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Trial registered on ANZCTR


Registration number
ACTRN12624000964516
Ethics application status
Approved
Date submitted
5/07/2024
Date registered
8/08/2024
Date last updated
27/10/2024
Date data sharing statement initially provided
8/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Role of Antibiotic Therapy or Immunoglobulin On iNfections in hAematoLogy Platform Trial (RATIONAL-PT) Domain Addendum - Starting Immunoglobulin (Start-Ig)
Scientific title
A randomised platform trial evaluating the role of interventions to prevent infection in patients with acquired hypogammaglobulinemia secondary to haematological malignancies - RATIONAL-PT (Start-Ig Domain)
Secondary ID [1] 312270 0
TRU-RPT-22
Universal Trial Number (UTN)
Trial acronym
RATIONAL-PT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
haematological malignancy 333986 0
hypogammaglobulinemia 333987 0
Condition category
Condition code
Cancer 330651 330651 0 0
Myeloma
Cancer 330652 330652 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 330653 330653 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A: Start prophylactic oral antibiotics:
- Once daily trimethoprim-sulfamethoxazole (co-trimoxazole) 160mg/800mg. Nb: Doxycycline 100mg daily as an alternative for patients with hypersensitivity to co-trimoxazole.
- Dose adjustments: If a participant has cytopenia or renal impairment a 50% dose reduction may be made depending on the cause and/or severity of the cytopenia or renal impairment. Participants may be switched to the alternative antibiotic or discontinued from their assigned trial treatment.
- If a participant experiences a serious adverse event or serious infectious complication, the local Investigator may choose to discontinue the participant from their assigned trial treatment if it is no longer in the participant’s best interest. In these cases, the participant may recommence immunoglobulin replacement therapy as directed by their treating clinician.
- Adherence to the intervention will be assessed via review of a study diary completed by the participants.

Duration of Intervention: 12 months.
Intervention code [1] 328727 0
Treatment: Drugs
Comparator / control treatment
Arm B: Start immunoglobulin replacement therapy (IVIg or SCIg):
- IVIg: Participants will receive monthly (every 4 weeks ± 1 week) intravenous immunoglobulin at a dose of 0.4g/kg, modified to achieve an IgG trough level of at least lower limit of age-specific 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. Dosing is usually given at 100mg/kg/week, modified to achieve an IgG steady state level of at least the lower limit of the serum reference range. A loading IVIg dose may be given in the first month if required.

Study participants allocated to the ‘comparator/control treatment’ will receive either IVIg or SCIg as determined by the treating clinician and local criteria for home-based self-administration of SCIg. Participants may transition from IVIg to SCIg, or vice versa, using a conversion factor of 1:1 for total monthly IV to SC dosing.
Control group
Active

Outcomes
Primary outcome [1] 338401 0
Event-free survival (EFS), defined as time from randomisation (or, in domains with a single treatment arm, time from registration) until occurrence of a Grade 3 or higher infection (as defined by CTCAE Version 5), or death from any cause.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [1] 338401 0
12 months following randomisation
Secondary outcome [1] 435783 0
Occurrence of at least one Grade 3 or higher infection(s) from randomisation to 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [1] 435783 0
12 months following randomisation
Secondary outcome [2] 435784 0
Occurrence of one or more clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [2] 435784 0
12 months following randomisation
Secondary outcome [3] 435785 0
Number of clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [3] 435785 0
12 months following randomisation
Secondary outcome [4] 435786 0
Occurrence of one or more microbiologically documented infections from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [4] 435786 0
12 months following randomisation
Secondary outcome [5] 435787 0
Number of microbiologically documented infections from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [5] 435787 0
12 months following randomisation.
Secondary outcome [6] 435788 0
All-cause mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [6] 435788 0
12 months following randomisation.
Secondary outcome [7] 435789 0
Infection-related mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [7] 435789 0
12 months following randomisation.
Secondary outcome [8] 435790 0
Time free from hospitalisation with antimicrobial administration with therapeutic intent from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [8] 435790 0
12 months following randomisation.
Secondary outcome [9] 435791 0
Occurrence of one or more treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [9] 435791 0
12 months following randomisation.
Secondary outcome [10] 435793 0
Number of treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [10] 435793 0
12 months following randomisation.
Secondary outcome [11] 435794 0
Isolation of fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms from randomisation to 12 months.
This will be assessed as a composite outcome.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [11] 435794 0
12 months following randomisation.
Secondary outcome [12] 435795 0
Number of infections with fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms isolated from randomisation to 12 months.
This will be assessed as a composite outcome.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [12] 435795 0
12 months following randomisation.
Secondary outcome [13] 435797 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months, using the EQ-5D-5L questionnaire.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [13] 435797 0
Prior to randomisation in each domain, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [14] 435798 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months, using the EORTC QLQ-C30 questionnaire.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [14] 435798 0
Prior to randomisation in each domain, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation.
Secondary outcome [15] 435799 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months, using the FACT-N questionnaire.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [15] 435799 0
Prior to randomisation in each domain, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation.
Secondary outcome [16] 435800 0
Costs associated with allocated treatment arm and infections during study. This will be assessed as a composite outcome.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [16] 435800 0
12 months following randomisation.

Eligibility
Key inclusion criteria
Patients are eligible for the Start-Ig domain of the RATIONAL-PT if they fulfil eligibility for both RATIONAL-PT and the Start-Ig domain.

RATIONAL-PT inclusion criteria:
1. Aged greater than or equal to 18 years of age
2. Diagnosis of haematological malignancy, including Chronic Lymphocytic Leukaemia (CLL), Multiple Myeloma (MM) or Non-Hodgkin's Lymphoma (NHL)
3. Eligible to receive or currently receiving Ig (IV or subcutaneous - SCIg) replacement for history of recurrent or severe infection(s) and IgG less than the lower limit of the reference range (excluding paraprotein) OR IgG<4g/L (excluding paraprotein)
4. Life expectancy > 12 months
5. Able to give informed consent

Start-Ig domain inclusion criteria:
None.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients are eligible for the Start-Ig domain of the RATIONAL-PT if they fulfil eligibility for both RATIONAL-PT and the Start-Ig domain.

RATIONAL-PT exclusion criteria:
1. Treating team deems enrolment in the study is not in the best interests of the patient

Start-Ig domain exclusion criteria:
1. Prior or planned allogeneic haematopoietic stem cell transplantation.
2. Already receiving systemic antibiotic prophylaxis for the purpose of preventing bacterial infection (NB: patients may receive antiviral, antifungal and Pneumocystis jirovecii Pneumonia (PJP) prophylaxis).
3. Received immunoglobulin replacement in the preceding three months.
4. Objection to receiving immunoglobulin products.
5. Known history of IgA deficiency with anti-IgA.
6. History of severe allergy to immunoglobulin products.
7. Current active infection requiring systemic antibiotics.
8. Allergy or intolerance of all domain antibiotic options.
9. Pregnant or breastfeeding.
10. Severe renal impairment (estimated or measured creatinine clearance of < 30 mL/min).
11. Previous splenectomy.
12. Previous participation in this domain.
13. Treating team deems enrolment in the domain is not in the best interest of the patient.

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)
Computer-generated, randomised, allocation sequences based on permuted blocks of variable size. Allocation will be stratified by haematological malignancy.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,SA,VIC

Funding & Sponsors
Funding source category [1] 316655 0
Government body
Name [1] 316655 0
Australian Department of Health and Aged Care, Medical Research Future Fund (MRFF)
Country [1] 316655 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 318841 0
None
Name [1] 318841 0
Address [1] 318841 0
Country [1] 318841 0
Other collaborator category [1] 283068 0
Other Collaborative groups
Name [1] 283068 0
Australasian Leukaemia & Lymphoma Group (ALLG)
Address [1] 283068 0
Country [1] 283068 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315435 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315435 0
https://www.alfredhealth.org.au/research/ethics-research-governance
Ethics committee country [1] 315435 0
Australia
Date submitted for ethics approval [1] 315435 0
13/11/2023
Approval date [1] 315435 0
04/01/2024
Ethics approval number [1] 315435 0
HREC/103986/Alfred-2023 (Local Reference: Project 726/23)

Summary
Brief summary
This research project forms part of the RATIONAL Platform Trial. This study is being conducted to find out how safe and effective different strategies of infection prevention are in comparison to each other, for preventing infection in patients with blood cancers.

While immunoglobulin is commonly used long term in patients with blood cancer, we don’t know whether oral antibiotics are just as good at preventing serious infections. The research project is investigating using oral antibiotics (in tablet form) to determine if they are as effective as IVIg or SCIg in reducing the risk of infections in people with blood cancers.

Who’s it for?
Patients with a blood cancer and low levels of certain antibodies (immunoglobulins) in the blood.

Your treating doctor will check your eligibility to participate in this study. You will need to undergo screening assessments to find out if it is safe for you to be involved in the study.

Study details:
In this clinical trial domain, participants will be divided into two groups (arms) to compare the different treatments. There is one usual care group and one investigational group. The two groups are:
1. Start immunoglobulin (IVIg or SCIg) replacement therapy.
2. Start oral antibiotics to take every day.
Each participant is put into a group by chance (randomly).

If eligible to participate in a domain of the RATIONAL-PT, your active study participation in that domain will last for 13 months and all participants will return to the hospital for a study visit every 3 months (4 more in-person visits after Day 1). During each month of the 12-month treatment period except the months in which you are attending in-person study visits, you will receive a phone call from your treating clinical team to check your progress (8 calls in total).

Even if you are recommended to, or choose to, stop your domain treatment during the 12-month treatment period, you will be asked to continue attending study visits and having phone calls until the end of the trial period (13 months in total) because we are still interested in your outcomes.

At the end of your participation on the study, your doctor will decide if you still require treatment to prevent infection, and if you do, whether to continue on the treatment you received during the study (immunoglobulins, antibiotics or none).

The results of this trial will inform clinical decision making about the use of immunoglobulin and oral antibiotics for patients with blood cancers. Your participation may help doctors who treat patients with blood diseases in the future to know whether to prescribe oral antibiotics or immunoglobulins to try to prevent the onset of serious infections.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134690 0
Prof Zoe McQuilten
Address 134690 0
Transfusion Research Unit, Public Health and Preventive Medicine, Monash University, Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134690 0
Australia
Phone 134690 0
+61 3 9903 0379
Fax 134690 0
Email 134690 0
[email protected]
Contact person for public queries
Name 134691 0
Zoe McQuilten
Address 134691 0
Transfusion Research Unit, Public Health and Preventive Medicine, Monash University, Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134691 0
Australia
Phone 134691 0
+61 3 9903 0379
Fax 134691 0
Email 134691 0
[email protected]
Contact person for scientific queries
Name 134692 0
Zoe McQuilten
Address 134692 0
Transfusion Research Unit, Public Health and Preventive Medicine, Monash University, Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134692 0
Australia
Phone 134692 0
+61 3 9903 0379
Fax 134692 0
Email 134692 0
[email protected]

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 will not be publicly available. Data will only be presented as a whole, no individual data will be published or presented.


What supporting documents are/will be available?

No Supporting Document Provided



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.