Controlled Trial of Omadacycline Randomized Treatment Given for Bone and Joint Infection (CORGI)

Omadacycline Versus Standard-of-Care Oral Antibiotic Treatment for Bone and Joint Infections: An Open-Label, Non- Inferiority, Randomized, Controlled Trial

The study design is a randomized, open-label, clinical trial of omadacycline vs Standard of Care (SOC) antibiotics for bone and join infection (BJI) treatment. Study participants will have their BJI regimen chosen by their treating physicians, (typically Infectious Diseases for hardware and prosthetic joint infections, or multidisciplinary Limb Salvage team for diabetic foot infections) prior to enrollment. Then participants will be randomized to an omadacycline-containing regimen versus the a priori chosen SOC regimen. Participants must require between 4 and 12 weeks of therapy for their BJI. The exact duration of therapy will be decided by the participants' treating physician. At 12 weeks, if the treating physician wishes to extend therapy, participants receiving omadacycline will be transitioned to other SOC antibiotics. Once enrolled, participants will be followed via in-person clinic visits at the following intervals: weeks 0, 2, 4, 8, and 12. A final in-person visit will occur 2 weeks post-treatment completion. A phone survey will occur 3 months post-treatment completion. Participants in the SOC group will follow the same schedule. Oral once-daily dosing options for S. aureus and Coagulase negative Staphylococcus are essentially non-existent. Thus, omadacycline possesses a novel and advantageous option for BJI treatment. Its convenient dosing regimen will almost certainly be associated with improved adherence, and higher adherence may, in turn, improve clinical outcome. Investigators hypothesize that omadacycline will be a well-tolerated and efficacious oral antibiotic for BJIs and will be associated with improved adherence compared with standard of care oral antibiotics. Investigators believe omadacycline addresses the unmet need for an oral antibiotic that is well-tolerated and efficacious for use as a prolonged therapy for BJIs. To this aim, investigators will perform a randomized, open-label clinical trial of omadacycline to SOC antibiotics for BJIs.

The study design is a randomized, open-label, clinical trial of omadacycline vs Standard of Care (SOC) antibiotics for bone and join infection (BJI) treatment. Study participants will have their BJI regimen chosen by their treating physicians, (typically Infectious Diseases for hardware and prosthetic joint infections, or multidisciplinary Limb Salvage team for diabetic foot infections) prior to enrollment. Then participants will be randomized to an omadacycline-containing regimen versus the a priori chosen SOC regimen. Participants must require between 4 and 12 weeks of therapy for their BJI. The exact duration of therapy will be decided by the participants' treating physician. At 12 weeks, if the treating physician wishes to extend therapy, participants receiving omadacycline will be transitioned to other SOC antibiotics. The primary endpoint is treatment efficacy 2-weeks after therapy completion. Investigators hypothesize that omadacycline will be non-inferior to SOC antibiotics for BJI treatment. For our primary analysis, investigators will dichotomize outcomes to treatment success and treatment failure. Treatment success will be defined as the lack of definite treatment failure. Treatment failure will be defined using the definition utilized in the OVIVA trial. Specifically, failure will be defined as the presence of at least one clinical criterion (draining sinus tract arising from bone or prosthesis or the presence of frank pus adjacent to bone or prosthesis), microbiologic criterion (phenotypically indistinguishable bacteria isolated from two or more deep-tissue samples or a pathogenic organism from a single closed aspirate or biopsy), or histologic criterion (presence of characteristic inflammatory infiltrate or microorganisms). For descriptive purposes, failure will be subdivided into definite failure, probable failure, and possible failure. Using definitions from the OVIVA trial, definite evidence of treatment failure will be defined by one or more of the following: a) isolating bacteria from 2 or more samples of bone/peri-prosthetic tissue, where the bacteria isolated from these samples were indistinguishable according to routine laboratory tests, including the antibiogram; b) a pathogenic organism (e.g. Staphylococcus aureus but not Staphylococcus epidermidis) on a single, closed, biopsy of native bone or periprosthetic tissue; c) diagnostic histology on bone/peri-prosthetic tissue; d) a draining sinus tract arising from bone/prosthesis; or e) frank pus adjacent to bone/ prosthesis. If any of these criteria are met, then the category "definitive" infection will be applied. Where these criteria are not met, the following criteria will be used to determine "probable" or "possible" infection: Infection will be categorized as "probable", where microbiological sampling had not been undertaken, AND none of the other criteria for definite infection had been fulfilled AND any one of the following are met: a) Radiological or operative findings of periosteal changes suggesting chronic osteomyelitis OR b) Radiological findings suggesting vertebral infection OR c) The development of a discharging wound after an orthopaedic procedure where prosthetic material had been implanted OR d) The presence of deep pus close to but not adjacent to bone/prosthetic joint/orthopedic device OR e) The presence of peri-prosthetic necrotic bone OR f) Rapid loosening of a joint prosthesis/orthopedic device (i.e. leading to localized pain in less than 3 months since implantation) in the absence of a mechanical explanation for rapid loosening. Infection will be categorized as "possible" where microbiological sampling had been undertaken with negative results (according to criteria described above for "definite" infection) AND other criteria for definite infection were not fulfilled AND in addition one or more of the criteria listed a) to f) above is met. Secondary endpoints include long-term efficacy, safety, tolerability, medication adherence, early discontinuation of the randomly assigned treatment strategy, and probable or possible treatment failure. Investigators will measure long-term efficacy by performing a phone survey 3 months after antibiotic completion. Definition of treatment efficacy will be same as primary endpoint, which is specified above. Unplanned surgical procedures prompted by inadequate infection control will be categorized as treatment failure. Recurrence of signs or symptoms of BJIs after resolution will be considered a long-term treatment failure. Once enrolled, participants will be followed via in-person clinic visits at the following intervals: weeks 0, 2, 4, 8, and 12. A final in-person visit will occur 2 weeks post-treatment completion. A phone survey will occur 3 months post-treatment completion. Participants in the SOC group will follow the same schedule. Oral once-daily dosing options for S. aureus and Coagulase negative Staphylococcus are essentially non-existent. Thus, omadacycline possesses a novel and advantageous option for BJI treatment. Its convenient dosing regimen will almost certainly be associated with improved adherence, and higher adherence may, in turn, improve clinical outcome. Investigators hypothesize that omadacycline will be a well-tolerated and efficacious oral antibiotic for BJIs and will be associated with improved adherence compared with standard of care oral antibiotics. Investigators believe omadacycline addresses the unmet need for an oral antibiotic that is well-tolerated and efficacious for use as a prolonged therapy for BJIs. To this aim, investigators will perform a randomized, open-label clinical trial of omadacycline to SOC antibiotics for BJIs.

Subjects will receive an omadacycline-containing regimen versus SOC. Prior to randomization, SOC antibacterial therapy will be selected by the subject's treating physician.

Prior to randomization, SOC antibacterial therapy will be selected by the subject's treating physician.

To compare the treatment success, as defined by lack of definite treatment failure, of omadacycline versus standard of care (SOC) antibiotics for bone and joint infections (BJIs) two weeks after therapy completion.

We will dichotomize outcomes to treatment success and treatment failure. Treatment success will be defined as the lack of definite treatment failure. Treatment failure will be defined using the definition utilized in the OVIVA trial. Specifically, failure will be defined as the presence of at least one clinical criterion (draining sinus tract arising from bone or prosthesis or the presence of frank pus adjacent to bone or prosthesis), microbiologic criterion (phenotypically indistinguishable bacteria isolated from two or more deep-tissue samples or a pathogenic organism from a single closed aspirate or biopsy), or histologic criterion (presence of characteristic inflammatory infiltrate or microorganisms).

Quantify the long term efficacy of omadacycline for BJIs, both non-hardware and hardware associated after therapy completion.

We will measure long-term efficacy by performing a phone survey 3 months after antibiotic completion. Definition of treatment efficacy will be same as primary endpoint. Unplanned surgical procedures prompted by inadequate infection control will be categorized as treatment failure. Recurrence of signs or symptoms of BJIs after resolution will be considered a long-term treatment failure.

Inclusion Criteria: Diagnosis of BJI or probable BJI as defined clinically using radiologic (e.g., MRI), surgical (e.g., intra-operative findings), and/or clinical (e.g., probe to bone) definitions 2. BJI caused by or suspected to be caused by organisms that are susceptible to omadacycline Planned treatment duration of 4-12 weeks Plans to continue or initiate treatment in outpatient setting Age 18-85 Limited planned course of antibiotics (i.e., no indefinite treatment plans for chronic suppression) Able to take oral medications Able to come to the research clinic for study follow-up visits for the study period If a woman is of childbearing potential, she must consistently use two acceptable methods of contraception (IUD, injectable contraceptive, birth control patch, OCP, barrier method, abstinence) from baseline through the course of antibiotics (4-12 weeks). If a male patient's sexual partner is of childbearing potential, the male patient must acknowledge that they will consistently use an acceptable method of contraception as defined above from baseline through the course of antibiotics (4-12 weeks). Exclusion Criteria: Pregnancy or breast feeding. Women of childbearing potential must have a negative urine or serum pregnancy test result within 1 day prior to initiation of study drug. Hypersensitivity to tetracycline-class antibiotics BJI caused by fungi or mycobacteria BJI complicated by endocarditis, central nervous system involvement such as subdural abscess, or any foci of metastatic infection, such as renal or splenic abscesses Prosthetic joint infections that have not undergone both stages of two stages of surgical treatments (i.e., subjects are only eligible after the 2nd stage surgery has been completed and typically 6 weeks of IV therapy has been completed) Hematogenous BJI prior to adequate treatment for bacteremia (i.e., subjects are only eligible after adequate IV course of bacteremia is completed and additional oral therapy is still required for infection "mop up") Any medical, psychological, or social condition that, in the opinion of the Investigator, would prevent the patient from fully participating in the study or would represent a concern for study compliance or constitute a safety concern to the patient