ANZCTR - Registration

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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]

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

Condition category

Condition code

Infection

Other infectious diseases

Metabolic and Endocrine

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]

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]

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]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [1]

Resolution of ulcer (PEDIS score)

Timepoint [1]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [2]

Time to treatment success as assessed by two blinded clinicians with all collected data and clinical photographs available.

Timepoint [2]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [3]

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]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [4]

Time to oral antibiotics

Review of trial records and calendar
Duration of empiric antibiotics until change to oral antibiotics

Timepoint [4]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [5]

Total duration of empiric antibiotic exposure

Review of trial records and calendar
Duration of empiric (blinded) antibiotic exposure

Timepoint [5]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [6]

Total duration of all antibiotic exposure

Review of trial records and calendar
Duration of all exposure to antibiotics, including oral antibiotics.

Timepoint [6]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [7]

Length of hospital stay

Duration from admission to discharge from hospital.

Timepoint [7]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [8]

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]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [9]

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]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [10]

Specimen microbial aetiology and culture sensitivity pattern

Microbiological data

Timepoint [10]

Day 3, 5, 7, 10, 14, discharge, 1 month, 2 months, 3 months

Secondary outcome [11]

All-cause mortality

Timepoint [11]

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]

Gold Coast University Hospital - Southport

Recruitment hospital [2]

Sunshine Coast University Hospital - Birtinya

Recruitment hospital [3]

Mater Adult Hospital - South Brisbane

Recruitment postcode(s) [1]

4215 - Southport

Recruitment postcode(s) [2]

4575 - Birtinya

Recruitment postcode(s) [3]

4101 - South Brisbane

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Gold Cost Hospital and Health Service

Address [1]

1 Hospital Blvd, Southport, QLD, 4215

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

Bond University

Address [1]

14 University Dr, Robina QLD 4226

Country [1]

Australia

Ethics approval

Ethics application status

Submitted, not yet approved

Ethics committee name [1]

Gold Coast Hospital and Health Service Human Research Ethics Committee

Ethics committee address [1]

Office for Research Governance and Development
Level 2, Pathology and Education Building
1 Hospital Boulevard
Southport QLD 4215

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

29/01/2020

Approval date [1]

Ethics approval number [1]

Summary

Brief summary

Purpose: The most recent national antibiotic recommendations for moderate DFI is to treat with IV Amoxicillin/Clavulanate (AUG).  Previous guidelines recommended Piperacillin/tazobactam (PTZ) but was changed to the current recommendation based on largely expert opinion and anecdotal evidence.  

Study hypothesis: AUG is non-inferior to PTZ in adults in empiric treatment of moderate DFI and can therefore be safely used as first line empiric therapy

Intervention: Participants will be randomised to receive either intravenous PTZ or intravenous AUG for at least 48hrs and ending at the direction of the treating clinician.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Kylie Alcorn

Address

Gold Coast University Hospital
c/o Department of Infectious Diseases
PED Building
1 Hospital Blvd, Southport
QLD, 4215

Country

Australia

Phone

+61 415277124

Fax

Email

kylie.alcorn@health.qld.gov.au

Contact person for public queries

Name

Kylie Alcorn

Address

Gold Coast University Hospital
c/o Department of Infectious Diseases
PED Building
1 Hospital Blvd, Southport
QLD, 4215

Country

Australia

Phone

+61 415277124

Fax

Email

kylie.alcorn@health.qld.gov.au

Contact person for scientific queries

Name

Kylie Alcorn

Address

Gold Coast University Hospital
c/o Department of Infectious Diseases
PED Building
1 Hospital Blvd, Southport
QLD, 4215

Country

Australia

Phone

+61 415277124

Fax

Email

kylie.alcorn@health.qld.gov.au

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.	Type	Citation	Link	Email	Other Details	Attachment
6809	Study protocol				The final protocol, after ethics approval, will be... [More Details]

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.