Non-Inferiority Study of Early Oral Antibiotic Transition in Pyogenic Vertebral Osteomyelitis: Ceftriaxone, Moxifloxacin, and Cloxacillin Evaluation

The primary objective of this study is to evaluate whether an early transition to oral **antibiotic** (AB) treatment after one week of intravenous (IV) treatment is non-inferior to the current national guideline, which recommends continued IV AB treatment for two to four weeks followed by oral AB treatment for **pyogenic vertebral osteomyelitis** (PVO). This is clinically relevant as it may lead to a reduction in hospital stay duration and associated healthcare costs, while maintaining treatment efficacy.

Secondary objectives include:

• Comparing the proportion of patients experiencing treatment-related adverse events between treatment arms at six months after oral AB treatment cessation.
• Comparing the average total number of hospital admission days between treatment arms at six months after oral AB treatment cessation.
• Comparing self-assessed health-related quality of life (EQ5D) during and until 12 months following cessation of antibiotic therapy.
• Assessing the economic impact of early shift from IV to oral AB at 6 months following cessation of antibiotic therapy.
• Assessment of sequencing of microbial cell-free DNA as a diagnostic tool in blood from patients with PVO.

The clinical trial focuses on individuals diagnosed with **pyogenic vertebral osteomyelitis**. The study population includes both male and female participants aged 18 years and older. Participants are required to have been diagnosed with the condition by a physician, based on clinical symptoms and diagnostic imaging, and must have received a maximum of seven days of appropriate intravenous antibiotic treatment for the condition at the time of randomization. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants have a decreased C-reactive protein level, indicating a response to initial treatment. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of an early transition from intravenous (IV) to oral antibiotic treatment in patients with **pyogenic vertebral osteomyelitis**. This study is a randomized, open-label, non-inferiority trial, comparing the standard treatment protocol of two to four weeks of IV antibiotics followed by oral antibiotics, against a regimen of one week of IV antibiotics followed by oral antibiotics. The trial is expected to commence on February 1, 2024, and conclude by June 30, 2027.

Participants will be randomly assigned to either the control group, receiving the standard treatment, or the experimental group, receiving the early transition treatment. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and a final end-of-study visit to assess the primary and secondary endpoints. The primary endpoint is a composite measure of all-cause mortality, unplanned surgical interventions, relapse of bacteremia, and other related complications occurring from the time of transition to oral antibiotics to six months post-treatment.

The expected duration of participant involvement is approximately 12 months, with the treatment phase lasting up to 12 weeks, depending on the assigned group. Participants may be withdrawn from the study early due to adverse events, patient preference, or other significant reasons. The trial will also assess secondary endpoints, including the occurrence of individual components of the primary endpoint, duration of hospital admissions, readmissions, and quality of life scores at various time points. The study aims to provide evidence on the safety and effectiveness of early transition to oral antibiotics, potentially influencing future treatment guidelines for pyogenic vertebral osteomyelitis.

The clinical trial involves the administration of several **antibiotics** to evaluate their efficacy in the treatment of pyogenic vertebral osteomyelitis. **Ceftriaxone** is administered intravenously with a maximum daily dose of 4 grams and a total maximum dose of 112 grams over a treatment period of up to 4 weeks. The pharmaceutical form is PHF00201MIG, and it is a chemical-origin substance.

**Moxifloxacin** is provided orally with a maximum daily dose of 400 milligrams and a total maximum dose of 33,600 milligrams over a 12-week period. The pharmaceutical form is PHF00230MIG, and it is also of chemical origin.

**Cloxacillin** is administered intravenously, with a maximum daily dose of 4 grams and a total maximum dose of 112 grams over a 4-week period. The pharmaceutical form is PHF675, and it is a chemical-origin substance.

**Sulfamethoxazole and Trimethoprim** are administered orally, with a maximum daily dose of 620 milligrams and a total maximum dose of 52,080 milligrams over a 12-week period. The pharmaceutical form is PHF00170MIG, and both substances are of chemical origin.

**Dicloxacillin** is provided orally, with a maximum daily dose of 4 grams and a total maximum dose of 336 grams over a 12-week period. The pharmaceutical form is PHF675, and it is a chemical-origin substance.

**Vancomycin** is administered intravenously, with a maximum daily dose of 2 grams and a total maximum dose of 56 grams over a 4-week period. The pharmaceutical form is PHF00230MIG, and it is a chemical-origin substance.

**Clindamycin** is provided orally, with a maximum daily dose of 1800 milligrams and a total maximum dose of 151,200 milligrams over a 12-week period. The pharmaceutical form is PHF00180MIG, and it is a chemical-origin substance.

**Flucloxacillin Sodium** is administered orally, with a maximum daily dose of 6 grams and a total maximum dose of 504 grams over a 12-week period. The pharmaceutical form is PHF00201MIG, and it is a chemical-origin substance.

**Linezolid** is provided orally, with a maximum daily dose of 1200 milligrams and a total maximum dose of 100,800 milligrams over a 12-week period. The pharmaceutical form is PHF00101MIG, and it is a chemical-origin substance.

**Rifampicin** is administered orally, with a maximum daily dose of 1200 milligrams and a total maximum dose of 100,800 milligrams over a 12-week period. The pharmaceutical form is PHF00170MIG, and it is a chemical-origin substance.

**Cefuroxime** is administered intravenously, with a maximum daily dose of 9 grams and a total maximum dose of 252 grams over a 4-week period. The pharmaceutical form is PHF00230MIG, and it is a chemical-origin substance.

**Ciprofloxacin** is provided orally, with a maximum daily dose of 1500 milligrams and a total maximum dose of 126,000 milligrams over a 12-week period. The pharmaceutical form is PHF00230MIG, and it is a chemical-origin substance.

**Meropenem** is administered intravenously, with a maximum daily dose of 6 grams and a total maximum dose of 504 grams over a 12-week period. The pharmaceutical form is a solution for injection/infusion, and it is not entirely of chemical origin.

**Amoxicillin** is provided orally, with a maximum daily dose of 4 grams and a total maximum dose of 336 grams over a 12-week period. The pharmaceutical form is PHF00170MIG, and it is a chemical-origin substance.

**Sodium Fusidate** is administered orally, with a maximum daily dose of 1500 milligrams and a total maximum dose of 126,000 milligrams over a 12-week period. The pharmaceutical form is a film-coated tablet, and it is a chemical-origin substance.

**Ampicillin** is administered intravenously, with a maximum daily dose of 12 grams and a total maximum dose of 1008 grams over a 12-week period. The pharmaceutical form is PHF00243MIG, and it is not entirely of chemical origin.

**Phenoxymethylpenicillin Benzathine** is provided orally, with a maximum daily dose of 8 million international units and a total maximum dose of 672 million international units over a 12-week period. The pharmaceutical form is PHF00170MIG, and it is a chemical-origin substance.

**Amoxicillin and Clavulanic Acid** are administered orally, with a maximum daily dose of 4000 milligrams and a total maximum dose of 336,000 milligrams over a 12-week period. The pharmaceutical form is PHF00082MIG, and both substances are of chemical origin.

**Benzylpenicillin** is administered intravenously, with a maximum daily dose of 20 million international units and a total maximum dose of 560 million international units over a 4-week period. The pharmaceutical form is PHF00231MIG, and it is a chemical-origin substance.

Participant compliance is monitored through regular assessments and adherence checks to ensure the correct administration of the medications as per the dosing schedules. The trial aims to determine the non-inferiority of early transition to oral antibiotic treatment compared to the standard intravenous treatment for pyogenic vertebral osteomyelitis.

Efficacy in this clinical trial will be assessed using a composite primary endpoint, which includes the following parameters: all-cause mortality, unplanned surgical intervention related to the spine, relapse of bacteremia with the primary pathogen, relapse of bacteria with the initial pathogen cultured from relevant material from infected areas, and a renewed course of intravenous antibiotics given for more than seven days for **pyogenic vertebral osteomyelitis** (PVO). These events will be monitored from the time of shift to oral antibiotic treatment to six months after the completion of oral antibiotic treatment.

Secondary endpoints will include the occurrence of each component of the composite primary endpoint, median duration of hospital admissions, number of readmissions, and the proportion of patients receiving additional oral antibiotic therapy beyond the protocol-defined duration. Additional secondary endpoints will assess the proportion of patients with early termination of treatment due to adverse events or other reasons, complications associated with intravenous treatment, severe adverse events from antibiotics, and adverse events from antibiotics. The trial will also evaluate the proportion of patients diagnosed with Clostridioides difficile-associated diarrhea, quality of life scores using EQ-5D at specified timepoints, and resource allocation/cost assessment. Biomarkers such as CRP, WBC, alkaline phosphatase, and procalcitonin will be measured at randomization and weekly during treatment, as well as at weeks 4, 12, and 24 after completion of oral antibiotic treatment. The presence of microbial cell-free DNA in blood samples will be assessed at randomization and six months after the end of oral antibiotic therapy.