Bosentan for Poorly Controlled Asthma

The Effect of the ET-1 Receptor Antagonist, Bosentan on Patients With Poorly Controlled Asthma-A 17 Week, Double-blind, Placebo Controlled Crossover Trial

Hypothesis: The endothelin-1 receptor antagonist, bosentan when added to the treatment of asthma patients who are symptomatic despite the use of controller therapy will improve asthma symptoms and physiology.

Twenty patients with a diagnosis of asthma, between the ages of 21 and 70 who are symptomatic despite the use of at least one controller medication will be randomized to either placebo or active medication for an 8 week period (initial 4 weeks is at 1/2 of final dose as per package insert and FDA approval). Measures of lung function and symptoms will be recorded. Patients will then cross over, so that patients initially on placebo will receive active drug for 8 weeks and those initially on active drug will receive placebo. The same endpoints will be measured. The acute bronchodilator effects of the drug will also be tested on the first day of therapy at the full therapeutic dose.

Study Overview

• Status: Terminated
• Conditions: Asthma
• Intervention / Treatment: Drug: bosentan; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Farmington, Connecticut, United States, 06030-2810
      • University of Connecticut Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of asthma, maintained on a minimum of 1 anti-inflammatory/controller and daily long acting B-agonist therapy with inadequate control of symptoms. (Defined as symptoms including wheezing, chest tightness or shortness of breath occurring at least 3 times a week or requiring use of "rescue" short-acting B-agonist at least 3 times a week).
• FEV1 less than 80% of predicted and greater than 40% at screening visit.
• A minimum of 12% reversibility of FEV1 after albuterol on screening visit or previously documented during the prior two years.
• Women of childbearing potential must use 2 non-hormonal methods of birth control (2 methods between the subject and her partner) while on the study and for 1 month after the last dose of study medication.
• Male subjects must use two non hormonal methods of birth control (2 methods between the subject and his partner) while on the study and for 1 month after the last dose of study medication.

Exclusion Criteria:

• History of liver disease, clinically significant cardiac disease, renal disease or pulmonary disease other than asthma. Patients with clinically significant laboratory abnormalities of LFTs/bilirubin (AST/ALT, TBili, alkaline phosphatase) and clinically significant anemia will be excluded. Clinically significant anemia will be defined as any anemia resulting in serum Hgb more than 1 gm/dl below the LLN, Patients with isolated minimal elevations of bilirubin (eg. as occurs in Gilbert's disease) or minimal elevations in transaminases (less than 1.2 x ULN) without a history of liver disease, risk factors for liver disease or symptoms of liver disease may still be included in the study at the investigator's discretion, but will have LFT testing at each study visit.)
• Cigarette history of >10 pack years.
• Predicted inability to adhere to medication regimen or documentation requirements of the study (symptom and medication diaries).
• Respiratory infection during 30 days preceding screening visit.
• Requirement for change in scheduled asthma medication use, including oral steroid dose change, or acute medical care for asthma during the 30 days preceding screening visit.
• Predicted inability to safely refrain from B-agonist use for the required amount of time on study visit days.
• Use of tiotropium
• Pregnancy, breast feeding or the use of hormonal methods of birth control as the only means of birth control during the study.
• Use of potent CYP3A4 and CYP2C9 inhibitors, including, but not limited to azole antifungals, amiodarone, glyburide, warfarin, cyclosporine, ritonavir, other medications potentially toxic to the liver or bone marrow.
• Use of any illegal drugs or alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: 1 Crossover

Drug: bosentan; Bosentan 62.5mg or placebo orally, twice a day for four weeks. After four weeks at this dose the subjects will have an increase to bosentan 125 mg or placebo orally twice daily for another four weeks. At week eight, subjects will crossover to bosentan or placebo depending upon their first randomization.; Drug: placebo; Bosentan 62.5mg or placebo orally, twice a day for four weeks. After four weeks at this dose the subjects will have an increase to bosentan 125 mg or placebo orally twice daily for another four weeks. At week eight, subjects will crossover to bosentan or placebo depending upon their first randomization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FEV1		1, 2, 4 hours after dosing
Peak Flow		last 7 days of each dosing period
Symptom Scores	Symptom score could range from a minimum of 7 (no symptoms) to 35 (severe symptoms)	Last 7 days of each dosing period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1		end of dosing period
Rescue Beta-agonist		end of each dosing period
Asthma Control Test Questionnaire	Patient reported outcome minimum 5 (no symptoms) maximum 25 (severe symptoms)	end of each dosing period

Other Outcome Measures

Outcome Measure	Time Frame
Requirement for Escalation of Controller Medication.	17 weeks
Requirement for Urgent Medical Care for Asthma.	17 weeks
Ability to Taper Systemic Steroids Among Those Patients Who Are on Systemic Steroids at Study Entry.	17 weeks

Collaborators and Investigators

• Sponsor: UConn Health
• Collaborators: Actelion
• Investigators: Principal Investigator: Mark L Metersky, MD, UConn Health

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: December 29, 2008
• First Submitted That Met QC Criteria: December 29, 2008
• First Posted (Estimate): December 30, 2008

Study Record Updates

• Last Update Posted (Estimate): October 1, 2012
• Last Update Submitted That Met QC Criteria: September 28, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: Asthma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: 08-287-1; 001 (NavyGHB)