Clinical trial NCT05382208: Doxycycline for Emphysema in People Living With HIV (The DEPTH Trial)
Official title: Doxycycline for Emphysema in People Living With HIV (The DEPTH Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Emphysema
HIV
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: University of California, Los Angeles
name: University of Iowa
name: University of Michigan
First posted: 2022-05-19
Enrollment: 250
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 72 weeks
Secondary outcomes:
measure: Change from baseline to week 48 in 6 minute walk test distance.
timeFrame: 48 weeks
measure: Change from baseline to week 72 in 6 minute walk test distance.
timeFrame: 72 weeks
measure: Change from baseline to week 48 in percent predicted diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin, carboxyhemoglobin and barometric pressure (ppDLCOadj).
timeFrame: 48 weeks
measure: Change from baseline to week 72 in percent predicted diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin, carboxyhemoglobin and barometric pressure (ppDLCOadj).
timeFrame: 72 weeks
measure: Change from baseline to week 72 in percentage of voxels < -950 Hounsfield Units (HU)
timeFrame: 72 weeks
measure: Change from baseline to week 48 in the COPD Activity Test (CAT) score
timeFrame: 48 weeks
measure: Change from baseline to week 72 in the COPD Activity Test (CAT) score
timeFrame: 72 weeks
measure: Change from baseline to week 48 in St. George's Respiratory Questionnaire (SGRQ) score
timeFrame: 48 weeks
measure: Change from baseline to week 72 in St. George's Respiratory Questionnaire (SGRQ) score
timeFrame: 72 weeks
measure: Change from baseline to week 48 in forced expiratory volume in 1 second (FEV1) (L)
timeFrame: 48 weeks
measure: Change from baseline to week 72 in forced expiratory volume in 1 second (FEV1) (L)
timeFrame: 72 weeks
measure: Change from baseline to week 48 in the ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC)
timeFrame: 48 weeks
measure: Change from baseline to week 72 in the ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC)
timeFrame: 72 weeks
measure: The number of adverse events
timeFrame: 72 weeks
measure: The proportion of participants with at least 1 adverse event
timeFrame: 72 weeks
measure: The number of serious adverse events.
timeFrame: 72 weeks
measure: The proportion of participants with at least 1 serious adverse event.
timeFrame: 72 weeks
measure: The proportion of participants with deaths.
timeFrame: 72 weeks
measure: The number of participants permanently discontinuing study medication due to adverse events.
timeFrame: 72 weeks
measure: The proportion of participants permanently discontinuing study medication due to adverse events.
timeFrame: 72 weeks
measure: 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).
timeFrame: 72 weeks
measure: 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).
timeFrame: 72 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Miami
country: United States
facility: Miami University
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Brooklyn
country: United States
facility: SUNY Downstate Medical School
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University School of Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati College of Medicine
state: Ohio
city: Cleveland
country: United States
facility: Case Western University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas, McGovern Medical School
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Weill Medical College of Cornell University
name: Marshall J Glesby, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Cathie Spino, ScD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College of Cornell University
name: Robert J Kaner, MD
role: PRINCIPAL_INVESTIGATOR
References: