Doxycycline for COPD in HIV-Infected Patients

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01744093
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 61
• Location: 1
• Arms: 2
• Actual Duration (Months): 72.7
• Patients Per Site Per Month: 0.8

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
HIV; Chronic Obstructive Pulmonary Disease (COPD); Emphysema	Drug: Doxycycline; Drug: Placebo (sugar pill)	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Doxycycline for COPD in HIV-Infected Patients
• Actual Study Start Date: Dec 8, 2014
• Actual Primary Completion Date: Jun 30, 2017
• Actual Study Completion Date: Dec 30, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Safety of Doxycycline, as Measured by the Number of Subjects With Any Treatment-related Adverse Events. [Up to 24 weeks]

   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.

2. Tolerability of Doxycycline, as Measured by the Number of Subjects With a Dose-limiting Toxicity [Up to 24 weeks]

   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

1. Clinical: Change in Pulmonary Function (FEV1) [24 Weeks]

   FEV1 is the volume of air exhaled during the first second of a forced expiratory maneuver.

2. Percent Change in BAL MMP-9 Activity [12 Weeks]

   Percent change of MMP-9 activity in bronchoalveolar lavage (BAL) fluid.

3. Doxycycline Levels [12 Weeks]

   Doxycycline level in serum

4. Doxycycline Levels in BAL [12 Week]

   Doxycycline levels in bronchoalveolar lavage (BAL) fluid.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Genetic Medicine	New York	New York	United States	10021

Sponsors and Collaborators

• Weill Medical College of Cornell University
• 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 Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 15, 2018

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01744093
• Other Study ID Numbers: 1208012780; R34HL117352
• First Posted: Dec 6, 2012
• Last Update Posted: Jul 21, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Weill Medical College of Cornell University: HIV; COPD; Chronic Obstructive Pulmonary Disease; Emphysema
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema; Doxycycline

Study Results

Participant Flow

Pre-assignment Detail	Of the 61 subjects enrolled into the study, 34 subjects did not pass screening.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	Doxycycline x 100 mg twice daily (BID orally) for 24 weeks	One pill twice daily (BID orally) for 24 weeks
Period Title: Overall Study
STARTED	18	9
Treated	16	8
COMPLETED	12	8
NOT COMPLETED	6	1

Baseline Characteristics

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)	Total
Arm/Group Description	Doxycycline x 100 mg BID (orally) for 24 weeks	Placebo (sugar pill) x 100 mg BID (orally) for 24 weeks	Total of all reporting groups
Overall Participants	18	9	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	9 100%	27 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	5 27.8%	1 11.1%	6 22.2%
Male	13 72.2%	8 88.9%	21 77.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 11.1%	0 0%	2 7.4%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	16 88.9%	9 100%	25 92.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 11.1%	0 0%	2 7.4%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 55.6%	7 77.8%	17 63%
White	4 22.2%	2 22.2%	6 22.2%
More than one race	2 11.1%	0 0%	2 7.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	18 100%	9 100%	27 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

2 subjects were randomized to the doxycycline arm, but withdrew prior to starting the study drug. 1 subject was randomized to the placebo arm, but withdrew prior to starting the study drug.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	Doxycycline x 100 mg BID (orally) for 24 weeks	Placebo (sugar pill) x 100 mg BID (orally) for 24 weeks
Measure Participants	16	8
Count of Participants [Participants]	3 16.7%	1 11.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxycycline
	Comments
	Type of Statistical Test	Other
	Comments	Descriptive proportion
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion (percent)
	Estimated Value	18.8
	Confidence Interval	(2-Sided) 95%; 4.0 to 45.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Exact two-sided 95% Clopper-Pearson confidence interval.

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

2 subjects were randomized to the doxycycline arm, but withdrew prior to starting the study drug. 1 subject was randomized to the placebo arm, but withdrew prior to starting the study drug.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	100 mg twice daily (BID orally) x 24 weeks Doxycycline: 100 mg twice daily (BID orally) x 24 weeks	100 mg twice daily (BID orally) x 24 weeks Placebo (sugar pill): 100 mg twice daily (BID orally) x 24 weeks
Measure Participants	16	8
Count of Participants [Participants]	1 5.6%	1 11.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxycycline
	Comments	Null hypothesis adverse event rate (grade 2 or higher toxicity) = 45.5%
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Proportion (percent)
	Estimated Value	6.3
	Confidence Interval	(2-Sided) 95%; 0.16 to 30.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Exact two-sided 95% Clopper-Pearson confidence interval.

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

At 24 Weeks, total 7 subjects were not analyzed at Week 24. With arm-Doxycycline, 6 subjects dropped out; with arm-Placebo, 1 subject dropped out.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	100 mg twice daily (BID orally) x 24 weeks Doxycycline: 100 mg twice daily (BID orally) x 24 Weeks	One pill twice daily (BID orally) x 24 Weeks Placebo (sugar pill): One pill twice daily (BID orally) x 24 Weeks
Measure Participants	12	8
Median (Inter-Quartile Range) [Percentage of predicted FEV1]	-1.5	1

4. Secondary Outcome

Title	Percent Change in BAL MMP-9 Activity
Description	Percent change of MMP-9 activity in bronchoalveolar lavage (BAL) fluid.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

With arm-Doxy, 8 subjects were not analyzed at Week 12 because 5 subjects dropped out, 2 subjects had an inadequate sample, 1 subject could not have the bronchoscopy. With arm-Placebo, 2 subjects were not analyzed at Week 12 because 1 subject dropped out and 1 subject could not have the bronchoscopy.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	100 mg twice daily (BID orally) x 24 Weeks	One pill twice daily (BID orally) x 24 Weeks
Measure Participants	10	7
Median (Inter-Quartile Range) [Percent change]	-42	21

5. Secondary Outcome

Title	Doxycycline Levels
Description	Doxycycline level in serum
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

With arm-Doxy, 6 subjects were not analyzed at Week 12 because 5 subjects dropped out, 1 subject did not provide a sample. With arm-Placebo, 2 subjects were not analyzed at Week 12 because 1 subject dropped out and 1 subject did not provide a sample.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	100 mg twice daily (BID orally) x 24 Weeks Doxycycline: 100 mg twice daily (BID orally) x 24 Weeks	One pill (BID orally) x 24 Weeks Placebo (sugar pill): One pill twice daily (BID orally) x 24 Weeks
Measure Participants	12	7
Median (Inter-Quartile Range) [ng/ml]	3005	0

6. Secondary Outcome

Title	Doxycycline Levels in BAL
Description	Doxycycline levels in bronchoalveolar lavage (BAL) fluid.
Time Frame	12 Week

Outcome Measure Data

Analysis Population Description

With arm-Doxy, 6 subjects were not analyzed at Week 12 because 5 subjects dropped out, 1 subject could not have the bronchoscopy. With arm-Placebo, 2 subjects were not analyzed at Week 12 because 1 subject dropped out and 1 subject could not have the bronchoscopy.

Arm/Group Title	Doxycycline	Placebo (Sugar Pill)
Arm/Group Description	100 mg twice daily (BID orally) x 24 Weeks Doxycycline: 100 mg twice daily (BID orally) x 24 Weeks	One pill (BID orally) x 24 Weeks Placebo (sugar pill): One pill twice daily (BID orally) x 24 Weeks
Measure Participants	12	7
Median (Inter-Quartile Range) [ng/ml]	16.75	0

Adverse Events

Time Frame	24 Weeks
Adverse Event Reporting Description	Clinical assessments included full physical examination at screening, targeted physical examinations at other visits, ongoing assessments for adverse events and new clinical diagnoses and CAT review at each visit. Safety labs were obtained at weeks 2, 6, 12, 18, and 24. 2 participants in the doxycycline arm and 1 participant in the placebo arm were not evaluated for adverse events because they did not take the study drug.
Arm/Group Title	Doxycycline		Placebo (Sugar Pill)
Arm/Group Description	Doxycycline x 100 mg BID (orally) for 24 weeks.		Placebo (sugar pill) x 100 mg BID (orally) for 24 weeks.
All Cause Mortality
	Doxycycline		Placebo (Sugar Pill)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/8 (0%)
Serious Adverse Events
	Doxycycline		Placebo (Sugar Pill)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Doxycycline		Placebo (Sugar Pill)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/16 (81.3%)		6/8 (75%)
Blood and lymphatic system disorders
Hemoglobin drop	1/16 (6.3%)	1	0/8 (0%)	0
Low absolute neutrophil count	1/16 (6.3%)	1	0/8 (0%)	0
Gastrointestinal disorders
Mouth lesions	1/16 (6.3%)	1	0/8 (0%)	0
Intermittent diarrhea for 4-5 wk	1/16 (6.3%)	1	0/8 (0%)	0
Vomiting	1/16 (6.3%)	1	0/8 (0%)	0
General disorders
Tiredness	1/16 (6.3%)	1	3/8 (37.5%)	3
Infections and infestations
Oral thrush	1/16 (6.3%)	1	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Pain on right side	1/16 (6.3%)	1	0/8 (0%)	0
Nervous system disorders
Headache	1/16 (6.3%)	1	0/8 (0%)	0
Renal and urinary disorders
Elevated Creatinine	0/16 (0%)	0	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/16 (6.3%)	1	2/8 (25%)	2
Hemoptysis (mild)	1/16 (6.3%)	1	1/8 (12.5%)	1
Skin and subcutaneous tissue disorders
Excoriated lesions on arms	1/16 (6.3%)	1	0/8 (0%)	0
Scattered maculopapular rash	1/16 (6.3%)	1	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.