Doxycycline for COPD in HIV-Infected Patients
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, HIV / AIDS, Pulmonary |
| Therapuetic Areas: | Immunology / Infectious Diseases, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 85 |
| Updated: | 10/12/2018 |
| Start Date: | July 17, 2014 |
| End Date: | December 30, 2019 |
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.
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.
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.
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.
Inclusion Criteria:
1. Documented HIV infection
2. CD4 cell count greater than 200 cells/mm3
3. HIV RNA less than 400 copies/ml
4. Stable antiretroviral therapy for greater than or equal to 12 weeks
5. Fulfills GOLD definition for COPD (post-bronchodilator FEV1/FVC less than 0.7) and/or
has radiographic evidence of emphysema
6. Current or history of smoking with minimum 3 pack-year history
7. ALT and AST less than 3 x upper limit of normal
8. For women of childbearing potential: willingness to use 2 forms of birth control
9. Subjects on therapy for COPD must be on stable therapy for at least 4 weeks
Exclusion Criteria:
1. Pulmonary infection, COPD exacerbation, or acute opportunistic infection within 30
days of entry
2. 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
3. Known allergy/intolerance to doxycycline, atropine, or any local anesthetic
4. Inability to provide informed consent
5. Pregnant or lactating women
6. 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
7. End stage renal disease
8. Cirrhosis
9. INR greater than 1.4
10. Platelets less than 80,000
11. 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
12. Active or planned participation in any other clinical trial or observational study
without prior approval from the PI
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