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Trial registered on ANZCTR


Registration number
ACTRN12619001190190
Ethics application status
Approved
Date submitted
6/08/2019
Date registered
26/08/2019
Date last updated
13/07/2021
Date data sharing statement initially provided
26/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Narrow versus broad antibiotic treatment for diabetic foot infections (NvB-DFI)
Scientific title
Randomised, controlled, non-inferiority trial comparing narrow versus broad-spectrum antibiotic regimens for mild to moderate diabetic foot infection
Secondary ID [1] 298713 0
Nil known
Universal Trial Number (UTN)
U1111-1236-8500
Trial acronym
NvB-DFI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic foot infection 313617 0
Condition category
Condition code
Infection 312051 312051 0 0
Studies of infection and infectious agents
Metabolic and Endocrine 312414 312414 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants are randomly assigned to receive either a narrow-spectrum antibiotic regimen or a broad-spectrum antibiotic regimen for treatment of their infected diabetic foot ulcer.

This treatment will be prescribed on a sliding scale dependant on participant response to infection.
The minimal duration of prescription will be 1 week, up to a maximum prescription of 3 weeks.

The narrow spectrum antibiotic prescription will be: Flucloxacillin or Dicloxacillin 500mg orally given 6 hourly. The decision between Flucloxacillin and Dicloxacillin will be guided by the advice of the local health policy and the prescribing physician.

If there is a true hypersensitivity to penicillin participants will be prescribed Clindamycin 450mg orally 8-hourly.

The mode of administration for all treatment arms will be an oral tablet(s).

Medication adherence will be encouraged through the use of short messaging service (text messaging) at the times the medication should be taken. Participants will also be provided with a diary to document when the dose should be taken.
Intervention code [1] 315129 0
Treatment: Drugs
Comparator / control treatment
Participants are randomly assigned to receive either a narrow-spectrum antibiotic regimen or a broad-spectrum antibiotic regimen for treatment of their infected diabetic foot ulcer.

This treatment will be prescribed on a sliding scale dependant on participant response to infection.
The minimal duration of prescription will be 1 week, up to a maximum prescription of 3 weeks.
The broad spectrum antibiotic prescription will be: Amoxycillin (875mg) + clavulanate (125mg) given orally 12-hourly.
If there is a true hypersensitivity to penicillin participants will be prescribed Clindamycin 450mg orally 8-hourly and Ciprofloxacin 500mg 12-hourly.

The mode of administration for all treatment arms will be an oral tablet(s).

Medication adherence will be encouraged through the use of short messaging service (text messaging) at the times the medication should be taken. Participants will also be provided with a diary to document when the dose should be taken.
Control group
Active

Outcomes
Primary outcome [1] 320873 0
The primary outcome is the clinical 'cure' of infection in response to antibiotic treatment, defined as resolution of the clinical evidence of the original infection.

This will be assessed by the primary investigators (medical and podiatric staff with experience managing diabetic foot disease) using the validated Diabetic Foot Infection Wound Score which is a composite score of clinical indicators of infection. This score will be done at each appointment. Participants will also have a tissue biopsy taken 'clinical resolution' to review for known pathogens, and participants will have a blood test to review inflammatory markers.
Timepoint [1] 320873 0
Participants will be reviewed and assessed on a weekly basis. The treatment period is a sliding scale of up to a total of 3 weeks.
Secondary outcome [1] 373179 0
Eradication (presence or absence) of wound pathogens as determined by standard microbial analysis of tissue wound specimens obtained after treatment for likely pathogens of infection.
Timepoint [1] 373179 0
Established through confirmation of Primary Outcome - tissue sampled once primary outcome identified (clinical cure of infection at timepoint 1-3 weeks).
Secondary outcome [2] 373180 0
Duration of antibiotic therapy used to treat the enrolled patient for DFI.

This will be assessed by the prescribed amount of antibiotic therapy provided to the patient, review of the medication log provided to the participant, and by checking at each weekly appointment if the participant is still taking the antibiotics.
Timepoint [2] 373180 0
Established once primary endpoint identified (clinical cure of infection at time point 1-3 weeks dependant on the sliding scale of response to therapy).
Secondary outcome [3] 373181 0
Rates of re-infection/s during 2 months follow up.

This will be assessed by investigators (medical and podiatric staff experienced in the management of diabetic foot disease) reviewing the patient weekly for a duration of 8 weeks following cessation of active treatment and recording re-infection through photography and clinical documentation in both the case report forms and clinical patient documentation in the medical records.
Timepoint [3] 373181 0
The 8 weeks of the review period following cessation of antibiotic therapy (antibiotic therapy duration is a sliding scale time point of 1-3 weeks).
Secondary outcome [4] 373182 0
Rates of re-ulceration/s during 2 months follow up
This will be assessed by investigators (medical and podiatric staff experienced in the management of diabetic foot disease) reviewing the patient weekly for a duration of 8 weeks following cessation of active treatment and recording re-infection through photography and clinical documentation in both the case report forms and clinical patient documentation in the medical records.
Timepoint [4] 373182 0
The 8 weeks of the review period following cessation of antibiotic therapy (antibiotic therapy duration is a sliding scale time point of 1-3 weeks).
Secondary outcome [5] 373183 0
Rates of treatment failure (>2 signs of symptoms of infection substantially worsening or a requirement to alter therapy: to a broader spectrum antibiotic or switch from oral to parenteral therapy; or any unplanned additional antibiotic therapy, surgery or hospitalisation required to control the index DFI)

The wound will also be assessed by the primary investigators (medical and podiatric staff with experience managing diabetic foot disease).
Treatment failure of infection worsening will be quantified through the Wound Ischemia foot Infection score (WIfI) which grades infections from 0 (no infection) to 4 (severe systemic infection).
It will also be scored using the validated Diabetic Foot Infection Wound Score which is a composite score of clinical indicators of infection.
Signs of infection include: local swelling, erythema (redness), local warmth, local tenderness or pain, and purulent discharge (pus).
Timepoint [5] 373183 0
While receiving active treatment (antibiotic therapy) - Weeks 0-3 on therapy
Secondary outcome [6] 373184 0
Participant quality of life as measured by the EQ-5D-5L Quality of Life measurement tool
Timepoint [6] 373184 0
At recruitment (week 0), cessation of antibiotic therapy (sliding scale of treatment from 1-3 weeks), and end of study (8 weeks following cessation of antibiotic therapy).
Secondary outcome [7] 373186 0
Changes in selected laboratory data (full blood counts, serum inflammatory markers) that reflect the inflammatory response (reviewed as a global composite response).
Timepoint [7] 373186 0
Measured at 1 week of antibiotic therapy and clinical cure of infection resulting in cessation of antibiotic therapy at timepoint 1-3 weeks.
Secondary outcome [8] 373870 0
Changes in microbiologic results of cultures and antibiotic sensitivities
This will be compared to defined pathogens of diabetic foot infection from tissue.
Timepoint [8] 373870 0
Measured at recruitment (week 0) and cessation of antibiotic therapy (timepoint 1-3 weeks).

Eligibility
Key inclusion criteria
- Type 1 or 2 Diabetes mellitus
- Newly diagnosed (<14 days) infective signs of symptoms
- No use of topical or systemic antimicrobial/antibiotic therapy 72 hours (3 days) prior to enrolment
- Mild to moderate Diabetic Foot Infection (PEDIS grade 2-3, IDSA mild or moderate foot infection, WIfI grade 1-2)
- Wound without bone involvement (Grade 1 and 2)
- Age >18 years
- Adequate peripheral vascular supply (good blood flow, measured as grade 0-2 WIfI)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participants with chronic infective symptoms who have received multiple (>2) antibiotic regimens within the previous 4 weeks or greater
- Proof of underlying bone involvement (osteomyelitis) based on; imaging (plain x-ray, computed tomography [CT], or magnetic resonance imaging [MRI]), clinical examination (exposed bone or positive probe to bone test) or culture/histopathology of bone specimen
- Diabetic foot ulcer of small size - <2cm in surface area
- Age under 18 years
- Documented peripheral arterial disease with either; ankle brachial indices < or equal to 0.4, toe brachial indices <0.5, toe pressure <40mmHg
- Pregnant women, women desiring pregnancy within the duration of the study, or those unwilling to practice contraception, women who are breastfeeding
- Stage 4-5 chronic kidney disease and/or an estimated glomerular filtration rate (eGFR) of <30ml/min/m
- Active liver disease as defined by an INR >2 (in the absence of oral anti-coagulation) and/or aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 3 upper limit of normal (ULN)
- Chronic liver disease as defined as clinical history of decompensating chronic liver disease (ascites, encephalopathy or variceal bleeding)
- otherwise assessed by study investigators as unsuitable to take tissue via biopsy or unable to follow trial protocols

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be via central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be assigned to their intervention group via online randomisation; Research Electronic Data Capture (REDCap).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The trial is designed to determine if narrow antibiotic therapy for mild to moderate DFI is non-inferior to broad spectrum antibiotic therapy.
Based on local data and previously published outcomes for DFI, it is expected that 90% of participants will experience infection resolution (clinical cure). To achieve an efficacy of >90% for the better of the two agents, the 95% confidence interval must cross zero and remain within a lower bound delta of 10%. The tolerance margin (non-inferior) margin is 10%.

Intention to treat (ITT) analysis will be conducted on the primary outcomes.
Continuous variables will be assessed by two sample t tests, while categorical variables will be assessed using a two-tailed Fisher exact test and chi square analyses.
All analyses will be done using the Statistical Package for Social Sciences (SPSS Inc).

An interim analysis will be completed at 25% recruitment.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
28/10/2019
Actual
11/02/2020
Date of last participant enrolment
Anticipated
30/10/2023
Actual
Date of last data collection
Anticipated
19/01/2024
Actual
Sample size
Target
340
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 14546 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 14547 0
Bankstown-Lidcombe Hospital - Bankstown
Recruitment hospital [3] 14548 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [4] 14549 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 14550 0
Prince of Wales Hospital - Randwick
Recruitment hospital [6] 16142 0
Blacktown Hospital - Blacktown
Recruitment postcode(s) [1] 27558 0
2170 - Liverpool
Recruitment postcode(s) [2] 27559 0
2200 - Bankstown
Recruitment postcode(s) [3] 27560 0
2560 - Campbelltown
Recruitment postcode(s) [4] 27561 0
2065 - St Leonards
Recruitment postcode(s) [5] 27562 0
2031 - Randwick
Recruitment postcode(s) [6] 29671 0
2148 - Blacktown

Funding & Sponsors
Funding source category [1] 303263 0
Hospital
Name [1] 303263 0
South Western Sydney Local Health District
Country [1] 303263 0
Australia
Primary sponsor type
Other
Name
South West Sydney Limb Preservation and Wound Research
Address
Ingham Institute of Applied Medical Research, 1 Campbell Street, Liverpool NSW, 2170
Country
Australia
Secondary sponsor category [1] 303461 0
Hospital
Name [1] 303461 0
Liverpool Hospital
Address [1] 303461 0
Liverpool Hospital
75 Elizabeth Street
Liverpool NSW 2170
Country [1] 303461 0
Australia
Secondary sponsor category [2] 303630 0
Hospital
Name [2] 303630 0
South Western Sydney Local Health District
Address [2] 303630 0
13 Elizabeth Street
Liverpool NSW 2170
Country [2] 303630 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303801 0
South Western Sydney Local Health District Ethics Committee
Ethics committee address [1] 303801 0
Ethics committee country [1] 303801 0
Australia
Date submitted for ethics approval [1] 303801 0
08/05/2019
Approval date [1] 303801 0
25/07/2019
Ethics approval number [1] 303801 0
ETH09886

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94858 0
Dr Matthew Malone
Address 94858 0
Ingham Institute of Applied Medical Research
1 Campbell Street
Liverpool 2170 NSW
Australia
Country 94858 0
Australia
Phone 94858 0
+61 02 8738 9260
Fax 94858 0
+61, 2, 8738 8297
Email 94858 0
matthew.malone@westernsydney.edu.au
Contact person for public queries
Name 94859 0
Alyson France
Address 94859 0
Ingham Institute of Applied Medical Research
1 Campbell Street
Liverpool 2170 NSW
Australia
Country 94859 0
Australia
Phone 94859 0
+61 02 8738 9361
Fax 94859 0
+61, 2, 8738 8297
Email 94859 0
alyson.france@health.nsw.gov.au
Contact person for scientific queries
Name 94860 0
Matthew Malone
Address 94860 0
Ingham Institute of Applied Medical Research
1 Campbell Street
Liverpool 2170 NSW
Australia
Country 94860 0
Australia
Phone 94860 0
+61 02 8738 9260
Fax 94860 0
+61, 2, 8738 8297
Email 94860 0
matthew.malone@westernsydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data is not necessarily reflective of the overall outcome.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.