RATIONAL PT | RATIONALISE

RATIONAL Platform Trial

Role of Antibiotic Therapy or Immunoglobulin On iNfections in hAematoLogy - Platform Trial (RATIONAL-PT)

RATIONAL-PT is conducted in collaboration with hospital sites across Australia, New Zealand and Canada.

Some blood cancers, or the medications used to treat them, can lead to hypogammaglobulinemia (low levels of immunoglobulin [antibodies] in the blood), resulting in an increased risk of serious infection. To treat this condition, patients are often given immunoglobulin (antibodies) to prevent serious infection.

The platform trial aims to address evidence gaps in immunoglobulin (Ig) use and infection prevention in patients with blood cancer. In the platform trial this is examined through three domains - Start-Ig, Stop-Ig and Dose-Ig - each designed to examine a different question around the use of immunoglobulin replacement therapy or prophylatic antibiotics for infection prevention.

The need for the platform trial

Studies supporting immunoglobulin use were conducted 20-30 years ago and we do not know the effects of immunoglobulin given to patients in the context of newer anti-cancer treatments.

There is variation in the international guidelines on when to administer immunoglobulin, and this is reflected in the different practice for immunoglobulin administration between different countries.

The optimal duration of immunoglobulin use is not clearly defined. The international guidelines vary considerably in their recommendations for if and when to trial a cessation of immunoglobulin.

Immunoglobulin is made from donated plasma, and it is expensive, so must be used wisely. The demand for immunoglobulin is also increasing, leading to increased challenges for meeting demand.

There is some evidence to support the rationale for using prophylactic oral antibiotics to treat patients with acquired hypogammaglobulinemia but their use in this context needs to be properly evaluated.

Overview

RATIONAL-PT is an adaptive platform trial enrolling participants with acquired hypogammaglobulinemia secondary to haematological malignancy (chronic lymphocytic leukaemia, multiple myeloma, or non-Hodgkin's lymphoma).

Start-Ig Domain

Eligible participants will be allocated on a 1:1 ratio to one of two treatment groups:

Start immunoglobulin replacement therapy (IVIg or ScIg)
Start daily prophylactic oral antibiotics

Stop-Ig Domain (RATIONALISE)

Eligible participants will be allocated on a 1:1:1 ratio to one of three treatment groups:

Stop immunoglobulin and commence daily prophylactic oral antibiotics
Stop immunoglobulin, and prescribed antibiotics to keep at home to use immediately if symptoms of infection develop, with immediate review by treating clinical team, nearest emergency department or medical practitioner
Continue to receive intravenous or sub-cutaneous immunoglobulin as per current treatment regimen

Dose-Ig Domain

Eligible participants will be allocated on a 1:1 ratio to one of two treatment groups:

Low dose intravenous immunoglobulin replacement
Standard dose intravenous immunoglobulin replacement

The primary outcome of the platform trial is event-free survival, defined from the date of randomisation until the earliest date of occurrence of Grade 3 or higher infection (as per CTCAE version 5) as reviewed by an Outcome Adjudication Committee, or death from any cause.

Sub-studies

Led by Dr Laura Fanning and Prof Dennis Petrie, Centre for Health Economics, Monash University:

A health-economic analysis will be conducted to assess the cost-effectiveness of the trial interventions.

Led by Dr Khai Li Chai and Dr Catriona Parker, Transfusion Research Unit, Monash University:

A qualitative study will explore patient perspectives on the use of immunoglobulin and oral antibiotics.

Led by Prof Orla Morrissey, Department of Infectious Diseases, Monash University:

Blood and faecal samples will be collected and sent to a central lab for testing. Samples will be analysed to better understand immune function in this patient group.

Led by Prof Jason Roberts, Centre for Clinical Research, University of Queensland:

Blood samples will be collected to analyse the time-course of immunoglobulin absorption and determine the relationship between immunoglobulin dose and its effects on the body. This sub-study will aid our understanding of how immunoglobulin works and the impact of different dosing strategies.

Find out more

For further information and all general platform-related enquiries, please contact the Monash University Project Team

Contact the Project Team

Alternatively, comprehensive trial information, including participating hospital sites can be found on the

Australian New Zealand Clinical Trials Registry (ANZCTR)

RATIONAL Platform Core Protocol

RATIONAL Platform Start-Ig Domain Protocol

RATIONAL Platform Stop-Ig Domain Protocol

RATIONAL Platform Dose-Ig Domain Protocol

The RATIONAL platform trial is sponsored by Monash University and is being conducted in collaboration with the Australasian Leukaemia and Lymphoma Group (ALLG). The trial forms part of the NHMRC Blood Synergy Program.

RATIONAL Platform Trial Coordinating Principal Investigators:

Prof Zoe McQuilten

Prof Erica Wood

Platform Trial Coordinating Centre:

The platform trial is being centrally coordinated by the Transfusion Research Unit within the School of Public Health and Preventive Medicine at Monash University.

Committees:

The project team would like to acknowledge the contribution of the membership of the following committees:

Trial Steering Committee
Data and Safety Monitoring Committee
Outcome Adjudication Committee

The RATIONAL platform trial is funded by a Medical Research Future Fund (MRFF) grant and has received ethics approval to be conducted at participating sites within Australia from the Alfred Health Human Research Ethics Committee.