Doxycycline for COPD in HIV-Infected Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Weill Medical College of Cornell University
Sponsor:
Information provided by (Responsible Party):
Robert J. Kaner, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT01744093
First received: November 20, 2012
Last updated: May 27, 2014
Last verified: May 2014
  Purpose

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, led by a pulmonologist/researcher with expertise in HIV-associated COPD and an infectious diseases specialist/clinical trials expert, is well positioned to propose such a trial to the NIH-funded AIDS Clinical Trials Group (ACTG).


Condition Intervention
HIV
Chronic Obstructive Pulmonary Disease (COPD)
Emphysema
Drug: Doxycycline

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Doxycycline for COPD in HIV-Infected Patients

Resource links provided by NLM:


Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:
  • Safety and tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    To determine the safety, tolerability, and biologic effects of twice daily doxycycline for 6 months in HIV-infected subjects with COPD and/or emphysema.


Secondary Outcome Measures:
  • Larger phase II clinical trial [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To prepare and submit an application for a phase II clinical trial of doxycycline for COPD in HIV-infected subjects


Estimated Enrollment: 30
Study Start Date: January 2014
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Doxycycline
100 mg BID (orally) for 6 months
Drug: Doxycycline
100 mg BID for six months
Other Name: Vibramycin
Placebo Comparator: Placebo (sugar pill)
100 mg BID for 6 months

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 aims are: (1) end, we first propose to conduct a pilot study to enable us to address the following Specific aims: Aim 1. To determine the safety, tolerability, and biologic effects of twice daily doxycycline for 6 months in HIV-infected subjects with COPD; and (2) to prepare and submit an application for a phase II clinical trial of doxycycline for COPD in HIV-infected subjects. To address the first 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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Documented HIV infection
  2. Cluster of differentiation 4 (CD4) cell count >200 cells/mm3
  3. HIV RNA < 400 copies/ml
  4. Stable antiretroviral therapy for at least 12 weeks
  5. Fulfills GOLD definition for COPD [post-bronchodilator with a forced expiratory volume at one second and forced vital capacity ration (FEV1/FVC) < 0.7] and/or has radiographic evidence of emphysema
  6. Current or history of smoking with minimum 3 pack-year history
  7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 3 x upper limit of normal
  8. For women of childbearing potential: willingness to use 2 forms of birth control

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 control 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 of participate in sperm donation during the study and for 6 weeks after discontinuing the drug
  7. Receipt of any investigational drug within 28 days
  8. End stage renal disease
  9. Cirrhosis
  10. International normalized ration (INR) > 1.4
  11. Platelets < 80,000
  12. 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01744093

Contacts
Contact: Charleen Hollmann, RN, PhD 646-962-2672 CORA@med.cornell.edu

Locations
United States, New York
Weill Cornell Medical College-New York Presbyterian Hospital Recruiting
New York, New York, United States, 10021
Contact: Charleen Hollmann, RN, PhD    646-962-2672    CORA@med.cornell.edu   
Principal Investigator: Robert Kaner, MD         
Sub-Investigator: Marshall Glesby, MD         
Sub-Investigator: Ronald Crystal, MD         
Sub-Investigator: Domenick Falcone, MD         
Sub-Investigator: Thomas Walsh, MD         
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Principal Investigator: Robert Kaner, MD Weill Cornell Medical College-New York Presbyterian Hospital
Study Chair: Marshall Glesby, MD Weill Cornell Medical College-New York Presbyterian Hospital
  More Information

No publications provided

Responsible Party: Robert J. Kaner, Associate Professor of Clinical Medicine, Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Genetic Medicine, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01744093     History of Changes
Other Study ID Numbers: 1208012780
Study First Received: November 20, 2012
Last Updated: May 27, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Weill Medical College of Cornell University:
HIV
COPD
Chronic Obstructive Pulmonary Disease
Emphysema

Additional relevant MeSH terms:
Emphysema
Pulmonary Emphysema
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Pathologic Processes
Respiratory Tract Diseases
Doxycycline
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on August 20, 2014