Asthma
Conditions
Keywords
Asthma
Brief summary
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.
Interventions
DRUGbosentan
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.
DRUGplacebo
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.
Sponsors
Actelion
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptom Scores | Last 7 days of each dosing period | Symptom score could range from a minimum of 7 (no symptoms) to 35 (severe symptoms) |
| Change in FEV1 | 1, 2, 4 hours after dosing | — |
| Peak Flow | last 7 days of each dosing period | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rescue Beta-agonist | end of each dosing period | — |
| FEV1 | end of dosing period | — |
| Asthma Control Test Questionnaire | end of each dosing period | Patient reported outcome minimum 5 (no symptoms) maximum 25 (severe symptoms) |
Other
| Measure | Time frame |
|---|---|
| Requirement for Escalation of Controller Medication. | 17 weeks |
| Ability to Taper Systemic Steroids Among Those Patients Who Are on Systemic Steroids at Study Entry. | 17 weeks |
| Requirement for Urgent Medical Care for Asthma. | 17 weeks |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants 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. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 9 | 1 / 11 |
Outcome results
Primary
Change in FEV1
Time frame: 1, 2, 4 hours after dosing
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Change in FEV1 | 1 hour FEV1 | 1.50 liters |
| Placebo | Change in FEV1 | 2 hour FEV1 | 1.53 liters |
| Placebo | Change in FEV1 | 4 hour FEV1 | 1.50 liters |
| Bosentan | Change in FEV1 | 1 hour FEV1 | 1.57 liters |
| Bosentan | Change in FEV1 | 2 hour FEV1 | 1.57 liters |
| Bosentan | Change in FEV1 | 4 hour FEV1 | 1.51 liters |
Primary
Peak Flow
Time frame: last 7 days of each dosing period
Population: Data not analyzed, study terminated early
Primary
Symptom Scores
Symptom score could range from a minimum of 7 (no symptoms) to 35 (severe symptoms)
Time frame: Last 7 days of each dosing period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Symptom Scores | 19.7 score on a scale | Standard Deviation 7.6 |
| Bosentan | Symptom Scores | 20.1 score on a scale | Standard Deviation 3.5 |
Secondary
Asthma Control Test Questionnaire
Patient reported outcome minimum 5 (no symptoms) maximum 25 (severe symptoms)
Time frame: end of each dosing period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Asthma Control Test Questionnaire | 13.6 scores on a scale | Standard Deviation 5 |
| Bosentan | Asthma Control Test Questionnaire | 13.1 scores on a scale | Standard Deviation 3.9 |
Secondary
FEV1
Time frame: end of dosing period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FEV1 | 1.46 liters | Standard Deviation 0.4 |
| Bosentan | FEV1 | 1.49 liters | Standard Deviation 0.47 |
Secondary
Rescue Beta-agonist
Time frame: end of each dosing period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Rescue Beta-agonist | 34.6 puffs of rescue inhaler | Standard Deviation 19.2 |
| Bosentan | Rescue Beta-agonist | 36.3 puffs of rescue inhaler | Standard Deviation 18.9 |
Other Pre-specified
Ability to Taper Systemic Steroids Among Those Patients Who Are on Systemic Steroids at Study Entry.
Time frame: 17 weeks
Other Pre-specified
Requirement for Escalation of Controller Medication.
Time frame: 17 weeks
Other Pre-specified
Requirement for Urgent Medical Care for Asthma.
Time frame: 17 weeks