A 2 Part Study Examining Doses Of GSK961081 In Healthy Volunteers And Then In COPD Patients

NCT00478738 | Completed Phase 2

• 1 other identifier: MAB104958
• Study Type: interventional
• Target: 82
• Locations: 2 countries
• Sites: 5

Brief Summary

GSK961081 has previously been administered to healthy subjects in a nebulised formulation and the first part of this study which will be conducted in healthy subjects proposes to bridge the change from nebulised to DPI formulation of GSK961081 before administration to patients. The second part of the study will be conducted in COPD patients and aims to assess the safety and bronchodilator profile of GSK961081 over 24 hours, during 14 days dosing.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

b-agonist,; COPD.; pharmacodynamic,; pharmacokinetic,; anti muscarinic,

Outcome Measures

Primary Outcomes (4)

• Part 1: Summary of area under the GSK961081 concentration-time curve (AUC) after a single dose

  Plasma samples for PK analysis were drawn on Day (D) 1 at indicated time points. The AUC from time zero (0M) to 2h (AUC 0-2) was area under the plasma concentration-time curve over the 2h time period. AUC(0-6) was area under the plasma concentration-time curve from 0M to 6h. AUC(0-t) was area under the plasma concentration-time curve from 0M to last quantifiable concentration. The AUC extrapolated to infinity (inf) (AUC\[0-inf\]) was calculated as the sum of AUC(0-t) and Ct/lambda z, where Ct is the observed GSK961081 concentration obtained from the log-linear regression analysis of the last quantifiable time-point and lambda z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. The number of time points used in the estimation of lambda z. Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the PK population.

  Pre-dose (0.0 hour [h]) and 15, 30, 45 minutes (M), 1, 2, 3, 4, 6, 8, 12 and 24 h post dose of each treatment period

• Part 1: Summary of maximum observed concentration (Cmax) of GSK961081 after a single dose

  Plasma samples for PK analysis were drawn on D1 at indicated time points. The first occurrence of the maximum observed GSK961081 concentration determined directly from the raw concentration-time data after each single dose. All participants were present at the time of measurement.

  Pre-dose (0.0h) and 15, 30, 45 M, 1, 2, 3, 4, 6, 8, 12 and 24 h post dose of each treatment period

• Part 1: Summary of last observed plasma concentration (t-last), time of maximum observed concentration (t-max) and terminal elimination half-life (t-half)

  Plasma samples for PK analysis were drawn on D1 at indicated time points. The t-last and t-max was determined directly from the raw concentration-time data after each single dose. The t-half was obtained as the ratio of ln2/lambda z, where ln(2) is the natural logarithm of 2 (approximately 0.693) and lambda z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data after each single dose. Data for adjusted mean is presented as least square mean. Only those participants available at the specified time points were analyzed (represented by n=x,x,x in the category titles). Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the All Subjects population.

  Pre-dose (0.0h) and 15, 30, 45 M, 1, 2, 3, 4, 6, 8, 12 and 24 h post dose of each treatment period

• Part 2: Forced Expiratory Volume in 1 second (FEV1) over 24 hours post-dose on D1 and 14

  Lung function tests (FEV1) was recorded whilst the participant was in a sitting position (if taken whilst the participant was on the bed, their legs should be over the edge). All lung function tests was repeated, until three technically acceptable measurements were made. Each measurement should be done at least 1 M apart. Participants must be resting in the body box for at least 30 seconds prior to any assessments. The FEV1 was measured at 15, 30 M, 1, 4, 12 and 24 h post dose of each treatment period on D1 and 14. Data for adjusted mean is presented as least square mean. Only those participants available at the specified time points were analyzed (represented by n=x,x,x,x in the category titles). Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the All Subjects population. Data for adjusted mean is presented as least square mean.

  Up to D14 of each treatment period (up to 16 weeks)

Secondary Outcomes (58)

• Part 1: Number of participants with Adverse Events (AE) and Serious adverse events (SAE)

  Up to 16 weeks

• Part 1: Mean values for urea, sodium, potassium, cholesterol, chloride, high density lipids-cholesterol (HDLC), and triglyceride

  Up to D1 of each treatment period (up to 16 weeks)

• Part 1: Mean values for creatinine and total bilirubin

  Up to D1of each treatment period (up to 16 weeks)

• Part 1: Mean values for total protein and albumin

  Up to D1of each treatment period (up to 16 weeks)

• Part 1: Mean values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine kinase and gamma glutamyl transferase (GGT). All participants were present at the time of measurement.

  Up to D1of each treatment period (up to 16 weeks)

Study Arms (1)

GSK961081

OTHER

GSK961081

Drug: GSK961081

Interventions

GSK961081 DRUG

GSK961081

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject is male or female (of non-child bearing potential) \> 40 years of age and \< 75 years of age.
• Non- child bearing potential is defined as physiologically incapable of becoming pregnant, including females who are post menopausal ( more than 2 years without menses with appropriate clinical history ie age, history of vasomotor symptoms-estradiol and FSH levels may be checked if indicated) and females who are surgically sterile (hysterectomy, tubal ligation or bilateral oophorectomy.
• Subject diagnosed with COPD (stage II) in accordance with ATS/ERS guidelines (see Appendix 2: COPD Guidelines).
• Subject is a smoker or an ex smoker with a history of at least 10 pack years (1 pack year= 20 cigarettes smoked per day for 1 year or equivalent)
• Subject has FEV1/FVC \< 0.7 post - bronchodilator (salbutamol)
• Subject has FEV1 \< 80 % of predicted normal for height, age, gender after inhalation of salbutamol
• Response to ipratropium bromide defined as:
• Either an increase in FEV1 of \> 12 % and \> 150 mLwithin 2 hour following inhalation of 80 µcg ipratropium bromide at the screening visit Or: a documented increase in FEV1 of \>12 % and \> 150 mL within 2 hour following inhalation of 80 µcg ipratropium bromide within 6 months of screening and an increase in FEV1 of \> 6 % and \> 100 mL within 2 h following inhalation of 80 mg ipratropium bromide at the screening visit (in order to allow for potential fluctuations in the response to ipratropium bromide in patients known to be responders to ipratropium bromide)
• Response to salbutamol defined as:
• Either an increase in FEV1 of \> 12 % and \> 150 mL within 2 hour following inhalation of 400 mg salbutamol at the screening visit Or: a documented increase in FEV1 of \>12 % and \> 150 mL within 2 hour following inhalation of 400 mg salbutamol within 6 months of screening and an increase in FEV1 of \> 6 % and \>100 mL within 2 h following inhalation of 400 mg salbutamol at the screening visit (in order to allow for potential fluctuations in the response to salbutamol in patients known to be responders to salbutamol)
• Body mass index within the range 18-35 kilograms/metre² (kg/m²).
• Subject is able and willing to give written informed consent to take part in the study.
• Subject is available to complete all study measurements

You may not qualify if:

• Subjects who have a past or present disease, which as judged by the Investigator and medical monitor may affect the outcome of the study or the safety of the subject
• Women who are pregnant or lactating
• An unwillingness of subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as IUD, diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants or tubal ligation if the woman could become pregnant from the time of the first dose study medication until 90 days post-dose
• The subject has a positive urine drug screen. A minimum list of drugs that will be screened for include Amphetamines, barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.
• The subject has a positive alcohol test (breath or urine) predose.
• A history, or suspected history, of alcohol abuse within the 6 months before the screening visit.
• A positive test for hepatitis C antibody, hepatitis B surface antigen, or HIV.
• The subject has participated in a clinical study with another New Chemical Entity within the past 2 months or a participated in a clinical study with any other drug during the previous month.
• The subject has donated a unit of blood within the 56 days or intends to donate within 56 days after completing the study.
• The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet.
• Subject has an FEV1 \< 50 % of predicted for age, height and gender after inhalation of salbutamol.
• The subject has a diagnosis of active tuberculosis, lung cancer, sarcoidosis, bronchiectasis, lung fibrosis, pulmonary hypertension or with a primary diagnosis of asthma
• The subject has a known allergy or hypersensitivity to ipratropium, salbutamol, tiotropium, salmeterol or lactose
• A subject in whom ipratropium, salbutamol, tiotropium and/or salmeterol is contraindicated
• Subjects with lung volume reduction surgery within 12 months of screening

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (5)

GSK Investigational Site

Mainz, Rhineland-Palatinate, 55131, Germany

Location

GSK Investigational Site

Berlin, State of Berlin, 14050, Germany

Location

GSK Investigational Site

Bloemfontein, 9301, South Africa

Location

GSK Investigational Site

George, 6530, South Africa

Location

GSK Investigational Site

Mowbray, 7700, South Africa

Location

Related Publications (1)

• Bateman ED, Kornmann O, Ambery C, Norris V. Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther. 2013 Oct;26(5):581-7. doi: 10.1016/j.pupt.2013.03.015. Epub 2013 Mar 26.

  PMID: 23538170 BACKGROUND

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

batefenterol

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2007
• First Posted: May 25, 2007
• Study Start: June 1, 2007
• Primary Completion: May 1, 2008
• Study Completion: May 1, 2008
• Last Updated: February 2, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will share

Locations

ZA (3); DE (2)