A Pilot Masked, Randomized Controlled Trial Evaluating Locally-applied Gentamicin Versus Saline in Open Tibia Fractures
Phase: NA
Conditions: Open Tibia Fracture
Sponsor: University of California, San Francisco

 
pGO-Tibia 
 
 
A Masked, Randomized Controlled Trial to Evaluate Local Gentamicin 
versus Saline in Open Tibia Fractures 
 
 
pGO-Tibia: a masked, randomized controlled trial evaluating Gentamicin versus saline in 
Open Tibia fractures 
 
ClinicalTrials.gov Identifier: NCT03559400  
 
Pilot GO Tibia PROTOCOL 
 
Version: FINAL 
 
Date: 18-May-2020 
 
This study is funded by the Orthopaedic Trauma Association, the UCSF Hellman Fellowship 
Program, and the UCSF Department of Orthopaedic Surgery SuperNova Grant 
 
The protocol is the confidential intellectual property of the Principal Investigators and GO Tibia 
Steering Committee, and the protocol cannot be used in any form without the expressed written 
permission of the Principal Investigators. 
 
 
 
 

 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................................ 4 
STUDY SUMMARY ............................................................................................................. 5 
1.0 INTRODUCTION ........................................................................................................... 7 
1.1 Open Tibia Fractures ........................................................................................................................... 7 
1.2 Prevention of Infection ........................................................................................................................ 7 
1.3 Rationale for Intrawound Antibiotics and Gentamicin Use ................................................................ 7 
2.0 STUDY AIMS AND HYPOTHESES ............................................................................... 8 
2.1 Definitive Trial Specific Aims: ........................................................................................................... 8 
2.2 Feasibility Trial Specific Aims: ........................................................................................................... 9 
3.0 TRIAL DESIGN .............................................................................................................. 9 
3.1 Summary: ............................................................................................................................................. 9 
4.0 METHODS .................................................................................................................... 10 
4.1 Study Setting: ..................................................................................................................................... 10 
4.2 Eligibility Criteria: ............................................................................................................................. 10 
4.3 Recruitment Strategy and Patient Screening: .................................................................................... 10 
4.3.1 Patient Retention ....................................................................................................................... 11 
4.4 Schedule of Events: ........................................................................................................................... 11 
4.5 Randomization Methods .................................................................................................................... 13 
4.6 Masking: ............................................................................................................................................ 13 
4.7 Description of Interventions .............................................................................................................. 13 
4.7.1 Study Solution Preparation and Storage .................................................................................... 13 
4.7.2 Study Solution Administration .................................................................................................. 14 
4.5.3 Perioperative Co-Interventions .................................................................................................. 14 
4.6 Description of Data Collection .......................................................................................................... 15 
4.6.1 Data collection ........................................................................................................................... 15 
4.6.2 Overview of Data Collection Instruments ................................................................................. 16 
4.6.3 Wound Measurement and Classification ................................................................................... 16 
4.6.4 Radiographs ............................................................................................................................... 16 
4.6.5 Economic Analysis .................................................................................................................... 17 
4.7 Outcome Measures ............................................................................................................................ 17 
4.7.1 Feasibility Trial Outcomes ........................................................................................................ 17 
4.7.2 Definitive Trial Outcomes ......................................................................................................... 18 
4.7.3 Steering Committee and Adjudication ....................................................................................... 19 
5.0 STATISTICAL PLAN ................................................................................................... 20 

 
 
 
 
 
 
 
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5.1 Preliminary Sample size determination: ............................................................................................ 20 
5.2 Statistical Methods ............................................................................................................................. 20 
5.2.1 Primary pre-specified analysis ................................................................................................... 21 
5.2.2 Additional analyses ................................................................................................................... 21 
6.0 DATA MANAGEMENT ................................................................................................ 22 
6.1 Case Report Forms and Data Transmission ....................................................................................... 22 
6.2 Data Integrity ..................................................................................................................................... 23 
7.0 ETHICS AND DISSEMINATION ................................................................................ 23 
7.1 Research Ethics Approval .................................................................................................................. 23 
7.2 Consent .............................................................................................................................................. 23 
7.3 Confidentiality ................................................................................................................................... 24 
7.4 Protocol Amendments ....................................................................................................................... 24 
7.5 Adverse Event Reporting and Definitions ......................................................................................... 24 
7.5.1 Adverse Event (AE) .................................................................................................................. 24 
7.5.2 Serious Adverse Event (SAE) ................................................................................................... 24 
7.5.3 Safety Monitoring ...................................................................................................................... 25 
7.5.4 Stopping Guidelines .................................................................................................................. 25 
7.5 Dissemination Policy ......................................................................................................................... 26 
8.0 REFERENCES .............................................................................................................. 27 
 
 
 

 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Explanation 
AE 
CI 
CRF 
CRP 
DSMC 
EQ-5D 
FIX-IT 
FRI 
GO Tibia 
 
GA 
HIC 
IGOT 
IRB 
LMIC 
MOI 
mRUST 
MUHAS 
NIMR 
PMMA 
RCT 
REDCap 
SAE 
SAP 
SSI 
SC 
UCSF 
Adverse event 
Confidence interval 
Case report form 
C-Reactive Protein 
Data Safety and Monitoring Committee 
EuroQol-5 Dimensions, 3-level questionnaire 
Function Index for Trauma 
Fracture-Related Infection 
Gentamicin versus No antibiotic for the treatment of Open Tibia 
fractures 
Gustilo Anderson 
High-Income Country 
Institute for Global Orthopaedics and Traumatology 
Institutional Review Board 
Low- and Middle-Income Country 
Muhimbili Orthopaedic Institute 
Modified Radiographic Union Score for Tibia 
Muhimbili University of Health and Allied Sciences 
National Institute for Medical Research 
Polymethylmethacrylate  
Randomized Controlled Trial 
Research Electronic Data Capture  
Serious adverse event 
Statistical analysis plan 
Surgical site infection 
Steering Committee 
University of California San Francisco 
 
 
 
 
 
 

 
 
 
 
 
 
 
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STUDY SUMMARY 
 
Methodology 
Masked, randomized controlled-trial  
Coordinating Center 
This study will be centrally coordinated by the Institute for Global 
Orthopaedics and Traumatology, University of California San 
Francisco (UCSF).  
Clinical Site 
Muhimbili Orthopaedic Institute (MOI), Dar es Salaam, Tanzania. 
Background 
The prevention of surgical site infections is important in patients with 
open fractures, as these wounds are often contaminated. Standard 
practice in the management of open fractures includes preoperative 
systemic antibiotics and surgical debridement. In addition to systemic 
antibiotics, local antibiotics applied directly to the surgical site have 
shown promise in reducing the rate of fracture-related infection 
(FRI). Gentamicin is a widely available, low cost antibiotic that holds 
promise for this application, but high-quality evidence supporting its 
use is lacking.     
Objectives 
The overall objective of this research program is to compare the 
effectiveness of intraoperative, locally administered gentamicin with 
no antibiotics for the management of open tibia fractures as measured 
by occurrence of fracture-related infection (FRI) (primary outcome) 
and occurrence of nonunion and unplanned fracture-related 
reoperations (secondary outcomes). The pilot trial specifically aims 
to assess feasibility of the definitive trial, including enrollment, 
retention, and data completeness.  
Diagnosis and Main 
Inclusion Criteria 
All patients 18 years of age or older who present to Muhimbili 
Orthopaedic Institute (MOI) for treatment of Gustilo-Anderson (GA) 
Type I, II or IIIA open tibia fractures will be screened for 
participation.  Eligible patients must present to the hospital within 48 
hours of their injury and receive surgical debridement of their open 
fracture wound within 7 days of their injury. The open wound must 
be primarily closable at the index debridement. 
Treatment Groups  
The pGO-Tibia trial will compare two solutions:  1) aqueous 
gentamicin solution (2mg/mL) in normal saline, or 2) normal saline 
only. A minimum of 5mL and a maximum of 40 mL of either 
solution will be injected into the fracture site immediately following 
primary closure of the traumatic wound. 

 
 
 
 
 
 
 
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Randomization 
Allocation to the study groups will be performed using a web-based 
randomization.  The randomization sequence was generated using 
randomly permutated blocks of 4, 6, and 8 with a 1:1 allocation 
ratio.  
Study Outcomes 
The definitive trial primary outcome is occurrence of FRI. 
Secondary outcomes of the definitive trial are the occurrence of 1) 
nonunion, and 2) unplanned fracture-related reoperation within 12 
months of definitive fixation. Definitive trial subsidiary outcomes 
include health-related quality of life, radiographic healing, and 
clinical healing. A blinded adjudication process will judge each 
study event on occurrence of FRIs, nonunions, and unplanned 
fracture-related reoperations. 
Feasibility Outcomes 
This pilot trial will focus on the following feasibility endpoints: 
Recruitment: number of patients screened, number and proportion 
of patients screened that are eligible, enrolled, randomized, and 
receive intervention. 
Retention: number and proportion of randomized patients who 
attend each follow-up visit.  
Data collection completeness, solution quality control, masking and 
concealment, and evaluation of primary and secondary outcomes 
(reliability of fracture-related infection and mRUST scoring, 
radiographic image quality, and completeness of EQ-5D and FIX-
IT). 
Follow-Up  
Study participants will be followed at 2 weeks, 6 weeks, 3 months, 6 
months, 9 months, and 12 months from their fracture.  
Sample Size 
50 individuals per arm will be included in the feasibility trial.  
Significance 
FRIs place a significant burden on both the patient and the healthcare 
system, as they increase patient mortality, delay healing, decrease 
functional outcomes and health-related quality of life, and often 
require prolonged hospitalization or reoperation, increasing the cost 
of care. Given the consequences of open fracture complications, 
maximizing the effectiveness of prophylactic procedures is essential. 
The GO Tibia trial will provide necessary evidence to guide the use 
of local antibiotic application in prevention of FRIs in open fractures, 

 
 
 
 
 
 
 
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1.0 INTRODUCTION 
1.1 Open Tibia Fractures 
Open tibia fractures often result from high-energy trauma1. These fractures represent an 
orthopaedic emergency associated with high morbidity and mortality. Fracture management 
includes systemic antibiotic prophylaxis, tetanus booster, wound irrigation and surgical 
debridement, and fracture stabilization2,3. Open fractures are contaminated1, and even with 
prompt treatment, infection can occur in up to 40% of cases3,4,5. SSIs place a significant burden 
on both the patient and the healthcare system, as they increase patient mortality, delay healing, 
decrease functional outcomes and health-related quality of life, and often require prolonged 
hospitalization or reoperation, increasing the cost of care6,4,7. 
1.2 Prevention of Infection 
Because surgical site infections have such profound consequences, prevention is crucial. 
Intravenous antibiotics are essential in reducing the risk of infection, but their dosage is limited 
by systemic toxicity, and local concentrations are diminished by the compromised blood supply 
at the site of injury5. Local antibiotics administered intraoperatively directly in the traumatic 
wound offer an additional method of infection prevention8–10. A recent meta-analysis found 
decreased incidence of infection in both spine and trauma surgeries, but this effect was absent 
with more rigorous study designs11. This study demonstrated that vancomycin significantly 
reduces gram-positive infections without appearing to affect the incidence of gram-negative 
infections, which are the second most common pathogen in SSIs after open fracture11. In 
addition, the relatively high cost of vancomycin may prohibit widespread use, particularly in 
low-income countries.  
1.3 Rationale for Intrawound Antibiotics and Gentamicin Use 
Some promising alternatives to vancomycin are aminoglycoside antibiotics, including 
gentamicin. These antibiotics are on the order of 10-100 times cheaper than vancomycin, with 
pricing in Tanzania less than $0.50 for one 80mg vial of liquid gentamicin compared with 
approximately 20 USD for 1g of vancomycin powder12. Aminoglycosides cover a broad 
spectrum of gram-negative and gram-positive bacteria, including both staphylococcus aureus and 
coagulase-negative staphylococcus, the two most common bacteria in fracture-related infection 
(FRI)13. Aminoglycosides impregnated into polymethylmethacrylate (PMMA) beads have been 
shown to reduce infection in open fractures, but a second surgery is required to remove the 
beads14. PMMA also costs $80-100 per 40-gram bag, which can be cost-prohibitive in low-
resource settings.  
A lower-cost alternative is injection of aqueous aminoglycosides after wound closure. Reduced 
rates of infection have been observed after local gentamicin injection in an animal model15 and 
and may significantly impact care and outcomes of open extremity 
fractures.  

 
 
 
 
 
 
 
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one large retrospective cohort study found a 50% reduction in the odds of deep and superficial 
infection after prophylactic local injection of aminoglycosides for open tibia fractures compared 
to no local antibiotics16. Although promising, the latter study’s limitations are numerous, 
including retrospective, non-randomized design, absence of masking, and variability in treatment 
protocols and definitions of infection.  There remains a clear gap in knowledge regarding the 
efficacy of locally-administered gentamicin in preventing fracture-related infection in open 
fractures.   
The GO-Tibia trial, A Masked, Randomized Controlled Trial to Evaluate Local Gentamicin versus 
Saline in Open Tibia Fractures, will address these gaps in the literature. 
2.0 STUDY AIMS AND HYPOTHESES   
 
The study described herein is a single-center pilot trial to evaluate the feasibility of necessary 
protocols including, recruitment, retention, masking and concealment, intervention, and follow-
up. The described pilot study will establish effect sizes for appropriate power calculations for a 
subsequent definitive trial.  
The overarching objective of the definitive trial is to test whether injection of intraoperative local 
gentamicin impacts the rate of fracture-related infection following GA Type I, II or IIIA open 
tibia fractures in Tanzania. We hypothesize that the risk of fracture-related infection will be 
reduced by the intraoperative use of locally administered gentamicin at the time of wound 
closure. 
2.1 Definitive Trial Specific Aims: 
1.   Compare the rate of fracture-related infection at one year after intraoperative local 
gentamicin injection or intraoperative local saline injection among adults treated 
operatively for GA Type I, II, or IIIA open tibia fractures. [Primary aim] 
2.   Compare the occurrence of 1) nonunion, and 2) unplanned fracture-related reoperation 
after intraoperative local gentamicin injection or intraoperative local saline injection among 
adults treated operatively for GA Type I, II, or IIIA open tibia fractures. [Secondary aims] 
3. Evaluate the economic impact of fracture-related infection (FRI) after open tibia fractures 
in Sub-Saharan Africa including direct medical costs and lost productivity. [Secondary 
aims] 
Null hypothesis: There is no difference in the rate of fracture-related infection between local 
gentamicin administration and saline administration for adult patients with GA Type I, II, or IIIA 
open tibia fractures treated in Sub-Saharan Africa. 

 
 
 
 
 
 
 
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Alternative hypothesis: Intraoperative local gentamicin administration decreases the occurrence 
of fracture-related infection in adult patients with GA Type I, II, or IIIA open tibia fractures 
treated in Sub-Saharan Africa. 
2.2 Feasibility Trial Specific Aims: 
Outcomes include rates of screening, enrollment, randomization, allocation, reliability of 
intervention, subject retention, and data completeness. 
Specifically, feasibility outcomes are: 
1. Recruitment: number of patients screened, number and proportion of patients screened 
that are eligible, enrolled, randomized, and receive intervention. 
2. Retention: number and proportion of randomized patients who attend each follow-up 
visit. We aim for an adherence rate at follow-up of 80% at one year. 
3. Data collection completeness: proportion of fracture-related infection criteria, EuroQol-5 
Dimensions, 3-level questionnaire (EQ-5D), Function Index for Trauma (FIX-IT), and 
Modified Radiographic Union Score for Tibia (mRUST)17 indices complete at each time 
point. 
4. Solution quality control: confirmation of the ongoing sensitivity of standard organisms to 
trial solutions via interval testing. 
5. Masking and concealment: determination of the continued masking of surgeons to 
solution identity via intraoperative surgeon survey. 
6. Evaluation of primary and secondary outcomes: reliability of fracture-related infection 
and mRUST scoring17, radiographic image quality, and completeness of EQ-5D and FIX-
IT. 
3.0 TRIAL DESIGN 
3.1 Summary: 
In the accompanying Clinical Research Protocol and Standard Operating Procedures document, 
we describe the protocols and procedures for a feasibility pilot trial for implementing a single-
center, double-masked, individually randomized, placebo-controlled study on the efficacy of 
intraoperative local gentamicin for the prevention of fracture-related infection in open Gustilo-
Anderson Type I-IIIA tibial fractures. The Clinical Research Protocol and Standard Operating 
Procedures document includes general trial information, aims and objectives, study design, trial 
procedures (including recruitment, enrollment, consent, randomization, masking, intervention, 
and follow-up protocols), and data management. 

 
 
 
 
 
 
 
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4.0 METHODS 
4.1 Study Setting: 
The GO Tibia randomized controlled trial will be conducted at the Muhimbili Orthopaedic 
Institute (MOI) in Dar es Salaam, Tanzania. MOI is a tertiary referral hospital with large 
catchment area and high volume of adult musculoskeletal trauma that, combined with its strong 
leadership and prior trial experience, has the capacity to manage this large-scale RCT.  
4.2 Eligibility Criteria: 
All patients presenting to the MOI emergency department age 18 years and older with an open 
tibia fracture will be screened for eligibility (Table 1). After surgical debridement, the surgeon 
will assess the wound to see if the wound can be primarily closed. If the wound can be primarily 
closed, the patient will continue with the RCT Study. If the wound cannot be primarily closed, 
the patient will be excluded from the study.  
 
Table 1: Inclusion and Exclusion Criteria 
Inclusion Criteria 
Exclusion Criteria 
1. Skeletally mature patients (>18 years 
old) 
1. Time from injury to presentation > 48 
hours 
2. Open tibial shaft fracture meeting the 
following criteria: 
2. Time from injury to surgery > 7 days 
a. OTA Type 42 
3. Aminoglycoside allergy 
b. Primarily closable wound 
4. GA IIIB or IIIC open fractures 
c. GA I, II, or IIIA 
5. Bilateral open tibial fractures 
 
6. Severe brain (GCS<12) or spinal cord 
injury 
 
7. Severe vascular injury 
 
8. Severe burns (>10% TBSA or >5% TBSA 
with full thickness or circumferential injury) 
 
9. Pathologic fracture 
 
10. History of active limb infection, 
ipsilaterally 
  
11. Unlikely to complete follow-up 
Abbreviations: Orthopaedic Trauma Association (OTA); Gustilo-Anderson (GA); Glasgow 
Coma Scale (GCS); Total body surface area (TBSA) 
 
4.3 Recruitment Strategy and Patient Screening: 
Recruiting patients: All adult (over age 18) patients admitted to MOI for acute open tibia fracture 
will be considered for inclusion in this study. Patients will be evaluated by the on-call 
orthopaedic surgery resident. The study protocol will be introduced to the patient either by the 

 
 
 
 
 
 
 
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resident or research coordinator. Patients interested in enrolling will be consented. All consenting 
patients will be treated per institutional protocol with immediate systemic ceftriaxone 
administration for open fracture prophylaxis and urgent debridement and bony stabilization with 
either internal or external fixation at the discretion of the operating surgeon. The study protocol 
will not influence the surgical plan for management of study participants. Type of fixation will 
not affect participant inclusion or study protocol. 
The surgeon will make a final assessment of the wound and exclude patients with a wound that is 
not amenable to primary closure. If the wound is determined amenable to primary closure, 
participants will be randomized intraoperatively by research coordinators after closure is 
complete to receive intra-operative local injection of either aqueous gentamicin solution 
(intervention) or normal saline solution (control). 
4.3.1 Patient Retention 
Study participants will not be directly financially compensated and will incur the standard fees 
for evaluation and treatment. To decrease the financial burden and increase follow-up, however, 
the following as described will be provided for study participants: 
• Systemic antibiotics (Ceftriaxone) cost during first hospital stay will be covered for all 
patients screened for the study 
• Gentamicin (intervention arm only), saline solution, and injection materials (syringes, 
needles) will be covered for all participants 
• Preoperative, postoperative, and 2-week creatinine levels will be covered for all 
participants 
• C-reactive protein (CRP) levels will be covered for all participants 
• Radiograph cost: Radiographs of the affected extremity will be obtained at the time of 
presentation and at post-operative follow-up appointments to adequately monitor healing. 
Imaging costs will be covered for all study participants. 
• Post-operative consultation fees: consultation fees for study participant follow-up clinical 
evaluations will be waived for study participants. 
• Follow-up visits will take place in a dedicated study clinic to minimize wait times 
• Three separate contacts will be obtained for each patient upon enrollment.  
• Follow-up clinic visit reminders will be given via phone call and by text message during 
the week prior to each visit 
• Reoperation fees: The cost of two intraoperative cultures will be covered for study 
participants who undergo reoperation. 
 
4.4 Schedule of Events: 
 
Following participant enrollment and informed consent, baseline clinical and demographic data 
are collected from the patient including socioeconomic status, medical and social history, injury 
characteristics, and estimated pre-injury health-related quality of life. Contact information for the 
patient and at least two close contacts is collected to optimize follow-up. Pre- and post-operative 

 
 
 
 
 
 
 
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radiographs will be obtained prior to hospital discharge and serum creatinine will be obtained 
pre-operatively and on postoperative day 2. If serum creatinine levels on postoperative day 2 are 
>1.5 times patient baseline and acute kidney injury is suspected, serum creatinine levels will be 
redrawn at two-week follow-up visit18. Personnel time and resources utilized will be directly 
observed using time and motion analysis, beginning from patient admission to the completion of 
surgery and transfer to the ward. The schedule of patient encounters and corresponding data to be 
collected is described in Table 2. 
 
Participants will return to clinic for follow-up at 2 weeks, 6 weeks, 3 months, 6 months, 9 
months, and 1 year following surgery.  
Specifically, follow-up visits will include the following: 
 
1. Two-week postoperative visit: The study investigator will review and record interval 
history since hospital discharge. The patient will complete a Visual Analog Scale for pain 
assessment. A physical examination will be performed to assess for signs of Fracture-
related Infection. C-reactive protein level will be obtained. If serum creatinine levels on 
postoperative day 2 are >1.5 times patient baseline and acute kidney injury is suspected, 
serum creatinine levels will be redrawn. 
2. Six-week postoperative visit: During the follow-up visit reminder telephone phone call, 
the study investigator will ask the five fracture-related infection (FRI) validation 
questions. At the visit, the study investigator will review and record interval history since 
the last appointment. The patient will complete a Visual Analog Scale for pain 
assessment. The study subject will complete a Work Productivity and Activity 
Impairment questionnaire (WPAI) to assess lost productivity, and patient reported 
outcome measure (EQ-5D). A physical examination will be performed to assess for signs 
of fracture-related infection (FRI). C-reactive protein level will be obtained. 
3. Three-month, six-month, nine-month, and 12-month postoperative visits: During the 
follow-up visit reminder telephone phone call, the study investigator will ask the five five 
fracture-related infection (FRI) validation questions. At the visit, the study investigator 
will review and record interval history since the last appointment. The patient will 
complete a Visual Analog Scale for pain assessment. The study subject will complete a 
Work and Activity Impairment questionnaire (WPAI), the FIX-IT score for clinical 
healing, additional questions to address indirect costs and economic impact associated 
with their treatment, and patient reported outcome measure (EQ-5D). A physical 
examination will be performed to assess for signs of fracture-related infection (FRI). AP 
and lateral radiographs will be taken. C-reactive protein level will be obtained. 
Table 2: Schedule of Events 
 
Hospital 
 
Outpatient 
 
Pre-Surgery 
 
Surgery 
 
Post-
Surgery 
 
 
 
 
 
 
 
Assessment 
Screening 
Enrollment 
 
 
 
<= 48hrs 
Post Op 
 
2-
weeks 
6-
weeks 
3-
months 
6-
months 
9-
months 
12-
months 

 
 
 
 
 
 
 
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Radiographs 
●  
 
 
 
 
●  
 
 
 
●  
●  
●  
●  
Informed Consent 
 
●  
 
 
 
 
 
 
 
 
 
 
 
Serum Creatinine* 
 
●  
 
 
 
●  
 
● 
 
 
 
 
 
Randomization 
 
 
 
●  
 
 
 
 
 
 
 
 
 
Intervention 
 
 
 
●  
 
 
 
 
 
 
 
 
 
Baseline Data** 
 
 
 
 
 
●  
 
 
 
 
 
 
 
Contact Information 
 
 
 
 
 
●  
 
 
 
 
 
 
 
EQ-5D 
 
 
 
 
 
●  
 
 
 
●  
●  
●  
●  
Outcomes 
Assessment*** 
 
 
 
 
 
 
 
●  
●  
●  
●  
●  
●  
FIX-IT 
 
 
 
 
 
 
 
 
 
●  
●  
●  
●  
WPAI 
 
 
 
 
 
 
 
 
●  
●  
●  
●  
●  
C-reactive protein 
 
 
 
 
 
 
 
●  
●  
●  
●  
●  
●  
Adverse Event 
Screen 
  
  
  
  
  
  
  
●  
●  
●  
●  
●  
●  
*** 2-week creatinine level will only be drawn if postoperative creatinine level is >1.5 times patient baseline and acute kidney injury is 
suspected 
** demographic, medical history, injury characteristics 
*** fracture-related infection, unplanned fracture-related reoperation 
 
 
4.5 Randomization Methods 
Allocation to the study groups will be randomly assigned using a web-based randomization tool 
as part of Research Electronic Data Capture (REDCap). The randomization sequence was 
generated using randomly permutated blocks of 4, 6, and 8 with a 1:1 allocation ratio. 
4.6 Masking: 
Trial participants are masked to treatment group allocation. All health care providers involved in 
care of the trial participants including physicians, surgeons, and nurses are masked to treatment 
group allocation. Research team members including research coordinators, data collectors, and 
data analysts, are masked to treatment group allocation. 
Masking is established and maintained by preparation of the study solutions in visually 
indistinguishable syringes labeled either “Solution A” or “Solution B”.  
Two UCSF research personnel are unmasked for the implementation and management of trial 
protocols, but do not have any contact with study participants and are not aware of the treatment 
group to which each participant is assigned. The study nurse responsible for preparation of study 
solutions at MOI is also unmasked, but does not have any contact with study participants and is 
not aware of the treatment group to which each participant is assigned.  
4.7 Description of Interventions 
4.7.1 Study Solution Preparation and Storage  

 
 
 
 
 
 
 
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A certified study nurse, who is one of three un-masked personnel, will prepare aqueous 
gentamicin and normal saline solutions. The gentamicin solution consists of 2mg/mL aqueous 
gentamicin while the control solution consists of normal saline without active agent.  
The working solutions are prepared in a locked room using sterile technique and are prepared in 
identical syringes labeled either “Solution A” or “Solution B”, according to the masking key. 
The masking key is kept in a locked cabinet in a locked office, only accessible by the study 
nurse. Solutions are labeled with date of preparation and date of expiration. The study nurse 
maintains a preparation log to ensure the integrity of the study solutions. 
Study solutions are stored at 4 degrees Celsius for up to 48 hours, in accordance with pharmacist 
guidelines. Solutions are stored in a locked, dedicated study refrigerator adjacent to the operating 
suite. Upon expiration, unused study solutions are discarded and new solutions prepared. The 
study refrigerator is checked daily by the study nurse and a use log is maintained to ensure the 
integrity of the study solutions. All gentamicin is obtained from Sichuan Long March 
Pharmaceutical Co., Ltd (Leshan, Sichuan Province, China) and normal saline is obtained from 
Otsuka Pharmaceutical India Private Limited (Ahmedabad, India). 
4.7.2 Study Solution Administration  
Following intraoperative randomization, the appropriate study solution is provided to the 
administering surgeon in a masked manner. The local solution injection is administered 
immediately following wound closure. As described previously by Lawing et al19, the solution is 
injected by inserting a 22-gauge needle down to bone through an anteromedial approach at the 
level of the fracture site such that the injected solution fills the wound cavity. A minimum of 
5mL of study solution may be injected, and the injection is continued until either extravasation is 
seen through the traumatic wound or a maximum of 40mL has been administered, whichever 
occurs first. 
For quality control, the efficacy of masked study solutions will be tested against standard 
organisms. This will occur once per month for the first 6 months and once every 3 months 
thereafter by the Muhimbili University of Health and Allied Sciences (MUHAS) microbiology 
lab, with results evaluated by unmasked study personnel. 
4.7.3 Perioperative Co-Interventions  
Systemic antibiotic prophylaxis  
All patients will receive prophylactic systemic antibiotics as soon as possible after presentation 
to the hospital regardless of whether they participate in the study. Patients will be given a single 
dose of ceftriaxone 1 gram intravenously, which provides 24 hours of coverage.  
 
Debridement 
All patients will undergo systematic debridement of the traumatic wound with removal of 
devitalized bone and soft-tissue. Wounds will be extended as necessary to remove contaminants 
and deliver the bone ends from the wound. The wound will be irrigated with a minimum of 2 
liters normal saline solution using low-pressure lavage. For cases of severe contamination, the 
wound may be washed with tap water prior to surgical prep.  

 
 
 
 
 
 
 
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Fracture stabilization 
Treatment of the fracture will be at surgeon discretion and may be temporizing or definitive 
using either external fixation (EF) or intramedullary nailing (IMN).  
 
 
External fixator: A uniplanar external fixator (AO Dispofix) will be used in all cases 
consisting of a minimum of two Schanz pins proximal to the fracture and two distal pins 
connected by a single stainless steel bar.   The choice to add additional pins or span 
adjacent joints will be at the discretion of the treating surgeon. At hospital discharge, the 
patient will be instructed on proper pin-care procedures. The pin care protocol will 
consist of cleaning each pin using methylated spirits (methyl alcohol) twice daily until 
the external fixator is removed. The external fixator will remain in place for a minimum 
of 4-6 weeks and maximum of 3 months.  
 
Intramedullary Nail: The SIGN Standard nail (SIGN Fracture Care International, 
Richland, WA) will be used in all cases. The nail will be inserted using an infrapatellar 
approach. Two proximal and two distal interlocking screws will be placed using an 
external jig. Intraoperative fluoroscopy will not be used.  
 
Wound closure 
The wound will be closed primarily when it is felt to be safe and feasible by the treating surgeon. 
A layered closure will be performed whenever possible using nylon for skin and a braided 
absorbable suture for the deeper layers.  
 
Postoperative Wound Care 
 
If the wound is dry at the 2-week wound check, the dressing will be removed. If the wound is 
still wet at 2 weeks, the dressing will be changed and the patient will be instructed to periodically 
revisit the hospital to change the dressing until the wound becomes dry. 
 
Weight Bearing Protocol 
 
All patients will be advised to be on toe-touch status for the first 6 weeks. Afterwards, the patient 
will be instructed to bear weight as permitted by pain.  
 
 
4.6 Description of Data Collection 
4.6.1 Data collection 
Three trained research coordinators with research and data collection experience will be 
responsible for all data collection. All data will be uploaded into REDCap (see section 6.0 
DATA MANAGEMENT) using portable laptops and tablet computers.    

 
 
 
 
 
 
 
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4.6.2 Overview of Data Collection Instruments 
Data will be collected in the schedule described in section 4.4 Schedule of Events, and includes: 
• Baseline patient data includes demographic information, such as age, gender, medical 
history, and injury characteristics.  
• The EuroQol-5 Dimensions, 3-level questionnaire (EQ-5D)20, Swahili version, which is a 
validated instrument for measuring patient quality of life. 
• The Function Index for Trauma  (FIX-IT)21, a validated instrument for evaluating healing 
in lower-extremity fractures. The scoring system includes a single-leg stand, ambulation, 
and palpation test.   
• The Modified Radiographic Union Score for Tibia  (mRUST)22 is a validated, 
radiographic measure of bony union.  
 
4.6.3 Wound Measurement and Classification 
 Wound Measurement and Classification 
A measurement of the wound is to be done in the operating room, both before and after 
debridement. The first measurement will be taken prior to debridement. The second 
measurement will be taken following surgical fixation but before wound closure. The wound 
should be measured using a centimeter ruler or the handle of a scalpel (rather than visually 
approximated). 
 
Only the maximum dimension of the wound (the longest length possible) needs to be recorded. 
This is irrespective of how the wound is oriented along the limb. The wound length should only 
include the part of the wound that is open (ignore any superficial abrasions that may be 
connected to the open part of the wound). In the event that there are multiple wounds, measure 
each wound that communicates with the fracture and sum the lengths of the individual wounds. 
Do not include the wounds that were made for the purpose of inserting an intramedullary nail or 
interlocking screws. 
OTA and Gustilo-Anderson Wound Classification 
Classification of the wound is done using the OTA Wound Classification questionnaire and the 
Gustilo-Anderson classification of injury severity.  Wound classification is to be done after 
surgical debridement, which allows the surgeon to fully assess the wound.  
 
4.6.4 Radiographs 
Orthogonal images will be obtained and digitally copied using screen capture. Images will then 
be uploaded into REDCap. Radiographs are then sent for review by the adjudication committee, 
and are assessed for radiographic signs of healing using the mRUST score by two fellowship-
trained orthopaedic trauma surgeons. In cases of disagreement between reviewers, decisions are 
made by consensus. 
 

 
 
 
 
 
 
 
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4.6.5 Economic Analysis 
Indirect Cost Assessment 
Lost productivity will be assessed using the Work Productivity and Activity Impairment (WPAI) 
survey modified for lower extremity injury. Employment type, hours worked, and wages earned 
will be assessed at each time point. Transportation costs associated with the injury and follow up 
care will be assessed at each time point. 
Direct Cost Assessment 
Direct costs will be measured using micro-costing methods. Resource utilization and time data 
will be collected through direct observation using time and motion (TM) analysis and patient 
charts. Specifically, each of the captured surgical interventions (each treatment strategy as well 
as reoperation for complication) is divided into discrete steps. For each step, resources used, 
personnel involved and duration of activity will be directly observed and recorded. This 
information will be used to assess personnel costs of each surgical procedure. Implant costs will 
be obtained from the suppliers. Surgical instrument costs will be obtained from the 
manufacturers, accounting for depreciation by assuming that the lifetime of surgical instruments 
is 10 years. The cost of intraoperative supplies, such as medications, disposables, intravenous 
fluids, blood products, and others, will be obtained from the suppliers. 
 
Cost per day of hospital stay will be estimated for three categories: index hospitalization, 
infected complication hospitalization, and uninfected complication hospitalization. This is based 
on the assumption that the cost per day of hospital stay will differ between these groups but not 
significantly within these groups. 
 
Utilization of medications and laboratory and radiology investigations will be assessed from the 
patient chart. Type and quantity of medications will be obtained from the patient chart, and costs 
will be obtained from the supplier. Labor and resource costs of laboratory and radiology 
interventions will be obtained from the hospital laboratory and radiology departments. 
 
4.7 Outcome Measures 
4.7.1 Feasibility Trial Outcomes 
7. Recruitment: number of patients screened, number and proportion of patients screened 
that are eligible, enrolled, randomized, and receive intervention. 
8. Retention: number and proportion of randomized patients who attend each follow-up 
visit. We aim for an adherence rate at follow-up of 80% at one year, which was achieved 
in our previous open tibia fracture trial performed through the same collaborative 
partnership. 
9. Data collection completeness: proportion of fracture-related infection criteria, EuroQol-5 
Dimensions, 3-level questionnaire (EQ-5D), Function Index for Trauma  (FIX-IT), and 

 
 
 
 
 
 
 
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Modified Radiographic Union Score for Tibia  (mRUST)17 indices complete at each time-
point. 
10. Solution quality control: confirmation of the ongoing sensitivity of standard organisms to 
trial solutions via interval testing. This will occur once per month for the first 6 months 
and once every 6 months thereafter by the Muhimbili University of Health and Allied 
Sciences (MUHAS) microbiology lab, with results evaluated by unmasked study 
personnel. 
 
11. Masking and concealment: determination of the continued masking of surgeons to 
solution identity via intraoperative surgeon survey. 
12. Evaluation of primary and secondary outcomes: reliability of fracture-related infection 
and mRUST scoring, validation of telephone criteria for fracture-related infection, 
radiographic image quality, and completeness of EQ-5D and FIX-IT. 
 
4.7.2 Definitive Trial Outcomes 
Primary Outcome 
The primary outcome is occurrence of fracture-related infection (FRI) a binary variable. FRI 
diagnosis is likely to peak between 3 and 6 months after surgery and has a non-normal time-to-
event distribution, with incident cases rarely presenting later than 12 months after surgery.  Any 
of the four following diagnostic criteria are confirmatory for infection: (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; or (4) presence of microorganisms in deep tissue taken during an 
operative intervention, as seen on histopathological examination.  
Secondary Outcomes 
The following secondary outcomes will be assessed: 
1. Occurrence of nonunion, a binary variable, as defined by: 
a. Any unplanned reoperation for promotion of bone healing; OR  
b. mRUST ≤10 AND either: FIX-IT score ≤11 at 12 month follow-up, OR 
recommendation by treating surgeon for nonunion repair surgery.   
2. Occurrence of unplanned fracture-related reoperation, a binary variable, for infection, 
wound healing, or fracture union, excluding removal of implants for 
prominence/irritation. This may include but is not limited to:  
a. Irrigation and debridement of surgical incisions or open fracture wounds due to 
infections or wound healing problems;  
b. Revision wound closure for dehiscence;  
c. Soft tissue coverage procedure for infected or necrotic wound;  
d. Fracture delayed union or nonunion surgery (such as bone grafting or implant 
exchange);  

 
 
 
 
 
 
 
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e. Reoperation for hardware or prosthesis failure due to infection or bone-healing 
problems;  
f. Amputation for infection, wound or fracture healing problem. 
Subsidiary Outcomes 
The following subsidiary outcomes will be assessed: 
1. Radiographic healing via the mRUST score, an ordinal scale ranging from 4 to 16.  
2. Clinical healing via the FIX-IT score, an ordinal scale from 0-12 that encompasses two 
domains, ability to weight-bear and pain at fracture site, each scored from 0-6: ability to 
weight-bear and pain at fracture site.  
3. Health-related quality of life via EQ-5D. 
4. FRI suggestive criteria, including clinical (wound redness, fever) and radiographic signs 
(sequestrum), elevated serum inflammatory markers, and new onset or increased wound 
drainage.  
5. C-reactive protein level, including preoperative level and postoperative level collected 
over longitudinal time points 
6. Direct and indirect costs as measured by Time and Motion analysis and WPAI 
Subgroup Analyses 
In order to examine the differential treatment effects of local gentamicin administration among 
clinically relevant subgroups defined by: i) GA classification, ii) severity of wound 
contamination, iii) time from injury to surgery, and iv) type of definitive fixation, the following 
subgroup analyses will be performed:  
1. Gustilo-Anderson classification of fracture (type 1 or 2 vs 3) 
2. Contamination (minimal or moderate versus severe based on the Orthopaedic Trauma 
Association Open Fracture Classification) 
3. Time to surgery (≤24 versus >24 hours after injury) 
4. Type of fixation (external fixation versus intramedullary nailing). 
4.7.3 Steering Committee and Adjudication  
 
The Steering Committee (SC) for the study will consist of Dr. David Shearer, Dr. Saam 
Morshed, Dr. Billy Haonga, Dr. Edmund Eliezer, and Dr. Travis Porco (principal trial 
statistician).  The Steering committee will be responsible for performing adjudication review and 
approving any sub-projects, as outlined below. 
 
Review of the following study events will require review from the members of the study steering 
committee: 
 
1. Death of a patient 
2. Surgical complications requiring reoperation 
 

 
 
 
 
 
 
 
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The review, comment, and voting process will occur on REDCAP. Three steering members will 
need to evaluate each event that is put up for review. The steering committee members are 
responsible for providing the following inputs for each event: 
 
1. Comments/opinions/justifications 
2. Vote (yes or no): question varies depending on the event 
a. Death event: question not applicable 
b. Surgical complications requiring reoperation: does the patient need a reoperation? 
3. Vote (yes or no): is this event a primary outcome of the study? 
 
Adjudication review will be conducted every 2 months. 
 
Additionally, the steering committee will meet monthly to review standardized REDCap data 
quality reports.  
5.0 STATISTICAL PLAN 
5.1 Preliminary Sample size determination: 
This study seeks to explore if local antibiotics are effective in reducing infection. Existing 
literature estimates the rate of infection after intramedullary nailing for open-tibia fracture at 6-
21%, with higher rates seen in developing countries23,24. Based on the previous randomized 
controlled trial conducted at MOI, the rate of deep infection in patients with open tibia fractures 
who do not receive local antibiotics during operative management was estimated to be 12%. For 
a relative risk reduction of 50% in the rate of deep surgical site infections, with an alpha (two-
sided) of 0.05 and power of 0.80, the estimated sample size was 712 patients (356 per group). 
Assuming a loss to follow-up of 20%, the final sample size needed was determined to be 890 
patients. Given the anticipated enrollment of 15 participants per month, enrollment would take 
approximately 5 years for a single center study. The study described herein is a pilot trial with a 
1-year enrollment period to include 100 patients, approximately 10-20% of the necessary sample 
size for the definitive trial. 
 
5.2 Statistical Methods 
Feasibility outcomes described in 4.7.1 will be summarized using means and proportions, 
without the use of inferential statistics.  Given the principle feasibility aim of this pilot trial, the 
following statistical methods are described primarily for planning purposes.  Statistical 
methodology to be performed in the analysis of each primary, secondary, and subsidiary 
outcome is outlined below. The statistical analysis plan (SAP) will provide additional detail on 
statistical analysis and will be modified as necessary based on data collected in this pilot trial.  
 
Outcomes Analysis Planned for Definitive Trial 
Outcome 
Data 
Method of analysis 

 
 
 
 
 
 
 
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Primary 
Rate of fracture-related 
infection 
FRI criteria 
Relative Hazard as estimated by two-
sided binomial regression with the 
complementary log-log link, with a type 
I error rate (alpha) of 0.05. 
 
 
 
Secondary 
Rate of unplanned 
reoperation 
Review of 
complications 
Fisher’s exact test on the 2 × 2 cross-
tabulation 
 
Rate of nonunion 
Nonunion criteria 
 
 
 
 
Subsidiary 
Quality of Life 
EQ-5D 
Comparison means of gentamicin-
treated group and placebo group using 
two-tailed students t-test (alpha=0.05) 
Inflammatory Markers 
CRP 
Radiographic Healing 
mRUST 
Clinical Healing 
Direct costs 
Indirect costs 
FIX-IT 
TM Analysis 
WPAI 
 
 
Fisher’s exact test on the 2 × 2 cross-
tabulation 
FRI Suggestive Criteria 
FRI criteria 
 
5.2.1 Primary pre-specified analysis  
Outcome Variable: the occurrence of FRI, as a binary outcome. We will denote this by Yi, for 
person i. For each individual, we also record the time under observation, Ti. This value will be 
censored at the end of the follow-up time.  
Primary Analysis: the primary analysis will be conducted as a binomial regression with the 
complementary log-log link. This allows the available person-time to be used.  
The estimated effect will be the relative hazard.  
The analysis will be two-sided, with a type I error rate (alpha) of 0.05. Because there is no 
intention of including patients from this pilot trial into a subsequent definitive study, each trial 
(pilot and definitive) is completely separate, with an independent alpha.  
5.2.2 Additional analyses  
Supplemental analyses. These analyses are designed to provide additional insight and support 
for the primary analysis, and to assess whether or not the methodological choices we made had 
an undue effect on the results. In reporting, they will be sharply distinguished from the primary 
outcome, and will not be highlighted as central or determinative findings in reports, publications, 

 
 
 
 
 
 
 
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abstracts, posters or other communications.  
Additional sensitivity analyses will be conducted based on the following variables as base- line 
covariates: Gustilo fracture type, lower extremity fracture, wound contamination, time from 
injury to first debridement, antiseptic wound dressing in the emergency department, method of 
fixation, wound closure at initial debridement, age, work-related injury, and employment status. 
Such analyses will be reported descriptively and with confidence intervals, but no significance P-
values will be given. Conclusions based on such subgroups or adjustments will be considered 
hypothesis-generating, and will not form the basis for highlighting in reports or publications.  
Fisher’s Exact Test. We will report the results of Fisher’s exact test on the 2 × 2 cross- 
tabulation of the reoperation binary outcome and the treatment assignment. This does not take 
into account observation time. This is an independent statistical procedure, and may yield 
statistically inconsistent results.◦  
Risk difference. We will report the 95% confidence interval for the risk difference between the 
groups. Because this will be conducted by an independent regression (binomial regression with 
the identity link), these new findings may be statistically inconsistent with the main analysis. 
Thus, we will only report 95% confidence intervals, omitting P-values. The risk difference is 
interpretively important and may be useful in future meta-analytic studies.  
Combined analysis. At the conclusion of both trials, an additional analysis will be con- ducted 
in which both data sets are combined into a single analysis. This analysis, bearing similarity to a 
meta-analysis of original data, will yield a combined effect estimate and confidence interval. 
deviation. No P-value will be reported. Thus, this secondary analysis does not constitute an 
additional risk for declaring significance and no multiple comparison adjustment is mandated.  
Statistical considerations. Intent to treat analysis is recommended, but impossible when the 
primary outcome is missing. We will conduct exploratory regression of missingness, and 
observation time, using the following predictors: gender, severity of injury, distance to clinic, 
and age. 
Secondary analyses. All secondary analyses will be sharply distinguished from the primary pre-
specified analysis and will be identified as such. Secondary analyses include outcome variables 
or planned subsets, which contribute either additional insight or address different scientific 
questions than the primary analysis.  
6.0 DATA MANAGEMENT 
6.1 Case Report Forms and Data Transmission 
Clinical sites will be provided with the trial case report forms (CRFs) prior to initiation of 
enrollment. Research personnel at each clinical site will submit the required data, as detailed on 

 
 
 
 
 
 
 
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the CRFs, using the Research Electronic Data Capture (REDCap) electronic data capture system. 
Clinical site personnel will receive a unique login and password.  
 
6.2 Data Integrity 
The REDCap system uses a variety of mechanisms for checking data at the time of entry including 
skip logic, range checks, and data type checks. Interim analyses will serve as a quality control 
method to assess missing, implausible, or inconsistent data.   
7.0 ETHICS AND DISSEMINATION 
7.1 Research Ethics Approval 
Ethical approval for this trial was obtained from the National Institute of Medical Research, 
Tanzania (Ref#: NIMR/HQ/R.8a/Vol. IX/2958), and the UCSF Human Subjects Research 
Internal Review Board (IRB# 17-23950, Ref#: 260102).  
The GO Tibia trial was registered at ClinicalTrials.gov (NCT03559400) on June 18, 2018 
(https://clinicaltrials.gov/ct2/show/NCT03559400).  
Any proposed protocol modifications will be submitted for approval to both ethical review 
boards. 
7.2 Consent 
If a patient is deemed eligible for the study, designated study personnel will obtain informed 
consent from the patient (preferred) or proxy as soon as feasibly possible. The consent process will 
typically take place in the emergency room, prior to surgical fixation of their open fracture. To 
discuss their participation, a member of the study team will approach potentially eligible patients.  
 
To obtain informed consent, study personnel should follow the below procedures: 
• Present study information in a manner that is understandable to the potential 
participant. 
• Discuss the study with the potential participant and answer any questions he or she 
asks. 
• Allow the potential participant an opportunity to discuss participation with their family, 
friends, or family physician, if desired.  
• Confirm that the participant understands the risks and benefits of participating in the 
study and that their participation is voluntary. 
• Complete and obtain signatures for informed consent form and obtain contact 
information from the participant. 
 
The process of obtaining and documenting informed consent forms will be completed in 
accordance with local Good Clinical Practice recommendations.  
 

 
 
 
 
 
 
 
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Upon providing informed consent, study participants will be followed for 12 months from their 
fracture. Given the short follow-up time, the need for a regular reassessment of consent will not 
apply; however, participants may withdraw their consent at any time.  
 
7.3 Confidentiality 
Information about study participants will be kept confidential and will be managed in accordance 
with the below rules: 
• All study-related information will be stored securely. 
• All CRFs will be identified only by a coded participant number and initials. 
• All databases will be password protected. 
 
In the event that a participant revokes authorization to collect or use personal health information, 
the clinical site retains the ability to use all information collected prior to the revocation of 
participant authorization. For participants who have revoked authorization to collect or use 
personal health information, attempts should be made to obtain permission to collect at least vital 
status (i.e., primary outcome data) at the end of their scheduled study period. 
7.4 Protocol Amendments 
Any amendments to the study protocol which may affect the conduct of the study or the potential 
safety of or benefits to participants (e.g., changes to the study objectives, study design, sample 
size, or study procedures) will require a formal amendment to the protocol. Any protocol 
amendments will be approved by the Principal Investigators and will require approval by the 
University of California IRB, the Tanzania NIMR, and the funders (as needed). Administrative 
changes (e.g., minor corrections or clarifications that have no effect on the way the study is 
conducted) will not need to undergo a formal amendment process. 
 
7.5 Adverse Event Reporting and Definitions 
7.5.1 Adverse Event (AE) 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition (not relevant in this study).  AE’s will be 
collected by means of a standard question on the follow-up questionnaire:  “Have you developed 
any new health problems since the previous visit?”  AE’s will be recorded at every visit. 
Spontaneously reported AE’s and/or observed AE’s will be recorded on a separate Adverse 
Events form with information about (1) date of onset and date of recovery, (2) seriousness, (3) 
severity and (4) outcome. 
 
7.5.2 Serious Adverse Event (SAE) 
A Serious Adverse Event is an adverse event occurring during any phase of the study, which 
fulfills one or more of the following criteria: 
1. 
Results in death; 
2. 
Is immediately life-threatening or requires in-subject hospitalization;  

 
 
 
 
 
 
 
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3. 
Results in persistent or significant disability or incapacity. 
 
The causality of Serious Adverse Events (i.e. the relationship to study treatment) will be assessed 
by the DSMC, who in completing the relevant REDCAP form must answer ‘yes’ or ‘no’ to the 
question “Is there a reasonable possibility that the event may have been caused by the local 
Gentamicin injection?”    
 
7.5.3 Safety Monitoring 
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an Adverse Event may have been caused by the investigational product. 
• Time course of events and exposure to drug – did the AE occur in a reasonable temporal 
relationship to the administration of the intervention? 
• No alternative cause - the AE cannot be reasonably explained by another etiology such as 
an underlying disease (not previously present), other drugs, or environmental factors. 
 
There would not be a “reasonable possibility” of causality if none of the above criteria apply or 
where there is evidence of exposure and a reasonable time course, but there is another more 
likely cause of the AE. 
 
The subjects will additionally be asked to assess the severity of each reported Adverse Event 
according to the following scale: 
 
Mild      
= awareness of sign or symptom, but easily tolerated 
Moderate    
= discomfort sufficient to cause interference with normal activities 
Severe     
= incapacitating, with inability to perform normal activities. 
 
Subjects will again be asked about the seriousness and severity of previously reported adverse 
events at subsequent follow-up visits, in order to track outcome. 
 
Adverse Events believed to be secondary to intervention or standard of care with “reasonable 
probability” will be reviewed at interim analyses, and reported by the DSMC at that time to all 
required parties. 
 
The Data and Safety Monitoring Committee (DSMC) for the study will consist of will consist of 
orthopedic surgeon Dr. Marc Tompkins (Minneapolis, MN, USA), emergency medicine 
physician Dr. Faraja Chiwanga (Dar es Salaam, Tanzania), and health services researcher Nathan 
O’Hara (Baltimore, MD, USA). Dr. Nathan O’Hara will serve as the committee chair.  
7.5.4 Stopping Guidelines 
The trial may be terminated for reasons of harm at the judgment of the DSMC. Several endpoints 
will be examined, including serious adverse events as described in the protocol. While the 
analysis would consider mal-distribution of predictive factors such as age, it is recognized that 
ethical considerations require careful considerations of statistical tests as well as qualitative 

 
 
 
 
 
 
 
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judgments in the light of experience. Any additional analyses required by the DSMC will be 
reported as needed.  
7.5 Dissemination Policy 
 
At the conclusion of the study there will be a principal manuscript reporting the findings of the 
feasibility trial primary study endpoints. This data will be used to inform the definitive trial.  
 
 

 
 
 
 
 
 
 
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