Doxycycline for COPD in HIV-Infected Patients

Study Overview
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Brief Summary
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In the context of improved survival from HIV infection itself, chronic obstructive pulmonary disease (COPD); a form of lung disease that includes emphysema, which makes breathing difficult) is emerging as an important cause of morbidity and perhaps ultimately mortality in this population. HIV-infected patients are at increased risk of chronic obstructive pulmonary disease, likely due to multiple factors, including an increased presence of smoking, chronic inflammation and progression of immunodeficiency, oxidant stress (excessive levels of natural chemicals called oxidants and free radicals that can damage tissue), and respiratory infections. While natural history data on COPD are limited in the era of potent antiretroviral therapy, earlier data suggest that the course of emphysema may be accelerated in this population. Our preliminary data suggest that several matrix metalloproteinases (MMPs) derived from alveolar macrophages (a type of immune cell found in the lungs) have an increased cellular response in HIV-infected smokers, which could contribute to accelerated emphysema. Matrix metalloproteinases are enzymes that break down the structural support of tissues, including the airways in the lung. Based on these observations, the investigators hypothesize that pharmacologic inhibition of matrix metalloproteinases by doxycycline will favorably modify the natural history of chronic obstructive pulmonary disease in HIV-infected patients. To test this hypothesis, the investigators propose conducting a proof of concept pilot study as a prelude to a possible phase II randomized, placebo-controlled trial (testing safety and efficacy in a larger population controlled with a sugar pill) of doxycycline for COPD in HIV-infected patients should the proof of concept be successful. Our research team is lead by a pulmonologist/researcher with expertise in HIV-associated COPD and an infectious diseases specialist/clinical trials expert.

Detailed Description
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Chronic obstructive pulmonary disease (COPD) is emerging as an important cause of morbidity in HIV-infected patients, likely due to multiple factors, including an increased prevalence of smoking, chronic inflammation and immune activation, oxidant stress and respiratory infections. Our preliminary data suggest that several lung matrix metalloproteinases (MMPs) are upregulated in HIV-infected smokers, which could contribute to accelerated emphysema by virtue of their ability to degrade extracellular matrix and basement membrane components. Our Specific Aim is to determine the safety, tolerability, and biologic effects of twice daily doxycycline for 6 months in HIV-infected subjects with COPD. To address this aim, we will conduct a randomized, double-blind, placebo-controlled pilot study of doxycycline 100 mg twice daily in 30 HIV-infected subjects with COPD (2:1 doxy:placebo). The primary endpoint will be safety/tolerability and secondary endpoints will include change in FEV1, reduction of MMP activity in epithelial lining fluid and cells obtained by bronchoscopy and doxycycline levels in blood, ELF and bronchoalveolar lavage (BAL) cell pellets. In addition to providing novel insights into the biologic effects of doxycycline in the lung, the pilot study will inform selection of endpoints for a phase II trial, which ultimately will address an unmet medical need for novel interventions for COPD/emphysema in HIV-infected patients.

Official Title
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Doxycycline for COPD in HIV-Infected Patients

Conditions
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HIV, Chronic Obstructive Pulmonary Disease (COPD), Emphysema

Intervention / Treatment
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* Drug: Doxycycline
* Drug: Placebo (sugar pill)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV infection CD4 cell count greater than 200 cells/mm3 HIV RNA less than 400 copies/ml Stable antiretroviral therapy for greater than or equal to 12 weeks Fulfills GOLD definition for COPD (post-bronchodilator FEV1/FVC less than 0.7) and/or has radiographic evidence of emphysema Current or history of smoking with minimum 3 pack-year history ALT and AST less than 3 x upper limit of normal For women of childbearing potential: willingness to use 2 forms of birth control Subjects on therapy for COPD must be on stable therapy for at least 4 weeks Exclusion Criteria: Pulmonary infection, COPD exacerbation, or acute opportunistic infection within 30 days of entry Conditions associated with increased sedation of bronchoscopy risk, including but not limited to Gold class 3 or 4 COPD, requirement for home oxygen, hypercapneic respiratory failure, poorly controlled hypertension Known allergy/intolerance to doxycycline, atropine, or any local anesthetic Inability to provide informed consent Pregnant or lactating women Men must agree not to attempt to make a woman pregnant or participate in sperm donation during the study and for 6 weeks after discontinuing the drug End stage renal disease Cirrhosis INR greater than 1.4 Platelets less than 80,000 Any condition including active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements or increase the risk of bronchoscopy Active or planned participation in any other clinical trial or observational study without prior approval from the PI

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Doxycycline<br>100 mg twice daily (BID orally) x 24 weeks | Drug: Doxycycline<br>* 100 mg twice daily (BID orally) x 24 weeks<br>* Other names: Vibramycin;|
| Placebo Comparator: Placebo (sugar pill)<br>100 mg twice daily (BID orally) x 24 weeks | Drug: Placebo (sugar pill)<br>* 100 mg twice daily (BID orally) x 24 weeks<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Doxycycline, as Measured by the Number of Subjects With Any Treatment-related Adverse Events. | To determine the safety of twice daily doxycycline for 24 weeks in HIV-infected subjects with COPD and/or emphysema as measured by the number of subjects with any treatment-related adverse events. | Up to 24 weeks | 
| Tolerability of Doxycycline, as Measured by the Number of Subjects With a Dose-limiting Toxicity | To determine the tolerability of twice daily doxycycline for 24 weeks in HIV-infected subjects with COPD and/or emphysema as measured by those subjects experiencing a dose-limiting toxicity | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical: Change in Pulmonary Function (FEV1) | FEV1 is the volume of air exhaled during the first second of a forced expiratory maneuver. | 24 Weeks | 
| Percent Change in BAL MMP-9 Activity | Percent change of MMP-9 activity in bronchoalveolar lavage (BAL) fluid. | 12 Weeks | 
| Doxycycline Levels | Doxycycline level in serum | 12 Weeks | 
| Doxycycline Levels in BAL | Doxycycline levels in bronchoalveolar lavage (BAL) fluid. | 12 Week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, COPD, Chronic Obstructive Pulmonary Disease, Emphysema