Efficacy and Safety Study of GSK679586 in Patients With Severe Asthma

A Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose Study to Evaluate the Efficacy and Safety of Intravenous GSK679586 in Patients With Severe Asthma

Treatment, Randomised, Double Blind, Parallel Assignment, Safety/efficacy Study

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: INTRAVENOUS GSK679586; Drug: FLUTICASONE PROPIONATE; Drug: INTRAVENOUS PLACEBO

Detailed Description

A Multi-Centre, Multi-country, Randomized, Double-Blind (Subject, Investigator), Placebo-Controlled, Repeat-Dose study to evaluate the Efficacy and Safety of Intravenous GSK679586 in Patients with Severe Asthma

• Study Type: Interventional
• Enrollment (Actual): 198
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lille, France, 59037 cedex
    • GSK Investigational Site
  • Marseille, France, 13009
    • GSK Investigational Site
  • Montpellier, France, 34295
    • GSK Investigational Site
  • Nantes, France, 44093
    • GSK Investigational Site
  • Saint Pierre Cedex, France, 97448
    • GSK Investigational Site
  • Strasbourg, France, 67091
    • GSK Investigational Site
  • Tarbes Cedex 09, France, 65013
    • GSK Investigational Site
• Germany
  • Hessen
    • Frankfurt, Hessen, Germany, 60596
      • GSK Investigational Site
    • Gelnhausen, Hessen, Germany, 63571
      • GSK Investigational Site
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany, 39112
      • GSK Investigational Site
• Netherlands
  • Eindhoven, Netherlands, 5623 EJ
    • GSK Investigational Site
  • Heerlen, Netherlands, 6419 PC
    • GSK Investigational Site
  • Hoorn, Netherlands, 1624 NP
    • GSK Investigational Site
• Norway
  • Elverum, Norway, 2408
    • GSK Investigational Site
  • Trondheim, Norway, 7006
    • GSK Investigational Site
• Poland
  • Bialystok, Poland, 15-276
    • GSK Investigational Site
  • Gidle, Poland, 97-540
    • GSK Investigational Site
  • Krakow, Poland, 31-023
    • GSK Investigational Site
  • Lodz, Poland, 90-153
    • GSK Investigational Site
  • Warszawa, Poland, 02-097
    • GSK Investigational Site
• South Africa
  • Bellville, South Africa, 7530
    • GSK Investigational Site
  • Bloemfontein, South Africa, 9301
    • GSK Investigational Site
  • Mowbray, South Africa, 7700
    • GSK Investigational Site
  • Gauteng
    • Cape Town, Gauteng, South Africa, 7505
      • GSK Investigational Site
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • GSK Investigational Site
  • London, United Kingdom, SE1 1YR
    • GSK Investigational Site
  • Nottingham, United Kingdom, NG5 1PB
    • GSK Investigational Site
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • GSK Investigational Site
  • Surrey
    • Guildford, Surrey, United Kingdom, GU2 7XP
      • GSK Investigational Site
• United States
  • Oregon
    • Medford, Oregon, United States, 97504
      • GSK Investigational Site
    • Portland, Oregon, United States, 97213
      • GSK Investigational Site
  • Pennsylvania
    • Pittsburg, Pennsylvania, United States, PA 15213
      • GSK Investigational Site
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • GSK Investigational Site
  • Texas
    • Boerne, Texas, United States, 78006
      • GSK Investigational Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• history of asthma for ≥ 6 months
• taking inhaled corticosteroids
• non-smoking
• Baseline (pre-bronchodilator) FEV1 35-80% predicted at screening.
• Reversible airways disease as indicated by an increase of FEV1 ≥12% from baseline after nebulised salbutamol or albuterol.
• symptomatic according to the ACQ-7

Exclusion Criteria:

• Unstable severe asthma
• Recent respiratory illness
• Presence of other respiratory disease or chronic pulmonary condition other than asthma
• Treatment with omalizumab within 4 months of study
• Recent gastrointestinal or respiratory parasitic infestation
• History of severe allergy to food or drugs

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GSK679586; Subjects will receive three, once monthly intravenous administration of 10 mg/kg of GSK679586, according to randomization	Drug: INTRAVENOUS GSK679586; GSK679586 will be provided as a clear or colorless to pale yellow liquid with the unit dose strength of 10mg/kg and will be infused over an hour. The infusion will be delivered by a programmable infusion pump; Drug: FLUTICASONE PROPIONATE; Subjects will be supplied fluticasone propionate at Screening, Run-in and when needed during the study. Subjects will be up-titrated to 1000 μg/day and those who were already taking greater than equal to 1000 μg/day fluticasone propionate or equivalent prior to the study will remain on their pre-study dose.
Placebo Comparator: PLACEBO; Subjects will receive three, once monthly intravenous administration of saline, according to randomization	Drug: FLUTICASONE PROPIONATE; Subjects will be supplied fluticasone propionate at Screening, Run-in and when needed during the study. Subjects will be up-titrated to 1000 μg/day and those who were already taking greater than equal to 1000 μg/day fluticasone propionate or equivalent prior to the study will remain on their pre-study dose.; Drug: INTRAVENOUS PLACEBO; Clear or colorless 0.9% sodium chloride saline solution will be infused over an hour. The infusion will be delivered by a programmable infusion pump

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Asthma Control Questionnaire (ACQ-7) Over 12 Weeks	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.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in ACQ-7 Over 16 Weeks and 24 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 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.	Week 16 and Week 24
Number of Participants Who Demonstrated a Clinically Meaningful Change in ACQ-7 Over the 12 Weeks Assessment Period.	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.	Upto 12 weeks
Change From Baseline in Forced Expiratory Volume (FEV1) Over 12 Weeks.	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.	Baseline to Week 12
Change From Baseline in FEV1 Over 16 Weeks and 24 Weeks	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.	Week 16 and 24
Percentage of Participants Who Demonstrated a Clinically Meaningful Increase in FEV1 Over the 12 Week Assessment Period	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.	Upto 12 weeks
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Up to Week 25
Number of Participants With Abnormal Vital Signs of Potential Clinical Importance: Systolic and Distolic Blood Pressure and Heart Rate.	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.	Screening, Day -28, 1, 15, 29, 50, 57 and 169 (follow-up 3)
Number of Participants With Clinically Significant Abnormality in 12-lead Electrocardiogram (ECG)	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.	Upto Week 25
Number of Participants With Abnormal Hematological Parameters of Potential Clinical Importance	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.	Upto Week 25
Number of Participants With Abnormal Clinical Chemistry Parameters of Potential Clinical Importance	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.	Upto Week 25
Number of Participants With Abnormal Urinanalysis Parameters of Potential Clinical Importance	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.	Upto Week 25
Pharmacokinetic (PK) Parameter: Area Under the Concentration-time Curve Over the Dosing Interval (AUC (0-τ)).	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).	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.
PK Parameter:Maximum Observed Concentration (Cmax)	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).	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.
PK Parameter: Systemic Clearance of Parent Drug	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).	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.
PK Parameter: Volume of Distribution	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).	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.
Number of Participants With Confirmed Positive Anti-GSK679586 Antibody Results After Initiation of Study Treatment	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.	Up to Week 25

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Anderson WH, Koshy BT, Huang L, Mosteller M, Stinnett SW, Condreay LD, Ortega H. Genetic analysis of asthma exacerbations. Ann Allergy Asthma Immunol. 2013 Jun;110(6):416-422.e2. doi: 10.1016/j.anai.2013.04.002.

Helpful Links

• Ginasthma.com is a website of the Global Initiative for Asthma. This study uses the GINA guidance, 2007 for diagnosis asthma patients who are eligible for entry this study.

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2008
• Primary Completion (Actual): July 25, 2010
• Study Completion (Actual): July 25, 2010

Study Registration Dates

• First Submitted: February 5, 2009
• First Submitted That Met QC Criteria: February 12, 2009
• First Posted (Estimate): February 13, 2009

Study Record Updates

• Last Update Posted (Actual): December 12, 2017
• Last Update Submitted That Met QC Criteria: November 13, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Asthma; Asthma control questionnaire
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Fluticasone; Xhance
• Other Study ID Numbers: 106870

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Study Protocol
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Annotated Case Report Form
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Clinical Study Report
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Dataset Specification
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Individual Participant Data Set
   Information identifier: 106870
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register