Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000359730
Ethics application status
Approved
Date submitted
11/02/2022
Date registered
28/02/2022
Date last updated
17/04/2024
Date data sharing statement initially provided
28/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Role of Antibiotic Therapy or Immunoglobulin On iNfections in hAematoLogy: Immunoglobulin Stopping or Extension (RATIONALISE)
Scientific title
A randomised controlled trial of continuing immunoglobulin therapy, or stopping with or without prophylactic antibiotics, on infection rate in patients with acquired hypogammaglobulinemia secondary to haematological malignancies.
Secondary ID [1] 306137 0
TRU-RLS-21
Universal Trial Number (UTN)
Trial acronym
RATIONALISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
haematological malignancy 324829 0
hypogammaglobulinemia 324830 0
Condition category
Condition code
Cancer 322266 322266 0 0
Myeloma
Cancer 322268 322268 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 322269 322269 0 0
Leukaemia - Acute 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 Ig.
- Participants will be prescribed amoxycillin/clavulanic acid, oral tablet, 1750-2000mg/250mg once only, and ciprofloxacin, oral tablet, 750 mg once only, 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.

Participants will be asked to complete a daily study diary to monitor oral antibiotic use and adherence to the interventions.
Intervention code [1] 322539 0
Treatment: Drugs
Comparator / control treatment
Arm C: Continue Ig

Participants will continue treatment with their current Ig replacement schedule. Participants will receive either Intravenous Ig (IVIg) or Subcutaneous Ig (SCIg)
- IVIg: Participants will be treated in accordance with the Criteria for Clinical Use of Immunoglobulin in Australia. 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. 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.

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] 330028 0
Event-Free Survival (EFS), defined from the date of randomisation until the earliest date of: occurrence of a Grade 3 or higher infection (CTCAE Version 5), as reviewed by the Outcome Adjudication Committee, or death from any cause.
Data collected from medical records will inform this outcome measure.
Timepoint [1] 330028 0
12 months following randomisation
Secondary outcome [1] 404644 0
Proportion of patients who develop at least one Grade 3 or higher infection(s) from randomisation to 12 months.
Data collected from medical records will inform this outcome measure.
Timepoint [1] 404644 0
12 months following randomisation
Secondary outcome [2] 405397 0
Proportion of patients with one or more clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) to 12 months.
Data will be collected from hospital medical records and participant self-report to the hospital trial team (via the study diary, telephone and/or in-person follow-up).
Timepoint [2] 405397 0
12 months following randomisation
Secondary outcome [3] 405398 0
Number of clinically documented infections (symptoms/signs of infection requiring antimicrobial treatment) to 12 months.
Data will be collected from hospital medical records and participant self-report to the hospital trial team (via the study diary, telephone and/or in-person follow-up).
Timepoint [3] 405398 0
12 months following randomisation
Secondary outcome [4] 405399 0
Proportion of patients with one or more microbiologically documented bacterial infections.
Data will be collected from hospital medical records and participant self-report to the hospital trial team (via the study diary, telephone and/or in-person follow-up).
Timepoint [4] 405399 0
12 months following randomisation
Secondary outcome [5] 405400 0
Number of microbiologically documented bacterial infections.
Data will be collected from hospital medical records and participant self-report to the hospital trial team (via the study diary, telephone and/or in-person follow-up).
Timepoint [5] 405400 0
12 months following randomisation
Secondary outcome [6] 405401 0
Time free from hospitalisation and antimicrobials with therapeutic intent.
Data will be collected from hospital medical records.
Timepoint [6] 405401 0
12 months following randomisation
Secondary outcome [7] 405402 0
Proportion of patients with one or more treatment-related adverse events.
An adverse event includes any untoward medical occurrence that is not necessarily caused by the trial treatment. Examples of adverse events might include symptoms such as nausea, diarrhoea or headache.
Adverse events will be collected via clinical examination, hospital medical record, or self-report to study team or via study diary. Adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Relationship to treatment will be assessed by an Investigator at the trial site.
Timepoint [7] 405402 0
12 months following randomisation
Secondary outcome [8] 405403 0
Number of treatment-related adverse events.
An adverse event includes any untoward medical occurrence that is not necessarily caused by the trial treatment. Examples of adverse events might include symptoms such as nausea, diarrhoea or headache.
Adverse events will be collected via clinical examination, hospital medical record, or self-report to study team or via study diary. Adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Relationship to treatment will be assessed by an Investigator at the trial site.
Timepoint [8] 405403 0
12 months following randomisation
Secondary outcome [9] 405404 0
Proportion of patients with fluoroquinolone-resistant organisms, co-trimoxazole-resistant organisms, extended spectrum beta lactamases or multidrug-resistant organisms isolated.
Data will be collected from hospital medical records.
Timepoint [9] 405404 0
12 months following randomisation
Secondary outcome [10] 405405 0
Number of infections with fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended spectrum beta lactamases or multidrug resistant organisms isolated.
Data will be collected from hospital medical records.
Timepoint [10] 405405 0
12 months following randomisation
Secondary outcome [11] 405406 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months, using the EQ-5D-5L questionnaire.
Timepoint [11] 405406 0
Randomisation, Month 3, Month 6, Month 9 and Month 12
Secondary outcome [12] 405407 0
Costs associated with allocated treatment arm and infections during study.
Costs of infections and trial interventions will be estimated based on trial treatment and adverse event data within the hospital medical record, as well as linked data obtained from the Medicare Benefits Scheme (MBS), Pharmaceutical Benefits Scheme (PBS) and Australian Immunisation Register (AIR). Data from the quality of life questionnaires will be used to calculate quality adjusted life years.
Timepoint [12] 405407 0
12 months following randomisation
Secondary outcome [13] 405408 0
Trough IgG levels at 3, 6, 9 and 12 months from baseline.
The results of routine blood tests will be recorded in the hospital medical record and used to assess this outcome.
Timepoint [13] 405408 0
3, 6, 9 and 12 Months from baseline.
Secondary outcome [14] 405409 0
Proportion of patients in Ig cessation treatment arms who restart Ig over 12 months.
Participants randomised to the Ig cessation arms will be followed for duration of the trial, even if they need to restart Ig while on-study. If participants recommence Ig, this will be documented in the hospital medical records and this data will be used to assess this outcome.
Timepoint [14] 405409 0
12 months following randomisation
Secondary outcome [15] 405410 0
Covid anti-spike protein levels at baseline, 3, 6, 9, and 12 months.
An additional (non-routine) blood sample will be taken at the specified timepoints, and shipped to the central laboratory. The results of the central laboratory analysis will be used to assess this outcome.
Timepoint [15] 405410 0
Baseline, Month 3, Month 6, Month 9 and Month 12
Secondary outcome [16] 406715 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months, using the EORTC QLQ-30 questionnaire.
Timepoint [16] 406715 0
Randomisation, Month 3, Month 6, Month 9 and Month 12
Secondary outcome [17] 406716 0
Quality of Life (QoL) measured at randomisation then 3, 6, 9 and 12 months, using the FACT-N questionnaire.
Timepoint [17] 406716 0
Randomisation, Month 3, Month 6, Month 9 and Month 12

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 18 years of age
2. Diagnosis of chronic lymphocytic leukaemia (CLL), multiple myeloma (MM) or non-Hodgkin lymphoma (NHL).
3. Patients must be receiving Ig (IV or subcutaneous - SCIg) replacement for prevention of bacterial infections due to hypogammaglobulinaemia for longer than 6 consecutive months.
4. Patient is eligible for trial of Ig cessation in the opinion of the treating clinician and local investigator.
5. Life expectancy greater than 12 months.
6. Able to give informed consent, and 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
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 antimicrobial treatment.
3. Already receiving daily antibiotic prophylaxis for the purpose of preventing bacterial infection (Note: patients may receive antiviral, antifungal and PJP prophylaxis).
4. Intolerance of all trial antibiotic options in either arm A or arm B.
5. Communication, compliance or logistical issues that are likely to limit 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 less than 30 mL/min).
8. Previous splenectomy.
9. Previous participation in this trial.
10. Treating team deems enrolment in the study 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
This trial was designed as a sequential (two-stage) Phase II/III randomised controlled trial, applying an adaptive learning approach. Prior to expansion of the trial from Phase II to Phase III, a Go/No Go/Indeterminate Outcome decision on non-inferiority of the intervention arms will take place.

Monitoring of the primary outcome Event Free Survival (EFS) in the intervention arms relative to control will commence once a set number of events have been observed. If this indicates an investigational arm is inferior to the control, it may be closed. If an arm is non-inferior to the control arm, the expansion phase (Phase III) may be implemented.

In order to calculate sample size, the probabilities that the Go/No Go criteria are met when monitoring of EFS commences were calculated for a range of hazard ratios. Based on these calculations, the trial will randomise at least 69 participants during the initial phase (Phase II). However, to allow for indeterminate outcomes, there is provision to randomise 90 participants into the Phase II. If the expansion phase (Phase III component) is implemented, a total of 300 patients are expected to be enrolled to the Phase II/III trial.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/05/2022
Actual
23/05/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
300
Accrual to date
13
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,VIC
Recruitment hospital [1] 21429 0
The Alfred - Melbourne
Recruitment hospital [2] 21430 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 21431 0
The Canberra Hospital - Garran
Recruitment hospital [4] 21432 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 21433 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [6] 21434 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [7] 21435 0
Western Hospital - Footscray - Footscray
Recruitment postcode(s) [1] 36335 0
2065 - St Leonards
Recruitment postcode(s) [2] 36333 0
2139 - Concord
Recruitment postcode(s) [3] 36332 0
2605 - Garran
Recruitment postcode(s) [4] 36330 0
3004 - Melbourne
Recruitment postcode(s) [5] 36336 0
3011 - Footscray
Recruitment postcode(s) [6] 36331 0
3084 - Heidelberg
Recruitment postcode(s) [7] 36334 0
3168 - Clayton
Recruitment outside Australia
Country [1] 24471 0
New Zealand
State/province [1] 24471 0
Wellington
Country [2] 24472 0
New Zealand
State/province [2] 24472 0
Waikato

Funding & Sponsors
Funding source category [1] 310480 0
Government body
Name [1] 310480 0
National Health and Medical Research Council
Country [1] 310480 0
Australia
Primary sponsor type
University
Name
Monash University
Address
553 St Kilda Road,
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 311635 0
None
Name [1] 311635 0
NA
Address [1] 311635 0
NA
Country [1] 311635 0
Other collaborator category [1] 282635 0
Other Collaborative groups
Name [1] 282635 0
Australasian Leukaemia & Lymphoma Group
Address [1] 282635 0
35 Elizabeth St, Richmond VIC 3121
Country [1] 282635 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310110 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 310110 0
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 310110 0
Australia
Date submitted for ethics approval [1] 310110 0
19/01/2022
Approval date [1] 310110 0
13/04/2022
Ethics approval number [1] 310110 0

Summary
Brief summary
The aim of the study is to find out if oral antibiotics can be used instead of immunoglobulin (Ig) for preventing infections in patients with blood cancers, and if the oral antibiotics should be taken every day or only once symptoms of infection occur.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, have an acquired hypogammaglobulinaemia secondary to a haematological malignancy, and have received Ig treatment for over 6 months.

Study details
Participants will be randomised (allocated by chance) to one of three treatment groups, as follows:
- stop Ig, and be given oral antiobiotics (such as co-trimoxazole (Trimethoprim-sulfamethoxazole) 160mg/800mg) to take every day
- stop Ig, and be given oral antibiotics (amoxycillin/clavulanic acid 1750-2000mg/250mg and ciprofloxacin 750 mg) to keep at home, and used only if infection symptoms occur
- continue receiving their usual Ig treatment
The duration of each treatment is for 12 months.

Over the course of the 13 month study participation period, participants will be asked to return to the hospital for a study visit every 3 months, with monthly telephone visits to check-in on your progress between each in-person visit. Participants will also be asked to complete a study diary, recording treatment compliance and signs/symptoms of infection experienced throughout the study period.

Types of assessments and data collected will include: medical history, demographics, physical examination, blood tests, stool sample, quality of life questionnaires, information about your general health, hospitalisations, medications and procedures. In order to assess and compare the cost-effectiveness of the treatment groups, the study team will also request authorisation from participants to access their Medicare Benefits Schedule (MBS), Pharmaceutical Benefits Scheme (PBS), and Australian Immunisation Register (AIR) data.

It is hoped that this study will confirm if Ig used to prevent infections can be safely stopped, and if oral antibiotics should be given as an alternative, thus improving treatment for people with blood cancer.
Trial website
https://www.rationalisetrial.com/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116510 0
Prof Erica Wood
Address 116510 0
Transfusion Research Unit
Public Health and Preventive Medicine
Monash University
Level 1, 553 St Kilda Road,
Melbourne, VIC 3004
Country 116510 0
Australia
Phone 116510 0
+61 3 9903 0051
Fax 116510 0
Email 116510 0
erica.wood@monash.edu
Contact person for public queries
Name 116511 0
Zoe McQuilten
Address 116511 0
Transfusion Research Unit
Public Health and Preventive Medicine
Monash University
Level 1, 553 St Kilda Road,
Melbourne, VIC 3004
Country 116511 0
Australia
Phone 116511 0
+61 3 9903 0379
Fax 116511 0
Email 116511 0
zoe.mcquilten@monash.edu
Contact person for scientific queries
Name 116512 0
A/Prof Zoe McQuilten
Address 116512 0
Transfusion Research Unit
Public Health and Preventive Medicine
Monash University
Level 1, 553 St Kilda Road,
Melbourne, VIC 3004
Country 116512 0
Australia
Phone 116512 0
+61 3 9903 0379
Fax 116512 0
Email 116512 0
zoe.mcquilten@monash.edu

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.