Novel strategies for treatment of Mycobacterium abscessus pulmonary disease

PROJECT SUMMARY Pulmonary disease due to Mycobacterium abscessus complex (MABC) causes significant morbidity, particularly in older women and people with underlying lung disease. MABC is intrinsically resistant to most antimicrobials. Existing treatments have poor efficacy, effectiveness and tolerability. Moreover, knowledge gaps have hampered the design and implementation of clinical trials of new antimicrobial therapies for this disease. Omadacycline is a relatively new tetracycline antibiotic that has promising in vitro and in vivo activity against MABC. Observational studies by our team and others support a role for omadacycline in treatment of MABC pulmonary disease, but rigorous clinical trials have not been performed. We propose a clinical trial that addresses two key knowledge gaps. First, in a randomized, blinded, placebo-controlled trial we seek to determine the efficacy and safety of omadacycline, in combination with other antimicrobials, for treatment of MABC pulmonary disease. Second, we seek to define a strategy for conducting clinical trials for treatment of MABC pulmonary disease, as currently there is no established clinical trial paradigm. To do this we will incorporate microbiologic, radiographic, and patient reported outcomes and explore pharmacokinetic drivers of efficacy and safety outcomes. The specific aims of this R34 clinical trial planning grant are AIM 1) to develop the detailed trial protocol and additional documentation required for initiation of the trial; AIM 2) to secure a study- specific supply of omadacycline and matched placebo; AIM 3) to identify additional enrollment sites (in addition to sites of the proposing investigators); AIM 4) to complete the regulatory approvals necessary for implementation of the trial; and AIM 5) to apply for NIH R-level funding to support the future conduct of the trial. We have gathered a team whose members have the requisite experience and expertise to successfully design, plan, and execute the future clinical trial. Regardless of outcome, the proposed novel clinical trial will meaningfully inform clinical practice and advance the science of clinical trials for MABC pulmonary disease, and thereby will have potential for high impact on the field and on health.