Pilot RCT Local Gentamicin for Open Tibial Fractures in Tanzania (pGO-Tibia)

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

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.

Study Overview

• Status: Completed
• Conditions: Open Tibia Fracture
• Intervention / Treatment: Drug: local gentamicin injection; Drug: placebo saline injection

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Tanzania
  • Dar Es Salaam, Tanzania
    • Muhimbili Orthopaedic Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.
Placebo Comparator: 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.	Drug: 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 weeks
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.	1 year
Direct Medical Costs	Direct medical costs of treatment (continuous), including medications, personnel, and supplies will be measured for both the intervention and control groups.	1 year
Indirect Medical Costs	Indirect (time) costs, such as lost productivity, will be measured using the Work Productivity and Activity Impairment questionaire (WPAI)	1 year

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Muhimbili Orthopaedic Institute
• Investigators: Principal Investigator: David Shearer, MD, University of California, San Francisco

Publications and helpful links

General Publications

• von Kaeppler EP, Donnelley C, Ali SH, Roberts HJ, Ibrahim JM, Wu HH, Eliezer EN, Porco TC, Haonga BT, Morshed S, Shearer DW. A study protocol for a Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin versus Saline in Open Tibia Fractures (pGO-Tibia) in Dar es Salaam, Tanzania. Pilot Feasibility Stud. 2021 Feb 10;7(1):47. doi: 10.1186/s40814-021-00766-7.

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2019
• Primary Completion (Actual): September 15, 2021
• Study Completion (Actual): September 15, 2021

Study Registration Dates

• First Submitted: June 6, 2018
• First Submitted That Met QC Criteria: June 6, 2018
• First Posted (Actual): June 18, 2018

Study Record Updates

• Last Update Posted (Actual): December 22, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Wounds and Injuries; Leg Injuries; Fractures, Bone; Tibial Fractures; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Gentamicins
• Other Study ID Numbers: 17-23950; K23AR079044 (U.S. NIH Grant/Contract)

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
• product manufactured in and exported from the U.S.: Yes