Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT03632642 |
| Other study ID # |
HREC/17/QRBW/620 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2019 |
| Est. completion date |
July 2020 |
Study information
| Verified date |
August 2018 |
| Source |
The University of Queensland |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
There is theroretical superiority with benzylpenicillin over orther anti-staphylococcal
penicillins (ASP) for treatment of penicillin susceptible S. aureus (PSSA) infections due to
a lower MIC distribution when compared with ASPs active against PSSA, combined with the
ability to obtain higher levels of free non-protein-bound plasma drug concentrations.
Although the data to support this theoretical advantage is limited, many clinicians in
Australia (and worldwide) use benzylpenicillin for therapy in this situation despite many
international guidelines cautioning against this. This uncertainty is significant given that
1) S. aureus bacteraemia (SAB) is associated with a high mortality and significant morbidity,
2) S. aureus is one of the most common organisms isolated from blood cultures, 3) SAB is the
most common reason for consultation with an Infectious Disease specialist (which itself has
been shown to improve outcomes) and 4) a significant proportion (up to 20%) of SAB isolates
in Australia will be reported as susceptible to penicillin, a proportion which appears to be
increasing over the past 10 years in Australia and internationally.
Given the frequency of PSSA and the associated morbidity and mortality related to SABs in
general, a definitive study to determine the optimal therapy for PSSA is required. In a
recent survey of Infectious Diseases Physicians and Clinical Microbiologists in Australasia,
87% of respondents were willing to randomise patients to either benzylpenicillin or
flucloxacillin for a clinical trial, whist 71% responded that they would switch therapy from
flucloxacillin to benzylpenicillin for treatment of PSSA BSIs in clinical practice
(unpublished data).
Therefore, the investigators see the opportunity to determine the feasibility of a definitive
study comparing benzylpenicillin against flucloxacillin (or other ASP) for treatment of PSSA
bloodstream infections.
Description:
Background and rationale:
Resistance to penicillin was discovered in Staphylococcus aureus in the mid-1940s, soon after
the introduction of penicillin as a therapeutic agent into clinical practice. The emergence
of penicillin resistant S. aureus (PRSA) was widely encountered in hospitals thereafter, with
some reports finding rates of PRSA rising from 14% to 38% in less than 1 year. Two mechanisms
are known that result in resistance to penicillin in staphylococci. The most common, and
earliest described, was by the production of a serine β-lactamase, known as penicillinase
(PC1), which hydrolyses the β-lactam ring resulting in the production of penicilloic acid. A
second mechanism leads to resistance to penicillin and other beta-lactam agents by production
of penicillin-binding protein, PBP2a, encoded by mecA. Following the emergence of PRSA, a new
class of anti-staphylococcal penicillins were developed that were resistant to hydrolysis of
the beta-lactam ring by penicillinase. The isoxazolyl-penicillins, semi-synthetic penicillin
derivatives that are stable during exposure to penicillinase, are now the most commonly used
agents for the treatment of S. aureus infections.
Despite widespread resistance to penicillin amongst S. aureus, a significant proportion of
invasive isolates remain susceptible. Although penicillin and isoxazolyl-penicillins have
been used in clinical practice for more than 50 years, the optimal therapy for patients with
invasive penicillin susceptible S. aureus (PSSA) remains controversial. Methicillin
susceptible S. aureus (MSSA) bloodstream infections are commonly sub-divided into categories
based upon the presence of penicillinase, the absence of which defines PSSA strains. Many
clinicians advocate treating both MSSA and PSSA the same, irrespective of whether
penicillinase is detected or not. One group who strongly supports this view is the American
Heart Association, which has published recently updated guidelines on infective endocarditis.
This recommendation is based upon literature suggesting that detection of penicillinase is
not reliable in some clinical laboratories. Multiple publications have demonstrated that the
previous widely used phenotypic method of penicillinase detection, by nitrocefin hydrolysis,
lacks adequate sensitivity for detecting penicillinase. Yet, treatment failure with
penicillin due to inability to detect penicillinase has not been previously described in the
medical literature to our knowledge. Regardless, many laboratories have now changed methods
to the penicillin disc test, where isolates harbouring penicillinase may be detected by
interrogation of the edge of the disc, with a sharp edge confirming the presence of
penicillinase and a tapered edge indicating an absence. This method is now employed in most
Pathology services and is the method approved by international governance organisations.
Other experts argue for potential superiority with penicillin due to a lower MIC distribution
when compared with other beta-lactam agents active against S. aureus, combined with the
ability to obtain high levels of free non-protein-bound plasma drug concentrations.
To date there is only one previous study that has directly compared the outcome between a
semi-synthetic penicillin derivative (dicloxacillin) and penicillin for PSSA infections. In
this retrospective study, no statistically significant difference was observed between
penicillin and dicloxacillin based on a mortality outcome. Although this study does not
support improved outcome with penicillin compared with dicloxacillin, it should be noted that
significantly more patients treated with penicillin had a higher Pitt bacteraemia score and
deep-seated infection such as endocarditis or osteomyelitis. Data from the ANZCOSS study, a
prospective observational study of SAB within Australia between 2007 - 2016, demonstrated a
possible 30-day crude mortality benefit for patients treated with benzylpenicillin compared
to flucloxacillin or dicloxacillin (unpublished data). Patients in this cohort were treated
2:1 with flucloxacillin over benzylpenicillin, however, benzylpenicillin treatment was
proportionally higher in patients with endocarditis or other deep-seated infections. In a
multivariate logistic regression model, Flucloxacillin therapy was associated with a
non-statistically significant increase in the odds ratio for 30-day mortality (OR 1.55, 95%
CI 0.99 - 2.47).
A number of recent studies internationally have reported a resurgence of PSSA, and in
particular within the Australian setting, it was noted that 20% of S. aureus bacteraemias
(SAB) were found to be susceptible to penicillin in 2013. Given the resurgence of PSSA and
the associated morbidity and mortality related to SABs in general, a definitive study to
determine the optimal therapy for PSSA is required.
A pilot randomised controlled trial is critical to determining the feasibility for a
definitive study due to PSSA BSIs and in order to calculate an appropriate sample size based
upon the proportion of deep-seated infections. A definitive trial would greatly enhance the
medical literature and help to define the optimum treatment which for both penicillin
susceptible and penicillin non-susceptible MSSA in invasive infections, at present, remains
unclear.
Objectives and hypothesis:
The investigators hypothesise that penicillin is superior to flucloxacillin for treatment of
penicillin susceptible S. aureus bloodstream infections based upon a lower distribution of
MICs for penicillin, a higher level of free non-protein-bound drug concentration and
favourable side effect profile.
Primary objective:
1. To determine feasibility of a randomised controlled trial of penicillin versus
flucloxacillin for definitive management of penicillin susceptible S. aureus bacteraemia
Secondary objective:
1. To assist in calculating an appropriate sample size for a definitive study
2. To determine the proportion of deep-seated infections
3. To determine the feasibility of desirability of outcome rankings (DOOR) as a clinical
endpoint
Study design:
The study will be a pilot open-label multicentre randomised trial that is
investigator-initiated comparing two drug regimens: benzylpenicillin vs. flucloxacillin for
penicillin susceptible S. aureus bloodstream infections. The investigators will aim to enroll
60 patients over a 24-month period. The participation duration for each enrolled patient is
90 days. Data will be collected for the participants from the date of when the first positive
blood culture was obtained, which will be within 72 hours of enrolment.
Consented patients will be randomised on day 1 (the day of randomisation) to either
benzylpenicillin or flucloxacillin. Data will be obtained from the medical records
(electronic or paper) of each participant. Data collected will include relevant
investigations (FBC, ELFT, blood culture results, and CRP), any SAE that have occurred,
antibiotics administered and evidence of relapse or treatment failure. Participants who are
discharged will be followed weekly in outpatients for the duration of intravenous therapy.
Participants will be reviewed at day 90 in outpatient clinic if they have been discharged (or
within 1-2 weeks thereafter). For participants who do not attend the outpatients clinic,
contact will be made by telephone. If attempts at contact are unsuccessful, then the site
investigator will review the medical records of the participants at 6-month time intervals
until either the vital status has been completed or the study period is complete.
Intervention Participants will be randomised to either benzylpencillin or flucloxacillin.
Dosage, frequency and duration of antibiotics will be determined by the treating clinician
based upon national guidelines, eTG (Therapeutic Guidelines 15th Edition) as summarised
below.
The study drug will be administered for a minimum of 2 weeks (the minimal currently accepted
duration of IV therapy for SAB.) Participants treated for 2 weeks will have to meet the
following criteria:
- Negative BC at 48-72 hours from first effective antibiotics
- Rapid resolution of fever
- Normal valvular morphology and no evidence of valvular lesions on TTE or TOE
- An identifiable source of infection that has been removed, including drainage of simple
skin infections
- No evidence of metastatic focus
- No intravascular prosthetic material
- No significant immunocompromise including any congenital or acquired quantitative or
qualitative deficiency of phagocytic cells, complement, or humoral or cell-mediated
immunity. This includes:
- Stem cell or organ transplant recipient
- Absolute neutrophil count less than 500/μl
- HIV
- Prednisolone > 25mg/kg/day for 1 month or cumulative dose > 700mg within 3 months
of onset of SAB
- Use of a monoclonal antibody within 1 month of SAB onset For participants who do
not fulfil these criteria, the duration of treatment will be 4 to 6 weeks and will
be made by the treating clinician.
Other antimicrobials active against S. aureus will be discouraged during the duration of IV
therapy:
Any missed doses of antibiotics will be recorded on the CRF. In order to ensure equivalence
amongst the sites, TDM will not be employed during the study for the purpose of tailored
antibiotic dosing. Therefore, to ensure participants are treated optimally, dosing will be
based upon standard uncomplicated BSIs or critical illness/deep-seated infection and dosed as
per eTG. Participants who were initially stratified as uncomplicated BSI may be changed to
deep-seated or critical illness if the participants fulfil the criteria after enrolment.
For participants with obesity or renal impairment, dosing may follow local guidelines. All
outpatient therapy will be administered by continuous intravenous infusion (CIV). CIV will be
discouraged for inpatients, however, if the treating clinician considers this to be
necessary, then it will be allowed and recorded in the CRF. Non-antibiotic related management
of the participants will be at the discretion of the treating clinician.
Dosing in renal impairment:
Flucloxacillin
- Standard Dose: 2g Q6H (8g/24 hours CIV if home IV therapy)
- Critical Illness or Deep-seated infection: 2g Q4H (12g/24 hours CIV if home IV therapy)
- CrCl <50 ml/min and > 10 ml/min: No change to dose
- CrCl <10 ml/min or on haemodialysis: 50% reduction of dose
- On continuous renal replacement therapy: 2g Q6H
Benzylpenicillin
- Standard Dose: 1.8g Q4H (10.8g/24 hours CIV if home IV therapy)
- Critical Illness or Deep-seated infection: 2.4g Q4H (14.4g/24 hours CIV if home IV
therapy)
- CrCl <50 ml/min and > 10 ml/min: 25% reduction of dose
- CrCl <10 ml/min or on haemodialysis: 50% reduction of dose
- On continuous renal replacement therapy:1.8g Q4H
Change of therapy:
Any change to the intervention drug will be discouraged, but left to the discretion of the
treating clinician. If an intervention drug needs to be changed (such as due to an adverse
event ie. rash) during the intravenous phase of therapy, then this will be a protocol
violation. The participant will still remain in the study and be analysed to the group they
were randomised, but will be excluded from the per-protocol analysis if the change occurred
within the first two weeks from enrolment.
Use of antibiotics with activity against S. aureus after randomisation:
The use of any other antibiotic with activity against S. aureus after randomisation will be
discouraged during the intravenous phase of the trial. If a participant requires additional
antibiotics due to an indication for broadening antibiotic therapy, the PI should recommend
an agent without useful activity towards S. aureus (such as gentamicin, ceftazidime or
aztreonam). If a patient receives an antibiotic with activity against S. aureus during the
first two weeks of the intravenous phase of the study, this will be recorded as a protocol
violation. The participant will still remain in the study and be analysed to the group they
were randomised, but will be excluded from the per-protocol analysis. If the participant
receives anti-staphylococcal therapy after the first two weeks from enrolment and is still on
intravenous therapy with the study drug, they will be included in the per-protocol
population. For patients that have completed their intravenous therapy phase of the study but
have an indication for ongoing oral therapy, any oral antibiotic may be prescribed and will
be recorded in the CRF. The choice of antibiotic and indication for oral therapy is at the
discretion of the treating clinician or PI.
Strategies to improve adherence to protocol:
All site PIs will be trained in the study protocol, SOPs and their reporting requirements by
the project manager, a study chief investigator or delegate, prior to the site being opened
for recruitment. All site PIs will complete a computer-based training course in Good Clinical
Practice.
A sticker will be placed in the patient's medical record (one on the progress notes on the
day of randomisation, and one in the front inside cover of the medical record if one exists).
This sticker will alert clinicians that the patient has been randomised to the PANFLUTE
study, with a brief explanation of the study, and confirmation that the participant (or the
person responsible) has provided written informed consent.
A copy of the study synopsis will be placed in the bedside chart (observations and drug
chart) of the patient. A checklist of study procedures will also be placed in the bedside
chart. For sites with electronic medical records and/or prescribing, an electronic "sticker"
will be used, and appropriate annotations will be made to the electronic drug chart.
The medication chart (be it paper or electronic) will be checked regularly by the site PI or
their delegate (registrar or research nurse) whilst the participant is an inpatient to ensure
adherence to the study protocol.
Sample Size:
Recruitment will be from any adult patient admitted to the study site hospital with a
bloodstream infection due to PSSA. Based upon previous retrospective case-control studies,
the mortality from S. aureus BSI ranges from 10-30%. A sample size of 60 was chosen based
upon feasibility of recruiting participants within the time frame for this pilot study from a
total of 8 sites.
Assignment of Intervention:
Participants will be randomised to either of the two arms in a 1:1 ratio using a web based
interactive randomisation system. Randomisation will be stratified by site. The randomised
sequence allocation will be held on a secure server and not accessible by any investigators
of members of study staff. The person enrolling the patient will, following obtaining written
informed consent, obtain the treatment allocation by logging onto the web-based database and
will then assign the allocated treatment to the patient. As the study will be an open-label
design, the site investigators will not be blinded to the intervention, however, the
investigators assessing the primary outcome will be.
Outcome Measurement:
This study aims to determine the feasibility of Desirability of Outcome Ranking (DOOR) as a
novel outcome method for outcome analysis in clinical trials. Participants are classified
according to outcomes by using ordinal categories with the aim to evaluate if an intervention
is superior to standard care strategy. This approach takes into account a risk/benefit
assessment by including participant centered outcomes such as treatment failure, adverse
events and complications of the disease process.
Participants will be ranked according to the following stratification:
1. Alive, Treatment failure or Infectious complication - No, Grade 2 or greater AE - No
2. Alive, Treatment failure or Infectious complication - No, Grade 2 or greater AE - Yes
3. Alive, Treatment failure or Infectious complication - Yes, Grade 2 or greater AE - No
4. Alive, Treatment failure or Infectious complication - Yes, Grade 2 or greater AE - Yes
5. Dead, Treatment failure or Infectious complication - Any, Grade 2 or greater AE - Any
Definitions of DOOR components:
Alive: 90 day status
Treatment Failure (Any one of the following):
- Relapse - Positive blood culture following at least 72 hours after a preceding negative
culture
- Persistence - Bacteraemia at day 7 or beyond post randomisation
- Readmission - Readmission to hospital attributable to PSSA infection
Infection complications (Any one of the following):
- Positive sterile site culture (excluding bloodstream) at least 7 days after
randomisation
- Positive culture from a new sterile site 48 hours or later after randomisation
- Septic shock or ICU admission 24 hours or later after randomization
- New metastatic event that was not present at randomization and occurs 48 hours or later
after randomization
Adverse Events:
Hepatotoxicity (defined according to the Common Terminology Criteria for Adverse Events,
version 4.0)
- Grade 1: ULN to 3x ULN of GGT/ALP or AST
- Grade 2: >3 to 5x ULN of GGT/ALP or AST
- Grade 3: 5 to 20x ULN of GGT/ALP or AST
- Grade 4: >20x ULN of GGT/ALP or AST
- Patients with pre-existing abnormal liver function tests:
For patients with pre-existing abnormal liver function tests, hepatotoxicity will still be
assessed but will include a greater than 2x rise compared to initial GGT/ALT or AST
Kidney Injury (defined according to the Common Terminology Criteria for Adverse Events,
version 4.0)
- Grade 1: Creatinine > 1.5 to 2x baseline and < 350 μmol/L
- Grade 2: Creatinine > 2 to 3x baseline and < 350 μmol/L
- Grade 3: Creatinine > 3x baseline and/or > 350 μmol/L
- Grade 4: Dialysis (if previously not on dialysis)
Phlebitis (Assess according to Visual Infusion Phlebitis Score)
- Grade 1: NA
- Grade 2: VIP score of 1 (Pain but no associated erythema and not requiring a change of
IVC or central line)
- Grade 3: VIP score of 2,3 or 4 (Pain, redness and swelling +/- palpable venous cord
requiring change of IVC or central line)
- Grade 4: VIP score of 5 (As above but with fever attributable to phlebitis)
Haematologic (Any of the following as defined according to the Common Terminology Criteria
for Adverse Events, version 4.0)
Platelets
- Grade 1: LLN - 75 x 10^9
- Grade 2: <75 - 50 x 10^9
- Grade 3: <50 - 25 x 10^9
- Grade 4: < 25 x 10^9
Neutrophil
- Grade 1: LLN - 1.5 x 10^9
- Grade 2: <1.5 - 1.0 x 10^9
- Grade 3: <1 - 0.5 x 10^9
- Grade 4: <0.5 x 10^9
Endpoint Assessment:
The primary endpoint will be assessed by a blinded adjudication committee in order to rank
participants according to the DOOR outcomes. This committee will include 2 independent
Infectious Diseases Physicians appointed by the trial management committee. The information
provided to the committee will not include any participant identifiers or any antibiotic
details. The data provided will include:
1. Demographic details (such as age and sex)
2. Comorbidities
3. Clinical details (including focus of infection and relevant investigation results)
4. Date and result of all blood cultures taken during days 1-90
5. Date and result of all other available clinical cultures taken from days 1-90 (e.g.,
cultures of aspirated pleural fluid or pus).
6. Any adverse events recorded
7. Vital status at day 90 and date of death if applicable.
Additional information will be provided to the adjudication committee providing it does not
contain antibiotic data or patient identifiers. Each of the committee members will
independently rank participants according to DOOR outcomes. If there is discrepancy between
the assessments, the committee will refer to a third independent assessor and the majority
will determine the rankings.
Discontinuation/withdrawal of participants from trial treatment:
The participants or NOK have the right to choose to withdraw from the study at any time and
the investigator may discontinue a participant from the study or from treatment if deemed
appropriate at any time. Reasons why a participant may be withdrawn from the study include,
but are not limited to, participant or person responsible request, primary treating
clinician's request, participant was enrolled and is ineligible (either arising during the
study or was overlooked at time of screening and enrolment). Participants will not be
withdrawn due to adverse events, unless the adverse event is life threatening. The decision
to withdraw a participant from the study must be discussed with the coordinating
investigators.
If the participant or person responsible withdraws consent from participating in the study
and also withdraws consent for collection of future information, no further evaluations will
be performed, and no additional data will be collected. The sponsors may retain and continue
to use any data or samples collected before such withdrawal of consent. Participants that
abscond will continue to be followed, if possible, until the end of the trial to avoid
missing data. Participants withdrawn from the treatment by the treating clinicians will
continue to be followed up to the end of the trial to avoid missing data and will be used in
the intention-to-treat analysis. Withdrawn participants will not be replaced. If a
participant is withdrawn the reason will be recorded in the database.
Statistical Analysis Plan:
Data for this study will be reported as per CONSORT guidelines. All-cause mortality will be
represented in a Kaplan-Meier graph. The primary analysis will be performed by a modified
intention to treat principle, whereby all participants with data available for the endpoint
will be assessed. A per-protocol analysis will also be performed, whereby participants in
this population will have to have received at least 2 weeks of the intravenous phase of the
study drug and 90 day outcome data.
A summary of baseline participant characteristics with totals and proportions (%) for
categorical variables, and minimum, maximum, inter-quartile ranges and standard deviations
for continuous variables will be presented. For assessment of the primary outcome, 2
independent clinicians, blinded to the therapy given to each participant, will assess all
participants and rank each participant's outcome according to the pre-designed DOOR groups.
The probability that a randomly selected patient will have a better DOOR if assigned to the
benzylpenicillin arm vs. the flucloxacillin arm will be estimated along with a confidence
interval. If there is no difference in DOOR distributions between the 2 arms, then the
probability will be near 50%.
