The design of this study is a prospective, open-label, randomized clinical trial of
omadacycline vs SOC antibiotics for the treatment of BJIs. We will follow subjects for
between 16 and 24 weeks, depending on the length of their antibiotic treatment, for the
purpose of determining tolerability, safety, and treatment success of prolonged use (> 4
weeks) of omadacycline in the treatment of BJIs. Subjects will be enrolled regardless of
race, ethnicity, or gender (as long as they are within 18 - 85 years of age).
Subjects will be given omadacycline-containing regimen versus SOC. Omadacycline will be
administered 300 mg orally daily without loading dose duration of therapy of between 4
and 12 weeks. The exact duration of therapy will be decided by the subject's treating
physician. In other words, the primary/consulting physician who is managing the treatment
of the subject's bone and joint infection will be the one who decides the length of the
antibiotic treatment.
Safety and tolerability of omadacycline through this study will be guaranteed for 12
weeks. At 12 weeks, if the treating physician wishes to extend therapy, subjects
receiving omadacycline will be transitioned to other SOC antibiotics. Medications will be
provided by the Investigational Drug Service (IDS) on The Lundquist Institute/Harbor-UCLA
campus, which supplies all research related medications to study subjects at our center.
Subjects will be enrolled as outpatients or as inpatients when discharge is expected in
the near future (< 1 week). Drs. Loren Miller and/or Amy Kang, the Co-Principal
Investigators, will advise the hospital staff of the study and seek their assistance in
identifying and notifying the study staff of possible subjects who have presented to the
Emergency Department, inpatient units, or outpatient clinic with BJI.
Our primary endpoint is treatment success 2-weeks after therapy completion. We
hypothesize that omadacycline will be non-inferior to SOC antibiotics for BJI treatment.
For descriptive purposes, treatment outcome will be further sub-categorized as one of the
following outcomes: treatment success, failure due (or probably due) to medication, and
failure not due (or unlikely due) to medication (e.g., surgical issues such as inadequate
source control). For our primary analysis, 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, definite 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, treatment failure will be subdivided into definite, probable,
and possible failure. Using definitions from the OVIVA trial, definite 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
orthopedic 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 treatment success, defined as lack of any category of
treatment failures (definite, probable, and possible) two weeks after therapy completion,
long-term treatment success, defined as lack of definite treatment failures 3 months
after treatment completion, long-term safety and tolerability, and medication adherence.
We will measure long-term treatment success by performing a phone survey 3 months after
antibiotic completion. Medication adherence will be measured by self-report. 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.
Subjects will receive an omadacycline-containing regimen versus SOC. Prior to
randomization, SOC antibacterial therapy will be selected by the subject's treating
physician. Omadacycline will be administered 300 mg orally daily without the loading
dose. We chose to omit the loading dose given that many of the enrolled subjects would
have received an IV therapy prior to omadacycline initiation and notable gastrointestinal
intolerabilities (nausea/vomiting) based on Phase-3 trial data. Subjects receiving
omadacycline will be counseled on appropriate timing of administration (fast for 4 hours
before dosing and no food for 2 hours after dosing) in light of the known food effects on
drug absorption. They will be instructed to avoid use of products containing aluminum,
calcium, or magnesium, bismuth subsalicylate, and iron containing preparations such as
dairy, antacids, and multivitamins for 4 hours post-dosing. Of note, omadacycline is
intrinsically resistant to Pseudomonas, Proteus, Providencia, and Morganella. If any of
these organisms are isolated and considered to be clinically relevant at the treating
physician's discretion, subject will receive concomitant oral or IV antibiotics in
addition to omadacycline. In the SOC group, oral therapy is required for S. aureus
treatment; adjunctive IV antibiotics will be permitted, similar to the omadacycline arm.