Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000230954p
Ethics application status
Submitted, not yet approved
Date submitted
6/02/2020
Date registered
25/02/2020
Date last updated
25/02/2020
Date data sharing statement initially provided
25/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A direct comparison of two intravenous antibiotics for the treatment of diabetic foot infections in adults
Scientific title
Comparison of intravenous Amoxicillin/Clavulanate to Piperacillin/Tazobactam for the empiric treatment of moderate diabetic foot infections in adults: A pragmatic, non-inferiority, randomised trial
Secondary ID [1] 300477 0
Nil known
Universal Trial Number (UTN)
U1111-1247-8384
Trial acronym
CAPTAIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic foot infection 316146 0
Condition category
Condition code
Infection 314435 314435 0 0
Other infectious diseases
Metabolic and Endocrine 314436 314436 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Amoxicillin/Clavulanic Acid 2.2g three times daily intravenously or
Amoxicillin/Clavulanic Acid 1.2g twice daily intravenously (if eGFR <20mL/min)

Duration: at least 48hrs and ending at the direction of the treating clinician.
Intervention code [1] 316771 0
Treatment: Drugs
Comparator / control treatment
Piperacillin/Tazobactam 4.5g three times daily intravenously or
Piperacillin/Tazobactam 4.5g twice daily intravenously (if eGFR <20mL/min)

Duration: at least 48hrs and ending at the direction of the treating clinician.
Control group
Active

Outcomes
Primary outcome [1] 322776 0
Proportion of participants achieving treatment success

Definition of treatment success:

For those who have a PEDIS score greater than 7 or vascular surgical opinion of requiring operative intervention at baseline:

No worsening of IDSA category – i.e. remains at category 3 (Moderate) or improves to category 2 (mild) or category 1 (uninfected);

For those who have a PEDIS score < 7 or vascular surgical opinion of NOT requiring operative intervention at baseline:

Improvement in IDSA category – i.e. improves to category 1 (uninfected)
Timepoint [1] 322776 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [1] 379688 0
Resolution of ulcer (PEDIS score)
Timepoint [1] 379688 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [2] 379689 0
Time to treatment success as assessed by two blinded clinicians with all collected data and clinical photographs available.
Timepoint [2] 379689 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [3] 379690 0
Number of unplanned surgery/amputations

Review of medical records
Any related surgery if vascular surgical opinion of NOT requiring operative intervention at baseline.
Timepoint [3] 379690 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [4] 379691 0
Time to oral antibiotics

Review of trial records and calendar
Duration of empiric antibiotics until change to oral antibiotics
Timepoint [4] 379691 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [5] 379692 0
Total duration of empiric antibiotic exposure

Review of trial records and calendar
Duration of empiric (blinded) antibiotic exposure
Timepoint [5] 379692 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [6] 379693 0
Total duration of all antibiotic exposure

Review of trial records and calendar
Duration of all exposure to antibiotics, including oral antibiotics.
Timepoint [6] 379693 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [7] 379694 0
Length of hospital stay

Duration from admission to discharge from hospital.
Timepoint [7] 379694 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [8] 379695 0
Adverse events

Including allergic reactions as well as nausea and vomiting, diarrhoea, rash, neutropenia, renal impairment, jaundice, hepatic dysfunction.

Assessed to be related to trial drug by treating clinicians and collected laboratory data.
Timepoint [8] 379695 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [9] 379696 0
Number of unplanned readmissions (indication for readmission)

Review of medical records
Any readmission during the follow up period that is not planned, ie elective surgery.
Timepoint [9] 379696 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [10] 379697 0
Specimen microbial aetiology and culture sensitivity pattern

Microbiological data
Timepoint [10] 379697 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months
Secondary outcome [11] 379698 0
All-cause mortality
Timepoint [11] 379698 0
Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Eligibility
Key inclusion criteria
18 years of age and older

Diabetes mellitus (type 1 or 2)

Moderate (Grade 3) diabetic foot infection (IDSA grading)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Severe (Grade 4) infection
Pregnant women
Documented allergy to penicillin
Received greater than 24hrs of trial drug prior to enrolment
Eligible for targeted therapy (i.e. have deep specimen bacteriological culture results).
Severe renal impairment (eGFR <10mL/min) or requiring renal replacement therapy
Unable to give consent for trial

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size

Our retrospective audit showed there was 83% treatment success for PTZ (standard treatment). Based on a non-inferiority RCT of amoxicillin/clavulanic acid (experimental treatment) versus PTZ and a non-inferiority margin of 10% (Doshi) if there is truly no difference between the standard and experimental treatment, then 484 patients are required to be 90% sure that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the standard group of more than 10% (Blackwelder). Based on Phase 1 data it is estimated that it will take around 2 years to recruit the required number of patients.

Statistical methods for analysing primary and secondary outcomes

We will compare the proportions of patients in each treatment group deemed to have had a clinical response to treatment (primary outcome) by reporting: (1) the proportions in each treatment group, (2) the difference between proportions, and (3) a 1-sided 95% confidence interval around the difference. Patients with unknown primary outcome status will be deemed to have not had a clinical response. Analysis will be by intention-to-treat. Time to event secondary outcomes will be compared using survival analysis: Kaplan Meier plots and hazards-based regression analysis. Mortality, unplanned readmission, and unplanned surgery/amputation will be compared by treatment group using Fishers exact test. Adverse events will be fully reported by treatment group and descriptively compared. We plan to conduct two secondary analyses of the primary outcome: (1) a per-protocol comparison where we restrict the analysis to only those patients that adhered to the protocol procedures; and (2) an adjusted intention-to-treat comparison where we adjust for the randomisation stratification factors as well as any other baseline factors that may be unbalanced between treatment groups.

No interim analysis is planned.

Doshi P, Hur P, Jones M, Albarmawi H, Jefferson T, Morgan DJ, et al. Informed consent to study purpose in randomized clinical trials of antibiotics, 1991 through 2011. JAMA Intern Med. 2017;177(10):1452–9.

Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials. 1982;3(4):345–53.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
16/03/2020
Actual
Date of last participant enrolment
Anticipated
30/11/2021
Actual
Date of last data collection
Anticipated
28/02/2022
Actual
Sample size
Target
484
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 15810 0
Gold Coast University Hospital - Southport
Recruitment hospital [2] 15811 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [3] 15812 0
Mater Adult Hospital - South Brisbane
Recruitment postcode(s) [1] 29245 0
4215 - Southport
Recruitment postcode(s) [2] 29246 0
4575 - Birtinya
Recruitment postcode(s) [3] 29247 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 304897 0
Hospital
Name [1] 304897 0
Gold Cost Hospital and Health Service
Country [1] 304897 0
Australia
Primary sponsor type
Hospital
Name
Gold Coast Hospital and Health Service
Address
1 Hospital Blvd, Southport, QLD, 4215
Country
Australia
Secondary sponsor category [1] 305238 0
None
Name [1] 305238 0
Address [1] 305238 0
Country [1] 305238 0
Other collaborator category [1] 281177 0
University
Name [1] 281177 0
Bond University
Address [1] 281177 0
14 University Dr, Robina QLD 4226
Country [1] 281177 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 305307 0
Gold Coast Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 305307 0
Ethics committee country [1] 305307 0
Australia
Date submitted for ethics approval [1] 305307 0
29/01/2020
Approval date [1] 305307 0
Ethics approval number [1] 305307 0

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

Contacts
Principal investigator
Name 99934 0
Dr Kylie Alcorn
Address 99934 0
Gold Coast University Hospital
c/o Department of Infectious Diseases
PED Building
1 Hospital Blvd, Southport
QLD, 4215
Country 99934 0
Australia
Phone 99934 0
+61 415277124
Fax 99934 0
Email 99934 0
[email protected]
Contact person for public queries
Name 99935 0
Kylie Alcorn
Address 99935 0
Gold Coast University Hospital
c/o Department of Infectious Diseases
PED Building
1 Hospital Blvd, Southport
QLD, 4215
Country 99935 0
Australia
Phone 99935 0
+61 415277124
Fax 99935 0
Email 99935 0
[email protected]
Contact person for scientific queries
Name 99936 0
Kylie Alcorn
Address 99936 0
Gold Coast University Hospital
c/o Department of Infectious Diseases
PED Building
1 Hospital Blvd, Southport
QLD, 4215
Country 99936 0
Australia
Phone 99936 0
+61 415277124
Fax 99936 0
Email 99936 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only after being de-identified
When will data be available (start and end dates)?
Start - after final data analysis
End - no end date determined
Available to whom?
Anyone with access to Open Science Framework
Available for what types of analyses?
any purpose
How or where can data be obtained?
Access via OSF (https://osf.io/)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
6809Study protocol    The final protocol, after ethics approval, will be... [More Details]



Results publications and other study-related documents

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