Open Tibia Fracture
Conditions
Brief summary
Local application of antibiotics directly to the traumatic wound is a promising strategy for the prevention of infection after open tibia fractures, which are a significant source of disease burden globally, particularly in low-income countries. This pilot study aims to assess feasibility of a randomized controlled trial to measure the effect of locally applied gentamicin on risk of infection for open tibial fractures in Tanzania. If proven effective, local gentamicin would be a highly cost-effective strategy to reduce complications and disability from open tibial fractures that could impact care in both high- and low-income countries.
Detailed description
This pilot study is being conducted in Dar es Salaam, Tanzania to assess the feasibility of a masked, placebo-controlled, randomized trial to compare local gentamicin injection to saline injection in open tibial shaft fractures. The study will enroll patients within 1 week of injury. The active or placebo agent will be administered during the initial surgical debridement based on a web-based randomization tool. Patients will be followed for 1 year after surgery to assess for the occurrence of fracture-related infection (FRI), a consensus definition of infection after open fracture or insertion of internal fixation to treat fracture. Additional clinical and economic endpoints will also be measured. Depending on the outcome of the feasibility study, we may undertake a definitive trial to test the effectiveness of local gentamicin to prevent FRI. If proven effective, local gentamicin would impact the clinical care of open fracture patients both in Tanzania and likely in high-income settings as well. These data will also deepen the understanding of the clinical and economic impact of FRI in open fracture populations.
Interventions
DRUGlocal gentamicin injection
Treatment includes debridement and administration of the local antibiotic which will consist of 80mg of liquid gentamicin diluted in 40mL normal saline injected after inserting a 22 gauge needle down to bone after wound closure. The injection will continue until either all 40cc are injected or there is fluid extravasation from the wound.
Treatment includes debridement and administration of the local antibiotic which will consist of 40mL normal saline injected after inserting a 22 gauge needle down to bone after wound closure. The injection will continue until either all 40cc are injected or there is fluid extravasation from the wound.
Sponsors
Muhimbili Orthopaedic Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Patients will receive gentamicin in saline solution or placebo saline injection while under anesthesia during the index surgery. Only the local research pharmacist, the UCSF clinical trial manager, and the DSMC will be unmasked.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Male or female patients age 18 or older 2. Diagnosis of an acute open tibial shaft fracture meeting the following criteria: 1. AO/OTA Type 42 2. Primarily closable wound 3. Type I, II, or IIIA Gustilo- Anderson (GA) Classification
Exclusion criteria
1. Time from injury to presentation \> 48 hours 2. Time from injury to surgery \>7 days 3. History of Aminoglycoside allergy 4. GA IIIB or IIIC open fractures 5. Bilateral open tibial fractures 6. Severe brain (GCS\<12) or spinal cord injury 7. Severe vascular injury 8. Sustained severe burns (\>10% total body surface area (TBSA) or \>5% TBSA with full thickness or circumferential injury) 9. Pathologic fracture 10. History of active limb infection, ipsilaterally
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Enrollment | Baseline | The number of participants enrolled in the clinical trial per month will be measured to assess feasibility of the definitive clinical trial. |
| Occurrence of Fracture-related Infection (FRI) | 1 year | The primary outcome for the definitive trial is occurrence of fracture-related infection (FRI), a binary variable. Any of the four following diagnostic criteria are confirmatory for FRI: 1. fistula, sinus or wound breakdown 2. purulent drainage from the wound or presence of pus during surgery 3. phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens 4. presence of microorganisms in deep tissue taken during an operative intervention, as seen on histopathological examination. All primary events will be reviewed by a masked adjudication committee comprised of 3 non-treating fellowship-trained orthopaedic trauma surgeons. |
| Rate of Retention | 1 year | The percentage of patients completing 1 year follow up relative to the total number of participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Function Index for Trauma (FIX-IT) Score | 1 year | Clinical healing of the fracture will be assessed using the Function index for trauma (FIX-IT) score, which evaluates weight bearing and pain in patients with lower extremity fractures. The FIX-IT score is a clinical outcomes assessment measure ranging from 0 to 12 points in two domains: the ability to bear weight (maximum 6 points) and pain at the fracture site (maximum 6 points). The maximum score of 12 indicates the highest level of function. |
| Euro-Qol 5 Dimensions (EQ-5D) | 1 year | EuroQol-5 Dimensions (EQ-5D) measures general health status in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The raw score will be translated to a utility score ranging from 0 (death or no health) to 1 (perfect health) on a continuous scale using health-state valuations from Zimbabwe. |
| Modified Radiographic Union Scale for Tibial Fractures (mRUST) Score | 1 year | Radiographic healing as measured by the modified Radiographic Union Scale for Tibial fractures (mRUST). mRUST scores each cortex on an AP and lateral radiograph from a score of 1 (no callus) to 4 (remodeled, fracture not visible). Thus, mRUST ranges from 4 (worst healing score) to 16 (best healing score). |
| Occurrence of Nonunion | 1 year | Nonunion is a binary variable defined by the following criteria: 1. any unplanned reoperation for promotion of bone healing; OR 2. mRUST\<=10 AND either: FIX-IT score \<=11 at 12-month follow-up OR recommendation by treating surgeon for nonunion repair surgery |
| Occurrence of Fracture-related Reoperation | 1 year | This binary variable includes reoperation for infection, wound healing, or fracture union, and excludes the removal of implants for prominence/irritation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Indirect Medical Costs | 1 year | Indirect (time) costs, such as lost productivity, will be measured using the Work Productivity and Activity Impairment questionaire (WPAI) |
| Microbiology of FRI | 1 year | For cases undergoing reoperation for which deep tissue cultures are taken, the frequency of each bacterial species will be reported as a percentage of total FRI for both treatment groups. |
| Direct Medical Costs | 1 year | Direct medical costs of treatment (continuous), including medications, personnel, and supplies will be measured for both the intervention and control groups. |
| C-Reactive Protein Level | 6 weeks | C-Reactive protein (CRP) is a known inflammatory marker which may show signs of early infection. The value will be measured in all patients and reported at 6 weeks post-surgery. |
Countries
Tanzania
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gentamicin Injection at Fracture Site Subjects with an open tibia fracture who receive gentamicin in saline solution administered after closure at the time of initial debridement.
local gentamicin injection: Treatment includes debridement and administration of the local antibiotic which will consist of 80mg of liquid gentamicin diluted in 40mL normal saline injected after inserting a 22 gauge needle down to bone after wound closure. The injection will continue until either all 40cc are injected or there is fluid extravasation from the wound. | 45 |
| Placebo Saline Injection at Fracture Site Subjects with an open tibia fracture who receive placebo saline solution administered after closure at the time of initial debridement.
placebo saline injection: Treatment includes debridement and administration of the local antibiotic which will consist of 40mL normal saline injected after inserting a 22 gauge needle down to bone after wound closure. The injection will continue until either all 40cc are injected or there is fluid extravasation from the wound. | 55 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 9 | 7 |
Baseline characteristics
| Characteristic | Gentamicin Injection at Fracture Site | Placebo Saline Injection at Fracture Site | Total |
|---|---|---|---|
| Age, Continuous | 34.9 years STANDARD_DEVIATION 14 | 32.5 years STANDARD_DEVIATION 11 | 33.6 years STANDARD_DEVIATION 12 |
| Mechanism of Injury Crush Injury | 2 Participants | 3 Participants | 5 Participants |
| Mechanism of Injury Fall | 2 Participants | 3 Participants | 5 Participants |
| Mechanism of Injury Gunshot | 2 Participants | 0 Participants | 2 Participants |
| Mechanism of Injury Other | 2 Participants | 2 Participants | 4 Participants |
| Mechanism of Injury Road Traffic Injury | 37 Participants | 47 Participants | 84 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Tanzania | 45 participants | 55 participants | 100 participants |
| Sex: Female, Male Female | 12 Participants | 8 Participants | 20 Participants |
| Sex: Female, Male Male | 33 Participants | 47 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 2 / 55 |
| other Total, other adverse events | 5 / 45 | 5 / 55 |
| serious Total, serious adverse events | 0 / 45 | 0 / 55 |
Outcome results
Primary
Occurrence of Fracture-related Infection (FRI)
The primary outcome for the definitive trial is occurrence of fracture-related infection (FRI), a binary variable. Any of the four following diagnostic criteria are confirmatory for FRI: 1. fistula, sinus or wound breakdown 2. purulent drainage from the wound or presence of pus during surgery 3. phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens 4. presence of microorganisms in deep tissue taken during an operative intervention, as seen on histopathological examination. All primary events will be reviewed by a masked adjudication committee comprised of 3 non-treating fellowship-trained orthopaedic trauma surgeons.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Enrollment | Occurrence of Fracture-related Infection (FRI) | 9 Participants |
| Placebo Saline Injection at Fracture Site | Occurrence of Fracture-related Infection (FRI) | 7 Participants |
Primary
Rate of Enrollment
The number of participants enrolled in the clinical trial per month will be measured to assess feasibility of the definitive clinical trial.
Time frame: Baseline
Population: For pilot trial feasibility aims, the outcomes are presented for all trial participants rather than by arm to match the a priori feasibility targets for the definitive trial.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Overall Enrollment | Rate of Enrollment | 12.5 Participants enrolled per month |
Primary
Rate of Retention
The percentage of patients completing 1 year follow up relative to the total number of participants
Time frame: 1 year
Population: For pilot trial feasibility aims, the outcomes are presented for all trial participants rather than by arm to match the a priori feasibility targets for the definitive trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Enrollment | Rate of Retention | 84 Participants |
Secondary
Euro-Qol 5 Dimensions (EQ-5D)
EuroQol-5 Dimensions (EQ-5D) measures general health status in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The raw score will be translated to a utility score ranging from 0 (death or no health) to 1 (perfect health) on a continuous scale using health-state valuations from Zimbabwe.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Enrollment | Euro-Qol 5 Dimensions (EQ-5D) | 0.950 units on a scale from 0 to 1 | Standard Deviation 0.101 |
| Placebo Saline Injection at Fracture Site | Euro-Qol 5 Dimensions (EQ-5D) | 0.938 units on a scale from 0 to 1 | Standard Deviation 0.195 |
Secondary
Function Index for Trauma (FIX-IT) Score
Clinical healing of the fracture will be assessed using the Function index for trauma (FIX-IT) score, which evaluates weight bearing and pain in patients with lower extremity fractures. The FIX-IT score is a clinical outcomes assessment measure ranging from 0 to 12 points in two domains: the ability to bear weight (maximum 6 points) and pain at the fracture site (maximum 6 points). The maximum score of 12 indicates the highest level of function.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Enrollment | Function Index for Trauma (FIX-IT) Score | 10.9 score on a scale | Standard Deviation 2.7 |
| Placebo Saline Injection at Fracture Site | Function Index for Trauma (FIX-IT) Score | 11.2 score on a scale | Standard Deviation 2.5 |
Secondary
Modified Radiographic Union Scale for Tibial Fractures (mRUST) Score
Radiographic healing as measured by the modified Radiographic Union Scale for Tibial fractures (mRUST). mRUST scores each cortex on an AP and lateral radiograph from a score of 1 (no callus) to 4 (remodeled, fracture not visible). Thus, mRUST ranges from 4 (worst healing score) to 16 (best healing score).
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Enrollment | Modified Radiographic Union Scale for Tibial Fractures (mRUST) Score | 11.9 score on a scale from 4-16 | Standard Deviation 2.9 |
| Placebo Saline Injection at Fracture Site | Modified Radiographic Union Scale for Tibial Fractures (mRUST) Score | 12.0 score on a scale from 4-16 | Standard Deviation 3.1 |
Secondary
Occurrence of Fracture-related Reoperation
This binary variable includes reoperation for infection, wound healing, or fracture union, and excludes the removal of implants for prominence/irritation.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Enrollment | Occurrence of Fracture-related Reoperation | 3 Participants |
| Placebo Saline Injection at Fracture Site | Occurrence of Fracture-related Reoperation | 1 Participants |
Secondary
Occurrence of Nonunion
Nonunion is a binary variable defined by the following criteria: 1. any unplanned reoperation for promotion of bone healing; OR 2. mRUST\<=10 AND either: FIX-IT score \<=11 at 12-month follow-up OR recommendation by treating surgeon for nonunion repair surgery
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Enrollment | Occurrence of Nonunion | 7 Participants |
| Placebo Saline Injection at Fracture Site | Occurrence of Nonunion | 6 Participants |
Other Pre-specified
C-Reactive Protein Level
C-Reactive protein (CRP) is a known inflammatory marker which may show signs of early infection. The value will be measured in all patients and reported at 6 weeks post-surgery.
Time frame: 6 weeks
Other Pre-specified
Direct Medical Costs
Direct medical costs of treatment (continuous), including medications, personnel, and supplies will be measured for both the intervention and control groups.
Time frame: 1 year
Other Pre-specified
Indirect Medical Costs
Indirect (time) costs, such as lost productivity, will be measured using the Work Productivity and Activity Impairment questionaire (WPAI)
Time frame: 1 year
Other Pre-specified
Microbiology of FRI
For cases undergoing reoperation for which deep tissue cultures are taken, the frequency of each bacterial species will be reported as a percentage of total FRI for both treatment groups.
Time frame: 1 year