Clinical trial NCT00478738: A 2 Part Study Examining Doses Of GSK961081 In Healthy Volunteers And Then In COPD Patients
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: b-agonist,
COPD.
pharmacodynamic,
pharmacokinetic,
anti muscarinic,
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-05-25
Enrollment: 82
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: 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).

Eligibility 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).

Primary outcomes:
measure: 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
measure: 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
measure: 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
measure: 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:
measure: Part 1: Number of participants with Adverse Events (AE) and Serious adverse events (SAE)
timeFrame: Up to 16 weeks
measure: 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)
measure: Part 1: Mean values for creatinine and total bilirubin
timeFrame: Up to D1of each treatment period (up to 16 weeks)
measure: Part 1: Mean values for total protein and albumin
timeFrame: Up to D1of each treatment period (up to 16 weeks)
measure: 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)
measure: Part 1: Mean values for platelet and white blood cell (WBC)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Mean values for hemoglobin and mean corpuscle hemoglobin concentration (MCHC)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Mean values for hematocrit
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Mean values for mean corpuscle volume (MCV)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Mean values for mean corpuscle hemoglobin (MCH)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: 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)
measure: Part 1: Mean values for red blood cells (RBC)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: 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)
measure: 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)
measure: 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)
measure: Part 1: Mean supine systolic blood pressure (SBP) maximum value (0-4 h)
timeFrame: Up to D1of each treatment period (up to 16 weeks)
measure: Part 1: Mean supine diastolic blood pressure (DBP) minimum change (0-4 h)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: 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)
measure: 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)
measure: 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)
measure: Part 1: Maximum change in postural SBP and DBP (0-4h)
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Maximum change from Baseline value (0-4h) for glucose
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Minimum change from Baseline value (0-4h) for potassium
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: Part 1: Maximum change from Baseline value (0-4h) for potassium
timeFrame: Up to D1 of each treatment period (up to 16 weeks)
measure: 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)
measure: 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)
measure: 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)
measure: Part 2: Number of participants with AE and SAE
timeFrame: Up to 16 weeks
measure: 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)
measure: Part 2: Mean values for creatinine and total bilirubin
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for total protein and albumin
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for AST, ALT, ALP, creatine kinase and GGT
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for hemoglobin and MCHC
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for hematocrit
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for MCV
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for MCH
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for total neutrophil, lymphocyte, monocyte, eosinophil and basophil
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for platelets and WBC
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for RBC
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean values for reticulocytes
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: 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)
measure: 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)
measure: Part 2: Maximum change from Baseline value (0-4h) for potassium
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: 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)
measure: 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)
measure: 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)
measure: Part 2: Mean supine SBP maximum value (0-4 h)
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Mean supine DBP minimum change (0-4 h)
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: 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)
measure: 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)
measure: 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)
measure: Part 2: Maximum change in postural SBP and DBP (0-4h)
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Minimum change from Baseline value (0-4h) for potassium
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: Part 2: Weighted mean change from baseline (0-4h) for potassium
timeFrame: Up to D14 of each treatment period (up to 16 weeks)
measure: 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.
measure: 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.
measure: 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.
measure: 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)
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Bloemfontein
country: South Africa
facility: GSK Investigational Site
city: George
country: South Africa
facility: GSK Investigational Site
city: Mowbray
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.