Intranasal SB-705498 in Allergic Rhinitis (AR) Patients

Nasal symptoms (nasal congestion, rhinorrhoea, itching and sneezing) were scored on a scale from 0 to 3 where 0= absent symptoms, 3 = severe symptoms. TNSS was calculated as the sum of the response for all 4 individual nasal symptom scores. TNSS ranged from 0 to 12, where 0=absent symptoms, 3=severe symptoms. Higher the score, more severe the symptoms. Weighted mean (WM) of TNSS and its individual components (nasal congestion, rhinorrhoea, itching and sneezing) are presented on Day 8. Weighted mean was calculated over the time interval 0 to 4 hours after start of allergen chamber challenge by calculating the area under the curve of TNSS/component from time of the first observation to time of the last observation (AUC [tf-t1 hours]) using the trapezoidal rule, and then dividing by the actual relevant time interval (tf-t1) required by participant to complete the chamber challenge assessments. A Bayesian analysis was conducted to derive the posterior probability for TNSS.

Nasal symptoms (nasal congestion, rhinorrhoea, itching and sneezing) were scored on a scale from 0 to 3 where 0= absent symptoms, 3 = severe symptoms. TNSS was calculated as the sum of the response for all 4 individual nasal symptom scores. TNSS ranged from 0 to 12, where 0=absent symptoms, 3=severe symptoms. Higher the score, more severe the symptoms. Mean of TNSS and its individual components is presented pre-evening (pm) dose on Days 4, 5, 6, 7 and pre-challenge [1 hour (hr)] on Day 8.

Total Nasal Airflow is calculated as the sum of the left nostril and the right nostril airflow values. AAR is a very sensitive method of assessing clinical parameters of nasal obstruction (nasal flow, nasal resistance and nasal flow increase). A participant was instructed to breathe through one nostril while a sensor in the other nostril measured the difference in pre-nasal and choanal pressure. The system was connected to a computer. Nasal flow and nasal resistance were observed at pressure levels of 75, 150 and 300 Pascal. The defined measuring range for the flow was +-1000 milliliter per second (mL/s). Weighted means for total nasal airflow Resistance was calculated by dividing the area under the curve between 1 and 4 hours (via the linear trapezoidal method) by the total duration that the participant took to complete the chamber challenge assessments.

The RQLQ composed of 28 items covering 7 domains of health. Each question is scored on a scale of 0 to 6 (where, 0 = not troubled and 6 = extremely troubled). 7 domains were: Activities (3 items):1, 2, 3;Sleep (3 items): 4, 5, 6; Non-nose/eye symptoms (7 items): 7, 8, 9, 10, 11, 12, 13; Practical Problems (3 items): 14, 15, 16; Nasal Symptoms (4 items): 17, 18, 19, 20; Eye Symptoms (4 items): 21, 22, 23, 24; Emotional (4 items): 25, 26, 27, 28 consisted of total 28 items. Domain activity score = total post-baseline score for individualized activity items answered on both visits divided by total Baseline score for individualized activity items answered on both visits multiplied by the Baseline score for item(s) missing post-baseline. The global RQLQ score was calculated by averaging all 28 item scores, which ranges from 0 to 6 (where, 0 = not troubled and 6 = extremely troubled). Higher scores indicate worsening of symptoms.

Plasma samples for pharmacokinetic (PK) analysis were drawn at indicated time points of each treatment period. AUC0-t was calculated by the linear trapezoidal method. AUC0-infinity was calculated as the sum of the AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant, where first-order elimination or terminal rate constant was calculated from a semi-log plot of the plasma concentration versus time curve. The parameter was calculated by linear least-squares regression analysis using the last three (or more) non-zero plasma concentrations. Values were reported as Least Squares Geometric Means with respective % CV.

Plasma samples for pharmacokinetic analysis were drawn at indicated time points of each treatment period. Cmax was defined as maximal measured plasma concentration over the time span specified. Values were reported as least squares geometric means with respective geometric coefficient of variation (% CV).

Vital signs assessment included heart rate, blood pressure, and temperature. Criteria for vital sign values meeting potential clinical concern included: systolic blood pressure (SBP) <85 and >160 millimeters of mercury (mm Hg), diastolic blood pressure (DBP) < 45 and > 100 mm Hg, temperature <36 and >37.5 Degree Celsius and heart Rate <40 and >110 beats per minute. Only parameters with PCI values are reported.

Single 12-lead ECGs were obtained at each time point during the study using an ECG machine that automatically calculated heart rate and measured PQ, QRS, QT, and QTc intervals. Baseline was assessment on Day 1. Change from Baseline was the values at specified time points subtracted by the Baseline value.

Single 12-lead ECGs were obtained at each time point during the study using an ECG machine that automatically calculated heart rate and measured PQ, QRS, QT, QTc corrected by Bazett's formula (QTcB) and QTc corrected by Fridericia's formula (QTcF). Baseline was assessment on Day 1. Change from Baseline was the values at specified time points subtracted by the Baseline value.

The PCC range for hematology parameters included white blood cell count, low: 0.67, high 1.82, neutrophil count, low: 0.83, Hemoglobin, male- high 1.03, female- high 1.13, hematocrit, male- high 1.02, female- high 1.17, Platelet Count, low: 0.67, high: 1.57, lymphocytes, low 0.81. Only parameters with PCI values are reported.

The PCC range for clinical chemistry parameters included albumin, low: 0.86, millimole per liter (mmol)/L, calcium, low: 0.91, high: 1.06, glucose. Low: 0.71, high: 1.41, Potassium, low: 0.86, high: 1.10, Sodium, low: 0.96, high: 1.03, Total CO2, Low: 0.86, high: 1.14, Creatinine, in male, Low: <75 micromole per liter (μmol/L), high: >110 μmol/L, female, Low: <65 μmol/L, high: >95, Blood Urea Nitrogen (BUN), high: >1.5xULN mmol/L, Uric Acid, in male, Low: < 180 μmol/L, high: > 480 μmol/L, female, Low: < 120 μmol/L, high: > 420. Only parameters with PCI values are reported.