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

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.

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:

• Mild, moderate, or severe emphysema assessed by central reader(s) at the CT Imaging Core; or
• 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.

• Screening (Visit 1) Pulmonary Function Test meets ATS quality criteria as determined by a central reviewer at the PFT Reading Core (UCLA)
• 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.