Doxycycline for COPD in HIV-Infected Patients

NCT ID: NCT01744093

Last Updated: 2022-07-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 61 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-08
• Study Completion Date: 2020-12-30

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.

Conditions

HIV; Chronic Obstructive Pulmonary Disease (COPD); Emphysema

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Doxycycline

100 mg twice daily (BID orally) x 24 weeks

Group Type: ACTIVE_COMPARATOR

Doxycycline

Intervention Type: DRUG

100 mg twice daily (BID orally) x 24 weeks

Placebo (sugar pill)

100 mg twice daily (BID orally) x 24 weeks

Group Type: PLACEBO_COMPARATOR

Placebo (sugar pill)

Intervention Type: DRUG

100 mg twice daily (BID orally) x 24 weeks

Interventions

Doxycycline

100 mg twice daily (BID orally) x 24 weeks

Intervention Type: DRUG

Placebo (sugar pill)

100 mg twice daily (BID orally) x 24 weeks

Intervention Type: DRUG

Other Intervention Names

Vibramycin; Placebo

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Weill Medical College of Cornell University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert Kaner, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Cornell Medical College-New York Presbyterian Hospital

Marshall Glesby, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Cornell Medical College-New York Presbyterian Hospital

Locations

Genetic Medicine

New York, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R34HL117352

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1208012780

Identifier Type: -

Identifier Source: org_study_id