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Trial registered on ANZCTR


Registration number
ACTRN12613000601730
Ethics application status
Approved
Date submitted
27/05/2013
Date registered
27/05/2013
Date last updated
5/03/2019
Date data sharing statement initially provided
5/03/2019
Date results information initially provided
5/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Paracetamol in febrile neutropenia feasibility study
Scientific title
A randomised placebo-controlled trial of paracetamol in febrile neutropenia: feasibility study
Secondary ID [1] 282577 0
Nil known
Universal Trial Number (UTN)
U1111-1143-6132
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infection: febrile neutropenia after intensive chemotherapy 289259 0
Condition category
Condition code
Cancer 289582 289582 0 0
Leukaemia - Acute leukaemia
Cancer 289583 289583 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Infection 289586 289586 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients due to receive chemotherapies carrying a high risk of febrile neutropenia will be screened and will give informed consent before febrile neutropenia onset. Patients who consent to the study will be randomised on a 1:1 ratio to receive oral paracetamol (1g six hourly) or matching placebo during the first 42 hours of febrile neutropenia. Upon the development of febrile neutropenia patients will commence their allocated treatment after starting antibiotic therapy.

Whilst in hospital with febrile neutropenia, study participants will have daily blood tests over and above those taken for standard of care. Tests will look at markers of inflammation and the level of bacteria in participants’ blood.

Participants will also be asked to fill in a short quality of life questionnaire each day. On the third day, two more detailed quality of life questionnaires and a questionnaire about their experience of the study will need to be completed.

All participants will be inpatients in Wellington hospital. Adherence to study treatment will be monitored by reviewing the participants' medication chart, as the study treatment/placebo will be prescribed on this and individual doses will be signed for by the administering nurse or doctor. If a participant is discharged home prior to completing the course of study treatment, that participant will come off study.
Intervention code [1] 287241 0
Treatment: Drugs
Comparator / control treatment
Participants randomised to the comparator arm will receive placebo in lieu of paracetamol. All other interventions will be as for the intervention arm of the study.
Control group
Placebo

Outcomes
Primary outcome [1] 289676 0
This is a feasibility study with the aim of proceeding to a multicentre study should the result of this study be positive. The study will collect information on the primary and secondary endpoints proposed for the full study. However, this feasibility study is not statistically powered to detect differences between the study groups in these endpoints.
Primary endpoint: The proportion of patients who are successfully treated by 72 hours from the time of initiation of study therapy. ‘Successful treatment’ will be defined as survival with no documented fever of greater than 38 degrees centigrade in the preceding 12 hours, with no change of initial antimicrobial therapy, with no serious medical event (defined as hypotension with systolic BP <90mmHg for >1 hour, respiratory failure requiring invasive or non-invasive ventilation, or intensive care transfer) in the preceding 72 hours, and no recurrence of fever seven days after cessation of first-line antibiotics.
Timepoint [1] 289676 0
Successful treatment will be determined by assessment at 72 hours and by review of medical notes and by follow-up telephone call 30 days after febrile neutropenia onset.
Secondary outcome [1] 302986 0
Quality of life
Timepoint [1] 302986 0
The EQ-5D-5L quality of life questionnaire will be assessed daily during the first 72 hours of febrile neutropenia. At 60 – 92 hours, quality of life will be assessed using the FACT-N questionnaire.
Secondary outcome [2] 302987 0
Bacterial load
Timepoint [2] 302987 0
Peripheral blood taken at 0, 24 and 72 hours of febrile neutropenia will be used to assess bacterial load by quantitative PCR for the conserved bacterial gene for 16S ribosomal RNA.
Secondary outcome [3] 302988 0
Duration of hospital stay
Timepoint [3] 302988 0
This will be determined by review of medical records on day 30 after febrile neutropenia onset
Secondary outcome [4] 302989 0
Overall survival
Timepoint [4] 302989 0
This will be determined by medical notes review and telephone call on day 30 after febrile neutropenia onset

Eligibility
Key inclusion criteria
1. Scheduled to receive a chemotherapy carrying a high risk (> 50%) of febrile neutropenia, such as: acute leukaemia intensive induction and consolidation, autologous stem cell transplantation, high-dose anthracycline-based regimen for aggressive lymphoma (Hyper-CVAD, Nordic MCL2, CODOX-M IVAC, GMALL 07/2003)
2. Aged 18 years or over
3. Weight 50 kg or over
4. Geographically accessible to the Wellington Blood and Cancer Centre in the event of febrile neutropenia onset
5. Satisfactory liver and renal function as indicated by:
i. Alanine Transaminase (ALT) less than or equal to 2 x Upper Limit of Normal (ULN)
ii. Alkaline Phosphatase (ALP) less than or equal to 2 x ULN
iii. Bilirubin less than or equal to 1.5 x ULN
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient using regular paracetamol (1 g or more on at least seven days over the 14 days before study entry) or regular non-steroidal anti-inflammatory drugs (on at least seven days over the 14 days before study entry; low dose aspirin < 100 mg/day is permitted)
2. Any known contraindication to paracetamol 4 g daily
3. Severe functional impairment that confines the patient to bed or chair for 50% or more of waking hours
4. Pregnancy
5. Allogeneic stem cell transplantation within the 12 months before study entry
6. Active graft versus host disease
7. Active hepatitis B, hepatitis C or HIV (HBsAg positive, anti-HCV positive or anti-HIV positive)
8. Previous randomisation into this feasibility study

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)
Placebo- and paracetamol-containing study packs will be prepared by Optimus Healthcare (4 Walls Road, Penrose, Auckland, PO Box 99-467, Newmarket, Auckland), and will be serially numbered according to a randomisation sequence generated by the study statistician. The packs will be produced in duplicate, and will be distinctly labelled, to allow distribution of one pack to the study participant, and a back-up pack to be held securely on the haemato-oncology ward in case the study participant presents with febrile neutropenia but without bringing their study pack. A 1:1 ratio of paracetamol to placebo will be used. There will be no stratification for this feasibility study.
Potential participants will be identified before the onset of febrile neutropenia, and offered study participation. Participants who agree to take part and sign consent will be screened to ensure they meet criteria for study entry. Participants who meet inclusion criteria and are not excluded will be given the next sealed study pack in numerical order. Staff and patients will be blinded to the treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated blocked randomisation sequence using randomly-selected block sizes will be produced by the study statistician. No stratification will be used.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a feasibility study designed to assess critical questions for the design of a subsequent phase III trial. It is not statistically powered to answer the primary or secondary endpoints of the main trial, although these endpoints will be assessed to evaluate the case report forms and study design.

This feasibility study will address four feasibility issues as follows:
1. Temperature separation: Temperature separation will be assessed by comparison of mean peak daily temperatures and mean average temperatures between the two randomised groups.
2. Acceptability of treatment: Acceptability of allocated treatment will be by measurement of the proportion of randomised participants in each group who were withdrawn from the study or received other methods of temperature control. A discontinuation form will assess reasons for exit from the study protocol to identify ways of mitigating withdrawal in a modified protocol.
3. Bacterial load: The utility of serial qPCR measurements of the gene encoding bacterial 16S rRNA will be assessed by receiver operating characteristic curves for the presence or absence of a good outcome. If the area under the curve for this outcome is greater than 0.75 then we plan to use this as a secondary outcome variable in the main study.
4. Recruitment rates: In order to complete recruitment in less than two years we need no less than 75% of the recruited participants to fully adhere to the treatment protocol based on a recruitment rate into the study of 75% so that the effective recruitment rate is greater than 56%. We anticipate that there will be 90% full adherence to the treatment protocol. The lower 95% CI for a proportion for 25/28 is 77.8%, so that if the achieved adherence rate is 90% in conjunction with a recruitment rate of 75% we are confident that the main study can complete recruitment in under two years. If adherence to our draft protocol is lower than anticipated we will need to change the protocol to improve adherence or recruit additional centres for any subsequent multicentre trial.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 5114 0
New Zealand
State/province [1] 5114 0
Wellington region

Funding & Sponsors
Funding source category [1] 287356 0
Government body
Name [1] 287356 0
Health Research Council of New Zealand
Address [1] 287356 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 287356 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Malaghan Institute of Medical Research
Address
Malaghan Institute of Medical Research
P O Box 7090
Wellington 6242
Country
New Zealand
Secondary sponsor category [1] 286102 0
None
Name [1] 286102 0
Address [1] 286102 0
Country [1] 286102 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289332 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 289332 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6145

Ethics committee country [1] 289332 0
New Zealand
Date submitted for ethics approval [1] 289332 0
01/06/2013
Approval date [1] 289332 0
20/06/2013
Ethics approval number [1] 289332 0
13/STH/55

Summary
Brief summary
The aim of the study is to discover the impact of using paracetamol during febrile neutropenia, a common type of infection after chemotherapy.
At present, about half of patients receive paracetamol to lower their temperature during febrile neutropenia in our hospital department. Whether or not someone receives paracetamol is at the discretion of the patient’s doctor or nurse. We do not know whether paracetamol is beneficial or not. On the one hand, paracetamol can lower fevers and can make people feel more comfortable. On the other hand, fevers are part of the body’s natural response to an infection and lowering a fever with paracetamol might delay recovery from an infection.

We propose a large study to answer the question of whether paracetamol should be used in febrile neutropenia or not. However, before we can do the large study necessary to answer this question, we need to do a smaller study (this study) to ensure that the large study can be achieved. Specifically, we need to check that people receiving paracetamol have a lower temperature than those receiving placebo, that the study treatment is acceptable, that we can detect bacteria in the blood at low levels, and that we can recruit enough patients for the large study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40346 0
Dr Robert Weinkove
Address 40346 0
Wellington Blood and Cancer Centre
Wellington Hospital
Private Bag 7902
Wellington 6242
Country 40346 0
New Zealand
Phone 40346 0
+64 4 385 5999
Fax 40346 0
+ 64 4 385 5843
Email 40346 0
Robert.Weinkove@ccdhb.org.nz
Contact person for public queries
Name 40347 0
Ms Catherine Wood
Address 40347 0
Wellington Blood and Cancer Centre
Wellington Hospital
Private Bag 7902
Wellington 6242
Country 40347 0
New Zealand
Phone 40347 0
+64 4 806 2091
Fax 40347 0
+ 64 4 385 5843
Email 40347 0
Catherine.Wood@ccdhb.org.nz
Contact person for scientific queries
Name 40348 0
Dr Robert Weinkove
Address 40348 0
Wellington Blood and Cancer Centre
Wellington Hospital
Private Bag 7902
Wellington 6242
Country 40348 0
New Zealand
Phone 40348 0
+64 4 385 5999
Fax 40348 0
+ 64 4 385 5843
Email 40348 0
Robert.Weinkove@ccdhb.org.nz

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 has not been uploaded for this published study, and this was not an expectation at the time this clinical trial was registered in 2013. Additional data can be requested from the investigator upon request.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary