Efficacy and Safety Study of GSK679586 in Patients With Severe Asthma

The ACQ-7 consists of 7 questions scored between zero (no impairment/ limitation) to 6 (total impairment/ limitation). The values of Week 1 is considered as Baseline. ACQ-7 was calculated as the average of the 7 scores. If any one individual score was missing, the ACQ-7 was set to missing.The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well.

The ACQ-7 is a 7-item questionnaire that provides a measure of a participant's asthma control. Participant responses were recorded on a 7-point scale ranging from zero (no impairment/ limitation) to 6 (total impairment/ limitation). The values of Week 1 is considered as Baseline. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. Change from Baseline of Week 16 and Week 24 are incorporated here which are Follow up weeks.

The ACQ-7 is a 7-item questionnaire that provides a measure of a participant's asthma control. Participant responses were recorded on a 7-point scale ranging from zero (no impairment/ limitation) to 6 (total impairment/ limitation). The percentage of participants who were classified as responders for ACQ-7, defined as a clinically meaningful decrease from baseline in ACQ-7 of at least 0.50, was generally similar between treatment groups at each visit and over the 12-week treatment period.

FEV1 is forced expiratory volume in 1 second.Change from Baseline FEV1 was calculated for each of the following visit: Visit 6, Visit 7, Visit 9 and Visit 11. A binary variable was created for each participant with 1 for the responder and 0 for the non nonresponder at each visit. Week 1 was considered as the Baseline. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well.

FEV1 is forced expiratory volume in 1 second.Change from Baseline FEV1 was calculated for each of the following visit: Visit 6, Visit 7, Visit 9 and Visit 11. A binary variable was created for each participant with 1 for the responder and 0 for the non nonresponder at each visit. Week 1 was considered as the Baseline. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. Change from Baseline of Week 16 and Week 24 are incorporated here which are Follow up weeks.

FEV1 is forced expiratory volume in 1 second.A participant is defined as a FEV1 responder if he/she achieves a change from baseline FEV1 of >=200ml. To evaluate whether the participant was a responder over 12 weeks, change from baseline FEV1 over 12 weeks was calculated by taking the mean of the changes at Visit 7, Visit 9 and Visit 11. A binary variable was created for each participant with 1 for the responder and 0 for the non-responder. If either Visit 9 or Visit 11 FEV1 data are missing, then the binary variable for the responder over 12 weeks was set to be missing. If Visit 7 data were missing, but Visit 9 and Visit 11 data were available, then the binary variable for the responder over 12 weeks was still calculated.

An AE is any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is 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.

Vital signs including systolic and diastolic blood pressure and heart rate taken at certain visits from screening to follow-up. Potential Clinical Importance Ranges were systolic blood pressure (<85 and >160millimeter of mercury [mmHg]), diastolic blood pressure (<45 and >100 mmHg) and heart rate (<40 and >110 beats per minute [BPM]). Number of participants with abnormal systolic blood pressure, diastolic blood pressure and heart rate values of potential clinical importance were summarized.

Single 12-lead ECGs were obtained at certain visits from screening to follow-up. ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals. Number of participants with clinically significant abnormality in 12-lead ECG readings were summarized.

Blood samples were collected on each visit from Week 1 to Week 25 to assess the haematological parameters. White Blood Cells count, Neutrophils, Haemoglobin, Hematocrit, Count and Lymphocytes were analyzed in haematology. Number of participants with any abnormal hematological parameters of potential clinical importance are summarized here.

Blood samples were collected on each visit from Week 1 to Week 25 to assess the clinical chemistry parameters. Albumin, Calcium, Glucose, Pottasium, Sodium and Total Carbon Di-oxide were analyzed in clinical chemistry. Number of participants with any abnormal clinical chemistry parameters of potential clinical importance are summarized here.

Samples were collected on each visit from Week 1 to Week 25 for urinalysis. Number of participants with any abnormal urinalysis parameters of potential clinical importance are summarized here.

Plasma concentration-time data were well described by a 2-compartment model with first order elimination. Plasma concentrations of GSK679586 were determined at Day 1 (Pre-dose, 0.25h, 1.00h), Day 4 (72h), Day 29 (672 h), Day 57 (1344h), Day 61 (1440h), Day 85 (2016h), Day 141 (3360h), Day 169 (4032h) and Follow up visits. However, the derived PK parameters were determined only for the day of infusion administration. i.e. Day 1, Day 29 and Day 57. The AUC at Day 1 indicates AUC(0-1 h), Day 29 indicated AUC(0-672 h) and Day 57 indicated AUC(0-1344h). AUC(0-τ) for each participant was reconstructed from sparse PK sampling using Bayesian prediction obtained from a population PK model using nonlinear mixed effects methods (NONMEM, version V).

Plasma concentration-time data were well described by a 2-compartment model with first order elimination. Plasma concentrations of GSK679586 were determined at Day 1 (Pre-dose, 0.25h, 1.00h), Day 4 (72h), Day 29 (672h), Day 57 (1344h), Day 61 (1440h), Day 85 (2016h), Day 141 (3360h), Day 169 (4032h) and Follow up visits. However, Cmax were determined only for the day of infusion administration. i.e. Day 1, Day 29 and Day 57. The Cmax at Day 1 indicates Cmax(0-1 h), Day 29 indicated Cmax(0-672 h) and Day 57 indicated Cmax(0-1344 h). Cmax for each participant was reconstructed from sparse PK sampling using Bayesian prediction obtained from a population PK model using nonlinear mixed effects methods (NONMEM, version V).

Plasma concentration-time data were well described by a 2-compartment model with first order elimination. Plasma concentrations of GSK679586 were determined at Day 1 (Pre-dose, 0.25h, 1.00h), Day 4 (72h), Day 29 (672h), Day 57 (1344h), Day 61 (1440h), Day 85 (2016h), Day 141 (3360h), Day 169 (4032h) and Follow up visits. However, systemic clearance were determined only for the day of infusion administration. i.e. Day 1, Day 29 and Day 57. The systemic clearance at Day 1 indicates systemic clearance(0-1 h), Day 29 indicated systemic clearance(0-672 h) and Day 57 indicated systemic clearance(0-1344 h). Systemic clearance of parent drug for each participant was reconstructed from sparse PK sampling using Bayesian prediction obtained from a population PK model using nonlinear mixed effects methods (NONMEM, version V).

Plasma concentration-time data were well described by a 2-compartment model with first order elimination. Plasma concentrations of GSK679586 were determined at Day 1 (Pre-dose, 0.25h, 1.00h), Day 4 (72h), Day 29 (672 h), Day 57 (1344h), Day 61 (1440h), Day 85 (2016h), Day 141 (3360h), Day 169 (4032h) and Follow up visits. However, volume of distribution were determined only for the day of infusion administration. i.e. Day 1, Day 29 and Day 57. The volume of distribution at Day 1 indicates volume of distribution(0-1 h), Day 29 indicated volume of distribution (0-672 h) and Day 57 indicated volume of distribution (0-1344 h). Volume of distribution for each participant was reconstructed from sparse PK sampling using Bayesian prediction obtained from a population PK model using nonlinear mixed effects methods (NONMEM, version V). The 2-compartment model provided the data for volume of distribution of central compartment (V1) and volume distribution of peripheral compartment (V2).

Serum samples were tested for presence of anti-GSK679586 antibodies. Blood samples were collected via an indwelling cannula or by direct venepuncture collected into a serum separator tube and allowed to clot for 1 to 2 hours. Samples were centrifuged and the resultant serum was transferred to 3 separate cryovials and stored at -80°C until shipped on dry ice to the central laboratory. Samples were analyzed in a tiered assay format. Number of participants with confirmed positive Anti-GSK679586 antibody results after initiation of study treatment were reported.