Doxycycline for COPD in HIV-Infected Patients
Primary Purpose
HIV, Chronic Obstructive Pulmonary Disease (COPD), Emphysema
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Doxycycline
Placebo (sugar pill)
Sponsored by
About this trial
This is an interventional treatment trial for HIV focused on measuring HIV, COPD, Chronic Obstructive Pulmonary Disease, Emphysema
Eligibility Criteria
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
Sites / Locations
- Genetic Medicine
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Doxycycline
Placebo (sugar pill)
Arm Description
100 mg twice daily (BID orally) x 24 weeks
100 mg twice daily (BID orally) x 24 weeks
Outcomes
Primary Outcome Measures
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.
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
Secondary Outcome Measures
Clinical: Change in Pulmonary Function (FEV1)
FEV1 is the volume of air exhaled during the first second of a forced expiratory maneuver.
Percent Change in BAL MMP-9 Activity
Percent change of MMP-9 activity in bronchoalveolar lavage (BAL) fluid.
Doxycycline Levels
Doxycycline level in serum
Doxycycline Levels in BAL
Doxycycline levels in bronchoalveolar lavage (BAL) fluid.
Full Information
NCT ID
NCT01744093
First Posted
November 20, 2012
Last Updated
July 13, 2022
Sponsor
Weill Medical College of Cornell University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT01744093
Brief Title
Doxycycline for COPD in HIV-Infected Patients
Official Title
Doxycycline for COPD in HIV-Infected Patients
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Completed
Study Start Date
December 8, 2014 (Actual)
Primary Completion Date
June 30, 2017 (Actual)
Study Completion Date
December 30, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV, Chronic Obstructive Pulmonary Disease (COPD), Emphysema
Keywords
HIV, COPD, Chronic Obstructive Pulmonary Disease, Emphysema
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
61 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Doxycycline
Arm Type
Active Comparator
Arm Description
100 mg twice daily (BID orally) x 24 weeks
Arm Title
Placebo (sugar pill)
Arm Type
Placebo Comparator
Arm Description
100 mg twice daily (BID orally) x 24 weeks
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Other Intervention Name(s)
Vibramycin
Intervention Description
100 mg twice daily (BID orally) x 24 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo (sugar pill)
Other Intervention Name(s)
Placebo
Intervention Description
100 mg twice daily (BID orally) x 24 weeks
Primary Outcome Measure Information:
Title
Safety of Doxycycline, as Measured by the Number of Subjects With Any Treatment-related Adverse Events.
Description
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.
Time Frame
Up to 24 weeks
Title
Tolerability of Doxycycline, as Measured by the Number of Subjects With a Dose-limiting Toxicity
Description
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
Time Frame
Up to 24 weeks
Secondary Outcome Measure Information:
Title
Clinical: Change in Pulmonary Function (FEV1)
Description
FEV1 is the volume of air exhaled during the first second of a forced expiratory maneuver.
Time Frame
24 Weeks
Title
Percent Change in BAL MMP-9 Activity
Description
Percent change of MMP-9 activity in bronchoalveolar lavage (BAL) fluid.
Time Frame
12 Weeks
Title
Doxycycline Levels
Description
Doxycycline level in serum
Time Frame
12 Weeks
Title
Doxycycline Levels in BAL
Description
Doxycycline levels in bronchoalveolar lavage (BAL) fluid.
Time Frame
12 Week
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Kaner, MD
Organizational Affiliation
Weill Cornell Medical College-New York Presbyterian Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marshall Glesby, MD
Organizational Affiliation
Weill Cornell Medical College-New York Presbyterian Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Genetic Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
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Doxycycline for COPD in HIV-Infected Patients
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