Doxycycline for Emphysema in People Living With HIV (The DEPTH Trial) (DEPTH)

The purpose of this study is to determine if doxycycline will reduce progression of emphysema in people living with HIV.

The secondary objectives are to examine the effects of doxycycline on change in quantity of emphysema, six minute walk distance, patient reported outcomes, ratio of forced expiratory volume in 1 second and forced vital capacity. Secondary objectives will also describe the safety and tolerability of doxycycline and determine if doxycycline is associated with development of antibiotic-resistant bacterial infections.

Study Overview

• Status: Recruiting
• Conditions: Emphysema; HIV
• Intervention / Treatment: Drug: Doxycycline; Drug: Placebo

Detailed Description

This study is a phase II, multicenter, randomized, double-blinded, placebo-controlled clinical trial in approximately 250 people living with HIV who have emphysema.

Eligible participants will be randomized in a 1:1 fashion to doxycycline or placebo. Participants will receive 100 mg doxycycline orally or matched placebo twice a day for 72 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robert J Kaner, MD; Phone Number: 646-962-2333; Email: rkaner@med.cornell.edu
• Study Contact Backup: Name: Alicia Morris; Phone Number: 646-962-2741; Email: ajm2017@med.cornell.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • University of Alabama at Birmingham
      • Contact: Mark Dransfield, MD; Phone Number: 205-934-5555; Email: mdransfield@uabmc.edu
      • Contact: E. Necole Seabron Harris; Phone Number: 205-934-9240; Email: nharris@uabmc.edu
      • Principal Investigator: Mark Dransfield, MD
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California Los Angeles
      • Contact: Igor Barjaktarevic, MD; Phone Number: 310-794-4224; Email: ibarjaktarevic@mednet.ucla.edu
      • Contact: Roslynn Marzan-McGill; Phone Number: 310-825-2616; Email: rmcgill@mednet.ucla.edu
      • Principal Investigator: Igor Barjaktarevic, MD
    • San Diego, California, United States, 92103
      • Recruiting
      • University of California San Diego
      • Contact: Maile Karris, MD; Phone Number: 858-342-3343; Email: m1young@health.ucsd.edu
      • Contact: Liliana Harkness; Phone Number: 619-543-8080; Email: ir003@health.ucsd.edu
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins University School of Medicine
      • Contact: Sarath Raju, MD; Phone Number: 951-529-0054; Email: sraju3@jhmi.edu
      • Contact: Marie Daniel; Phone Number: 410-550-0800; Email: mdaniel@jhmi.edu
      • Principal Investigator: Sarath Raju, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Crystal North; Phone Number: 617-724-0287; Email: CNORTH@mgh.harvard.edu
      • Contact: Matthew Planchon; Phone Number: 617-726-5596; Email: mplanchon@mgh.harvard.edu
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Rachel Presti, MD; Phone Number: 314-286-0345; Email: prestir@wustl.edu
      • Contact: Michael Klebert; Phone Number: 314-747-1098; Email: mklebert@wustl.edu
      • Principal Investigator: Rachel Presti, MD
  • New York
    • Brooklyn, New York, United States, 11203
      • Not yet recruiting
      • SUNY Downstate Medical School
      • Contact: Robert Foronjy, MD; Phone Number: 718-270-1662; Email: Robert.Foronjy@downstate.edu
      • Contact: Cassandra Charles; Phone Number: 718-270-1364; Email: cassandra.charles@downstate.edu
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medicine
      • Contact: Marshall J Glesby, MD, PhD; Phone Number: 212-746-4177; Email: mag2005@med.cornell.edu
      • Contact: Keisha Ballentine-Carter, NP; Email: keb4006@med.cornell.edu
      • Principal Investigator: Marshall J Glesby, MD, PhD
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • The University of North Carolina
      • Contact: Subhashini Sellers, MD; Phone Number: 984-974-5703; Email: sasellers@med.unc.edu
      • Contact: Ann Collins; Phone Number: (919) 843-4375; Email: Ann_Collins@med.unc.edu
    • Durham, North Carolina, United States, 27704
      • Recruiting
      • Duke University School of Medicine
      • Contact: David M Murdoch, MD, MPH; Phone Number: 919-470-4000; Email: david.murdoch@duke.edu
      • Contact: Ethan Bott; Phone Number: (907) 252-7029; Email: ethan.bott@duke.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Recruiting
      • University of Cincinnati College of Medicine
      • Contact: Carl Fichtenbaum, MD; Phone Number: 513-584-6361; Email: fichtecj@ucmail.uc.edu
      • Contact: Michelle Saemann; Phone Number: 513-584-2245; Email: saemanmd@UCMAIL.UC.EDU
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
      • Contact: Phillip T Diaz, MD; Phone Number: 614-293-4925; Email: philip.diaz@osumc.edu
      • Contact: Janice Drake; Phone Number: 614-366-2186; Email: janice.drake@osumc.edu
      • Principal Investigator: Phillip T Diaz, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Recruiting
      • Temple University
      • Contact: Gerard Criner, MD; Email: Gerard.Criner@tuhs.temple.edu
      • Contact: Joseph Lambert; Phone Number: 215-707-1359; Email: joseph.lambert@tuhs.temple.edu
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh
      • Contact: Allison Morris, MD; Phone Number: 412-624-8900; Email: Morrisa@upmc.edu
      • Contact: Cathy Kessinger; Phone Number: 412-624-8330; Email: kessingercj@upmc.edu
      • Principal Investigator: Allison Morris, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Not yet recruiting
      • University of Texas, McGovern Medical School
      • Contact: Jordan Lake, MD; Phone Number: 713-500-6767
      • Contact: Paula Debroy Monzon, MD; Phone Number: 713 500-6767
  • Washington
    • Seattle, Washington, United States, 98104
      • Recruiting
      • University of Washington
      • Contact: Lindsay Legg, LPN; Phone Number: 206-744-8748; Email: lmlegg@uw.edu
      • Contact: Engi Attia, MD; Phone Number: (206) 744-3356; Email: eattia@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female age 30 years and older at screening visit.
• HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to the enrollment visit, and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
• Current or former smoker with at least a 3 pack-year history of cigarette smoking at screening visit.

• Evidence of emphysema on high resolution CT (HRCT) of the chest done at pre-entry visit (Visit 2). Emphysema is defined as either:

  1. Mild, moderate, or severe emphysema assessed by central reader(s) at the CT Imaging Core; or
  2. Quantification of ≥ 5% of voxels with density < -950 Hounsfield Units (HU) as quantified by the CT Imaging Core.

All participants with emphysema by either or both criteria must have ≤ 35% of voxels with density < -950 HU.

• Screening and Entry DLCO measurements must be within 15% of each other. The PFT quality at both visits must be acceptable based on ATS Quality Criteria.

  1. Screening (Visit 1) Pulmonary Function Test meets ATS quality criteria as determined by a central reviewer at the PFT Reading Core (UCLA)
  2. Baseline (Visit 2) Pulmonary Function Test meets ATS quality criteria as determined by the central reviewer at the PFT Reading Core (UCLA), Site Investigator, or DEPTH Trial Leadership.
• HIV-1 RNA level < 200 copies/ml within 90 days prior to the Entry/Baseline visit by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
• CD4 cell count > 100 cells/mm3 within 90 days prior to the Entry/Baseline visit.by any US laboratory that has a CLIA certification or its equivalent.
• Stable antiretroviral therapy for greater than or equal to 8 weeks prior to the Entry/Baseline visit. Substitutions of one formulation of a drug for another are not considered changes in antiretroviral therapy for the purpose of defining stable therapy..
• Serum ALT and AST < 3 x upper limit of normal within 60 days prior to the Entry/Baseline visit.
• Participants on therapy for COPD must be on stable therapy for at least 4 weeks prior to the Entry/Baseline visit.
• Documentation of serum alpha-1-antitrypsin level above the lower limit of normal from a test done at any time prior to the Entry/Baseline visit.
• Provision of signed and dated written informed consent.
• Stated willingness to adhere to all study procedures and anticipated availability for the duration of the study.
• Life expectancy > 2 years in the opinion of the site investigator.
• Ability to take oral medication and willingness to adhere to the study drug.
• For individuals of reproductive potential, negative serum or urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL at the screening visit. This will be repeated at the Entry/Baseline visit.

Exclusion Criteria:

• Pulmonary infection, acute COPD exacerbation, acute opportunistic infection within 30 days prior to the Screening Visit 1 or Entry/Baseline Visit 2.
• Any acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to the Entry/Baseline visit.
• Decompensated cirrhosis defined as an acute deterioration in liver function in a patient with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage.
• History of, or planned, wedge resection, lobectomy, pneumonectomy, or lung volume reduction surgery.
• History of, or planned, endobronchial valve placement for lung volume reduction.
• Significant parenchymal lung disease other than emphysema or chronic bronchitis (e.g. sarcoidosis, MAI infection, pulmonary fibrosis, lung cancer, bullae/cysts from prior Pneumocystis pneumonia) that would preclude accurate quantification of emphysema.
• Previous allergy or intolerance to doxycycline or other drugs in the tetracycline class (e.g. minocycline, tetracycline).
• Breastfeeding individuals.
• Receipt of any investigational* drug within 30 days prior to the Entry/Baseline visit. Note: for the purpose of this protocol, investigational drug refers to a drug that is not FDA approved for any indication. COVID vaccines available under emergency use authorization are allowed.
• Need for concomitant use of barbiturates; carbamazepine; phenytoin
• Use of systemic retinoids (eg. Isotretinoin [Accutane]) or Vitamin A within 30 days prior to the Entry/Baseline visit. Note: Multivitamin containing Vitamin A use is permitted.
• Use of any systemic antibiotic (e.g., doxycycline or other tetracycline, azithromycin) within 7 days prior to the Entry/Baseline visit.
• 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.
• History of recurrent C. difficile infection or C. difficile infection within 30 days prior to the Entry/Baseline visit.
• Inability to stop supplemental oxygen for 15 minutes to perform a DLCO maneuver.
• Has changes to the chest that preclude adequate HRCT imaging (e.g. Metallic objects in the chest such as shrapnel or pacemaker leads)
• Current receipt of, or anticipated need to initiate, hemodialysis or peritoneal dialysis.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxycycline; Doxycycline 100mg orally twice a day	Drug: Doxycycline; Doxycycline 100 mg orally twice a day.
Placebo Comparator: Placebo; Matching placebo orally twice a day	Drug: Placebo; Matching placebo orally twice a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of decline (slope) of percent predicted diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin, carboxyhemoglobin and barometric pressure (indicated as ppDLCOadj) over the 72 week treatment period.	72 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline to week 48 in 6 minute walk test distance.		48 weeks
Change from baseline to week 72 in 6 minute walk test distance.		72 weeks
Change from baseline to week 48 in percent predicted diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin, carboxyhemoglobin and barometric pressure (ppDLCOadj).		48 weeks
Change from baseline to week 72 in percent predicted diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin, carboxyhemoglobin and barometric pressure (ppDLCOadj).		72 weeks
Change from baseline to week 72 in percentage of voxels < -950 Hounsfield Units (HU)		72 weeks
Change from baseline to week 48 in the COPD Activity Test (CAT) score	The COPD Assessment Test (CAT): CAT is an 8-item self-administered questionnaire. Scores range from 0 to 40. Higher scores denote a more severe impact of COPD on a patient's life.	48 weeks
Change from baseline to week 72 in the COPD Activity Test (CAT) score	The COPD Assessment Test (CAT): CAT is an 8-item self-administered questionnaire. Scores range from 0 to 40. Higher scores denote a more severe impact of COPD on a patient's life.	72 weeks
Change from baseline to week 48 in St. George's Respiratory Questionnaire (SGRQ) score	St. George's Respiratory Questionnaire (SGRQ): SGRQ is a 50-item respiratory disease-specific health-related quality of life (HRQOL) instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations.	48 weeks
Change from baseline to week 72 in St. George's Respiratory Questionnaire (SGRQ) score	St. George's Respiratory Questionnaire (SGRQ): SGRQ is a 50-item respiratory disease-specific health-related quality of life (HRQOL) instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations.	72 weeks
Change from baseline to week 48 in forced expiratory volume in 1 second (FEV1) (L)		48 weeks
Change from baseline to week 72 in forced expiratory volume in 1 second (FEV1) (L)		72 weeks
Change from baseline to week 48 in the ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC)		48 weeks
Change from baseline to week 72 in the ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC)		72 weeks
The number of adverse events	The number of adverse events regardless of relatedness to the intervention	72 weeks
The proportion of participants with at least 1 adverse event	The proportion of participants with at least 1 adverse event regardless of relatedness to the intervention	72 weeks
The number of serious adverse events.	Serious adverse events (SAEs) will include all treatment-emergent SAEs.	72 weeks
The proportion of participants with at least 1 serious adverse event.	The proportion of participants with at least 1 Serious adverse event (SAE). SAEs will include all treatment-emergent SAEs.	72 weeks
The proportion of participants with deaths.		72 weeks
The number of participants permanently discontinuing study medication due to adverse events.	The number of participants permanently discontinuing study medication due to treatment-emergent adverse events.	72 weeks
The proportion of participants permanently discontinuing study medication due to adverse events.	The proportion of participants permanently discontinuing study medication due to treatment-emergent adverse events.	72 weeks
The number of participants with development of culture proven antibiotic-resistant bacterial infection with reduced susceptibility or resistance to doxycycline (adverse event of special interest).		72 weeks
The proportion of participants with development of culture proven antibiotic-resistant bacterial infection with reduced susceptibility or resistance to doxycycline (adverse event of special interest).		72 weeks

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of California, Los Angeles; University of Michigan; University of Iowa
• Investigators: Principal Investigator: Marshall J Glesby, MD, PhD, Weill Medical College of Cornell University; Principal Investigator: Cathie Spino, ScD, University of Michigan; Principal Investigator: Robert J Kaner, MD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2022
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 19, 2022

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Chronic Disease; Pulmonary Emphysema; Emphysema; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: 22-02-307/22-04024730; DEPTH-001 (Other Identifier: Weill Cornell Medicine); UG3HL154944 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The de-identified analytic data will be prepared as SAS transport files or ASCII comma-delimited files with accompanying codebooks that describe the data and data structure. The redaction will employ best practices and will be consistent with NHLBI data sharing policies.
• IPD Sharing Time Frame: Study data will be shared through the NHLBI data repository, no later than 3 years after the end of the study or 2 years after the main paper reporting the results of the trial, whichever comes first.
• IPD Sharing Access Criteria: Data will be shared through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes