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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]

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

hypogammaglobulinemia

Condition category

Condition code

Cancer

Myeloma

Cancer

Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Cancer

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]

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]

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]

12 months following randomisation

Secondary outcome [1]

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]

12 months following randomisation

Secondary outcome [2]

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]

12 months following randomisation

Secondary outcome [3]

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]

12 months following randomisation

Secondary outcome [4]

Occurrence of one or more microbiologically documented infections from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.

Timepoint [4]

12 months following randomisation

Secondary outcome [5]

Number of microbiologically documented infections from randomisation to 12 months.
Nb: This is a RATIONAL-PT core outcome measure.

Timepoint [5]

12 months following randomisation.

Secondary outcome [6]

All-cause mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.

Timepoint [6]

12 months following randomisation.

Secondary outcome [7]

Infection-related mortality at 12 months
Nb: This is a RATIONAL-PT core outcome measure.

Timepoint [7]

12 months following randomisation.

Secondary outcome [8]

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]

12 months following randomisation.

Secondary outcome [9]

Occurrence of one or more treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.

Timepoint [9]

12 months following randomisation.

Secondary outcome [10]

Number of treatment-related adverse events.
Nb: This is a RATIONAL-PT core outcome measure.

Timepoint [10]

12 months following randomisation.

Secondary outcome [11]

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]

12 months following randomisation.

Secondary outcome [12]

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]

12 months following randomisation.

Secondary outcome [13]

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]

Prior to randomisation, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation

Secondary outcome [14]

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]

Prior to randomisation, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation

Secondary outcome [15]

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]

Prior to randomisation, then at Month 3, Month 6, Month 9 and Month 12 post-randomisation

Secondary outcome [16]

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]

12 months following randomisation.

Secondary outcome [17]

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]

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?

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]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Country [1]

Australia

Primary sponsor type

University

Name

Monash University

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Other Collaborative groups

Name [1]

Australasian Leukaemia & Lymphoma Group (ALLG)

Address [1]

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

https://www.alfredhealth.org.au/research/ethics-research-governance

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

13/11/2023

Approval date [1]

04/01/2024

Ethics approval number [1]

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 patients with blood cancers receiving immunoglobulin for the purpose of preventing infections can safely stop after six months of therapy, and take oral antibiotics instead to prevent serious infections. The study will also test if the oral antibiotics should be taken every day or only as soon as an infection starts.

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 three groups (arms) to compare the different treatments. There is one usual care group and two investigational groups. The three groups are:
1. Continue receiving immunoglobulin (IVIg or SCIg) – this is the usual care group.
2. Stop immunoglobulin (IVIg or SCIg) and be given oral antibiotics to take every day.
3. Stop immunoglobulin (IVIg or SCIg) and be given oral antibiotics to keep at home to use as soon as symptoms of an infection develop.

Each participant has a one in three chance of being in each group. Each participant has a two in three chance of receiving oral antibiotics. Half of the participants receiving oral antibiotics will be asked to taken them every day, the other half will be asked to take them only if symptoms of infection develop.
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

Prof Erica Wood

Address

Transfusion Research Unit Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Road, Melbourne, VIC 3004

Country

Australia

Phone

+61 3 9903 0051

Fax

[email protected]

Contact person for public queries

Name

Zoe McQuilten

Address

Transfusion Research Unit Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Road, Melbourne, VIC 3004

Country

Australia

Phone

+61 3 9903 0379

Fax

[email protected]

Contact person for scientific queries

Name

Zoe McQuilten

Address

Transfusion Research Unit Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Road, Melbourne, VIC 3004

Country

Australia

Phone

+61 3 9903 0379

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

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No additional documents have been identified.

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