A Randomised Platform Trial Evaluating the Role of Interventions to Prevent Infection in Patients With Acquired Hypogammaglobulinemia Secondary to Haematological Malignancies - RATIONAL-PT (Core)
Phase: PHASE2
Conditions: Myeloma, Non-Hodgkin's Lymphoma, Leukemia
Sponsor: Monash University

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 1 of 40 
 
 
RATIONAL-PT 
Role of Antibiotic Therapy or Immunoglobulin On 
iNfections in hAematoLogy Platform Trial: 
Core Protocol 
 
PROTOCOL NUMBER: 
 
TRU-RPT-22 
CHIEF INVESTIGATORS:   
Prof Zoe McQuilten 
 
Prof Erica Wood 
SPONSOR: 
 
 
Monash University 
VERSION NUMBER: 
 
1.0 
DATE OF PROTOCOL: 
 
12NOVEMBER 2023 
A randomised platform trial evaluating the role of interventions to prevent infection in patients with 
acquired hypogammaglobulinemia secondary to haematological malignancies. 
Development Protocol History 
Version Number 
Date 
Author 
Change 
1.0 
12-Nov-2023 
Prof Zoe McQuilten 
Original version 
 
 
 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 2 of 40 
Protocol Development Group: 
Name  
Affiliation 
Authors Contributions 
Prof Zoe 
McQuilten 
Monash University, 
Melbourne, Australia 
ZM and EW initiated the trial design and 
implementation. 
EW and ZM  are the grant holders.  
JR, ER and TL provided statistical expertise in clinical 
trial design and are conducting the primary statistical 
analysis.  
All authors contributed to refinement of the trial 
protocol and approved the final version. 
LF and DP designed the health economics analysis. 
OM designed the correlative sampling protocol. 
KLC and CP designed the qualitative substudy 
protocol. 
Dr Khai Li Chai 
Monash University, 
Melbourne, Australia 
A/Prof John 
Reynolds 
Monash University, 
Melbourne, Australia 
Prof Erica 
Wood 
Monash University, 
Melbourne, Australia 
Dr Laura 
Fanning 
Monash University, 
Melbourne, Australia 
Prof Dennis 
Petrie 
Monash University, 
Melbourne, Australia 
Prof Orla 
Morrissey 
Monash University, 
Melbourne, Australia 
Dr Catriona 
Parker 
Monash University, 
Melbourne, Australia 
Dr Elizabeth 
Ryan 
Monash University, 
Melbourne, Australia 
Dr Thao Le 
Monash University, 
Melbourne, Australia 
Dr Robert 
Weinkove 
Malaghan Institute of 
Medical Research, 
Wellington, New Zealand 
Prof Jeannie 
Callum 
Queen’s University, 
Ontario, Canada 
 
 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 3 of 40 
TABLE OF CONTENTS 
 
GENERAL INFORMATION ................................................................................................................ 7 
1.1. Trial Synopsis ................................................................................................................................ 7 
1.2. Schedule of Assessments ........................................................................................................... 10 
 
INTRODUCTION ............................................................................................................................. 13 
2.1. Background and rationale .......................................................................................................... 13 
2.1.1. Overview ............................................................................................................................. 13 
2.1.2. Bayesian adaptive platform trials ....................................................................................... 15 
2.1.3. Objectives ............................................................................................................................ 15 
2.2. PROTOCOL STRUCTURE ............................................................................................................. 16 
2.2.1. Core Protocol ...................................................................................................................... 16 
2.2.2. Domain-Specific Appendices ............................................................................................... 17 
2.2.3. Statistical Analysis Appendix ............................................................................................... 17 
2.2.4. Region-specific Appendices ................................................................................................ 18 
2.2.5. Sub-study and Biospecimen Appendices ............................................................................ 18 
2.3. STUDY GOVERNANCE ................................................................................................................. 18 
2.3.1. International Trial Steering Committee .............................................................................. 19 
2.3.2. Trial Management Group (TMG) ........................................................................................ 20 
2.3.3. Regional Specific Working Groups (RSWG) ......................................................................... 20 
2.3.4. Domain-Specific Working Groups (DSWG) ......................................................................... 20 
2.3.5. Data Safety and Monitoring Committee ............................................................................. 20 
2.3.6. Role of the Sponsor ............................................................................................................. 21 
2.3.7. Role of trial funder(s) .......................................................................................................... 21 
2.4. TRIAL DESIGN ............................................................................................................................. 21 
 
AIMS AND OUTCOMES .................................................................................................................. 22 
3.1. AIMS .......................................................................................................................................... 22 
3.2. OUTCOMES ................................................................................................................................ 22 
3.2.1. Primary outcome ................................................................................................................ 22 
3.2.2. Secondary outcomes ........................................................................................................... 22 
 
METHODS ...................................................................................................................................... 23 
4.1. STUDY SETTING .......................................................................................................................... 23 
4.2. SELECTION OF SITES/CLINICIANS ............................................................................................... 23 
4.3. SELECTION AND WITHDRAWAL OF PARTICIPANTS .................................................................... 23 
4.3.1. Core participant Inclusion criteria ....................................................................................... 24 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 4 of 40 
4.3.2. Core participant exclusion criteria ...................................................................................... 24 
4.4. CO-ENROLMENT GUIDELINES .................................................................................................... 24 
4.5. TRIAL PROCEDURES .................................................................................................................... 24 
4.5.1. Participant timeline ............................................................................................................. 24 
4.5.2. Screening/recruitment ........................................................................................................ 24 
4.5.3. Treatment allocation ........................................................................................................... 25 
4.5.4. Blinding ............................................................................................................................... 25 
4.5.5. Withdrawal of participants ................................................................................................. 25 
4.5.6. Treatment of participants ................................................................................................... 26 
4.5.7. Trial assessment schedule .................................................................................................. 26 
4.5.8. Assessments by visit ............................................................................................................ 26 
4.6. OUTCOME ADJUDICATION COMMITTEE (OAC) ......................................................................... 28 
 
Statistical Methods ....................................................................................................................... 28 
 
SAFETY ASSESSMENT .................................................................................................................... 29 
6.1. Definitions of adverse events .................................................................................................... 30 
6.1.1. Adverse Event (AE) .............................................................................................................. 30 
6.1.2. Adverse Reaction (AR) ........................................................................................................ 30 
6.1.3. Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) ......................................... 30 
6.1.4. Unexpected Adverse Reaction (UAR).................................................................................. 30 
6.1.5. Suspected Unexpected Serious Adverse Reaction (SUSAR)................................................ 31 
6.1.6. Significant Safety Issues (SSIs) and Urgent Safety Measures (USMs) ................................. 31 
6.2. Adverse event reporting ............................................................................................................ 31 
6.2.1. All Adverse Events (AEs) ...................................................................................................... 31 
6.3. Reporting of Serious Adverse Events (SAE)................................................................................ 32 
6.3.1. Adverse Events that require expedited reporting (within 24 hours) .................................. 33 
6.3.2. Death ................................................................................................................................... 33 
6.3.3. Investigator responsibilities ................................................................................................ 33 
6.3.4. Sponsor responsibilities ...................................................................................................... 34 
6.3.5. Statutory reporting ............................................................................................................. 34 
6.3.6. Out of hours emergency contact information .................................................................... 34 
 
ETHICAL CONSIDERATIONS ........................................................................................................... 34 
7.1. Compliance ................................................................................................................................ 35 
7.2. Ethical conduct of the trial ......................................................................................................... 35 
7.3. Protocol amendments ............................................................................................................... 35 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 5 of 40 
7.4. Consent ...................................................................................................................................... 36 
7.5. Patient confidentiality and access to data ................................................................................. 36 
 
INDEMNITY AND FINANCE ............................................................................................................ 37 
 
PUBLICATION ................................................................................................................................ 37 
9.1. Dissemination ............................................................................................................................ 37 
9.2. Authorship ................................................................................................................................. 37 
9.3. Timing ......................................................................................................................................... 37 
9.4. Acknowledgements .................................................................................................................... 37 
 REFERENCES .................................................................................................................................. 39 
 
 
 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 6 of 40 
Acronyms and Abbreviations  
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AR 
Adverse reaction 
AST 
Aspartate transaminase 
CI 
Chief Investigators 
CLL 
Chronic lymphocytic leukaemia 
CTCAE 
Common terminology criteria for adverse events 
DSMC 
Data safety monitoring committee 
DSSAP 
Domain-specific statistical analysis plan 
eCRF 
Electronic case report form 
EFS 
Event-free survival 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set  
FBE 
Full blood examination  
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
HREC 
Human research ethics committee 
ICH 
International conference on harmonisation 
Ig 
Immunoglobulin 
IgRT 
Immunoglobulin replacement therapy 
ITSC 
International Trial Steering Committee 
IV 
Intravenous 
IVIg 
Intravenous immunoglobulin 
MM 
Multiple myeloma 
NHL 
Non-Hodgkin Lymphoma 
NHMRC 
National Health and Medical Research Council (Australia) 
OAC 
Outcome adjudication committee 
PI 
Principal Investigator 
QoL 
Quality of Life  
RCT 
Randomised Clinical Trial 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SCIg 
Subcutaneous immunoglobulin 
SUSAR 
Suspected unexpected serious adverse reaction 
TMC 
Trial management committee 
UAR 
Unexpected adverse reaction 
 
 
 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 7 of 40 
 GENERAL INFORMATION 
1.1. Trial Synopsis 
Scientific title of clinical 
trial 
Role of Antibiotic Therapy or Immunoglobulin On iNfections in 
hAematoLogy Platform Trial 
Public title of clinical trial 
Role of Antibiotic Therapy or Immunoglobulin On iNfections in 
hAematoLogy Platform Trial 
Protocol short 
title/Acronym 
RATIONAL-PT 
Protocol version and date 
Version 1.0, dated 21-Aug-2023 
Primary sponsor 
Monash University 
Sponsor contact details 
Transfusion Research Unit  
Department of Epidemiology and Preventive Medicine  
School of Public Health and Preventive Medicine, Monash University  
553 St Kilda Road  
Melbourne, Victoria, 3004  
AUSTRALIA  
Phone: +61 3 9903 0791 or 1800 811 326  
Funders 
Australian National Health and Medical Research Council, Medical 
Research Future Fund 
Primary clinical trials 
registry number 
ANZCTR: TBC 
ClinicalTrials.gov: TBC 
Date trial registered 
 
Trial design 
Adaptive platform trial 
Health condition(s) or 
problem(s) studied 
Patients with hypogammaglobulinemia secondary to haematological 
malignancies 
Key inclusion and 
exclusion criteria 
Core Inclusion criteria 
1. Aged ≥ 18 years of age 
2. Diagnosis of haematological malignancy, including CLL, MM or 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  
Core Exclusion criteria 
1. Treating team deems enrolment in the study is not in the best 
interests of the patient. 
Additional eligibility criteria will apply for each domain and will be 
described within the relevant DSA. 
Setting 
This trial will be conducted by haematology or haematology/oncology 
units at participating hospitals in participating regions.    
Aims 
The primary aim of this platform trial is to determine the optimal 
supportive care interventions for patients with haematological 
malignancies. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 8 of 40 
Primary outcome measure 
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.     
This is the primary outcome for trial results for each domain, unless 
otherwise specified in the Domain Specific Appendix. 
Core secondary outcome 
measures 
1. Occurrence of at least 1 Grade 3 or higher infection(s) from 
randomisation to 12 months.   
2. Occurrence of one or more clinically documented infections 
(symptoms/signs of infection requiring antimicrobial treatment) from 
randomisation to 12 months. 
3. Number of clinically documented infections (symptoms/signs of 
infection requiring antimicrobial treatment) from randomisation to 12 
months.  
4. Occurrence of one or more microbiologically documented infections 
from randomisation to 12 months.  
5. Number of microbiologically documented infections from 
randomisation to 12 months.  
6. All-cause mortality at 12 months 
7. Infection-related mortality at 12 months 
8. Time free from hospitalisation with antimicrobial administration with 
therapeutic intent from randomisation to 12 months.  
9. Occurrence of one or more treatment-related adverse events 
10. Number of treatment-related adverse events.   
11. Isolation of fluoroquinolone resistant organisms, co-trimoxazole 
resistant organisms, extended spectrum beta lactamases or multidrug 
resistant organisms from randomisation to 12 months. 
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 
13. QoL measured at randomisation, 3, 6, 9 and 12 months (EQ-5D-5L, 
EORTC QLQ-30 and FACT-N.).  
14. Costs associated with allocated treatment arm and infections during 
study. 
Duration of trial 
There is no set duration of the trial as this is an adaptive platform trial. 
The trial may be extended with addition of new domains and 
interventions. 
Target sample size 
There is no set sample size as this is an adaptive platform trial. The 
sample size may change with addition of new domains and interventions 
Contact details for public 
queries 
sphpm.rationalise@monash.edu 
Contact details for 
scientific queries 
Prof Zoe McQuilten: zoe.mcquilten@monash.edu 
Lay summary of trial 
Some blood cancers, or the medications used to treat them, can cause 
low levels of immunoglobulins (antibodies) in the blood, resulting in 
increased risks of serious infection. Immunoglobulin (Ig, a blood product 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 9 of 40 
made from human plasma) is commonly prescribed to reduce the risk of 
infection in patients with blood cancers but the evidence for Ig 
replacement therapy is based on historical data and it is uncertain if this is 
still beneficial as there have been many changes to treatment of cancer 
and infection. Ig is also very expensive and Australia is one of the highest 
users of Ig in the world, at a cost of $130 million annually for this 
indication alone.  
 
There is considerable variation in the approach to Ig replacement therapy 
both internationally and within Australia, including the ideal duration of 
therapy and requirements for alternative therapies. Some countries 
require a trial of oral antibiotics prior to commencing Ig therapy. 
 
Even though blood products like Ig are very safe, they do still carry some 
risks and should only be used when needed. Other options (such as long 
term, low-dose antibiotics) also carry risks (for example, risk of antibiotic 
resistance). We need more information on how different treatment 
options compare in terms of benefits, risks and costs. 
 
The RATIONAL Platform trial seeks to determine which treatments are 
most effective in reducing infections and which patients are most likely to 
benefit from the treatments.  

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 10 of 40 
1.2. Schedule of Assessments 
The following Schedule of Assessments is to be followed for all participants who are enrolled in the platform and any one of the domains. Refer to the Domain-
Specific Appendix for additional domain-specific assessments (if applicable). 
Period 
Screening 
Treatment Period% 
Follow-up 
Procedure 
Visit BL 
Visit  
D1* 
Visit   
M1 
Visit   
M2 
Visit 
M3  
Visit 
M4 
Visit 
M5 
Visit 
M6 
Visit 
M7 
Visit 
M8 
Visit 
M9 
Visit 
M10 
Visit 
M11 
Visit 
M12/EOT^ 
Time 
≤2 weeks  
prior to D1 
+/- 3d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
Phone call 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Clinic visit 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Platform informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis details 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platform eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infections review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hospitalisations review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status (ECOG) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Haematology assessment: FBE (all 
timepoints), lymphocyte subsets (BL) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Biochemistry assessment! 
- Renal and liver function 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Ig Levels (trough)+ 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 11 of 40 
Biobank substudy, additional blood 
collection 
 
Xβ 
 
 
X 
 
 
X 
 
 
X 
 
 
X- 
For patients on biobank substudy, 
faecal sample collection@ 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
For patients on qualitative substudy, 
interview to be scheduled between D1 
& M12.   
 
Xβ 
 
 
 
 
 
 
 
 
 
 
 
X 
For patients on PK/PD sub-study, 
additional Ig samples to be scheduled 
around one Ig dose from D1 to M11. 
 
X~ 
 
 
 
 
 
 
 
 
 
 
 
 
For patients on Patient Preferences 
study, online discrete choice experiment 
survey to be completed prior to D1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of life: EQ-5D-5L, EORTC QLQ-
C30# and FACT-N 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Treatment compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Refer to relevant DSA for definition of D1 
%For the purpose of scheduling and follow-up, each trial month is defined as 4 weeks (or 28 days). Please note M1 is to be scheduled 4 weeks (+/-7 days) after D1. 
^End of Treatment visit (EOT): These assessments should be performed at a clinic visit, 4 weeks (+/-7 days) after the final administration of the participant’s assigned treatment. EOT 
visits/assessments may line up with a scheduled visit. 
βPrior to initial treatment dose. 
+Ig trough levels (steady-state if on SCIg) to be taken prior to the next Ig treatment for participants receiving Ig; Ig levels include IgG, IgA and IgM and IgG subclass if reported 
#If participant reports having had an infection requiring treatment, an additional EORTC QLQ C-30 is to be completed retrospectively for period of infection, once the infection has 
resolved.  
!Liver function tests: Bilirubin, ALT, and ALP. Renal function tests: Electrolytes, creatinine. 
@If collected at home, participants must return their faecal samples to site within 24 hours of collection. 
-Correlative blood samples are not required at the EOT visit, unless the visit coincides with the M12 visit. 
~PK/PD samples to only be collected for participants who are randomised to receive IgRT and have consented to the PK/PD sub-study. All PK/PD samples must be taken prior to the next 
administration of IgRT and are to be collected as follows: 
SCIg PK/PD samples: pre-infusion (-120 to -1min), 10 ±5 min prior to end of infusion, 2 ±1 h after infusion, and 1, 2, 3, 4 and 7 days after infusion.  
IVIg PK/PD samples: pre-infusion (-60 to -1 min), 3 to 20 min post-infusion, 24 ±2 h, 3 ±1 days, 7 ±1 days, 10 ±1 days, 14 ±1 days, 21 ±1 days and 28 ±2 days post-infusion. NB: participants 
receiving IVIg on a 3-weekly schedule will not require the PK/PD sample 28 days post-infusion. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 12 of 40 
BL – baseline; ECOG – European Cooperative Oncology Group; FBE – full blood examination; Ig – immunoglobulin; PD – pharmacodynamic; PK – pharmacokinetic; 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 13 of 40 
 INTRODUCTION 
2.1.  Background and rationale 
2.1.1. Overview 
 Infections in patients with blood cancers 
Serious or major infection is common in patients with chronic lymphocytic leukaemia (CLL), multiple 
myeloma (MM) and non-Hodgkin lymphoma (NHL). These blood cancers are associated with major 
morbidity and mortality, substantial impact on patient quality of life (QoL), and high health resource 
use and costs. Infections occur secondary to a multifactorial immune deficiency attributable to both 
the underlying cancer and/or its treatment.1-4 Hypogammaglobulinaemia occurs in up to 85% of 
people with CLL, >90% newly diagnosed MM and variably in NHL, and is associated with recurrent 
and/or severe bacterial, fungal & viral infections.3,5,6 Infections account for up to 50% of all CLL 
deaths, and 50% of early MM deaths.5,7 When serious infections occur, they are complex and costly 
to manage, and impair cancer treatment delivery by causing dose reductions or treatment delays. 
Prevalence and severity of immune deficiency generally correlates with disease stage and duration; 
however infectious risk prediction for individual patients remains difficult. Identifying interventions 
to prevent infection is therefore a priority to improve infectious outcomes, survival and QoL of 
patients living with these cancers. 
 Immunoglobulin replacement and other interventions to prevent infection 
Immunoglobulin (Ig) replacement therapy (IgRT) is commonly used to prevent recurrent bacterial 
infection, with access provided under Australian Criteria for government-funded Ig – with the caveat 
of “Evidence of probable benefit – more research needed”.8 This recommendation is based on 
outdated data: the most recent Cochrane review which showed infection reduction with Ig for 
patients with secondary hypogammaglobulinemia due to blood cancers included only 3 trials (1988-
95) with a total of only 205 patients.6,9-11 There is no evidence that IgRT improves mortality, however 
prior trials had very small numbers, and since these trials, there have been major changes to cancer 
therapy and supportive care, and hence many confounding factors potentially explaining the lack of 
a survival signal. Intensive and novel therapies result in better outcomes for some patients, with 
varying degrees of immunological recovery. Therefore, it is very uncertain whether results from 
these early trials of IgRT still apply to our current practice and can be used to inform which patients 
should receive Ig replacement, when it should be started, and when it is safe to stop treatment. 
Similar evidence gaps exist for use of prophylactic antibiotics. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 14 of 40 
Ig therapy also carries risks: while mostly well tolerated, it is not uncommon for patients to stop 
therapy due to side-effects (see below) which can occasionally be serious.12  
Australia has one of the highest uses per capita of intravenous Ig (IVIg) in the world, with Canada and 
the United Kingdom also high users of Ig per capita.  Patients with acquired 
hypogammaglobulinaemia due to haematological malignancies are the largest single group for 
whom IVIg is issued in Australia, accounting for 23% of all IVIg issued in 2018, with an estimated 
product costs for these patients in 2019-2020 of approximately $95 million rising to nearly $130 
million by 2023-2024.4,8,13,14  
Substantial variation exists in the approach to IgRT, both internationally and within Australia, in 
relation to optimal duration of Ig therapy and requirements for alternative therapies.4,15  
 Need for a trial to evaluate interventions to prevent infections in patients with blood 
cancers 
Infections are common in patients with secondary hypogammaglobulinemia due to haematological 
malignancies. At present, the most proven intervention to prevent infections is Ig replacement, 
however significant evidence gaps exist: 
• There have been significant changes to patient populations, therapeutic agents and protocols 
and consequent effects on immune function and supportive care since the largest clinical trials of 
Ig were performed. Whether results of these trials are still applicable to current practice is 
unknown. 
• Effectiveness of Ig compared with other potential options, such as prophylactic antibiotics or 
vaccinations, in terms of compliance with therapy, clinical outcomes, adverse effects, QoL, and 
healthcare costs, is unknown. 
• Clinical demand for Ig replacement continues to increase, with haematological malignancies the 
largest single indication. Identifying which patients are most likely to benefit is therefore a 
priority for the blood sector in order to meet growing demand.  
• No high-quality studies that have compared different methods of administration (intravenous 
versus subcutaneous), different dosing schedules or when to commence or cease Ig therapy 
• Emerging and pandemic infections, shifts in antimicrobial resistance patterns, and changes in 
vaccines and vaccination strategies are likely to impact the type and burden of infections among 
people with secondary hypogammaglobulinaemia. There is a need to evaluate immunoglobulin 
and other existing and new means to prevent infections in this population. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 15 of 40 
Clinical trials are required to inform clinical policies and healthcare resource allocation, and guide 
day-to-day patient management and efficient use of Ig. 
 
2.1.2. Bayesian adaptive platform trials 
Adaptive platform trials are an innovative trials methodology that is increasingly being used for 
oncology trials (I-SPY 216) and infectious diseases (SNAP17, REMAP-CAP18).  
Conventional randomised controlled trials (RCTs), at the time of design, make assumptions about 
plausible effect size, incidence of the primary outcome, and sample size, holding these assumptions 
until trial completion. Adaptive Platform Trials incorporate multiple statistical and design features 
that are not reliant on these types of pre-trial assumptions. These include the ability to perform 
analyses on data as they accumulate, with poorly performing interventions being removed, and the 
potential for new promising interventions to be added. Platform Trials allow multiple questions to be 
evaluated simultaneously and sequentially within the platform to achieve the goal of determining 
the optimal interventions as rapidly as possible. 
The RATIONAL platform trial will use a number of adaptive platform trial design features to enhance 
trial efficiency and rapid implementation of trial findings, including: 
-Universal core or master protocol with several domains. By addressing multiple questions in parallel 
the platform will reduce the time required to reach definitive conclusions on optimal therapy. 
- Ability for patients to rotate to another domain appropriate to their changed clinical status, rather 
than randomising to fixed sequence of interventions in advance. 
- Frequent interim analyses will be used so that questions can be concluded as soon as there is 
robust statistical confidence, not when a pre-specified sample size has been recruited. The results of 
each interim analysis will be reviewed by an independent Data and Safety Monitoring Board (DSMB) 
responsible for making declarations based on the analysis of accumulating data. Pre-specified 
stopping rules, informed by pre-trial simulations, will be provided to the DSMB. Details of 
simulations are provided in the Statistical Appendices for the Core Protocol and Domain Specific 
Appendices. 
2.1.3. Objectives 
The overarching objective of the RATIONAL Platform Trial is, for patients with haematological 
malignancies, to identify the interventional regimen (including, but not limited to: when to start, 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 16 of 40 
when to cease and how to dose IgRT and comparisons with alternative therapies) associated with 
the highest chance of event-free survival (EFS), defined as time from randomisation until occurrence 
of a Grade 3 or higher infection (as defined by CTCAE Version 5), or death from any cause. 
The trial enrols individuals with haematological malignancies, including but not limited to CLL, MM, 
and NHL, who have low Ig levels and/or a history of recurrent or severe infection. 
2.2. PROTOCOL STRUCTURE 
2.2.1. Core Protocol 
The structure of this protocol is different to a conventional trial because this trial is adaptive, 
designed to allow the trial to evolve over time with the introduction of new domains. The structure 
of the protocol is outlined in Figure 1. The Core Protocol provides the framework on which different 
interventions within domains can exist within this trial. The Core Protocol provides the following 
information: 
• 
Background and rationale for studying Ig replacement and other interventions to prevent 
infections in individuals with haematological malignancies 
• 
The trial design, including eligibility criteria for entry into the trial platform, randomisation 
and treatment allocation procedures, trial endpoints, methods to control bias, general 
principles of the statistical analysis of data, and criteria for termination of the trial 
• 
The trial conduct, including methods of recruitment, data collection and management, and 
procedures related to participant safety and monitoring 
• 
The trial governance structure (see also Figure 2) 
Figure 1: Platform protocol outline 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 17 of 40 
 
2.2.2. Domain-Specific Appendices 
Domain-specific appendices (DSAs) contain more detailed information about specifications of the 
interventions studied within each domain. Each new DSA will be submitted for ethical approval prior 
to commencement. Each DSA has the following structure:  
• 
Background and rationale for each of the interventions within that domain 
• 
Domain-specific eligibility criteria  
• 
Domain-specific exclusion criteria  
• 
A description of the interventions and procedures for their delivery 
• 
Domain-specific data collection and outcomes that are additional to those specified in the 
Core Protocol 
• 
Domain-specific ethical considerations  
• 
Domain-specific organisational considerations 
2.2.3. Master Statistical Analysis Appendix 
The Master Statistical Analysis Appendix contains a detailed description of generic analyses that are 
used for assessing the effect of interventions in more than one domain and any platform-wide 
analyses.  This will include the Core definition of the primary endpoint estimand.   

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 18 of 40 
2.2.4. Domain-Specific Statistical Analysis Plans (DDSAP) 
Domain-Specific Statistical Analysis Plans (DSSAPs) will be developed for each domain. These will 
include detailed description of the analyses specific to the domain.  
2.2.5. Region-Specific Appendices  
The RATIONAL-PT will be conducted in multiple countries with varying legislative, ethical and 
governance requirements. Region-Specific Appendices (RSAs) contain information specific to the 
conduct of the trial in that region, including: 
• 
Definition of the region 
• 
The governance structure within a region 
• 
Ethical and governance issues relevant to a region not covered in the Core Protocol 
• 
The availability of trial domains and interventions within a region 
• 
Region-specific treatment allocation and data management procedures 
2.2.6. Sub-study and Biospecimen Appendices 
Sub-studies will be fully described within appendices. These will contain the following information 
relevant to the sub-study: 
• 
Background and rationale for the sub-study 
• 
Sub-study procedures required for the conduct of the sub-study 
2.3. STUDY GOVERNANCE 
The trial governance structure is shown in Figure 2. 
Figure 2: Trial Governance Structure 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 19 of 40 
 
 
2.3.1. International Trial Steering Committee 
The International Trial Steering Committee (ITSC) will include members with experience and 
knowledge regarding the overall study design, domain-specific expertise and regional-specific 
expertise. The responsibilities of the ITSC are: 
• 
Development and amendment of the Core Protocol 
• 
Recruitment and approval of new regions (including Regional Sponsors) to the platform 
• 
Liaison with Sponsors in various countries or regions 
• 
Liaison with the Data Safety and Monitoring Committee (DSMC) (see below) and Outcome 
Adjudication Committee (OAC, see section 4.6) 
• 
Consideration of requests and approval of the addition of domains and their interventions to 
the platform, including prioritisation of new domains and new interventions within a domain  

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 20 of 40 
• 
The analysis and reporting of results, in conjunction with the DSWGs  
• 
Approval of manuscripts reporting results 
• 
Obtain ongoing funding for the platform 
• 
Determine the strategic direction of the platform 
2.3.2. Trial Management Group (TMG) 
The Trial Management Group (TMG) will oversee the day-to-day management and overall conduct of 
the trial. 
2.3.3. Regional Specific Working Groups (RSWG) 
The operation of the platform in each region is undertaken by that region’s RSWG, the composition 
of which is to be determined by investigators in each region. The responsibilities of the RSWGs are: 
• 
Development and amendment of the RSA for that region 
• 
Liaison with Regional Sponsor 
• 
Identification and management of sites in that region 
• 
Liaison with regional funding bodies 
• 
Consideration of the feasibility and suitability of interventions (and domains) for that region 
2.3.4. Domain-Specific Working Groups (DSWG) 
Each active and future domain (or closely related set of domains) will be administered by a DSWG. 
The responsibility of each DSWG are: 
• 
Development and amendment of the DSA 
• 
Proposal and development of new interventions within a domain 
• 
In conjunction with the ITSC, analysis and reporting results from the domain 
• 
Obtaining funding to support the domain 
2.3.5. Data Safety and Monitoring Committee 
An independent Data Safety and Monitoring Committee (DSMC), comprising experts in 
haematology, infectious diseases and statistics will be established before patient enrolment. The 
DSMC will be responsible for safeguarding the interests of trial participants and assessing the safety 
and efficacy of the trial. The DSMC will monitor evidence for treatment harm and compliance with 
the protocol. The DSMC will be advisory to the ITSC. The ITSC will be responsible for promptly 
reviewing the DSMC recommendations, to decide whether to continue or discontinue treatments 
within a domain, and to determine whether amendments to the protocol or changes in trial conduct 
are required. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 21 of 40 
The DSMC will be guided by a DSMC Charter that delineates the roles and responsibilities of the 
DSMC, including lines of communication between trial investigators, trial data coordinating centre, 
and Monash University. 
2.3.6. Role of the Sponsor 
Monash University plays a lead role in the design and central management of this trial. Monash 
University will have ultimate authority over the trial design; collection, management, analysis, and 
interpretation of data; writing of the report; or the decision to submit the report for publication. 
Monash University is the sponsor of the trial in Australia. 
The Platform can have multiple regional Sponsors. Sponsors are organisations that take overall 
responsibility of the conduct, governance and insurance of the trial in a defined region. The role of 
the Sponsor in each region is specified in each RSA.  
2.3.7. Role of trial funder(s) 
The Australian National Health and Medical Research Council (NHMRC) and Medical Research Future 
Fund (MRFF) are the initial funders of the platform. The funders have no role in the design of the 
trial and will not have any role during its execution, analyses, interpretation of the data, or decision 
to submit results for presentation or publication. 
 
2.4. TRIAL DESIGN 
This trial is an investigator-initiated open-label, randomised controlled adaptive platform trial open 
in multiple sites. The platform design allows many treatment approaches to be tested 
simultaneously, and for pre-specified interim analyses that can be used to stop recruitment early to 
arms showing insufficient evidence of efficacy or overwhelming evidence of efficacy. The overview 
of the platform is shown in Figure 3. Participants who have enrolled in and completed one domain 
may be rotated and invited to participate in another domain appropriate to their changed status and 
subject to meeting domain-specific eligibility criteria.  
Figure 3: Overview of trial platform 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 22 of 40 
 
 AIMS AND OUTCOMES 
3.1. AIMS 
The primary aim of this platform trial is, for patients with haematological malignancies, to determine 
the optimal supportive care interventions. 
3.2. OUTCOMES 
3.2.1. Primary outcome 
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.     
This is the primary outcome for trial results for each domain, unless otherwise specified in the 
Domain Specific Appendix. 
3.2.2. Secondary outcomes 
1. Occurrence of at least 1 Grade 3 or higher infection(s) from randomisation to 12 months.   
2. Occurrence of one or more clinically documented infections (symptoms/signs of infection 
requiring antimicrobial treatment) from randomisation to 12 months. 
3. Number of clinically documented infections (symptoms/signs of infection requiring antimicrobial 
treatment) from randomisation to 12 months.  
4. Occurrence of one or more microbiologically documented infections from randomisation to 12 
months.  
5. Number of microbiologically documented infections from randomisation to 12 months.  
6. All-cause mortality at 12 months 
7. Infection-related mortality at 12 months 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 23 of 40 
8. Time free from hospitalisation with antimicrobial administration with therapeutic intent from 
randomisation to 12 months.  
9. Occurrence of one or more treatment-related adverse events 
10. Number of treatment-related adverse events.   
11. Isolation of fluoroquinolone resistant organisms, co-trimoxazole resistant organisms, extended 
spectrum beta lactamases or multidrug resistant organisms from randomisation to 12 months. 
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 
13. QoL measured at randomisation, 3, 6, 9 and 12 months (EQ-5D-5L, EORTC QLQ-30 and FACT-N.).  
14. Costs associated with allocated treatment arm and infections during study. 
 METHODS 
4.1. STUDY SETTING 
This trial will be conducted by haematology or haematology/oncology units at participating hospitals 
in participating regions.    
4.2. SELECTION OF SITES/CLINICIANS 
The platform will be coordinated by the Monash University Transfusion Research Unit. 
Participating sites must complete and sign a clinical trial research agreement (CTRA).  
All sites participating in the platform will complete a delegation log and forward this to the Trial 
Management Group (TMG). Each person working on the trial must sign off a section of this log 
indicating their responsibilities. The TMG must be notified of any changes to trial personnel and/or 
their responsibilities and an updated delegation log completed.  
Following substantial amendments, sites will be notified of relevant documents and training 
required and if and when they are able to participate in the trial. 
4.3. SELECTION OF PARTICIPANTS 
Patients will be considered eligible for enrolment in this platform based on eligibility criteria applied 
at two levels. The first level is the inclusion and exclusion criteria that determine eligibility for 
enrolment within the platform. Once eligible for inclusion within the platform trial, additional 
criteria are applied that are specific to each domain.   
Patients are eligible for this trial if they fulfil all the inclusion criteria and none of the exclusion 
criteria in the core protocol, and the criteria for at least one of the domains.  

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 24 of 40 
4.3.1. Core participant Inclusion criteria 
1. Aged ≥ 18 years of age 
2. Diagnosis of haematological malignancy, including CLL, MM or 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  
4.3.2. Core participant exclusion criteria 
1. Treating team deems enrolment in the study is not in the best interests of the patient. 
 
Additional eligibility criteria will apply for each domain and will be described within the relevant 
DSA. 
 
4.4. CO-ENROLMENT GUIDELINES 
The RATIONAL-PT platform trial seeks to evaluate supportive care interventions to prevent infection, 
including in therapeutic settings. Co-enrolment to other therapeutic studies is not excluded, except 
where these studies include interventions which might directly affect the interventions or endpoint 
assessments within RATIONAL-PT. In case of uncertainty, the ITSC will evaluate suitability for co-
enrolment. 
 
4.5. TRIAL PROCEDURES 
4.5.1. Participant timeline 
A summary of the study and follow up schedule is shown in Figure 3 and Table 1 (Schedule of 
Assessments). 
4.5.2. Screening/recruitment 
The local PI or delegate will be responsible for identifying suitable patients by reviewing the 
eligibility criteria and inviting them to participate in the trial. 
A screening log will be completed on all patients considered for the trial including those approached 
but who decline to participate and ineligible patients. Patients will be screened against the eligibility 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 25 of 40 
criteria outlined in this core protocol as well as those in the domain-specific appendix for which the 
participant is being considered.  
Before commencing screening activities of patients for trial participation, consent from patients will 
be sought using the participant information and consent form (PICF). 
All screening assessments are part of routine clinical care, therefore results from tests that are 
performed no more than 14 days prior to registration can be used to assess patient eligibility. 
Each participant will be assigned a unique trial number when they are enrolled in the platform. 
4.5.3. Treatment allocation 
Participants will receive a treatment allocation after confirmation of eligibility for the Platform and 
at least one domain. For domains involving randomisation, randomisation will be conducted through 
a password-protected secure website using a central randomisation programme. Eligibility for 
randomisation will be assessed with reference to the inclusion and exclusion criteria and there will 
be no exception to eligibility requirements at the time of randomisation. 
After completion of trial procedures in one domain, participants may then be eligible to rotate to a 
different domain. In this case, participants will re-enter the screening period at the time of informed 
consent to the subsequent domain. If the participant is eligible for the subsequent domain, they will 
be reassessed against platform criteria and then be randomised within that domain and continue to 
be followed according to the Schedule of Assessments.  
4.5.4. Blinding 
Acknowledging the difficulty in blinding to regular administration of parenteral immunoglobulin 
replacement, the current standard of care in many regions, treatments will be provided on an open-
label basis, unless otherwise specified in the DSA. Where interventions are conducted on an open-
label basis, all members of the ITSC will remain blinded to aggregate reports until a platform 
conclusion is reported by the DSMC.  
4.5.5. Withdrawal of participants 
 Early withdrawal from trial 
Participants should be encouraged to remain in the trial and complete continue to follow  the 
Schedule of Assessments, including adverse events and infection review, until M12, even if they 
discontinue their assigned trial treatment. Participants who simply discontinue trial treatment are 
not considered an early withdrawal. Investigators can withdraw participants at any time if they 
consider this in the best interests of the participant.  

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 26 of 40 
Any participant withdrawn from the trial at any time, for any reason, before the last follow up visit is 
considered an early withdrawal. An End of Domain eCRF form is to be completed for all participants 
withdrawing from a domain prior to the last domain scheduled visit. Unless a participant withdraws 
completely (i.e. does not consent to any follow-up), participants will be followed for all adverse 
reactions and infectious outcomes up to 30 days after their last on-study treatment dose.  
 Participants lost to follow-up 
Every effort should be made to obtain information on patients who do not attend a scheduled 
appointment, to obtain at least minimal efficacy and safety data (including Serious Adverse 
Events). A patient will be considered lost to follow-up if they miss 3 consecutive visits and cannot 
be contacted by the site on 3 separate, consecutive attempts (these attempts must be 
documented on the patient’s notes). 
4.5.6. Treatment of participants 
Treatments are outlined in the relevant Domain Specific Appendices.  
4.5.7. Trial assessment schedule 
Please see Schedule of Assessments in Section 1.2. 
For the purpose of scheduling and follow-up, each trial month is defined as 4 weeks (or 28 days). 
4.5.8. Assessments by visit 
The following data will be collected: 
 Screening/baseline 
• 
Medical history, including 
o Demographics 
o Disease information 
o Disease-specific therapy, including: 
▪ 
Prior anticancer therapy for the underlying malignancy 
▪ 
Prior additional steroid use for the underlying malignancy in the prior 12 
months to screening 
o Concomitant medications (ALL) (including vaccinations, and current, ongoing 
anticancer therapy ) 
o Covid-19 vaccination history 
o Pneumococcal antibody response (if available) 
o Infection history for the 12 months prior to screening 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 27 of 40 
• 
ECOG Performance Status 
• 
Haematology – FBE, lymphocyte subsets by flow cytometry (if available) 
• 
Biochemistry – Renal function tests (Electrolytes and creatinine) and liver function tests 
(includes Bilirubin, ALT and ALP), IgG  
• 
Quality of life (EQ-5D-5L, EORTC QLQ-C30 & FACT-N) 
 Day 1 
• 
ECOG Performance Status 
• 
Concomitant medications (ALL) 
• 
Ig levels (trough if on 4-weekly IVIg, steady-state if on SCIg) 
• 
Safety monitoring 
• 
Infectious event details 
• 
Biobank sub-study only 
o Peripheral blood (whole blood and serum) for correlative studies, including COVID-
19 anti-spike protein levels. 
o Faecal sample   
 Clinic Visits – M3, M6, M9, M12/EOT 
• 
ECOG Performance Status 
• 
Haematology - FBE 
• 
Biochemistry – Renal function tests (Electrolytes and creatinine) and liver function tests 
(includes Bilirubin, ALT and ALP) 
• 
Ig levels (trough if on 4-weekly IVIg, steady-state if on SCIg) 
• 
Concomitant medications: Treatment for underlying haematological malignancy, other 
immunosuppressive therapies (including steroids) for any indication, and non-trial 
antibiotic, antifungal and antiviral use and vaccinations. See site manual and eCRF for 
further details.  
• 
Safety monitoring 
• 
Infectious event details (including review of patient diary entries) 
• 
Compliance with therapy 
• 
Quality of life assessment (EQ-5D-5L, EORTC QLQ-C30 & FACT-N)  
• 
Biobank sub-study only  

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 28 of 40 
o Peripheral blood (whole blood and serum) for correlative studies, including COVID-
19 anti-spike protein levels (Month 3, Month 6, Month 9 and Month 12 only. Not 
required at EOT unless the EOT visit coincides with Month 12) 
o Faecal sample  (Month 3 and Month 12/EOT only) 
If for any reason it is not considered in the participant’s best interests to attend the trial site for an 
in-clinic assessment (as per local Investigator discretion), this Protocol allows for tele-health 
appointments to be conducted instead of on-site visits. Any such decisions are to be documented in 
the participant’s source notes. 
 Monthly phone calls – M1, M2, M4, M5, M7, M8, M10, M11 
• 
Concomitant medications: Treatment for underlying haematological malignancy, other 
immunosuppressive therapies (including steroids) for any indication, vaccines and non-trial 
antibiotic, antifungal and antiviral use. See site manual and eCRF for further details.  
• 
Safety monitoring 
• 
Infectious event details (including review of patient diary entries) 
• 
Compliance with therapy 
 
4.6. OUTCOME ADJUDICATION COMMITTEE (OAC) 
An independent outcome adjudication committee, comprising of infectious disease experts and 
haematologists, will be established. The OAC will be responsible for reviewing and adjudicating on: 
grade of all infection outcomes, time of major infections; clinically documented infections; 
microbiologically documented infection; susceptibility profile of microbiologically documented 
infections and infection-related mortality.     
The OAC will be provided with the details of all infectious events. Details will be provided in a 
blinded fashion, to ensure that the OAC are not aware of which treatment arm the participant was 
receiving. Committee members will individually assess the events according to the secondary 
outcomes as outlined above. All members will subsequently participate in a series of 
teleconferences for final consensus decision on the primary and secondary end-points for each trial 
patient.  
 Statistical Methods 
Summary statistics, analyses and data visualisations will be generated using R version 4.0.0 or later 
or documented procedures in SAS (9.4 or later) or Stata (V. 17 or later) as appropriate.  A detailed 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 29 of 40 
description of the trial estimands, approaches to reporting, statistical models, adaptations and 
decision criteria, and justification of the trial design by simulation are presented in the Master 
Statistical Analysis Appendix to the Core Protocol and the Domain-specific Statistical Analysis Plans 
(SAPs). A Simulations Appendix will be updated periodically as an operational document which will 
contain the results of Monte Carlo simulations that are conducted to demonstrate and understand 
the operating characteristics of a domain or comparison of interest, across a range of plausible 
assumptions regarding the outcome rates, treatment effects, and recruitment rates. 
The RATIONAL-PT has an adaptive platform design which means that it does not have a fixed sample 
size that determines when the study will end. Individual domains may have fixed caps on sample size 
as described within their DSAs. 
The primary analysis will be a standalone analysis of each comparison within each domain of the 
RATIONAL-PT. 
Interim analyses will be conducted according to the schedules specified in the relevant domain-
specific appendices/SAPs and DSMC Charter, which will be reviewed and approved by the DSMC. 
The adaptations that can be made may be domain-specific and will be conducted according to pre-
specified rules that will be used to reach conclusions regarding the effectiveness of the interventions 
that are under investigation. These may include: declaration of proof-of-concept, early stopping of 
arms for futility, early stopping of arms for efficacy and response adaptive randomisation (RAR). The 
values for the thresholds for the adaptations will be domain-specific and will take into account the 
design and monitoring plan for the domain. These will be appraised and ratified by the ITSC prior to 
the first interim analysis being conducted. The results of the interim analyses will remain confidential 
unless a trigger has been met and a recommendation is made by the DSMC to the ITSC that a 
conclusion has been reached and that they should be unblinded.  
Blinding and randomisation: If domain-specific RAR is not invoked, computer-generated, randomised, 
allocation sequences will be based on permuted blocks of variable size; fixed allocation proportions 
will be adopted in the randomization of patients to the treatment arms in the domain and 
randomisation will be stratified by haematological malignancy.  
 
 SAFETY ASSESSMENT 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 30 of 40 
6.1. Definitions of adverse events 
6.1.1. Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal 
product and that does not necessarily have a causal relationship with this treatment. 
6.1.2. Adverse Reaction (AR) 
Any untoward and unintended response to an investigational medicinal product related to any dose 
administered. All adverse events judged by either the reporting investigator or the sponsor as having 
a reasonable possibility of a causal relationship to an investigational medicinal product would qualify 
as adverse reactions. A causal relationship between the trial treatment (or medication error, 
misuse/abuse of medicinal product) and an adverse event occurs where there is at least a 
reasonable possibility that the trial treatment caused the event, i.e. the relationship cannot be ruled 
out. 
6.1.3. Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) 
Any adverse event/adverse reaction, at any dose, that 
• 
Results in death 
• 
Is life-threatening (NB: ‘life-threatening’ refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event that hypothetically 
might have caused death if it were more severe.) 
• 
Results in persistent or significant disability/incapacity 
• 
Requires in-patient hospitalisation or prolongs existing hospitalisation 
• 
Results in congenital anomaly or birth defect 
• 
Is otherwise medically significant (i.e. all accidental or intentional overdoses whether they 
result in an adverse event or not, or any event which the investigator considers significant 
but which is not covered by the above) 
Planned hospitalisations for a pre-existing condition, without serious deterioration in health, is not 
considered a serious adverse event. 
6.1.4. Unexpected Adverse Reaction (UAR) 
This is defined as an adverse reaction, the nature or severity of which is not consistent with the 
trial’s reference safety information (i.e. current Investigator’s Brochure or Product Information). 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 31 of 40 
6.1.5. Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An adverse reaction to one or more of the interventions administered in this study, that is both 
serious and unexpected. 
A serious event or reaction is not defined as a SUSAR when: 
• 
it is serious but expected 
• 
it does not fit the definition of an SAE, whether expected or not 
6.1.6. Significant Safety Issues (SSIs) and Urgent Safety Measures (USMs) 
An SSI is defined as a safety issue that could adversely affect the safety of participants or materially 
impact on the continued ethical acceptability or conduct of the trial. An example of an SSI is an SAE 
associated with trial procedures that requires modification to trial conduct. 
An USM is a measure required to be taken in order to eliminate an immediate hazard to a 
participant’s health and safety. An USM is a type of SSI that requires the Investigator or Sponsor to 
act immediately to protect the participant. For this reason, USMs can be instigated by an 
Investigator or Sponsor before seeking approval from HRECs or Institutions.  
All Urgent Safety Measures instigated at the site must be reported to Monash University as soon as 
possible and within 24 hours of the measure being taken. 
6.2. Adverse event reporting 
6.2.1. All Adverse Events (AEs) 
All AEs that occur between the first trial-related procedure (i.e. screening) and 30 days following end 
of domain intervention must be recorded on the AE log.  
Investigators must record their opinion concerning details of the nature, onset, duration and severity 
of the AE, and assess any relationship to the trial intervention. Assessment criteria are defined 
below.Severity 
Severity for each adverse event, including any lab abnormality, will be determined by the 
Investigator using the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) as a guideline, 
wherever possible. In those cases where the CTCAE criteria do not apply and where there is no 
accepted alternative grading system, severity should be defined according to the following criteria: 
Mild 
 
 
Awareness of sign or symptom, but easily tolerated 
Moderate 
 
Discomfort enough to cause interference with normal daily activities 
Severe  
 
Inability to perform normal daily activities 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 32 of 40 
Life-threatening  
Immediate risk of death from the reaction as it occurred. 
Causality 
Relationship to trial treatment will be determined by the Investigator as follows: 
Unrelated 
No relationship between the experience and the administration of the trial 
treatment; related to other aetiologies such as concomitant medications or 
participant’s clinical state 
Unlikely 
 
The current state of knowledge indicates that the relationship is unlikely 
Possibly related  
Temporal association, but other aetiologies are likely to be the cause 
Probably related 
Temporal association, other aetiologies are possible but unlikely 
Related 
Established temporal or other association and event not reasonably 
explained by the participant’s known clinical state or other modes of 
therapy administered 
Expectedness 
An expectedness assessment needs to be conducted for all SAEs by the Sponsor with regard to the 
trial intervention, using the appropriate investigator brochure or treatment information.  
Expected    
The event is listed in the investigator brochure or the trial protocol as expected with 
the trial treatment or is commonly seen in clinical experience (patient population, 
dosage).  
Unexpected  
The event is not listed in the investigator brochure or in the trial protocol, or the   
severity of the event is greater than that listed in the investigator brochure or the 
trial protocol. 
6.3. Reporting of Serious Adverse Events (SAE) 
An adverse event that meets one of the seriousness criteria (6.1.3) is classified as a SAE. SAEs are 
reported on the SAE eCRF which is emailed to the Transfusion Research Unit at Monash University 
(sphpm.rationalise@monash.edu). A copy of the report will be forwarded to the site Pharmacy.  
At a minimum, the following attributes must be assigned at the initial report: 
• 
Adverse event term  
• 
Seriousness criterion 
• 
Date of onset and outcome 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 33 of 40 
• 
Severity of the event (CTCAE Grade) 
• 
Assessment of relatedness to the assigned intervention (Section 6.2 Causality)  
• 
Assessment of expectedness for the assigned trial intervention  
Subsequent reports must contain: 
• 
A detailed description of the event 
• 
Relevant laboratory findings and hospital reports 
• 
Other concomitant drugs or devices 
All SAEs will be followed until resolution. The investigator will be asked to provide interim and 
follow-up reports, as necessary, if the SAE has not resolved at the time of initial report. 
6.3.1. Adverse Events that require expedited reporting (within 24 hours) 
Any SAEs or SARs or unexpected (but not serious) adverse reactions (UARs) must be reported to 
Monash University within 24 hours of the investigator becoming aware of the event, unless these 
have been specifically excluded from expedited reporting. These are SAEs that are associated with 
the participant’s underlying disease, and will not impact on the scientific interpretation of the results 
of the trial.  
Due to the seriousness of the underlying diseases from which the participants in this trial are 
suffering, the following situations that fulfil the definition of an SAE are excluded from expedited 
notification, but should be recorded on the SAE form and reported within 5 working days: 
• 
Hospitalisation for pre-existing conditions that, in the investigator’s opinion, have not been 
exacerbated by trial intervention 
• 
Any other serious event related to the underlying disease or other medications used to treat 
the disease. Serious infections are not excluded from expedited notification.  
6.3.2. Death 
All deaths occurring on trial must be reported as an outcome on the SAE form and on the eCRFs. For 
all deaths, available autopsy reports (or death certificate if available) should be sent with the 
notification. 
NB: Death is the outcome of a SAE; it cannot be the AE term unless no other information is available. 
6.3.3. Investigator responsibilities 
All SAEs must be assessed by, and reports signed, by an Investigator. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 34 of 40 
It will be left to the investigator’s clinical judgment whether or not an adverse reaction is of 
sufficient severity to require that the participants should be discontinued from the treatment. A 
participant may also voluntarily withdraw from treatment due to what they perceive as an 
intolerable adverse event. If either of these occurs, it must be made clear if the participant is being 
withdrawn from the trial or just the trial intervention.  
The Investigator is responsible for reporting SUSARs arising at their site, Significant Safety Issues 
(SSIs) and Urgent Safety Measures (USMs) to their Institution. 
6.3.4. Sponsor responsibilities 
Monash University is the trial sponsor and has ultimate responsibility for the ongoing safety 
evaluation of the trial. Where required, Monash University is responsible for the reporting of 
Australian SUSARs to the Therapeutic Goods Administration (TGA), annual safety reports to the 
HREC, and Significant Safety Issues (SSIs) and Urgent Safety Measures (USMs) to the TGA, HREC and 
Investigators. Reporting requirements in other regions is outlined in the relevant RSA. 
All adverse events will be reviewed by the Chief Investigator (or a medically qualified delegate). The 
Chief Investigator will provide listings of all events for review by the DSMC and reports of AEs will be 
forwarded to the DSMC for review as often as required by the DSMC.  
6.3.5. Statutory reporting 
 Reporting to the Therapeutic Goods Administration 
For trials conducted under the Clinical Trials Notification (CTN) scheme Sponsors must report AEs 
that meet TGA criteria. 
 Reporting of suspected reactions to trial treatments 
Adverse events or suspected transfusion reactions to Ig should be reported to the site’s transfusion 
service in accordance with hospital requirements, and to the product sponsor, national blood service 
and/or haemovigilance programs in line with national guidelines and reporting criteria.  UARs to trial 
antibiotics should also be reported in accordance with site and national pharmacovigilance program 
requirements.  
6.3.6. Out of hours emergency contact information 
Phone: +61 3 9903 8291 
 
  ETHICAL CONSIDERATIONS 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 35 of 40 
7.1. Compliance 
This trial is to be performed in accordance with the ethical principles of the Declaration of Helsinki 
(October 2013), the Integrated Addendum to ICH E6 (R1): guideline for Good Clinical Practice ICH E6 
(R2) (November 2016) annotated with Therapeutic Goods Administration comments, and the 
NHMRC National Statement on Ethical Conduct in Human Research 2007 (Updated 2018). Sites in 
jurisdictions other than Australia are responsible for ensuring that their safety and ethical reports 
also comply with their region, as documented in the RSA.  
7.2. Ethical conduct of the trial 
In order to safeguard the rights, safety and well-being of participants, this protocol will be submitted 
to a Human Research and Ethics Committee (HREC) constituted according to the local requirements. 
Approval of the protocol, template Patient Information and Consent Form (PICF), participant 
education and recruitment materials, and other relevant trial documents will be obtained prior to 
the start of the trial.  
The Sponsor will ensure that all conditions for approval of the trial are met and that subsequent 
amendments are notified to, and approved by the HREC prior to implementation. 
The Sponsor will produce progress and safety reports for the HREC in accordance with their 
requirements. The Sponsor will keep an up to date record of all applicable documentation and 
correspondence with the HREC. 
It is the responsibility of the Principal Investigator at each participating site to ensure that the 
protocol, site-specific PICF, participant education and recruitment materials, and other requested 
documents, as well as all subsequent amendments, are notified to the applicable local governance 
office. Approval must be obtained from the Sponsor, ethics committee and local governance office 
for the platform, and any domains in which the site plan to participate, prior to participation in those 
domains.  
7.3. Protocol amendments 
Any modifications to the protocol which may impact on the conduct of the study, potential benefit 
of the patient or may affect patient safety, including changes of study objectives, study design, 
patient population, sample sizes, study procedures, or significant administrative aspects will require 
a formal amendment to the protocol. Such amendment will be agreed upon by the ITSC, and 
approved by the HREC prior to implementation and notified to the health authorities in accordance 
with local regulations. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 36 of 40 
Administrative changes of the protocol are minor corrections and/or clarifications that have no 
effect on the way the study is to be conducted. These administrative changes will be agreed upon by 
the TMG, and will be documented in a memorandum. The HREC may be notified of administrative 
changes at the discretion of the TMG. 
7.4. Consent 
Informed consent will be sought by the Principal Investigator or appropriately trained delegates. The 
method of obtaining and documenting the informed consent and the contents of the consent will 
comply with ICH GCP and all applicable regulatory requirements. Additionally, where required per 
national or local guidelines, local consent for a specific study intervention (e.g. immunoglobulin 
replacement) will be taken by the investigator or a delegate, and stored in institutional records - this 
is the responsibility of the Principal Investigator. 
The participant will be provided with a Patient Information and Consent Form (PICF) about the trial 
and written consent sought once the participant has been given the opportunity to discuss the trial 
with the PI or delegate.  
Participants will not take part in the trial unless fully-informed consent has been obtained. No trial-
specific procedures may be conducted prior to informed consent. However, any tests or procedures 
conducted as part of participants’ routine clinical care (e.g., non-trial-specific blood tests etc.), may 
be utilised for baseline purposes, provided those procedures were conducted within the designated 
baseline period, and according to protocol requirements.  
Participants who are already enrolled in the platform and are rotating from one domain to the next 
will not need to be re-consented to the platform at the time of rotation, but they will need to be 
consented to the subsequent domain. Per local Investigator discretion and local site procedures, the 
participant may be reconsented to the platform if a considerable amount of time has lapsed since 
the original platform consent was obtained.  
7.5. Patient confidentiality and access to data 
CRFs, clinical notes and administrative documentation should be kept in a secure location (for 
example, locked filing cabinets in a room with restricted access) and held for a minimum of 15 years 
after the end of the trial, depending on regional requirements. During this period, all data should be 
accessible to the competent authorities and the Sponsor with suitable notice.  
All laboratory specimens, reports, data collection, process, and administrative forms will be 
identified by a coded ID [identification] number only to maintain participant confidentiality.  

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 37 of 40 
Following completion of analysis, the trial database will be archived for at least 15 years in 
accordance with Monash University policy. 
 
  INDEMNITY AND FINANCE 
Indemnity arrangements will be described in the clinical trial research agreement (CTRA) which will 
be in place with each participating site.  
Initial funding for this trial has been provided by the National Health and Medical Research Council 
(NHMRC) and Medical Research Future Fund with clinical trial management support from the TRU, 
Monash University, Australia.  Details of payments to sites to cover the research costs will be 
provided in the CTRA. 
Declaration of interests 
None of the individuals named in this protocol have any competing interests to declare.  
 
  PUBLICATION 
9.1. Dissemination 
The results from different centres will be analysed together and published as soon as possible. 
Individual clinicians must not publish data concerning their patients that are directly relevant to 
questions posed by the trial until the ITSC has published its report. The ITSC will form the basis of the 
Writing Committee and will advise on the nature of publications. 
9.2. Authorship 
Authorship of final papers will consist of persons who have made a significant contribution to design, 
management and/or recruitment of the clinical trial and in accordance with the trial authorship 
policy.  Authorship of the publication and significant contribution shall be considered by the Trial 
Writing Committee.  
9.3. Timing 
No data may be made public before publication and never without agreement from the CIs. 
9.4. Acknowledgements 
The Study Funder, Sponsor and the relevant Trial Committees must be acknowledged on all 
publications as well as the role of the Clinical Trials Unit in providing support for and running this 
study. All contributing PIs must be listed.   

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 38 of 40 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 39 of 40 
 REFERENCES 
1. 
Teh BW, Harrison SJ, Worth LJ, Thursky KA, Slavin MA. Infection risk with 
immunomodulatory and proteasome inhibitor-based therapies across treatment 
phases for multiple myeloma: A systematic review and meta-analysis. Eur J Cancer. 
2016;67:21-37. 
2. 
Crassini K, Best OG, Mulligan SP. Immune failure, infection and survival in chronic 
lymphocytic leukemia. Haematologica. 2018;103(7):e329. 
3. 
Freeman J, Crassini KR, Best OG, et al. Immunoglobulin G subclass deficiency and 
infection risk in 150 patients with chronic lymphocytic leukemia. Leuk Lymphoma. 
2013;54(1):99-104. 
4. 
Keegan A, Dennington PM, Dhondy N, Mulligan SP. Immunoglobulin Replacement 
Therapy in Chronic Lymphocytic Leukaemia patients with hypogammaglobulinaemia 
and infection; analysis of total national utilisation data in Australia 2008-2013. now 
updated as preprint, available at medRxiv. 2022:2021.2012.2029.21268534. 
5. 
Dhalla F, Lucas M, Schuh A, et al. Antibody deficiency secondary to chronic 
lymphocytic leukemia: Should patients be treated with prophylactic replacement 
immunoglobulin? J Clin Immunol. 2014;34(3):277-282. 
6. 
Raanani P, Gafter‐Gvili A, Paul M, Ben‐Bassat I, Leibovici L, Shpilberg O. 
Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem 
cell transplantation. Cochrane Database Syst Rev. 2008(4). 
7. 
Holmstrom MO, Gimsing P, Abildgaard N, et al. Causes of early death in multiple 
myeloma patients who are ineligible for high-dose therapy with hematopoietic stem 
cell support: A study based on the nationwide Danish Myeloma Database. Am J 
Hematol. 2015;90(4):E73-74. 
8. 
NBA. Criteria for Immunoglobulin Use in Australia. 2018. 
9. 
Gale RP, Chapel HM, Bunch C, et al. Intravenous immunoglobulin for the prevention 
of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. 
N Engl J Med. 1988;319(14):902-907. 
10. 
Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG. Randomised trial of 
intravenous immunoglobulin as prophylaxis against infection in plateau-phase 
multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in 
Multiple Myeloma. Lancet. 1994;343(8905):1059-1063. 
11. 
Griffiths H, Brennan V, Lea J, Bunch C, Lee M, Chapel H. Crossover study of 
immunoglobulin replacement therapy in patients with low-grade B-cell tumors. 
Blood. 1989;73(2):366-368. 
12. 
Ammann EM, Jones MP, Link BK, et al. Intravenous immune globulin and 
thromboembolic adverse events in patients with hematologic malignancy. Blood. 
2016;127(2):200-207. 
13. 
Authority NB. National Report on the issue and use of immunoglobulin, 2013-2014. 
2014. 
14. 
Immunoglobulin for acquired hypogammaglobulinaemia secondary to 
haematological malignancies, or post-haemopoietic stem cell transplantation. MSAC 
Assessment Report 2019. 
15. 
Paxton L, Hawkins C, Crispin P. Selecting haematological malignancy patients for 
intravenous immunoglobulin. Intern Med J. 2016;46(10):1216-1218. 

 
RATIONAL Platform Trial (RATIONAL-PT) Core Protocol version 1.0, dated 12-Nov-2023 
Page 40 of 40 
16. 
Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an 
adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin 
Pharmacol Ther. 2009;86(1):97-100. 
17. 
Tong SYC, Mora J, Bowen AC, et al. The Staphylococcus aureus Network Adaptive 
Platform Trial Protocol: New Tools for an Old Foe. Clin Infect Dis. 2022;75(11):2027-
2034. 
18. 
Writing Committee for the R-CAPI, Estcourt LJ, Turgeon AF, et al. Effect of 
Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With 
COVID-19: A Randomized Clinical Trial. JAMA. 2021;326(17):1690-1702.