Trial Outcomes & Findings for Efficacy and Safety Study of GSK679586 in Patients With Severe Asthma (NCT NCT00843193)

NCT ID: NCT00843193

Last Updated: 2017-12-12

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 198 participants
• Primary outcome timeframe: Baseline to Week 12
• Results posted on: 2017-12-12

Participant Flow

The study was conducted in participants with severe asthmatics from 9-Dec-2008 to 19-July-2010 at 35 study centers in France (7), United States (6), United Kingdom (5), Poland (5), South Africa (4), Germany (3), Netherlands (3) and Norway (2).

During run-in period of 28 days each participant's inhaled corticosteroid (ICS) dose was up-titrated to 1000 microgram (μg)/day fluticasone propionate. Participants already taking ≥ 1000 µg/day fluticasone propionate or equivalent prior to study remained on their pre-study dose. Total of 198 participants were randomized and treated in the study.

Participant milestones

Measure	Placebo Participants received a total of three once-monthly intravenous (IV) infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10mg (Milligram)/kg(Kilogram) Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/ milliliter (mL). The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Overall Study STARTED	99	99
Overall Study COMPLETED	91	88
Overall Study NOT COMPLETED	8	11

Reasons for withdrawal

Measure	Placebo Participants received a total of three once-monthly intravenous (IV) infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10mg (Milligram)/kg(Kilogram) Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/ milliliter (mL). The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Overall Study Adverse Event	2	4
Overall Study Lack of Efficacy	1	1
Overall Study Protocol Violation	1	2
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	0	1
Overall Study Withdrawal by Subject	3	3

Baseline Characteristics

Efficacy and Safety Study of GSK679586 in Patients With Severe Asthma

Baseline characteristics by cohort

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	Total n=198 Participants Total of all reporting groups
Age, Continuous	51.2 Years STANDARD_DEVIATION 11.78 • n=5 Participants	51.2 Years STANDARD_DEVIATION 11.13 • n=7 Participants	51.2 Years STANDARD_DEVIATION 11.43 • n=5 Participants
Sex: Female, Male Female	49 Participants n=5 Participants	51 Participants n=7 Participants	100 Participants n=5 Participants
Sex: Female, Male Male	50 Participants n=5 Participants	48 Participants n=7 Participants	98 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Japanese/East Asian/South East Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	95 Participants n=5 Participants	96 Participants n=7 Participants	191 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 12

Population: Intent-to-Treat (ITT) population was comprised of all participants who are randomized and receive at least the first dose of study medication. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Change From Baseline in Asthma Control Questionnaire (ACQ-7) Over 12 Weeks Week 2	-0.1 Scores on Scale Standard Error 0.06	-0.2 Scores on Scale Standard Error 0.06
Change From Baseline in Asthma Control Questionnaire (ACQ-7) Over 12 Weeks Week 4	-0.1 Scores on Scale Standard Error 0.06	-0.3 Scores on Scale Standard Error 0.05
Change From Baseline in Asthma Control Questionnaire (ACQ-7) Over 12 Weeks Week 8	-0.2 Scores on Scale Standard Error 0.07	-0.3 Scores on Scale Standard Error 0.07
Change From Baseline in Asthma Control Questionnaire (ACQ-7) Over 12 Weeks Week 12	-0.3 Scores on Scale Standard Error 0.08	-0.4 Scores on Scale Standard Error 0.09

SECONDARY outcome

Timeframe: Week 16 and Week 24

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Change From Baseline in ACQ-7 Over 16 Weeks and 24 Weeks Week 16	-0.3 Scores on Scale Standard Error 0.08	-0.4 Scores on Scale Standard Error 0.08
Change From Baseline in ACQ-7 Over 16 Weeks and 24 Weeks Week 24	-0.3 Scores on Scale Standard Error 0.09	-0.2 Scores on Scale Standard Error 0.08

SECONDARY outcome

Timeframe: Upto 12 weeks

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants Who Demonstrated a Clinically Meaningful Change in ACQ-7 Over the 12 Weeks Assessment Period. Week 2	16 Participants	20 Participants
Number of Participants Who Demonstrated a Clinically Meaningful Change in ACQ-7 Over the 12 Weeks Assessment Period. Week 4	22 Participants	29 Participants
Number of Participants Who Demonstrated a Clinically Meaningful Change in ACQ-7 Over the 12 Weeks Assessment Period. Week 8	31 Participants	26 Participants
Number of Participants Who Demonstrated a Clinically Meaningful Change in ACQ-7 Over the 12 Weeks Assessment Period. Week 12	33 Participants	36 Participants

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Change From Baseline in Forced Expiratory Volume (FEV1) Over 12 Weeks. Week 2	0.009 Millilitre (mL) Standard Error 0.0275	0.002 Millilitre (mL) Standard Error 0.0277
Change From Baseline in Forced Expiratory Volume (FEV1) Over 12 Weeks. Week 4	0.033 Millilitre (mL) Standard Error 0.0331	0.037 Millilitre (mL) Standard Error 0.0288
Change From Baseline in Forced Expiratory Volume (FEV1) Over 12 Weeks. Week 8	0.035 Millilitre (mL) Standard Error 0.0335	-0.009 Millilitre (mL) Standard Error 0.0313
Change From Baseline in Forced Expiratory Volume (FEV1) Over 12 Weeks. Week 12	0.078 Millilitre (mL) Standard Error 0.0331	-0.016 Millilitre (mL) Standard Error 0.0373

SECONDARY outcome

Timeframe: Week 16 and 24

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Change From Baseline in FEV1 Over 16 Weeks and 24 Weeks Week 24	0.065 mL Standard Error 0.0356	-0.021 mL Standard Error 0.0368
Change From Baseline in FEV1 Over 16 Weeks and 24 Weeks Week 16	0.109 mL Standard Error 0.0345	0.010 mL Standard Error 0.0392

SECONDARY outcome

Timeframe: Upto 12 weeks

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Percentage of Participants Who Demonstrated a Clinically Meaningful Increase in FEV1 Over the 12 Week Assessment Period Week 8	25 Percentage of Participants	15 Percentage of Participants
Percentage of Participants Who Demonstrated a Clinically Meaningful Increase in FEV1 Over the 12 Week Assessment Period Week 2	16 Percentage of Participants	20 Percentage of Participants
Percentage of Participants Who Demonstrated a Clinically Meaningful Increase in FEV1 Over the 12 Week Assessment Period Week 4	22 Percentage of Participants	23 Percentage of Participants
Percentage of Participants Who Demonstrated a Clinically Meaningful Increase in FEV1 Over the 12 Week Assessment Period Week 12	34 Percentage of Participants	20 Percentage of Participants

SECONDARY outcome

Timeframe: Up to Week 25

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AEs	49 Participants	52 Participants
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Any SAEs	5 Participants	8 Participants

SECONDARY outcome

Timeframe: Screening, Day -28, 1, 15, 29, 50, 57 and 169 (follow-up 3)

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Abnormal Vital Signs of Potential Clinical Importance: Systolic and Distolic Blood Pressure and Heart Rate. Systolic Blood Pressure, High	6 Participants	6 Participants
Number of Participants With Abnormal Vital Signs of Potential Clinical Importance: Systolic and Distolic Blood Pressure and Heart Rate. Diastolic Blood Pressure, High	8 Participants	4 Participants
Number of Participants With Abnormal Vital Signs of Potential Clinical Importance: Systolic and Distolic Blood Pressure and Heart Rate. Heart Rate	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Upto Week 25

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Clinically Significant Abnormality in 12-lead Electrocardiogram (ECG) Day 29, 1.5 hours	0 Participants	1 Participants
Number of Participants With Clinically Significant Abnormality in 12-lead Electrocardiogram (ECG) Day 29, 6 hours	0 Participants	1 Participants
Number of Participants With Clinically Significant Abnormality in 12-lead Electrocardiogram (ECG) Day 50	0 Participants	2 Participants

SECONDARY outcome

Timeframe: Upto Week 25

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Abnormal Hematological Parameters of Potential Clinical Importance Low neutrophils count	3 Participants	4 Participants
Number of Participants With Abnormal Hematological Parameters of Potential Clinical Importance Low platelet count	1 Participants	1 Participants
Number of Participants With Abnormal Hematological Parameters of Potential Clinical Importance Low lymphocyte count	5 Participants	3 Participants
Number of Participants With Abnormal Hematological Parameters of Potential Clinical Importance Increased white blood cell count	3 Participants	1 Participants

SECONDARY outcome

Timeframe: Upto Week 25

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance High glucose	10 Participants	17 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Increased AST	1 Participants	2 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Low total carbondioxide	14 Participants	17 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Low glucose	4 Participants	3 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Increased total bilirubin	2 Participants	2 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Increased ALT	2 Participants	1 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Increased alkaline phosphatase	1 Participants	0 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Increased serum potassium	0 Participants	2 Participants
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance Increased serum calcium	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Upto Week 25

Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Abnormal Urinanalysis Parameters of Potential Clinical Importance	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

Population: PK Population comprised of participants in the ITT population for whom a pharmacokinetic samples were obtained and analyzed. Only those participants with data available at the indicated time points were analyzed.

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).

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over the Dosing Interval (AUC (0-τ)). Day 1	64787259 nanogram*hour/mL Geometric Coefficient of Variation 16.16	—
Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over the Dosing Interval (AUC (0-τ)). Day 29	86256087 nanogram*hour/mL Geometric Coefficient of Variation 18.21	—
Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over the Dosing Interval (AUC (0-τ)). Day 57	93710588 nanogram*hour/mL Geometric Coefficient of Variation 22.83	—

SECONDARY outcome

Timeframe: 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.

Population: PK Population. Only those participants with data available at the indicated time points were analyzed.

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).

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
PK Parameter:Maximum Observed Concentration (Cmax) Day 29	332528.4 nanogram (ng)/mL Geometric Coefficient of Variation 30.85	—
PK Parameter:Maximum Observed Concentration (Cmax) Day 1	278610.6 nanogram (ng)/mL Geometric Coefficient of Variation 33.40	—
PK Parameter:Maximum Observed Concentration (Cmax) Day 57	355177.0 nanogram (ng)/mL Geometric Coefficient of Variation 30.31	—

SECONDARY outcome

Timeframe: 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.

Population: PK Population. Only those participants with data available at the indicated time points were analyzed.

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).

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
PK Parameter: Systemic Clearance of Parent Drug Day 1	0.00010 L/h/kg Geometric Coefficient of Variation 22.76	—
PK Parameter: Systemic Clearance of Parent Drug Day 29	0.00010 L/h/kg Geometric Coefficient of Variation 22.28	—
PK Parameter: Systemic Clearance of Parent Drug Day 57	0.00010 L/h/kg Geometric Coefficient of Variation 22.48	—

SECONDARY outcome

Timeframe: 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.

Population: PK Population. Only those participants with data available at the indicated time points were analyzed.

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).

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
PK Parameter: Volume of Distribution V1, Day 29	0.0355 L/Kg Geometric Coefficient of Variation 34.43	—
PK Parameter: Volume of Distribution V1, Day 1	0.0356 L/Kg Geometric Coefficient of Variation 33.73	—
PK Parameter: Volume of Distribution V1, Day 57	0.0354 L/Kg Geometric Coefficient of Variation 34.77	—
PK Parameter: Volume of Distribution V2, Day 1	0.0296 L/Kg Geometric Coefficient of Variation 0.00	—
PK Parameter: Volume of Distribution V2, Day 29	0.0296 L/Kg Geometric Coefficient of Variation 0.00	—
PK Parameter: Volume of Distribution V2, Day 57	0.0296 L/Kg Geometric Coefficient of Variation 0.00	—

SECONDARY outcome

Timeframe: Up to Week 25

Population: ITT Population.

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.

Outcome measures

Measure	Placebo n=99 Participants Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 Participants Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Number of Participants With Confirmed Positive Anti-GSK679586 Antibody Results After Initiation of Study Treatment	4 Participants	2 Participants

Adverse Events

Placebo

Serious events: 5 serious events

Other events: 19 other events

Deaths: 0 deaths

GSK679586 10 mg/kg

Serious events: 8 serious events

Other events: 27 other events

Deaths: 1 deaths

Serious adverse events

Measure	Placebo n=99 participants at risk Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 participants at risk Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Cardiac disorders Myocardial infarction	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Cardiac disorders Supraventricular extrasystoles	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Respiratory, thoracic and mediastinal disorders Asthma	2.0% 2/99 • Number of events 2 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Injury, poisoning and procedural complications Fall	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Injury, poisoning and procedural complications Rib fracture	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Injury, poisoning and procedural complications Wrist fracture	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	2.0% 2/99 • Number of events 2 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Nervous system disorders Lethargy	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Infections and infestations bronchitis	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Hepatobiliary disorders Cholesystitis	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Injury, poisoning and procedural complications Narcotic intoxication	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Vascular disorders Hypertension	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Gastrointestinal disorders Rectal haemorrhage/	0.00% 0/99 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	1.0% 1/99 • Number of events 1 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population

Other adverse events

Measure	Placebo n=99 participants at risk Participants received a total of three once-monthly IV infusions of sodium chloride placebo in a volume matched to the volume that would had been administered if the participant had been randomized to active treatment in order to maintain the integrity of the study blind. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.	GSK679586 10 mg/kg n=99 participants at risk Participants received a total of 3 once-monthly IV infusions of 10 mg/kg GSK679586 diluted with sterile, normal saline to a concentration of 25 mg/mL. The final solution volume was 40 to 60 mL, depending on participants weight. The IV infusions were administered by qualified study personnel, and were administered over 1 hour using a programmable infusion pump.
Infections and infestations Nasopharyngitis	5.1% 5/99 • Number of events 5 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	10.1% 10/99 • Number of events 11 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Infections and infestations Upper respiratory tract infection	6.1% 6/99 • Number of events 6 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	4.0% 4/99 • Number of events 5 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Infections and infestations Pharyngitis	2.0% 2/99 • Number of events 2 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	5.1% 5/99 • Number of events 5 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population
Nervous system disorders Headache	6.1% 6/99 • Number of events 7 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population	13.1% 13/99 • Number of events 22 • All SAEs and Non-SAE were collected from Screening (Week -8) to Follow-up Visit 3 (Week 25). SAEs were reported on ITT population

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER