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Trial registered on ANZCTR


Registration number
ACTRN12624000962538
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 - Dosing Immunoglobulin (Dose-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 (Dose-Ig Domain)
Secondary ID [1] 312278 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 334000 0
hypogammaglobulinemia 334001 0
Condition category
Condition code
Cancer 330673 330673 0 0
Myeloma
Cancer 330674 330674 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 330675 330675 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A: Low dose intravenous immunoglobulin replacement
- Participants will be treated with intravenous immunoglobulin monthly (every 4 weeks ± 1 week) at a dose of 0.25g/kg. No dose adjustment for trough serum IgG levels is required.
- If a participant experiences a serious infectious complication, they may recommence standard dose immunoglobulin replacement therapy (IgRT), as directed by their treating clinician. In the absence of a serious infectious complication, the treating clinician may increase the dose of IgRT if this is deemed in the participant’s best interest.
- Adherence to the intervention will be assessed via review of participant medical records.

Duration of Intervention: 12 months.
Intervention code [1] 328740 0
Treatment: Drugs
Comparator / control treatment
Arm B: Standard dose intravenous immunoglobulin replacement
- Participants will be treated with intravenous immunoglobulin monthly (every 4 weeks ± 1 week) 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.
- Doses will be modified to achieve the IgG trough level according to local standard of care practices and as directed by the treating clinician. The lower limit of the age-specific serum IgG reference range will be determined using the local laboratory reference ranges.

Duration of Intervention: 12 months.
Control group
Active

Outcomes
Primary outcome [1] 338421 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] 338421 0
12 months following randomisation
Secondary outcome [1] 435851 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] 435851 0
12 months following randomisation
Secondary outcome [2] 435852 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] 435852 0
12 months following randomisation
Secondary outcome [3] 435853 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] 435853 0
12 months following randomisation
Secondary outcome [4] 435855 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] 435855 0
12 months following randomisation
Secondary outcome [5] 435856 0
Number of microbiologically documented infections from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [5] 435856 0
12 months following randomisation.
Secondary outcome [6] 435857 0
All-cause mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [6] 435857 0
12 months following randomisation.
Secondary outcome [7] 435858 0
Infection-related mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [7] 435858 0
12 months following randomisation.
Secondary outcome [8] 435859 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] 435859 0
12 months following randomisation.
Secondary outcome [9] 435861 0
Occurrence of one or more treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [9] 435861 0
12 months following randomisation.
Secondary outcome [10] 435862 0
Number of treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [10] 435862 0
12 months following randomisation.
Secondary outcome [11] 435863 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] 435863 0
12 months following randomisation.
Secondary outcome [12] 435864 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] 435864 0
12 months following randomisation.
Secondary outcome [13] 435865 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] 435865 0
Prior to randomisation in each domain, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [14] 435866 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] 435866 0
Prior to randomisation in each domain, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [15] 435867 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] 435867 0
Prior to randomisation in each domain, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [16] 435868 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] 435868 0
12 months following randomisation.

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

Dose-Ig domain inclusion criteria:
1. Patients must be receiving IVIg replacement at standard dose for prevention of bacterial infections due to hypogammaglobulinaemia for at least 6 consecutive months.
2. Patient is not eligible for trial of Ig cessation in the opinion of the treating clinician and local investigator.
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 Dose-Ig domain of the RATIONAL-PT if they fulfil eligibility for both RATIONAL-PT and the Dose-Ig domain.

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

Dose-Ig domain exclusion criteria:
1. Prior or planned allogeneic haematopoietic stem cell transplantation.
2. Major infection (Grade 3 or higher) in preceding 3 months, and or current active infection requiring systemic antimicrobial treatment.
3. Previous splenectomy.
4. Known history of bronchiectasis.
5. Previous participation in this domain.
6. 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] 316667 0
Government body
Name [1] 316667 0
Australian Department of Health and Aged Care, Medical Research Future Fund (MRFF)
Country [1] 316667 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 318851 0
None
Name [1] 318851 0
Address [1] 318851 0
Country [1] 318851 0
Other collaborator category [1] 283070 0
Other Collaborative groups
Name [1] 283070 0
Australasian Leukaemia & Lymphoma Group (ALLG)
Address [1] 283070 0
Country [1] 283070 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315445 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315445 0
https://www.alfredhealth.org.au/research/ethics-research-governance
Ethics committee country [1] 315445 0
Australia
Date submitted for ethics approval [1] 315445 0
13/11/2023
Approval date [1] 315445 0
04/01/2024
Ethics approval number [1] 315445 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 if a lower dose of immunoglobin is as effective in preventing infections in patients with blood cancers receiving immunoglobulin who have trialled stopping in the past without success or are not suitable to trial stopping immunoglobulin. This research will investigate if patients can safely reduce their immunoglobulin dose after six months of therapy.

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, 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. Continue standard-dose immunoglobulin (IVIg) replacement therapy
2. Commence low-dose immunoglobulin (IVIg) replacement therapy
Each participant is put into a group by chance (randomly). Half of the participants will receive standard-dose immunoglobulin, the other half will commence low-dose immunoglobulin replacement therapy.
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 (standard-dose or low-dose immunoglobulin).
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 what dose of immunoglobulins should be prescribed to try to prevent the onset of serious infections.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134722 0
Prof Zoe McQuilten
Address 134722 0
Transfusion Research Unit, Public Health and Preventive Medicine, Monash University, Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134722 0
Australia
Phone 134722 0
+61 3 9903 0379
Fax 134722 0
Email 134722 0
[email protected]
Contact person for public queries
Name 134723 0
Zoe McQuilten
Address 134723 0
Transfusion Research Unit, Public Health and Preventive Medicine, Monash University, Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134723 0
Australia
Phone 134723 0
+61 3 9903 0379
Fax 134723 0
Email 134723 0
[email protected]
Contact person for scientific queries
Name 134724 0
Zoe McQuilten
Address 134724 0
Transfusion Research Unit, Public Health and Preventive Medicine, Monash University, Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134724 0
Australia
Phone 134724 0
+61 3 9903 0379
Fax 134724 0
Email 134724 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.