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An Investigation Of The Interaction Of GSK961081 With Inhaled Beta-Agonist And Anti-Muscarinic Drugs.

Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Disease, Chronic Obstructive

Intervention: 400 microgrammes GSK961081 (Drug); 1200 microgrammes GSK961081 (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

Summary

GSK961081 is a potent dual pharmacophore that demonstrates both antimuscarinic and beta-agonist pharmacology in preclinical studies, both pharmacologies being of long duration. If reproduced in man, GSK961081 has the potential to deliver a medicine that can be given once daily. The bronchodilatation after inhalation of single doses of GSK961081 alone and in the presence of the short acting beta agonist salbutamol and the short acting muscarinic antagonist, ipratropium bromide will be measured in this study. Any residual bronchodilatation post-inhalation of GSK961081 and demonstrated by addition of salbutamol or ipratropium bromide may provide an indirect assessment of the beta-agonist and antimuscarinic components of GSK961081

Clinical Details

Official title: A Randomized, Double-blind, Crossover Study to Investigate the Bronchodilatation Post-inhalation of GSK961081 Alone and With the Addition of Cumulative Doses of Short Acting Bronchodilators (Salbutamol and Ipratropium Bromide) in Patients With COPD

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Maximal increase from pre-dose short-acting bronchodilator (salbutamol or ipratropium bromide) in FEV1 after inhalation of short-acting bronchodilator at 1h, 12h and 24h.

Secondary outcome:

Maximal increase from pre-dose short-acting bronchodilator (salbutamol or ipratropium bromide) in FVC after inhalation of short-acting bronchodilator at 1h, 12h and 24h.

Adverse events, clinical laboratory safety tests, vital signs, 12-lead ECG parameters including QTc(B) and QTc(F), blood glucose and serum potassium.

The following endpoints will be derived for the increase from baseline in supine systolic blood pressure, supine heart rate, QTc(F) and QTc(B). • Maximum increase (0-4h) and (0- 27h) and time to maximum increase (0-4h) and (0-27h) • Weighted mean(0-4h)

The following endpoints will be derived for the supine diastolic blood pressure. • Minimum value (0-4h) and (0- 27h) and time to minimum value (0-4h) and (0-27h) • Weighted mean (0-4h)

The following endpoints will be derived for the blood glucose and serum potassium. • Maximum increase from baseline value (0-4h) and (0-27h) for blood glucose and time to maximum increase (0-4h) and (0-27h)

Plasma concentrations of GSK961081 and derived pharmacokinetic parameters

Maximum decrease from baseline value (0-4h) and (0-27h) for serum potassium and time to minimum value • Weighted mean change from baseline (0-4h) for glucose and potassium

Detailed description: GSK961081 is a potent dual pharmacophore that demonstrates both antimuscarinic and beta-agonist pharmacology in preclinical studies, both pharmacologies being of long duration. If reproduced in man, GSK961081 has the potential to deliver a medicine that can be given once daily. The bronchodilatation after inhalation of single doses of GSK961081 alone and in the presence of the short acting beta agonist salbutamol and the short acting muscarinic antagonist, ipratropium bromide will be measured in this study. Any residual bronchodilatation post-inhalation of GSK961081 and demonstrated by addition of salbutamol or ipratropium bromide may provide an indirect assessment of the beta-agonist and antimuscarinic components of GSK961081

Eligibility

Minimum age: 40 Years. Maximum age: 75 Years. Gender(s): Both.

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 i. e. 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 in accordance with ATS/ERS guidelines (as per protocol).

- 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 ipatropium bromide defined as:

- Either an increase in FEV1 of > 12 % and > 150 mL within 2 hours following inhalation

of 80 µg ipratopium bromide (Atrovent MDI via spacer) at the screening visit

- Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following

inhalation of 80 µg ipratopium bromide within 6 months of screening and an increase in FEV1 of > 6 % and > 100 mL within 2h following inhalation of 80 µg ipratopium bromide (Atrovent MDI via spacer) 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 hours following inhalation

of 400 µg salbutamol MDI (via spacer) at the screening visit

- Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following

inhalation of 400 µg salbutamol MDI within 6 months of screening and an increase in FEV1 of > 6 % and >100 mL within 2h following inhalation of 400 µg salbutamol MDI (via spacer) 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 (BMI) within the range 18-35 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 assessments

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

- Subjects with clinically relevant findings on laboratory safety tests. Subjects with

laboratory values outside the reference range may be include in the study if the Investigator and medical monitor agree that these findings would not put the subject at risk or interfere with the objectives of the study

- 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 drugs of abuse screen. A minimum list of drugs that

will be screened for include amphetamines, barbituates, cocaine, opiates, cannabinoids and benzodiazepines.

- 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 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 of dosing or intends to

donate within 56 days after completing the study.

- Subject has an FEV1 < 40 % 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 bromide,

salbutamol, or lactose

- A subject in whom ipratropium bromide or salbutamol 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 ß2-

agonists, nebulised anticholinergics or leukotriene antagonists

- Subject is unable to abstain from long acting ß2-agonist from 72 hours before

screening and throughout the dosing period

- Subject is unable to abstain from tiotropium bromide from 28 days before screening

and throughout the dosing period

- Subject is predicted to be unable to abstain from short acting inhaled ß2-agonists or

short acting antimuscarinics for 6 hours before screening and for 6 hours before dosing with GSK961081 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 µg 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

- Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck

obstruction that in the opinion of the study investigator would prevent use of an inhaled anticholinergic

- The subject is unable to use the dosing devices (MDPI/ MDI/ spacer) 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

or a finding on screening 24h Holter monitor that would contraindicate the subject's participation in the study

- 12- lead ECG abnormality which is either clinically significant or may interfere with

QTc measurement or QTc > 450 msec or PR interval outside the range 120 to 220 msec.

- A supine mean heart rate outside the range 40-90 bpm at screening.

- Persistently elevated supine blood pressure higher than 160/95 at screening.

- Subject is receiving a high-dose diuretic and/ or ß2-adrenergic antagonist

- Subject has a serum potassium level below the reference range at screening.

- 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.

Locations and Contacts

GSK Investigational Site, Wellington 6035, New Zealand

GSK Investigational Site, Chiangmai 50200, Thailand

GSK Investigational Site, Khon Kaen 40002, Thailand

GSK Investigational Site, Manchester M23 9LT, United Kingdom

Additional Information

Starting date: April 2008
Last updated: October 25, 2012

Page last updated: August 23, 2015

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