Examination of the Bronchoprotective Effect of Endothelin Receptor Blockade in Asthma

Sponsor

University of Glasgow (Other)

Overall Status

Unknown status

CT.gov ID

NCT01617746

Collaborator

NHS Greater Glasgow and Clyde (Other)

Enrollment

Location

Arms

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study will be to determine if blockade of endothelin 1 signalling via endothelin receptor A using ambrisentan or dual blockade (A&B) via bosentan can provide protection against methacholine induced bronchoconstriction in asthma.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Ambrisentan Drug: Bosentan Drug: Placebo	Phase 2

Detailed Description

Endothelin 1 may have a role in the development of acute airway narrowing in asthma. Blockade of the endothelin system may thereby protect against airway narrowing. Two receptors exist for endothelin 1, Endothelin A & B. Both can be blocked by Bosentan, and the A receptor by ambrisentan. Both medications are currently in use for the treatment of pulmonary arterial hypertension. The investigators will endeavour to examine the potential role of endothelin 1 in the development of airway narrowing in asthma through blockade of the endothelin receptors A&B through the use of bosentan and ambrisentan.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Examination of the Bronchoprotective Effect of Endothelin Receptor Blockade in Asthma

Study Start Date :

Nov 1, 2012

Anticipated Primary Completion Date :

May 1, 2014

Anticipated Study Completion Date :

Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ambrisentan 5mg od ambrisentan	Drug: Ambrisentan 5mg od two weeks Other Names: Volibris
Experimental: Bosentan 62.5mg bosentan	Drug: Bosentan 62.5mg bd two weeks Other Names: Tracleer
Placebo Comparator: Placebo	Drug: Placebo bd for two weeks

Arm

Intervention/Treatment

Experimental: Ambrisentan

5mg od ambrisentan

Drug: Ambrisentan

5mg od two weeks

Other Names:

Volibris

Experimental: Bosentan

62.5mg bosentan

Drug: Bosentan

62.5mg bd two weeks

Other Names:

Tracleer

Placebo Comparator: Placebo

Drug: Placebo

bd for two weeks

Outcome Measures

Primary Outcome Measures

Difference in doubling dose of methacholine to produce bronchoconstriction compared to placebo [2 weeks]
Both active treatments will be compared against placebo with respect to protection against methacholine induced bronchoconstriction

Secondary Outcome Measures

Which of the endothelin receptors A&B are most bronchoprotective against methacholine [2 weeks]
Both bostentan and ambrisentans effect on airway response to methacholine will be compared to placebo. The relative efficacy will be compared, in terms of doubling doses of methacholine.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Physician diagnosis of asthma confirmed objectively by airway hyperactivity to methacholine (as determined by a ≥ 20% drop in FEV at a methacholine dose of ≤ 8mg/ml after β-agonist withdrawal as per ATS guidelines)
Age range 18-60 years
FEV1 ≥ 60% predicted
Duration of asthma > 6 months and on stable medication for 4 weeks
Prescribed and compliant with inhaled corticosteroid up to a maximum of 2000mcg beclomethasone or equivalent
No history of previous regular smoking and current non-smoker

Exclusion Criteria:

Unstable asthma; defined as the presence of 1 or more of the following events in the month prior to study [Emergency/'out of hours' visit to GP for asthma exacerbation; GP visit to patient at home for asthma exacerbation or A & E/hospital admission for asthma exacerbation]
Treatment with oral corticosteroids in the past month
Need for maintenance oral corticosteroid therapy
Pregnancy or planning to become pregnant over course of study and up to one month after
Excessive risk of hepatotoxicity from endothelin receptor antagonists;

Alcohol excess (defined as regular consumption above government daily recommend limits; currently defined as 28 units per wk for men, 21 units per week for women)
Previous intravenous drug use
Current or known history of liver disease (with the exception of Gilberts disease and gallstones)
Chronic hepatitis (either viral (e.g. hepatitis B or C) or autoimmune)
Bilirubin, alanine aminotransferase (ALT) or asparate aminotransferase (AST) greater than the upper limit of normal at screening

Anaemia (defined as haemoglobin below the lower reference range for sex) at screening
Renal failure (defined as eGFR less than 50 mL/minute/1.73 m2) at screening
Known HIV positivity
History of inability to tolerate bosentan or ambrisentan
Significant medical conditions other than asthma felt by investigator to preclude participation in study. This could be either in patients best interest or due to potential to significantly alter responses to medication and hence alter power of clinical trial (examples include; significant heart failure (NYHA grades II-IV), diabetes mellitus, bronchiectasis or haematological malignancy).