1/2 doxycycline for emphysema in people living with HIV: the depth trial - the depth trial represents an innovative approach to slowing the progression of emphysema in people living with HIV (plwh), a…

1/2 doxycycline for emphysema in people living with HIV: the depth trial - the depth trial represents an innovative approach to slowing the progression of emphysema in people living with HIV (plwh), a population that has accelerated disease progression for which there is no targeted therapy. We propose a phase II, multi-center, randomized, double-blind, placebo-controlled trial of doxycycline 100 MG PO bid to slow the progression of emphysema as assessed by change in diffusing capacity (dlco) among plwh who are current or former smokers. Eligible participants with emphysema and well-controlled HIV will be randomized 1:1 to doxycycline or placebo, stratified by smoking status (current VS former smoker) and clinical site, utilizing dynamic randomization. The primary endpoint of the study is the rate of decline (slope) of percent predicted dlco over the 72-week treatment period. We have assembled a team of experienced clinical sites that has the patient population and expertise to efficiently enroll and conduct this trial. In our previous studies, we observed that HIV+ individuals with early emphysema have increased matrix metalloproteinases (MMP-2, -7, -9, -12; each implicated in emphysema pathogenesis) in bronchoalveolar lavage (BAL) fluid samples. Mmps are therefore potential targets for intervention aimed at modifying progression of emphysema specifically in people with HIV. We successfully demonstrated the feasibility of this approach in our nhlbi-funded single-center randomized, double-blind, placebo-controlled pilot study to test the safety and tolerability of doxycycline (FDA-approved as an MMP inhibitor to prevent tissue breakdown in GUM disease) over 24 weeks (NCT 01744093). We studied 27 individuals with HIV and copd/emphysema randomized 2:1 to doxycycline 100 MG PO bid or placebo. In addition to acceptable safety and tolerability, there were trends toward stabilization of the diffusing capacity (dlco) and a reduction of BAL fluid MMP-9 activity in participants assigned to the doxycycline arm. The depth trial will extend these promising pilot data to a formal phase II clinical trial. We anticipate that upon completion of this proposed study, our data will support repurposing the inexpensive antibiotic doxycycline, to slow emphysema progression in plwh. Specifically we expect to show: 1. Doxycycline slows the progression of emphysema in plwh, as assessed primarily by dlco and secondarily by hrct. 2. Doxycycline is safe and tolerable when taken orally for 72 weeks in plwh who have emphysema. 3. Doxycycline improves respiratory quality of life and functional status in plwh who have emphysema.