1/2 Doxycycline for Emphysema in People Living with HIV: The DEPTH Trial

深度试验代表了一种延缓人类肺气肿进展的创新方法。 感染艾滋病毒(PLWH)的人群加速了疾病的发展，但没有针对性的目标 心理治疗。我们提出了一项II期、多中心、随机、双盲、安慰剂对照试验。 多西环素100 mg口服延缓肺气肿的进展 现吸烟者或曾经吸烟者的总吸烟量(DLCO)。符合条件的肺气肿参与者 控制良好的艾滋病毒将被随机分为多西环素或安慰剂，按吸烟状况分层(目前 与既往吸烟者相比)和临床地点，采用动态随机分组。这项研究的主要终点是 在72周的治疗期间，预计DLCO的下降率(斜率)。我们已经组建了一支 经验丰富的临床站点团队，拥有有效登记和实施的患者群体和专业知识 这场审判。 在我们之前的研究中，我们观察到HIV+早期肺气肿患者的基质增加。 细支气管肺泡组织中的金属蛋白酶(基质金属蛋白酶-2、-7、-9、-12，均与肺气肿发病有关) 灌洗(BAL)液体样本。因此，MMP是旨在修改的潜在干预目标 肺气肿的进展，特别是在艾滋病毒携带者中。我们成功地证明了这一点的可行性 在我们的NHLBI资助的单中心随机、双盲、安慰剂对照的先导研究中进行测试的方法 多西环素(FDA批准作为一种基质金属蛋白酶抑制剂)的安全性和耐受性，以防止组织破裂 牙周病)超过24周(新台币01744093)。我们研究了27名艾滋病和慢性阻塞性肺病/肺气肿患者。 多西环素随机2：1口服，每日2次或安慰剂100 mg。除了可接受的安全性和耐受性外， 弥散能力(DLCO)趋于稳定，肺泡灌洗液基质金属蛋白酶-9(MMP9)减少 被分配到多西环素手臂的参与者的活动。深度试验将延长这些有希望的试点数据 进行正式的二期临床试验。 我们预计，在完成这项拟议的研究后，我们的数据将支持将廉价的 抗生素多西环素，用于延缓PLWH的肺气肿进展。具体地说，我们希望展示： 1.多西环素延缓PLWH中肺气肿的进展，主要由DLCO和 其次是HRCT。 2.多西环素口服治疗肺气肿患者72周是安全、耐受的。 3.多西环素可改善肺气肿患者的呼吸生活质量和功能状态。

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.