Last updated: 11/04/2018 09:01:21

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

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GSK study ID

MAB104958

See study documents

Clinicaltrials.gov ID

NCT00478738

See results summary

EudraCT ID

2006-006240-63

EU CT Number

Not applicable

Trial status

Study complete

Overview

Eligibility

Locations

Study documents

Results summary

Plain language summaries

Additional information

Trial overview

Official title: A study to assess the pharmacokinetics of single escalating doses of inhaled GSK961081 DPI (a dual pharmacophore) in healthy subjects (Part 1) and a randomised, double-blind, double dummy, crossover (incomplete block) study to assess the safety, tolerability, pharmacodynamics (pulmonary and systemic) and pharmacokinetics of 14 days dosing with inhaled GSK961081 DPI compared with placebo and tiotropium plus salmeterol in patients with COPD (Part 2)

Trial description: 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.

Primary purpose:

Treatment

Trial design:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Allocation:

Randomized

Primary outcomes:

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

Timeframe: 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

Timeframe: 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)

Timeframe: 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

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

Secondary outcomes:

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

Timeframe: Up to 16 weeks

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

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

Part 1: Mean values for creatinine and total bilirubin

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

Part 1: Mean values for total protein and albumin

Timeframe: 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.

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

Part 1: Mean values for platelet and white blood cell (WBC)

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

Part 1: Mean values for hemoglobin and mean corpuscle hemoglobin concentration (MCHC)

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

Part 1: Mean values for hematocrit

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

Part 1: Mean values for mean corpuscle volume (MCV)

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

Part 1: Mean values for mean corpuscle hemoglobin (MCH)

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

Part 1: Mean values for reticulocytes, total neutrophil, lymphocyte, monocyte, eosinophil and basophil

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

Part 1: Mean values for red blood cells (RBC)

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

Part 1: Summary of Results of Statistical Serial Time point Analysis of FEV1 Data-Treatment Differences

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

Part 1: Change from Baseline derived Electrocardiogram (ECG) parameters- QT interval corrected according to Bazzet’s formula (QTcF) and QT interval corrected according to Fridericia’s formula (QTcB) Maximum value (0-4 h)

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

Part 1: Change from Baseline derived ECG parameters-QTc(F) and QTc(B) Weighted mean (0-4 h)-Part

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

Part 1: Mean supine systolic blood pressure (SBP) maximum value (0-4 h)

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

Part 1: Mean supine diastolic blood pressure (DBP) minimum value (0-4 h)

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

Part 1: Mean supine SBP and supine DBP Weighted mean (0-4 h)

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

Part 1: Change from Baseline supine heart rate maximum value (0-4 h)

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

Part 1: Change from Baseline supine heart rate Weighted mean (0-4 h)

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

Part 1: Maximum Change in Postural SBP and DBP (0-4h)

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

Part 1: Maximum change from Baseline value (0-4h) for glucose

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

Part 1: Minimum change from Baseline value (0-4h) for potassium

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

Part 1: Maximum change from Baseline value (0-4h) for potassium

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

Part 1: Weighted mean change from baseline (0-4h) for glucose and potassium

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

Part 1: Number of participants with abnormal Holter ECG findings as a function of cardiac monitoring

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

Part 1: Number of participants with abnormal Lead II ECG findings as a function of cardiac monitoring

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

Part 2: Number of participants with AE and SAE

Timeframe: Up to 16 weeks

Part 2: Mean values for urea, sodium, potassium, cholesterol, chloride, high density lipids-cholesterol (HDLC), and triglyceride

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

Part 2: Mean values for creatinine and total bilirubin

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

Part 2: Mean values for total protein and albumin

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

Part 2: Mean values for AST, ALT, ALP, creatine kinase and GGT

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

Part 2: Mean values for hemoglobin and MCHC

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

Part 2: Mean values for hematocrit

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

Part 2: Mean values for MCV

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

Part 2: Mean values for MCH

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

Part 2: Mean values for total neutrophil, lymphocyte, monocyte, eosinophil and basophil

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

Part 2: Mean values for platelets and WBC

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

Part 2: Mean values for RBC

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

Part 2: Mean values for reticulocytes

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

Part 2: Change from Baseline derived ECG parameters- QTcF and QTcB Maximum value (0-4 h)

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

Part 2: Change from Baseline derived ECG parameters-QTcF and QTcB Weighted mean (0-4 h)

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

Part 2: Maximum change from Baseline value (0-4h) for potassium

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

Part 2: Ambulatory blood pressure: maximum, minimum, time to maximum, time to minimum and weighted mean for systolic and diastolic blood pressure, and weighted mean arterial pressure over 0-8 and 8-24 h after dosing on Days 1 and 14

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

Part 2: Number of participants with abnormal Holter ECG findings as a function of cardiac monitoring

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

Part 2: Number of participants with abnormal Lead II ECG findings as a function of cardiac monitoring

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

Part 2: Mean supine SBP maximum value (0-4 h)

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

Part 2: Mean supine DBP minimum value (0-4 h)

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

Part 2: Mean supine SBP and supine DBP Weighted mean (0-4 h)

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

Part 2: Change from Baseline supine heart rate maximum value (0-4 h)

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

Part 2: Change from Baseline supine heart rate Weighted mean (0-4 h)

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

Part 2: Maximum change in postural SBP and DBP (0-4h)

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

Part 2: Minimum change from Baseline value (0-4h) for potassium

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

Part 2: Weighted mean change from baseline (0-4h) for potassium

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

Part 2: Summary of AUC after a single dose

Timeframe: Pre-dose (0.0 h) and 30 M, 1, 2, 4, 6, 8, 12 and 24 h post dose of each treatment period on D1 and D14; Pre-dose (0.0 h) and 30 M, 1, 2, 4 and 6 h post dose of each treatment period on D7.

Part 2: Summary of Cmax of GSK961081 after a single dose

Timeframe: Pre-dose (0.0 h) and 30 M, 1, 2, 4, 6, 8, 12 and 24 h post dose of each treatment period on D1 and D14; Pre-dose (0.0 h) and 30 M, 1, 2, 4 and 6 h post dose of each treatment period on D7.

Part 2: Summary of t-last, t-max and t-half

Timeframe: Pre-dose (0.0 h) and 30 M, 1, 2, 4, 6, 8, 12 and 24 h post dose of each treatment period on D1 and D14; Pre-dose (0.0 h) and 30 M, 1, 2, 4 and 6 h post dose of each treatment period on D7.

Part 2: Serial sGaw measurement over 24 hours post-dose on D1 and 14

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

Interventions:

Drug: GSK961081

Drug: Placebo

Drug: Tiotropium

Drug: Salmeterol

Enrollment:

Primary completion date:

2008-23-05

Observational study model:

Not applicable

Time perspective:

Not applicable

Clinical publications:

Bateman E, Kornmann O, Ambery C, Norris V. Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther.

Bateman E, Kornmann O, Ambery C, Norris V.Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD.Pulm Pharmacol Ther.2013;26(5):581-7

Medical condition

Pulmonary Disease, Chronic Obstructive

Product

batefenterol, salmeterol

Collaborators

Not applicable

Study date(s)

June 2007 to May 2008

Type

Interventional

Phase

Participation criteria

Sex

Female & Male

Age

40 - 75 years

Accepts healthy volunteers

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.

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

Inclusion and exclusion criteria

Inclusion criteria:

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

Exclusion criteria:

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
Poorly controlled COPD defined as: Either: acute worsening of COPD that is managed by the subject at home by treatment with increased corticosteroids or antibiotics in the 6 weeks before screening Or: more than 2 exacerbations in the previous 12 months before screening that required a course of oral steroids or antibiotics, and/or required hospitalisation
Subject has had a respiratory tract infection in the 4 weeks before screening
Subject requires treatment with inhaled cromolyn sodium, theophyline, oral beta agonists, nebulised anticholinergics or leukotriene antagonists
Subject is unable to abstain from long acting beta agonist from 72 hours before screening and throughout the dosing period
Subject is unable to abstain from tiotropium from 28 days before screening and throughout the dosing period
Subject is predicted to be unable to abstain from short acting inhaled beta agonists (to be used as rescue medication during the study) for 6 hours before screening and before study visits, when required, until all post dose lung function tests have been completed for a given study day.
Subject has received oral corticosteroids within the 6 weeks before screening
Subject is receiving > 1000 mg FP (or equivalent) a day of inhaled corticosteroid or has changed dose within the 6 weeks before screening or is predicted not to be able to maintain a constant dose during the study
Subject is receiving oxygen therapy or nocturnal positive pressure treatment
Subject has prostate hypertrophy or narrow angle glaucoma
The subject is unable to use the dosing devices correctly.
Subject with carcinoma that has not been in complete remission for at least 5 years (with the exception of carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma if the subject is considered cured)
A history of congestive heart failure, coronary insufficiency or cardiac arrhythmia
Abnormal 12- lead ECG abnormality which is either clinically significant or may interfere with QTc measurement
A supine mean heart rate outside the range 40-90 beats per minute (bpm) at screening.
Elevated supine blood pressure higher than 160/95 at screening.
Subject is receiving a diuretic and/ or beta adrenergic antagonist.
Subject has a serum potassium level below the reference range at screening.
Strict vegetarians;
Shift-worker unable to comply with the study;
Inability to understand the protocol requirements, instructions and study-related restrictions; the nature, scope and possible consequences of the study;
Unlikely to complete the study; e.g., uncooperative attitude, inability to return for Follow-up Visits;
Subject is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff, or relative thereof directly involved in the conduct of the study;
Vulnerable individuals (e.g., persons kept in detention).

Trial location(s)

Location

Status

Location

GSK Investigational Site

Mainz, Rheinland-Pfalz, Germany, 55131

Status

Study Complete

Location

GSK Investigational Site

Bloemfontein, South Africa, 9301

Status

Recruiting

Location

GSK Investigational Site

Berlin, Berlin, Germany, 14050

Status

Will Be Recruiting

Location

GSK Investigational Site

George, South Africa, 6530

Status

Recruiting

Location

GSK Investigational Site

Mowbray, South Africa, 7700

Status

Study Complete

Study documents

Clinical study report

Available language(s): English

Download document(s)

Scientific result summary

Available language(s): English

Download document(s)

If you wish to request for full study report, please contact - [email protected]

Results overview

Results posted on ClinicalTrials.gov

Recruitment status

Study complete

Actual primary completion date

2008-23-05

Actual study completion date

2008-23-05

Plain language summaries

Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

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