Doxycycline for COPD in HIV-Infected Patients
Condition: HIV; Chronic Obstructive Pulmonary Disease (COPD); Emphysema
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Doxycycline; Placebo (sugar pill)
Intervention type(s): Drug; Drug
Intervention description(s): 100 mg twice daily (BID orally) x 24 weeks; 100 mg twice daily (BID orally) x 24 weeks
Other intervention name(s): Vibramycin; Placebo
Intervention MeSH terms: Doxycycline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: HIV; COPD; Chronic Obstructive Pulmonary Disease; Emphysema