Bosentan for Poorly Controlled Asthma

• Change in FEV1 [ Time Frame: 1, 2, 4 hours after dosing ] [ Designated as safety issue: No ]
• Peak Flow [ Time Frame: last 7 days of each dosing period ] [ Designated as safety issue: No ]
• Symptom Scores [ Time Frame: Last 7 days of each dosing period ] [ Designated as safety issue: No ]
  Symptom score could range from a minimum of 7 (no symptoms) to 35 (severe symptoms)

• Peak flow measurements during last 7 days of each 125 mg dosing period. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Symptom scores during last 7 days of 125 mg dosing period of drug vs placebo (means with comparisons between drug and placebo scores for each patient and between baseline and drug). [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]

• FEV1 [ Time Frame: end of dosing period ] [ Designated as safety issue: No ]
• Rescue Beta-agonist [ Time Frame: end of each dosing period ] [ Designated as safety issue: No ]
• Asthma Control Test Questionnaire [ Time Frame: end of each dosing period ] [ Designated as safety issue: No ]
  Patient reported outcome minimum 5 (no symptoms) maximum 25 (severe symptoms)

• FEV1 on drug vs placebo at end of 125 mg dosing period [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Rescue Beta-agonist use during last week of each 125 mg dosing period. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Requirement for escalation of controller medication. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Requirement for urgent medical care for asthma. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Peak flow measurements during last 7 days of each dosing period. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Ability to taper systemic steroids among those patients who are on systemic steroids at study entry. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Acute FEV1 change 1, 2, 4 hours after initial 125 mg dose of bosentan. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Asthma control test questionnaire [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]

• Requirement for Escalation of Controller Medication. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Requirement for Urgent Medical Care for Asthma. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]
• Ability to Taper Systemic Steroids Among Those Patients Who Are on Systemic Steroids at Study Entry. [ Time Frame: 17 weeks ] [ Designated as safety issue: No ]

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.

• 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.

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.