Doxycycline for COPD in HIV-Infected Patients

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.

Study Overview

• Status: Completed
• Conditions: Emphysema; HIV; Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: Doxycycline; Drug: Placebo (sugar pill)

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Genetic Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Doxycycline; 100 mg twice daily (BID orally) x 24 weeks	Drug: Doxycycline; 100 mg twice daily (BID orally) x 24 weeks; Other Names: Vibramycin
Placebo Comparator: Placebo (sugar pill); 100 mg twice daily (BID orally) x 24 weeks	Drug: Placebo (sugar pill); 100 mg twice daily (BID orally) x 24 weeks; Other Names: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Robert Kaner, MD, Weill Cornell Medical College-New York Presbyterian Hospital; Principal Investigator: Marshall Glesby, MD, Weill Cornell Medical College-New York Presbyterian Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2014
• Primary Completion (Actual): June 30, 2017
• Study Completion (Actual): December 30, 2020

Study Registration Dates

• First Submitted: November 20, 2012
• First Submitted That Met QC Criteria: December 4, 2012
• First Posted (Estimate): December 6, 2012

Study Record Updates

• Last Update Posted (Actual): July 21, 2022
• Last Update Submitted That Met QC Criteria: July 13, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: HIV; COPD; Chronic Obstructive Pulmonary Disease; Emphysema
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: 1208012780; R34HL117352 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• product manufactured in and exported from the U.S.: No