant for whom the pain intensity became unacceptable during any stage of the study was permitted to initiate rescue analgesic therapy with the protocol defined rescue medication of paracetamol up to two 500 mg tablets BID (i.e., maximum paracetamol 2 g per 24 hour period). Total paracetamol use included rescue medication and also paracetamol consumed in over-the-counter remedies including cold, allergy, sleep and pain preparations. Participants were requested not to take any paracetamol up to 24 hours before a treatment Visit. The use of rescue medication was recorded on the diary cards by the participants and use of recue medication during the treatment visit was recorded in case report form (CRF). Data is reported for number of participants who used rescue medication.

Evoked potentials were planned to be recorded from midline electrodes. Responses from ten stimuli were planned to be recorded from each participant with the thermode placed over 3 sites -the lateral calf, lateral forearm and face (cheek). This involved a CHEPS with a thermode area of 572.5 mm^2 and a heating thermo foil covered with a 25 uncertainty of measurement (Um) layer of thermo conductive plastic. The thermode heating rate was planned at 70 °C per second and the cooling rate 40°C per second. The Baseline temperature was planned at 32 °C, destination temperature 51 °C, and stimulus interval was 7 seconds. Stimuli was planned to be applied to the dermatome of interest. The participant could withdraw at any time. The assessment was planned at the affected area and control area which was the mirror image site area. The assessment for this outcome measure was optional during the study and data was not collected for this outcome measure.

Evoked potentials were planned to be recorded from midline electrodes. Responses from ten stimuli was planned to be recorded from each participant with the thermode placed over 3 sites -the lateral calf, lateral forearm and face (cheek). This involved a CHEPS with a thermode area of 572.5 mm^2 and a heating thermo foil covered with a 25 uncertainty of measurement (Um) layer of thermo conductive plastic. The thermode heating rate was planned at 70 °C per second and the cooling rate 40°C per second. The Baseline temperature was planned at 32 °C, destination temperature 51 °C, and stimulus interval was 7 seconds. Stimuli was planned to be applied to the dermatome of interest. The participant could withdraw at any time. The assessment was planned at the affected area and control area which was the mirror image site area. The assessment for this outcome measure was optional during the study and data was not collected for this outcome measure.

Assessemnt of capsaicin and heat receptor TRPV1 immunoreactivity and mechanism-related markers (NGF, CGRP) in skin biopsies was optional outcome measure, planned to be conducted on participants proceeding to surgery. However the data for this outcome measure was not collected and result summary was not produced.

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

The parameters of clinical chemistry included sodium, potassium, urea, creatinine, total protein, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), calcium, magnesium, phosphate, cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, glucose and creatinine kinase. The assessments were done at Day 1, 7 and 14 of each treatment period. Only those parameters for which at least one value of PCC was reported are summarized

The parameters of hematology included hemoglobin (Hb), packed cell volume (PCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), red blood cell count (RBC), white blood cell count (WBC), platelets, differential WBC count and examination of film. The assessments were done at Day 1, 7 and 14 of each treatment period. Only those parameters for which at least one value of PCC was reported are summarized.

Vital signs assessment included heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), done while participant lying supine and having rested in this position for at least 10 minutes before each reading. Criteria for vital sign values meeting PCC included: SBP < 85 and > 160 millimeters of mercury (mmHg) and increase or decrease from Baseline >= 20 and >= 40 mmHg; DBP < 45 and > 100 mmHg and increase or decrease from Baseline >= 10 and >= 20 mmHg; HR < 40 and > 110 beats per minute (bpm) and increase or decrease from Baseline >= 15 and >= 30 bpm. The assessments were done at Day 1, Day 7 and Day 14 (pre dose and 1.5 hour post dose) of each treatment period. Only those parameters for which at least one value of PCC was reported are summarized.

Full 12 lead ECGs were recorded using an ECG machine that automatically calculated the HR and measured PR, QRS, QT, Bazzette formula corrected QT (QTcb) interval and Fridericia formula corrected QT (QTcF) interval. Overall ECG findings were summarized at Day 1, Day 7 and Day 14 of each treatment period (pre-dose and 1.5 hour post-dose). Normal and abnormal ECG findings were categorized. The abnormal PCC ranges were: absolute QTc interval >450 msec and increase from baseline QTc >=60 and <=59; PR interval <110 and >220 msec; QRS interval <75 and >110 msec.

Urine human chorionic gonadotrophin (β-hCG) pregnancy test was performed in all female participants of childbearing potential only at Day 1 and Day 14 of each treatment period and Follow-up. In the case of a positive urine β-hCG test, pregnancy was confirmed with a serum β-hCG test.