Clinical trial NCT05699174: PO vs IV Antibiotics for the Treatment of Infected Nonunion of Fractures After Fixation
Official title: PO Versus IV Antibiotics for the Treatment of Infected Nonunion of Fractures After Fixation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Infections
Infected Wound
Nonunion of Fracture
Injury Leg
Amputation
Internal Fixation; Complications, Infection or Inflammation
Fracture
Lower Extremity Fracture
Antibiotic Side Effect
Lead sponsor: Major Extremity Trauma Research Consortium
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2023-01-26
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two arm, randomized controlled multicenter Phase III trial
Primary purpose: TREATMENT

Brief summary: This is a Phase III clinical randomized control trial to investigate differences between patient with an infected nonunion treated by PO vs. IV antibiotics. The study population will be 250 patients, 18 years or older, being treated for infected nonunion after internal fixation of a fracture with a segmental defect less than one centimeter. Patients will be randomly assigned to either the treatment (group 1) PO antibiotics for 6 weeks or the control group (group 2) IV antibiotics for 6 weeks. The primary hypothesis is that the effectiveness of oral antibiotic therapy is equivalent to traditional intravenous antibiotic therapy for the treatment of infected nonunion after fracture internal fixation, when such therapy is combined with appropriate surgical management. Clinical effectiveness will be measured as the primary outcome as the number of secondary re-admissions related to injury and secondary outcomes of treatment failure (re-infection, nonunion, antibiotic complications) within the first one year of follow-up, as defined by specified criteria and determined by a blinded data assessment panel. In addition, treatment compliance, the cost of treatment, the number of surgeries required, the type and incidence of complications, and the duration of hospitalization will be measured.

Detailed description: This is a Phase III clinical randomized control trial to investigate differences between patient with an infected nonunion treated by PO vs. IV antibiotics. The study population will be 250 patients, 18 years or older, being treated for infected nonunion after internal fixation of a fracture with a segmental defect less than one centimeter. Patients will be randomly assigned to either the treatment (group 1) PO antibiotics for 6 weeks or the control group (group 2) IV antibiotics for 6 weeks. The primary hypothesis is that the effectiveness of oral antibiotic therapy is equivalent to traditional intravenous antibiotic therapy for the treatment of infected nonunion after fracture internal fixation, when such therapy is combined with appropriate surgical management. Clinical effectiveness will be measured as the primary outcome as the number of secondary re-admissions related to injury and secondary outcomes of treatment failure (re-infection, nonunion, antibiotic complications) within the first one year of follow-up, as defined by specified criteria and determined by a blinded data assessment panel. In addition, treatment compliance, the cost of treatment, the number of surgeries required, the type and incidence of complications, and the duration of hospitalization will be measured.

The specific Aims of this study are to:

Specific Aim 1. Evaluate the effect of treatment of infected nonunion in bone fractures treated with revision fixation and either: (Group 1) operative debridement and PO antibiotic suppression for 6 weeks; or (Group 2) operative debridement and 6 weeks IV antibiotics.

Primary Hypothesis 1a: The rate of re-hospitalization for injury-related complication by one year in Group 1 will be non-inferior to the rate in Group 2.

Hypothesis 1b:. The rate of treatment failure by one year in Group 1 will be non-inferior to the rate in Group 2.

Hypothesis 1c: The rate of persistent infection by one year in Group 1 will be non-inferior to the rate in Group 2.

Hypothesis 1d: The rate of persistent nonunion by one year in Group 1 will be non-inferior to the rate in Group 2.

Hypothesis 1e: The rate of amputation by one year in Group 1 will be non-inferior to the rate in Group 2. Hypothesis 1f: Per patient total costs at 1 year will be lower in Group 1 than in Group 2.

Hypothesis 1g: Compliance in Group 1 will be non-inferior to compliance in Group 2.

Specific Aim 2. Build and validate a risk prediction model for failure of treatment of infected nonunion after fixation of fractures.

Hypothesis 2a: Demographic and injury characteristics will be highly predictive of treatment failure.

Hypothesis 2b: Open fractures will have a higher treatment failure rate than closed fractures.

Hypothesis 2c: Lower extremity fractures will have a higher treatment failure rate than upper extremity fractures.

Hypothesis 2d: Multiple organism infections will have a higher treatment failure rate than single organism infections.

Hypothesis 2e: Gram positive infections will have a higher treatment failure rate than gram negative infections.

Hypothesis 2f: Revision fixation with IMN and treatment failure will be non-inferior to the rate of treatment failure in revision fixation with plates.

Hypothesis 2g: Revision fixation with external fixation and treatment failure will be non-inferior to the rate of treatment failure in revision fixation with IMN or plates.

Hypothesis 2h: One Stage revision fixation strategies will be non-inferior to the rate of treatment failure in Two Staged revision fixation strategies

Study design: At time of treatment for infected nonunion, patients will be randomized to oral (PO) antibiotics group or intravenous (IV) antibiotics group. Patients will receive PO or IV antibiotics for 6 weeks at discharge from the hospitalization to treat the infected nonunion. Both groups will otherwise receive standard care treatment by attending orthopedic surgeon and healthcare team, including debridement and soft tissue coverage of wounds; laboratory evaluation of inflammatory markers at 2 weeks, and 6 weeks; clinical follow at 2 weeks, 6 weeks, 3 months, 6 months, and 12 months to assess recurrence of wound infection; and radiographic follow up at 6 weeks and 3 months or until boney union is confirmed.

Follow-Up: Assessments at baseline and at 2 weeks, 6 weeks, 3 months, 6 months and 12 months following hospital discharge will determine rates of re-hospitalization, treatment failure, infection, nonunion and amputation and patient compliance with antibiotic treatment.

Eligibility criteria: Inclusion Criteria:

1. Nonunion of a fracture that has previously undergone fixation. A Nonunion is defined as unplanned surgery with the primary purpose to promote union based on clinical/radiographic evidence \>3 months after last fixation
2. Infection as determined by either

   1. FRI criteria
   2. CDC criteria (without the timeframe) This includes the possibility of culture negative, but determined to be infection by treating surgeon
3. Systemic antibiotic treatment regimen scheduled for at least 6 weeks

Exclusion Criteria:

1. Patients with a high risk of amputation based on the initial managing physician
2. Patients undergoing treatment of any other investigational therapy within the month preceding infection treatment or planned within the 12 months following infection treatment
3. Incarcerated or institutionalized patients
4. Patients who are unable to return for required follow-up visits and/or medical co-morbidities which preclude treatment with a general anesthetic
5. Patients with a prior history of chronic infection at the index site before fracture fixation
6. Patients with pathological fractures from a neoplastic process
7. History of Paget's Disease
8. The patient, or a designated proxy, unwilling to provide consent
9. The patient must be available for follow-up for at least 12 months following infection treatment

Primary outcomes:
measure: Number of patients with a hospital re-admission
timeFrame: 1 year
Secondary outcomes:
measure: Number of patients with treatment failure
timeFrame: 1 year
measure: Number of patients with a re-hospitalization for a complication
timeFrame: 1 year
measure: Number of patients with an additional infection
timeFrame: 1 year
measure: Number of patients that experienced amputation
timeFrame: 1 year
measure: Medical Costs
timeFrame: 1 year
measure: Patient Reported Outcomes
timeFrame: 1 year
measure: Physical and Psychosocial Function Assessment
timeFrame: 1 year
measure: Adherence
timeFrame: 6 months
measure: Compliance
timeFrame: 6 months
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland , MD Department of Orthopaedics
state: Maryland
city: Minneapolis
country: United States
facility: Hennepin Health
state: Minnesota
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: Charlotte
country: United States
facility: Atrium Health, Carolinas Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Hershey
country: United States
facility: Penn State University M.S. Hershey Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Seattle
country: United States
facility: University of Washington Harborview Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Vanderbilt Medical Center
name: William Obremskey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins Bloomberg School of Public Health
name: Renan Castillo, PhD
role: PRINCIPAL_INVESTIGATOR
References: