Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000963527
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 - Immunoglobulin Stopping or Extension (Stop-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 (Stop-Ig Domain)
Secondary ID [1] 312181 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 333836 0
hypogammaglobulinemia 333837 0
Condition category
Condition code
Cancer 330512 330512 0 0
Myeloma
Cancer 330513 330513 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 330514 330514 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A: Stop Immunoglobulin (Ig) and commence prophylactic oral antibiotics.
- Once daily trimethoprim-sulfamethoxazole (co-trimoxazole), oral tablet, 160mg/800mg. Nb: Doxycycline 100mg daily as an alternative for participants 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 Ig, or discontinued from their assigned trial treatment.

Arm B: Stop Immunoglobulin without commencement of prophylactic oral antibiotics.
- Participants will be prescribed amoxycillin/clavulanic acid, oral tablet, 1750-2000mg/250mg, and ciprofloxacin, oral tablet, 750 mg, to keep at home for initial use if symptoms of infection develop, with immediate review by their treating clinical team, or nearest emergency department or medical practitioner with phone contact to treating team if most practical. Nb: clindamycin 600 mg is permitted as an alternative to amoxycillin/clavulanic acid for participants with hypersensitivity to penicillin.

Duration of Arm A and Arm B Intervention: 12 months.

If a participant on Arm A or Arm B experiences a Grade 3 or higher infectious complication, they may recommence Ig replacement, as directed by their treating clinician.

The treating clinician may discontinue participants from their assigned treatment if continued participation is no longer in the participant's best interest. If a participant is discontinued from their assigned treatment, participation in the trial will not end. Trial follow-up and data collection will continue for the remaining time of the 12-month intervention period.

Participants will be asked to complete a daily study diary to monitor oral antibiotic use and adherence to the interventions.
Intervention code [1] 328627 0
Treatment: Drugs
Comparator / control treatment
Arm C: Continue immunoglobulin replacement therapy

Participants will continue treatment with their current Ig replacement schedule. Participants will receive either Intravenous Ig (IVIg) or Subcutaneous Ig (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. For patients who have already had their Ig dose titrated to IgG trough level, they may continue on their current monthly dose of Ig replacement..
- 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.

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, using a conversion factor of 1:1 for total monthly IV to SC dosing.

Duration of Arm C Treatment: 12 months.

The treating clinician may discontinue participants from their assigned treatment if continued participation is no longer in the participant's best interest. If a participant is discontinued from their assigned treatment, participation in the trial will not end. Trial follow-up and data collection will continue.
Control group
Active

Outcomes
Primary outcome [1] 338279 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] 338279 0
12 months following randomisation
Secondary outcome [1] 435252 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] 435252 0
12 months following randomisation
Secondary outcome [2] 435253 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] 435253 0
12 months following randomisation
Secondary outcome [3] 435254 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] 435254 0
12 months following randomisation
Secondary outcome [4] 435255 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] 435255 0
12 months following randomisation
Secondary outcome [5] 435256 0
Number of microbiologically documented infections from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [5] 435256 0
12 months following randomisation.
Secondary outcome [6] 435258 0
All-cause mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [6] 435258 0
12 months following randomisation.
Secondary outcome [7] 435259 0
Infection-related mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [7] 435259 0
12 months following randomisation.
Secondary outcome [8] 435260 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] 435260 0
12 months following randomisation.
Secondary outcome [9] 435262 0
Occurrence of one or more treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [9] 435262 0
12 months following randomisation.
Secondary outcome [10] 435263 0
Number of treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.
Timepoint [10] 435263 0
12 months following randomisation.
Secondary outcome [11] 435264 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] 435264 0
12 months following randomisation.
Secondary outcome [12] 435291 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] 435291 0
12 months following randomisation.
Secondary outcome [13] 435292 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] 435292 0
Prior to randomisation, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [14] 435293 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] 435293 0
Prior to randomisation, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [15] 435294 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] 435294 0
Prior to randomisation, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation
Secondary outcome [16] 435295 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] 435295 0
12 months following randomisation.
Secondary outcome [17] 435296 0
Resumption of Ig treatment over 12 months for patients in Ig cessation treatment arms.
Nb: This is a Stop=Ig domain-specific outcome measure.
Timepoint [17] 435296 0
12 months following randomisation.

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

Stop-Ig domain inclusion criteria:
1. Patients must be receiving Ig (IV or subcutaneous - SCIg) replacement for prevention of bacterial infections due to hypogammaglobulinaemia for at least 6 consecutive months.
2. Patient is eligible for trial of Ig cessation in the opinion of the treating clinician and local investigator.
3. Willing and able to comply with each of the treatment arms.
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 Stop-Ig domain of the RATIONAL-PT if they fulfil eligibility for both RATIONAL-PT and the Stop-Ig domain.

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

Stop-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. Already receiving systemic antibiotic prophylaxis for the purpose of preventing bacterial infection (NB: patients may receive antiviral, antifungal and Pneumocystis jirovecii Pneumonia (PJP) prophylaxis).
4. Intolerance of all trial antibiotic options in either arm A or arm B.
5. Communication, compliance or logistical issues (e.g. living long distance from medical facility) that are likely to limit a patient’s ability to take prophylactic or emergency antibiotics, or to obtain urgent medical attention for symptoms of infection.
6. Pregnant or breastfeeding.
7. Severe renal impairment (estimated or measured creatinine clearance of <30mL/min).
8. Previous splenectomy.
9. Previous participation in this domain
10. Treating team deems enrolment in the domain is not in the best interests 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] 316549 0
Government body
Name [1] 316549 0
National Health and Medical Research Council
Country [1] 316549 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 318732 0
None
Name [1] 318732 0
Address [1] 318732 0
Country [1] 318732 0
Other collaborator category [1] 283069 0
Other Collaborative groups
Name [1] 283069 0
Australasian Leukaemia & Lymphoma Group (ALLG)
Address [1] 283069 0
Country [1] 283069 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315342 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315342 0
Ethics committee country [1] 315342 0
Australia
Date submitted for ethics approval [1] 315342 0
13/11/2023
Approval date [1] 315342 0
04/01/2024
Ethics approval number [1] 315342 0
HREC/103986/Alfred-2023 (Local Reference: Project 726/23)

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134398 0
Prof Erica Wood
Address 134398 0
Transfusion Research Unit Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134398 0
Australia
Phone 134398 0
+61 3 9903 0051
Fax 134398 0
Email 134398 0
[email protected]
Contact person for public queries
Name 134399 0
Zoe McQuilten
Address 134399 0
Transfusion Research Unit Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134399 0
Australia
Phone 134399 0
+61 3 9903 0379
Fax 134399 0
Email 134399 0
[email protected]
Contact person for scientific queries
Name 134400 0
Zoe McQuilten
Address 134400 0
Transfusion Research Unit Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Road, Melbourne, VIC 3004
Country 134400 0
Australia
Phone 134400 0
+61 3 9903 0379
Fax 134400 0
Email 134400 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.