Pilot RCT Local Gentamicin for Open Tibial Fractures in Tanzania

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin Versus Saline in Open Tibia Fractures

Conditions
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Open Tibia Fracture

Intervention / Treatment
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* Drug: local gentamicin injection
* Drug: placebo saline injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients age 18 or older Diagnosis of an acute open tibial shaft fracture meeting the following criteria: AO/OTA Type 42 Primarily closable wound Type I, II, or IIIA Gustilo- Anderson (GA) Classification Exclusion Criteria: Time from injury to presentation > 48 hours Time from injury to surgery >7 days History of Aminoglycoside allergy GA IIIB or IIIC open fractures Bilateral open tibial fractures Severe brain (GCS<12) or spinal cord injury Severe vascular injury Sustained severe burns (>10% total body surface area (TBSA) or >5% TBSA with full thickness or circumferential injury) Pathologic fracture History of active limb infection, ipsilaterally

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: gentamicin injection at fracture site<br>Subjects with an open tibia fracture who receive gentamicin in saline solution administered after closure at the time of initial debridement. | Drug: local gentamicin injection<br>* 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.<br>|
| Placebo Comparator: placebo saline injection at fracture site<br>Subjects with an open tibia fracture who receive placebo saline solution administered after closure at the time of initial debridement. | Drug: placebo saline injection<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline | 
| Rate of Retention | The percentage of patients completing 1 year follow up relative to the total number of participants | 1 year | 
| 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: fistula, sinus or wound breakdown purulent drainage from the wound or presence of pus during surgery phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 
| 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). | 1 year | 
| 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. | 1 year | 
| Occurrence of Nonunion | Nonunion is a binary variable defined by the following criteria: any unplanned reoperation for promotion of bone healing; OR mRUST<=10 AND either: FIX-IT score <=11 at 12-month follow-up OR recommendation by treating surgeon for nonunion repair surgery | 1 year | 
| 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. | 1 year |