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Trial registered on ANZCTR


Registration number
ACTRN12616001723471
Ethics application status
Approved
Date submitted
9/12/2016
Date registered
16/12/2016
Date last updated
22/11/2018
Date data sharing statement initially provided
22/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Trial to evaluate treatments for patients with haematological disease who also have low levels of immunoglobulins (antibodies) in the blood (hypogammaglobulinemia).
Scientific title
A randomised controlled feasibility trial comparing the efficacy of prophylactic intravenous immunoglobulin with prophylactic antibiotics in patients with acquired hypogammaglobulinemia secondary to haematological malignancies
Secondary ID [1] 290718 0
Nil
Universal Trial Number (UTN)
Trial acronym
RATIONAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
haematological malignancy 301291 0
hypogammaglobulinemia 301292 0
Condition category
Condition code
Cancer 301045 301045 0 0
Myeloma
Cancer 301055 301055 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 301072 301072 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Prophylactic oral antibiotics: For up to 12 months.
Trimethoprim-sulfamethoxazole (co-trimoxazole) 160mg/800mg once daily tablet.
For patients with hypersensitivity to co-trimoxazole, doxycycline 100mg once daily tablet.
If a participant on the antibiotic arm has a Grade 3 or higher infectious complication, he/she will be discontinued on the treatment arm and be allowed to cross-over into the Ig (IVIg/SCIg) arm. Patients will not come off study. Data about such an event will be collected using a specific case report form. The decision to discontinue treatment will be made by the treating clinician
Intervention code [1] 296617 0
Treatment: Drugs
Comparator / control treatment
The control treatment is standard care treatment with IVIg or SCIg for up to 12 months
IVIg:
In accordance with National (Australian) Criteria for the Clinical Use of IVIg in Australia. Monthly (every 4 weeks +/- 1 week) dose starting at 0.4g/kg, modified to achieve an IgG trough level of at least lower limit of serum IgG reference range. In the first month of therapy, if IgG < 4g/L then an additional (loading) dose of 0.4g/kg may be given at the clinician’s discretion.
SCIg:
Subcutaneous immunoglobulin weekly may be used in patients who meet local criteria for home-based self-administration in centres with established SCIg programs. A loading IVIg dose may be given in the first month if required. Thereafter, dosing at 100mg/kg/week, modified to achieve an IgG steady state level of at least the lower limit of the serum reference range. Study participants may transition to or from IVIg to SCIg, using a conversion factor of 1:1 for total monthly IV to SC dosing. Where the term IVIg is used in this protocol, unless explicitly stated, it shall be taken to include SCIg.
For patients on Ig who have a Grade 3 or higher infectious complication, their treatment will be according to usual standard care. If patients have a grade 3-4 adverse event they will be discontinued on allocated treatment. Patients will not come off study and will continue to have data collected. The decision to discontinue or change treatment will be made by the treating clinician.
Control group
Active

Outcomes
Primary outcome [1] 300466 0
Proportion of patients alive who remain on assigned treatment arm at 12 months following randomisation. This will be assessed using medical records.
Timepoint [1] 300466 0
12 months following randomisation
Secondary outcome [1] 330028 0
Time to first major infection (Grade 3 or higher according to CTCAE) assessed using medical records
Timepoint [1] 330028 0
12 months following randomisation
Secondary outcome [2] 330094 0
Number of clinically significant infections (defined as presence of symptoms or signs of infection requiring treatment). assessed using medical records
Timepoint [2] 330094 0
12 months following randomisation
Secondary outcome [3] 330096 0
Time to first microbiologically confirmed infection . This will be assessed by culture of various specimens as clinically indicated (e.g. blood cultures, sputum culture, urine culture, faecal culture) and serology or PCR of various specimens as clinically indicated (e.g. looking for atypical pneumonia, looking for respiratory virus)
Timepoint [3] 330096 0
12 months following randomisation
Secondary outcome [4] 330097 0
All-cause mortality. Assessed using medical records.
Timepoint [4] 330097 0
12 months following randomisation
Secondary outcome [5] 330098 0
Infection-related mortality (defined as death within 7 days of diagnosis of infection, confirmed by microbiological means). Assessed using medical records.
Timepoint [5] 330098 0
12 months following randomisation
Secondary outcome [6] 330099 0
Number of treatment-related adverse events. Assessed using medical records.
Timepoint [6] 330099 0
12 months following randomisation
Secondary outcome [7] 330100 0
Trough IgG level (or steady state level for SCIg) Assessed using medical records.
Timepoint [7] 330100 0
3, 6, 9, 12 months following randomisation.
Secondary outcome [8] 330101 0
Quality of life (QoL) measures.Assessed using EQ-5D-5L, EORTC QLQ-C30 & FACT-N assessment tools .
Timepoint [8] 330101 0
at randomisation, 3, 6, 9 and 12 month

Eligibility
Key inclusion criteria
Patients are eligible for this trial if:
1 Age greater than or equal to 18 years
2 Acquired hypogammaglobulinaemia secondary to a haematological malignancy
3 Meet the Australian National Blood Authority Criteria for the Clinical Use of intravenous immunoglobulin (IVIg) for secondary hypogammaglobulinaemia (i.e. total IgG below local lower limit of reference range [excluding paraprotein] and history of recurrent or severe bacterial infection(s) OR IgG < 4 g/L [excluding paraprotein])
4 Life expectancy > 12 months.
5 Willing and able to attend for monthly IVIg infusion or to self-administer subcutaneous immunoglobulin.
6 Able to give informed consent to participate.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will not be eligible for this study if they fulfil any of the following criteria:
1 Patient unwilling or unable to give informed consent.
2 llogeneic haematopoietic stem cell transplantation recipient.
3 Patient has an objection to receiving immunoglobulin.
4 Known severe IgA deficiency
5 History of anaphylactic reaction to human immunoglobulin preparation
6 Patient already receiving daily antibiotic prophylaxis for the purpose of preventing bacterial infection. Patients receiving dapsone or intermittently-dosed cotrimoxazole for PJP prophylaxis are not excluded from the study.
7 Patient has received immunoglobulin replacement in the preceding 3 months
8 Current active infection requiring systemic antimicrobial agents
9 Anticipated prolonged significant cytopenias, defined by neutrophils < 0.5 x10^9/L or platelets < 50 x10^9/L, precluding regular cotrimoxazole. Temporary cytopenia/s due to therapy are not an exclusion.
10 History of epilepsy
11 Pregnant or breastfeeding
12 Severe renal impairment (creatinine clearance of <30ml/min)
13 Previous splenectomy

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 is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software

Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Patients and clinicians will not be blinded in this study, however outcomes will be assessed by an independent committee blinded to treatment allocation.
Randomised in a 2:1 ratio (Intervention : Control)
Randomisation will be stratified by site and balanced within blocks of varying, undisclosed sizes.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a feasability trial.
Our chosen sample size (n=60) is based on primary outcome of proportion of participants (alive) who remain on assigned treatment arm at 12 months following randomisation.
With a sample size of 60 patients (40 in the antibiotic arm and 20 in the IVIg arm), we will be able to estimate an adherence rate to the protocol of 80% to within a 95% confidence interval of +/- 10%.
Our cautious estimate is for 1-2 patients/month per site, allowing recruitment of 60 participants over 12-18 months.

Recruitment
Recruitment status
Recruiting
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 in Australia
Recruitment state(s)
ACT,NSW,TAS,WA,VIC
Recruitment hospital [1] 7097 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 7098 0
Concord Private Hospital - Concord
Recruitment hospital [3] 7099 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 7100 0
The Canberra Hospital - Garran
Recruitment hospital [5] 12511 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 14853 0
3168 - Clayton
Recruitment postcode(s) [2] 14854 0
2137 - Concord
Recruitment postcode(s) [3] 14855 0
6150 - Murdoch
Recruitment postcode(s) [4] 14856 0
2605 - Garran
Recruitment postcode(s) [5] 24891 0
7000 - Hobart
Recruitment outside Australia
Country [1] 8472 0
New Zealand
State/province [1] 8472 0
Wellington, Capital & Coast District
Country [2] 21059 0
New Zealand
State/province [2] 21059 0
Waikato

Funding & Sponsors
Funding source category [1] 295150 0
Government body
Name [1] 295150 0
National Blood Authority
Address [1] 295150 0
Level 2,
243 Northbourne Avenue,
Lyneham ACT 2602
Country [1] 295150 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Road,
Clayton VIC 3800
Country
Australia
Secondary sponsor category [1] 293969 0
None
Name [1] 293969 0
Address [1] 293969 0
Country [1] 293969 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296495 0
Monash Health HREC
Ethics committee address [1] 296495 0
Research Support Services
Monash Health
Level 2, I Block
Monash Medical Centre
246 Clayton Road
Clayton Victoria 3168
Ethics committee country [1] 296495 0
Australia
Date submitted for ethics approval [1] 296495 0
16/11/2016
Approval date [1] 296495 0
04/01/2017
Ethics approval number [1] 296495 0
HREC/16/MonH/392

Summary
Brief summary
The aim of this study is to examine whether oral antibiotics can be used instead of intravenous immunoglobulin (IVIg) to reduce the risk of infections in people with blood cancers.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have an acquired hypogammaglobulinaemia secondary to a haematological malignancy.

Study details
Participants will be randomised (allocated by chance) to one of two treatment groups in a 2:1 ratio meaning that you are twice as likely to receive intervention treatment. Participants in one group (intervention) will receive co-trimoxazole (Trimethoprim-sulfamethoxazole) 160mg/800mg orally once a day or doxycycline 100mg once daily for those hypersensitive to co-trimoxazole. Participants in the second group (control) will receive standard care treatment with intravenous or subcutaneous immunoglobulin (IVIg or SCIg) in accordance with national Criteria: Monthly (every 4 weeks +/- 1 week) dose of 0.4g/kg, modified to achieve an IgG trough level of at least lower limit of age specific serum IgG reference range.

The duration of each treatment is for 12 months from study entry, or until the treating physician determines that the patient should come off the treatment.

The following data will be collected: Patient demographics (age, gender, diagnosis, stage of disease), baseline investigations (including IgG levels), grade 3 or 4 infections and other clinically significant infections – at monthly intervals for 12 months.

This project aims to improve how we use IVIg in Australia by asking: Are prophylactic (preventive) oral antibiotics equivalent to immunoglobulin
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71070 0
A/Prof Erica Wood
Address 71070 0
Monash University
Department of Epidemiology and Preventive Medicine
The Alfred Centre
99 Commercial Road
Melbourne, VIC 3004
Country 71070 0
Australia
Phone 71070 0
+61 3 99030051
Fax 71070 0
+61 3 99030556
Email 71070 0
erica.wood@monash.edu
Contact person for public queries
Name 71071 0
Dr Zoe McQuilten
Address 71071 0
Monash University
Department of Epidemiology and Preventive Medicine
The Alfred Centre
99 Commercial Road
Melbourne, VIC 3004
Country 71071 0
Australia
Phone 71071 0
+61 3 99030379
Fax 71071 0
Email 71071 0
zoe.mcquilten@monash.edu
Contact person for scientific queries
Name 71072 0
Dr Zoe McQuilten
Address 71072 0
Monash University
Department of Epidemiology and Preventive Medicine
The Alfred Centre
99 Commercial Road
Melbourne, VIC 3004
Country 71072 0
Australia
Phone 71072 0
+61 3 99030379
Fax 71072 0
Email 71072 0
zoe.mcquilten@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Not applicable