Phosphodiesterase 4 Inhibitor, Roflumilast, and the Effects of Inhibition in Severe Asthma

Study Overview
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Brief Summary
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This study evaluates the effects of roflumilast on restoring response β2 adrenoreceptor agonists in low T2, obese asthmatics. One group of participants will receive roflumilast for 3 months, while the other will receive a placebo.

Detailed Description
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T2 low asthma is common in obese asthmatics. New evidence suggests that hyperinsulinemia and insulin resistance, both common in obesity, are associated with an increased risk of concurrent asthma. Targeting Phosphodiesterase 4 inhibitors (PDE4) allows for examination of a mechanism potentially linking obesity and asthma as well as identification of readily available and safe options to treat hyperinsulinemic, overweight asthmatics. It is hypothesized that obesity and hyperinsulinemia contribute to asthma by impairing β2 adrenoreceptor function and that this can be rescued the PDE4 inhibitor, roflumilast.

Official Title
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Phosphodiesterase 4 Inhibitor, Roflumilast, Improves Beta Agonist Responsiveness Compared to Placebo in Low T2 Asthma Patients.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Roflumilast
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a physician diagnosis of asthma. Require treatment with moderate to high-dose >2500mcg/day of fluticasone or equivalent, or use of oral steroids Also two of the following: Requirement for additional daily treatment with other controller medication Daily Asthma symptoms Forced Expiratory Volume / Forced Vital Capacity (FEV1/FVC) < 70% and FEV1< 80% predicted ≥1 urgent care visits/year ≥3 oral steroid bursts/year Near-fatal asthma event. Exhaled Nitric oxide (FeNO)<30 ppb Peripheral blood eosinophil count < 300 (x10-6/ul) Obesity, BMI≥30 Exclusion Criteria: Less than 18 years of age baseline FEV1 <30% predicted pregnant or nursing women current smokers or subject with >20 pack year history any history of intolerance of, or reaction to, Roflumilast. Prisoners Patients with liver disease Subjects with Hepatic impairment (contraindicated in moderate-to-severe liver impairment: Child-Pugh Score Class B/C) for example. Patients with clinically significant psychiatric history (i.e., suicidality, etc.) and psychiatric illness Patients using strong CYP 450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Roflumilast<br>Roflumilast 500mcg by mouth, once daily, for 70 days (10 weeks). | Drug: Roflumilast<br>* Roflumilast capsule<br>* Other names: Daliresp;|
| Placebo Comparator: Placebo<br>Placebo by mouth, once daily, for 70 days (10 weeks). | Drug: Placebo<br>* Sugar pill manufactured to mimic look of Roflumilast capsule<br>* Other names: Placebo for Roflumilast;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Beta 2 Agonist response from Baseline | Determine whether β2 receptor responsiveness is improved in response to albuterol in Group 1 (Roflumilast) patients compared to Group 2 (Placebo) patients at the study entry. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exhaled nitric oxide | Determine where exhaled nitric oxide is lower in Group 1 vs Group 2 | 3 months | 
| Asthma Control Test score | The Asthma Control Test (TM © 2002 by QualityMetric) is a validated instrument to measure symptom control in asthma patients. There are 5 questions each with a score of 1-5 (25 total points). Poor asthma control is considered with a score less than 20 out of 25. Determine whether Asthma Control Test score is improved in Group 1 vs Group 2 Asthma Control TestTM In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school or at home? During the past 4 weeks, how often have you had shortness of breath? During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning? In the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication (such as albuterol)? How would you rate your asthma control during the past 4 weeks? | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperinsulinemia, Phosphodiesterase 4 Inhibitor