SAVE- Oral Antibiotics for Treatment of Vertebral Osteomyelitis (SAVE)

Early Shift to Oral Antibiotic Treatment for Pyogenic Vertebral Osteomyelitis (SAVE) - a Open Label Non-inferiority Nation-wide Study

Background The current Danish National Guideline for treatment of pyogenic vertebral osteomyelitis (PVO) recommends 6 weeks antibiotic (AB) treatment, with a 2-week intravenous (IV) AB lead-in followed by 4 weeks oral AB for uncomplicated PVO, and 12 weeks AB treatment with a 2-4-week IV AB lead-in followed by 8 weeks oral AB for complicated PVO.

The primary objective of the current study is to investigate whether shortening the duration of IV AB to one week for both complicated and uncomplicated PVO is non-inferior to the current Danish National Guideline.

Study Overview

• Status: Recruiting
• Conditions: Osteomyelitis; Vertebra
• Intervention / Treatment: Other: Early shift til oral antibiotic treatment for osteomyelitis

• Study Type: Observational
• Enrollment (Estimated): 530

Contacts and Locations

• Study Contact: Name: Anne-Mette Lebech, MD; Phone Number: +4535458622; Email: anne-mette.lebech@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
    • Contact: Anne-Mette C Lebech, MD; Phone Number: +4535458622; Email: anne-mette.lebech@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study will be a nationwide, multicenter, investigator initiated, randomized, controlled, parallel group, open label, non-inferiority trial.

The study will be conducted at departments of infectious diseases in Denmark and in collaboration with spinal surgery units carrying out infection-related spinal surgery.

All patients diagnosed with PVO will be assessed for eligibility. Patients will be eligible for inclusion if they fulfill all the inclusion and none of the exclusion criteria.

Description

Inclusion Criteria:

1. Age ≥18 years
2. Diagnosed with PVO by a physician based on clinical symptoms and findings consistent with PVO in combination with diagnostic imaging (MRI, PET/CT or PET/MRI)
3. The physician responsible for the patient decides to treat the patient for PVO
4. At time of randomization CRP has decreased to < 75% of peak value or to < 20 mg/l
5. At the time of randomization patient has received maximum 7 days of appropriate IV AB for PVO -

Exclusion Criteria:

1. Previous episodes of PVO within the past 24 months
2. Spinal implants inserted prior to current episode of PVO
3. Hypersensitivity to an AB intended for use in the patient and no alternative drugs available.
4. Oral ABs not possible due to suspicion of reduced absorption
5. Oral Abs not possible due to verified or expected bacterial susceptibility or due to expected toxicity of available regimen
6. Identification of fungus, mold, TB, Brucella, Actinomyces, Nocardia and P. aeruginosa as etiology
7. Severe immunocompromise defined as primary immunodeficiencies, uncontrolled HIV/AIDS, organ transplant recipients, hematological malignancies, patients undergoing biological therapy or chemotherapy and patients treated with prednisolone >=20 mg daily >14 days
8. Verified or expected reduced compliance (for example iv drug use)
9. Pregnancy
10. Breastfeeding
11. Women of childbearing potential, who at the time of inclusion are not using and/or who will not use an effective anticonception method during the treatment period.
12. Patients not capable of providing informed consent at time of screening for inclusion
13. Diagnosed or suspected concomitant or unrelated infections necessitating IV AB therapy beyond 7 days of duration at the time of randomization -

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Standart of care; Standard of care (comparator); Uncomplicated PVO: 2 weeks IV ABs followed by oral ABs for 4 weeks.; Complicated PVO: 2-4 weeks IV ABs followed by oral ABs for 8 weeks.
Early shift; Early shift to oral ABs (intervention); Uncomplicated PVO: 1 week IV ABs followed by 5 weeks of oral ABs.; Complicated PVO: 1 week IV ABs followed by 11 weeks of oral ABs.	Other: Early shift til oral antibiotic treatment for osteomyelitis; To investigate whether early transition to oral AB treatment after one week of IV treatment is non-inferior to the current national guideline of continued IV AB treatment for two to four weeks followed by oral AB treatment for PVO.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary outcome	All-cause mortality	Six months after completion of oral antibiotic treatment
Primary outcome	Unplanned surgical intervention in relation to the spine	Six months after completion of oral antibiotic treatment
Primary outcome	Relapse of bacteremia with primary pathogen	Six months after completion of oral antibiotic treatment
Primary outcome	Relapse of bacteria with the initial pathogen being cultured from relevant material from infected areas in relation to the spine or iliopsoas muscle (detected by culture)	Six months after completion of oral antibiotic treatment
Primary outcome	Renewed course of intravenous antibiotic given for more than 7 days for treatment of pyogenic vertebral osteomyelitis	Six months after completion of oral antibiotic treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary outcome 1	Occurrence of each component of the composite primary endpoint from the time of shift to oral AB treatment to six months after completion of oral AB treatment.	Six months after completion of oral antibiotic treatment
Secondary outcome 2	Median duration of hospital admission(s) from the time of shift to oral AB treatment to six months after completion of oral AB treatment (Admission defined as overnight stay at the department)	Six months after completion of oral antibiotic treatment
Secondary outcome 3	Number of readmissions from the time of shift to oral AB treatment to six months after completion of oral AB treatment	Six months after completion of oral antibiotic treatment
Secondary outcome 4	Proportion of patients receiving additional oral AB therapy beyond the duration defined in the protocol	Six months after completion of oral antibiotic treatment
Secondary outcome 5	Proportion of patients having early termination of allocated treatment strategy due to adverse events, patient preference, or any other reason	Six months after completion of oral antibiotic treatment
Secondary outcome 6	Proportion of patients experiencing complications associated with IV treatment (e.g., catheter infections, phlebitis, bleeding, venous thrombosis, need for replacement of catheter) from the time of initiation of IV treatment for PVO to six months after completion of oral AB treatment	Six months after completion of oral antibiotic treatment
Secondary outcome 7	Proportion of patients experiencing severe adverse events from ABs from the time of initiation of IV treatment for PVO to six months after completion of oral AB treatment	Six months after completion of oral antibiotic treatment
Secondary outcome 8	Proportion of patients experiencing adverse events from ABs from the time of initiation of IV treatment for PVO to six months after completion of oral AB treatment	Six months after completion of oral antibiotic treatment
Secondary outcome 9	Proportion of patients diagnosed with Clostridioides difficile associated diarrhea from the time of initiation of IV treatment for PVO to six months after completion of oral AB treatment	Six months after completion of oral antibiotic treatment
Secondary outcome 10	Quality of life scores (EQ-5D) at the following timepoints: Randomization, 1 week after the end of AB therapy, 1 month after the end of AB therapy, 6 months after the end of oral AB therapy, and 12 months after the end of oral AB therapy	Six months after completion of oral antibiotic treatment
Secondary outcome 11	Resource allocation/cost assessment determined by a combination of EQ5D, DALYs, Days of hospital admission and antibiotic prescribing costs	Six months after completion of oral antibiotic treatment
Secondary outcome 12	CRP, WBC, alkaline phosphatase and procalcitonin at randomization as well as CRP, WBC, alkaline phosphatase weekly during treatment and at week 4, 12 and 24 after completion of oral AB treatment.	Six months after completion of oral antibiotic treatment
Secondary outcome 13	Presence of microbial cell-free DNA in blood samples at the time of randomization and 6 months after the end of oral AB therapy	Six months after completion of oral antibiotic treatment

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: November 29, 2023
• First Submitted That Met QC Criteria: January 31, 2024
• First Posted (Actual): February 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Infectious; Osteomyelitis; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: 2023-507617-96-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No