Role of Antibiotic Therapy or Immunoglobulin On iNfections in hAematoLogy (Dose-Ig)
Phase: PHASE2
Conditions: Myeloma, Non Hodgkin&#39;s Lymphoma, Leukemia
Sponsor: Monash University

 
RATIONAL Platform Trial Dose Ig Domain-Specific Appendix Protocol version 1.0, dated 12-Nov-2023 
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RATIONAL Platform Trial 
Role of Antibiotic Therapy or Immunoglobulin  
On iNfections in hAematoLogy  
Domain-Specific Appendix: 
Dosing Immunoglobulin  (Dose Ig) 
 
PROTOCOL NUMBER: 
 
TRU-RPT-22 
CHIEF INVESTIGATORS:   
Prof Zoe McQuilten 
 
Prof Erica Wood 
SPONSOR: 
 
 
Monash University 
VERSION NUMBER: 
 
1.0 
DATE OF PROTOCOL: 
 
12 NOVEMBER 2023 
 
Dose Ig Domain-Specific Appendix Development Protocol History 
Version Number 
Date 
Author 
Change 
1.0 
12-Nov-2023 
Prof Zoe McQuilten 
Original version 
 
 
 

 
RATIONAL Platform Trial Dose Ig Domain-Specific Appendix Protocol version 1.0, dated 12-Nov-2023 
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Domain Specific Appendix 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 Dose Ig Domain-Specific Appendix Protocol version 1.0, dated 12-Nov-2023 
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TABLE OF CONTENTS 
 
DOMAIN SUMMARY ........................................................................................................................ 7 
1.1. Domain Summary......................................................................................................................... 7 
 
PROTOCOL APPENDIX STRUCTURE ................................................................................................. 8 
 
DOMAIN GOVERNANCE .................................................................................................................. 9 
3.1. Domain members ......................................................................................................................... 9 
3.2. Dose Ig Domain-Specific Working Group Authorisation .............................................................. 9 
 
BACKGROUND AND RATIONALE ................................................................................................... 10 
4.1. Domain definition ...................................................................................................................... 10 
4.2. Domain-specific background ..................................................................................................... 10 
4.2.1. Overview ............................................................................................................................. 10 
4.2.2. Immunoglobulin replacement therapy in acquired hypogammaglobulinemia due to 
haematological malignancies ........................................................................................................ 10 
4.2.3. Dose of IgRT used in clinical trials in secondary hypogammaglobulinemia due to 
haematological malignancies ........................................................................................................ 10 
4.2.4. Pharmacokinetics of immunoglobulin replacement in other patient populations ............ 11 
4.2.5. Serum IgG levels in RATIONAL pilot randomised controlled trial ....................................... 12 
4.2.6. Risks of different dosing strategies of IgRT ........................................................................ 13 
4.2.7. Improving cost effectiveness of immunoglobulin replacement ......................................... 14 
4.2.8. The need for a trial comparing low dose IgRT with standard dose IgRT ............................ 14 
4.2.9. Domain hypothesis ............................................................................................................. 15 
 
DOMAIN OBJECTIVES .................................................................................................................... 15 
5.1. Aims ........................................................................................................................................... 15 
 
DOMAIN DESIGN ........................................................................................................................... 15 
 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ....................................................................... 15 
7.1. Population .................................................................................................................................. 15 
7.2. Eligibility criteria......................................................................................................................... 16 
7.2.1. Domain inclusion criteria .................................................................................................... 16 
7.2.2. Domain exclusion criteria ................................................................................................... 16 
7.2.3. Intervention exclusion criteria ............................................................................................ 16 
7.3. Randomisation ........................................................................................................................... 16 
 
TREATMENT OF PARTICIPANTS ..................................................................................................... 16 
8.1. Interventions .............................................................................................................................. 17 
8.1.1. Interventions ....................................................................................................................... 17 

 
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8.1.2. Low dose immunoglobulin replacement (Arm A) ............................................................... 17 
8.1.3. Commencement of immunoglobulin replacement (Arm B) ............................................... 17 
8.1.4. Cross-over to standard dose IgRT ....................................................................................... 17 
8.1.5. Duration of therapy ............................................................................................................ 17 
8.1.6. Discontinuation of study assigned treatment protocol ...................................................... 18 
8.1.7. Concomitant care ................................................................................................................ 18 
 
DOMAIN ENDPOINTS .................................................................................................................... 18 
9.1. Primary Endpoint ....................................................................................................................... 19 
9.2. Secondary Endpoints ................................................................................................................. 19 
 ASSESSMENTS AND FOLLOW-UP .................................................................................................. 19 
10.1. Domain Schedule of Assessments ........................................................................................... 19 
10.2. Domain-specific data collection ............................................................................................... 21 
10.3. Blinding .................................................................................................................................... 21 
 SAFETY ASSESSMENT .................................................................................................................... 21 
 STATISTICAL CONSIDERATIONS ..................................................................................................... 21 
12.1.1. Domain Sub-groups ........................................................................................................... 21 
 ETHICAL CONSIDERATIONS ........................................................................................................... 21 
13.1. Risks and benefits of participation ........................................................................................... 21 
 GOVERNANCE ISSUES.................................................................................................................... 21 
14.1. Funding of the Dose Ig Domain ................................................................................................ 21 
 REFERENCES .................................................................................................................................. 22 
 
 

 
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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 
DSA 
Domain-specific Appendix 
DSMC 
Data safety monitoring committee 
DSSAP 
Domain-Specific Statistical Analysis Plan (DSSAP) 
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 
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 
PID 
Primary immunodeficiency 
QoL 
Quality of Life  
RCT 
Randomised Clinical Trial 

 
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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 
 
 
 

 
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 DOMAIN SUMMARY 
1.1. Domain Summary 
Strata 
Myeloma, Non-Hodgkin Lymphoma and Chronic Lymphocytic 
Leukaemia 
Domain-specific inclusion 
criteria 
1. Patients must be receiving IVIg replacement at standard dose for 
prevention of bacterial infections due to 
hypogammaglobulinaemia for at least 6 consecutive months.  
2. Patient is not eligible for trial of Ig cessation in the opinion of the 
treating clinician and local investigator.  
Domain-specific 
exclusion criteria 
Exclusion Criteria 
Patients will not be eligible for this domain if they fulfil any of the 
following 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. Previous splenectomy. 
4. Known history of bronchiectasis. 
5. Previous participation in this domain. 
6. Treating team deems enrolment in the domain is not in the best 
interest of the patient.  
Interventions to be 
compared 
 
 
Arm A: Low dose IgRT: Participants will be treated with intravenous 
immunoglobulin monthly (every 4 weeks ± 1 week) at a dose of 
0.25g/kg.  No dose adjustment for trough serum IgG levels is 
required.  
Arm B: Usual dose: Participants will be treated with intravenous 
immunoglobulin monthly (every 4 weeks ± 1 week) 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.  
Trial hypotheses 
1. That a lower dose of IgRT is non-inferior to the standard IgRT 
replacement dose for the prevention of severe, and/or recurrent 
infection in patients with secondary hypogammaglobulinaemia 
due to B-cell malignancies. 
Primary outcome 
measure 
Primary RATIONAL-PT Endpoint: refer to RATIONAL-PT Core Protocol 
Secondary outcome 
measures 
Secondary RATIONAL-PT Endpoints: refer to the RATIONAL-PT Core 
Protocol. 

 
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 PROTOCOL APPENDIX STRUCTURE  
The structure of the RATIONAL Platform Trial protocol is different to that used for conventional trials 
because this trial is adaptive and the description of these adaptations is better understood and 
specified using a ‘modular’ protocol design.  
The protocol has multiple modules, in brief, comprising a Core Protocol (overview and design 
features of the study); a Master Statistical Analysis Appendix (details of the current statistical 
analysis plan and models); Domain-Specific Appendices (DSA) (detailing all interventions currently 
being studied in each domain); and Region-Specific Appendices (RSA) (detailing regional 
management and governance).  
The Core Protocol contains all information that is generic to the trial, irrespective of the regional 
location in which the trial is conducted and the domains or interventions that are being tested.  
The DSA contains information about the intervention(s), within each domain, because one of the 
trial adaptations is that domains and interventions will change over time. These Appendices are 
anticipated to change over time, and each modification to a DSA will be subject to a separate ethics 
application for approval.  
Information that is specific to a particular region in which the trial is conducted is contained within a 
RSA. This includes information related to local management, governance, and ethical and regulatory 
aspects. Within each region, only that region’s RSA, and any subsequent modifications, will be 
submitted for ethical review in that region. 
In addition to the Master Statistical Analysis Appendix, a Domain-Specific Statistical Analysis Plan 
(DSSAP) will be prepared that will outline additional aspects of the statistical analysis for this 
domain. 
 
 
 

 
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 DOMAIN GOVERNANCE 
3.1. Domain members 
Chair: Prof Zoe McQuilten 
The members of the Dose Ig Domain are members of the ITSC. 
3.2. Dose Ig Domain-Specific Working Group Authorisation 
The Dose Ig Domain-Specific Working Group have read this appendix and authorise it as the official 
Dose Ig Domain-Specific Appendix for the RATIONAL Platform Trial. Signed on behalf of the 
committee 
 
Chair 
 
 
 
 
 
 
Date 
 
 

 
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 BACKGROUND AND RATIONALE 
4.1.  Domain definition 
This is a domain within the RATIONAL Platform Trial to test the effectiveness and safety of lower 
dose Ig replacement compared to standard dose Ig replacement.  
4.2. Domain-specific background 
4.2.1. Overview 
4.2.2. Immunoglobulin replacement therapy in acquired hypogammaglobulinemia due to 
haematological malignancies 
Evidence supporting the use of Ig replacement therapy (IgRT) in patients with haematological 
malignancies is limited. Whilst the most recent Cochrane review which showed IgRT reduced 
infections in patients with secondary hypogammaglobulinemia due to haematological malignancies, 
it included only 3 trials published between 1988 and 1995 with a total of only 205 patients.1-4 In our 
recently completed systematic review of interventions to prevent infections in chronic lymphocytic 
leukaemia (CLL), multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) we did not identify any 
new evidence to guide Ig use.5  We found no difference in risk of all-cause mortality in patients 
allocated to IgRT compared to standard of care (relative risk [RR] 1.35, 95% CI 0.57-3.18), and a 
reduction in risk of clinically documented infections (RR 0.70, 95% CI 0.54-0.96). However, our 
certainty in the evidence was low due to small sample size of included trials, high risk of bias in the 
included studies and lack of contemporary data applicable to the current standard of care.5 Since 
these trials, there have been major changes to cancer therapy and supportive care. Intensive and 
novel therapies have improved outcomes for patients who respond, with varying degrees of 
immunological recovery. Therefore, it is very uncertain as to whether results from these early trials 
of IgRT still apply to our current practice.  
4.2.3. Dose of IgRT used in clinical trials in secondary hypogammaglobulinemia due to 
haematological malignancies 
The current standard of care for IgRT in patients with acquired hypogammaglobulinaemia secondary 
to haematological malignancies is intravenous immunoglobulin (IVIg) 0.4g/kg every 4 weeks, 
adjusted to maintain IgG trough levels within normal reference range. However, the evidence to 
support this dosing is weak, derived from a few small studies from the 1990s which evaluated doses 
ranging from 0.2g/kg to 0.5g/kg every three to four weeks.5 

 
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In our meta-analysis which showed that IgRT reduced clinically documented infections, the doses 
used in the included studies were 18g IVIg every 3 weeks,6, 0.3g/kg IVIg every 4 weeks,7,8 and 0.4g/kg  
IVIg every 4 weeks.3,4,9. Our systematic review5 only identified one study that compared two doses of 
IVIg, 0.25g/kg compared to 0.5g/kg every 4 weeks.10. 
These studies suggest that the evidence to support current practice is weak, and that doses lower 
than the current standard dose may be effective at preventing infections. It is known from 
pharmacokinetic studies in primary immunodeficiency that half-life of IgG varies in and between 
patients and that disease-related factors may play a role in determining the IgG dose to prevent 
infections. However, no such dosing studies have been performed in patients with haematological 
malignancies. 
4.2.4. Pharmacokinetics of immunoglobulin replacement in other patient populations 
The pharmacokinetics of therapeutic polyclonal IgG is highly variable with the terminal half-life of 
intravenous IgG ranging from 20 to 30 days in healthy adults and neonates, 12-56 days in patients 
with primary immunodeficiency (PID), 6 days in bone marrow transplant patients and 3-7 days in 
patients suffering from burns.11 The differences in half-life observed in the various diseases may be 
due to the pathophysiological elements of the underlying disease.  
Following intravenous administration, the serum concentration of IgG declines rapidly in the first 
seven days (α phase), followed by a more gradual decline (β phase). The rapid decline during the α 
phase is caused by the redistribution of IgG into extravascular spaces and IgG elimination, while the 
β phase only represents IgG elimination.11  
There are key pharmacokinetic differences between subcutaneous Ig (SCIg) and IVIg administration. 
IVIg is infused directly into the intravascular space, resulting in an early, high peak of Ig 
concentration followed by a redistribution phase (first-order kinetics, concentration-dependent 
elimination),11 whereas SCIg must first diffuse through the lymphatic system into the bloodstream 
(retained as a depot in the SC tissue and slowly redistributed into the intravascular space, first-order 
absorption),11 resulting in a more gradual and stable increase in Ig concentration over 2 to 3 days 
without a high IgG serum peak. Because bioavailability is lower with SCIg versus IVIg, the dose of 
SCIg must be increased to achieve equivalent immunoglobulin G exposure. Current 
recommendations indicate that patients receiving SCIG should use a monthly dose that is 130% or 
137% of their previous IVIg monthly dose, depending on the concentration of the SCIg product.12  

 
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The majority of research has mainly focused on the minimum trough levels required to achieve 
adequate protection against infections, while the upper limit of IgG levels has received much less 
attention. Instead, adequate dose requirement is mainly driven by clinical responses and cost 
considerations.11  
The first evidence that serum IgG levels of ≥5 g/L lead to substantial reduction of acute infections in 
primary immunodeficiency (PID) patients was published over 30 years ago. Since then, studies have 
shown that higher serum IgG concentrations may be associated with better protection against 
infections and decrease in incidence or progression of bronchiectasis in patients with PID.  
However, a number of publications have confirmed that there is no absolute protective level for 
everybody and IgG replacement therapy should be individualised to target the unique “biological” 
IgG level of every single PID patient.13 This is based on observations from PID cohorts that there is a 
wide range in serum IgG levels required to keep patients infection free, with only some patients 
needing the largest doses.14  
The evidence for the association between serum IgG levels, “biological” IgG levels and infection risk 
are all derived from studies in patients with PID. No similar data are available for patients with 
secondary hypogammaglobulinemia. Given the known variability in the pharmacokinetics of IgG 
according to underlying disease, studies specific to patients with haematological malignancies are 
required to inform dosing in this patient populations. 
4.2.5. Serum IgG levels in RATIONAL pilot randomised controlled trial 
Our recently completed RATIONAL phase II feasibility trial (ACTRN12616001723471) compared the 
use of IgRT vs prophylactic oral antibiotics in 63 patients with CLL, MM & NHL. The dose of IgRT was 
according to current standard of care in Australia (0.4g/kg every 4 weeks). We measured trough IgG 
levels in both treatment groups (Figure 1), which demonstrate that with current dosing the trough 
level is maintained much higher than 5g/L. The median (interquartile range) trough IgG level in 
participants allocated to IgRT was 8.9 (1.5) at 3 months following randomisation, 9.2 (2.9) at 6 
months, 9.9 (4.8) at 9 months and 8.4 (3.5) at 12 months. RATIONAL infection rates are shown in 
Figure 2.15 

 
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4.2.6. Risks of different dosing strategies of IgRT 
Regular IgRT is associated with hospital day-admissions (for intravenous administration) and known 
adverse effects associated with Ig use. Common adverse effects include headache, lethargy, 
Figure 2: Time to first major infection 
Figure 1: Median trough serum IgG levels in RATIONAL pilot by treatment arm 

 
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nausea/vomiting, allergic reactions, arthralgia, myalgia, hypersensitivity reactions, abdominal pain 
and dyspnoea. Aseptic meningitis can also occur, although this is less common. Regular use of Ig has 
also been associated with risk of thromboembolic events.16 Renal impairment and renal failure have 
also been reported in patients receiving IVIg.  
There is a risk that a lower dose of IgRT may increase infection risk if there is an association with 
higher serum trough IgG levels and infection risk in this patient population. However, higher doses of 
IgRT may also be associated with greater risk of adverse events.  
 
4.2.7. Improving cost effectiveness of immunoglobulin replacement 
A recent review of the cost effectiveness by the Australian Government Medical Services Advisory 
Committee found that Ig replacement was not a cost-effective therapy to manage infections in 
patients with secondary hypogammaglobulinemia secondary to hematological malignancies, noting 
the small and incomplete evidence base and high and uncertain incremental cost effectiveness ratio. 
One area highlighted for further research was generating evidence on dosing strategies to improve 
cost-effectiveness. If lower doses of IgRT were protective for infection risk, then this may improve 
the cost-effectiveness of immunoglobulin replacement.  
 
4.2.8. The need for a trial comparing low dose IgRT with standard dose IgRT 
It is essential to establish the optimal dosing of IgRT. The current standard of care for IgRT in patients 
with acquired hypogammaglobulinaemia secondary to haematological malignancies is IVIg 0.4g/kg 
every 4 weeks, adjusted to maintain IgG trough levels within normal reference range. However, the 
evidence to support this dosing is weak, derived from a few small studies from the 1990s which 
evaluated doses ranging from 0.2g/kg to 0.5g/kg every three to four weeks. These studies, and our 
pilot data, suggest that doses lower than the current standard dose may be effective at preventing 
infections. It is known from pharmacokinetic studies in PID that half-life of IgG varies in and between 
patients, that disease-related factors may play a role in determining the IgG dose to prevent 
infections, and that an individualised “biological IgG” level may be more important than serum 
trough IgG levels. However, no such dosing studies have been performed in patients with 
haematological malignancies. 

 
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4.2.9. Domain hypothesis 
• 
That a lower dose of IgRT is  non-inferior to the standard IgRT replacement dose for the 
prevention of severe, and/or recurrent infection in patients with secondary 
hypogammaglobulinaemia due to B-cell malignancies. 
 
 
 DOMAIN OBJECTIVES 
5.1. Aims 
The aim of this domain is to determine the effectiveness of a lower dose of IgRT in patients with 
haematological malignancies and secondary hypogammaglobulinaemia on event-free survival (as 
defined in the core protocol). 
 DOMAIN DESIGN 
This RATIONAL Platform 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 on different patient subpopulations, within the same framework, 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 platform allows the addition of new 
domains via protocol amendments and DSAs to answer new questions of interest, including different 
treatments or patient groups. Details of the overall platform trial design are included in the Core 
Protocol. 
The Dose Ig DSA is one of multiple domains in the RATIONAL platform. This domain is testing 
whether a lower dose of IgRT is non-inferior to the standard dose of IgRT in patients with secondary 
hypogammaglobulinemia due to haematological malignancies. 
 SELECTION AND WITHDRAWAL OF PARTICIPANTS 
7.1. Population 
The RATIONAL Platform Trial enrols patients with acquired hypogammaglobulinemia due to  
haematological malignancies, including MM, CLL and NHL. This domain is available for patients who 
are currently receiving standard dose IgRT for prevention of bacterial infections due to 

 
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hypogammaglobulinaemia and are not suitable for a trial of IgRT cessation (as per the Stop Ig 
domain).  
7.2. Eligibility criteria 
Patients are eligible for the RATIONAL Platform Trial if they meet all of the platform-level inclusion 
and none of the platform-level exclusion criteria outlined in the Core Protocol. Patients eligible for 
the RATIONAL Platform Trial may have conditions that exclude them from this Domain.   
7.2.1. Domain inclusion criteria 
1. Patients must be receiving IVIg replacement at standard dose for prevention of bacterial 
infections due to hypogammaglobulinaemia for at least 6 consecutive months.  
2. Patient is not eligible for trial of Ig cessation in the opinion of the treating clinician and local 
investigator.  
7.2.2. 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. Previous splenectomy. 
4. Known history of bronchiectasis. 
5. Previous participation in this domain. 
6. Treating team deems enrolment in the domain is not in the best interest of the patient. 
 
7.2.3. Intervention exclusion criteria 
Nil 
7.3. Randomisation 
Randomisation will occur following confirmation of participant eligibility for the domain, between 
the baseline and Dose Domain Day 1 visit. 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 Platform-level and Domain-level inclusion and exclusion criteria 
and there will be no exception to eligibility requirements at the time of randomisation. 
 TREATMENT OF PARTICIPANTS 

 
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8.1. Interventions 
8.1.1. Interventions 
This domain has two interventions: 
• 
Low dose intravenous immunoglobulin replacement (Arm A) 
• 
Standard dose intravenous immunoglobulin replacement (Arm B) 
8.1.2. Low dose immunoglobulin replacement (Arm A) 
Participants will be treated with intravenous immunoglobulin monthly (every 4 weeks ± 1 week) at a 
dose of 0.25g/kg.  No dose adjustment for trough serum IgG levels is required.  
8.1.3. Commencement of immunoglobulin replacement (Arm B) 
 Intravenous immunoglobulin (IVIg) 
Participants will be treated with intravenous immunoglobulin monthly (every 4 weeks ± 1 week) 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.  
8.1.4. Cross-over to standard dose IgRT 
If a participant on the low dose IgRT intervention arm (Arm A) experiences a Grade 3 or higher 
infectious complication, they may recommence standard dose IgRT, as directed by their treating 
clinician.  
In the absence of a Grade 3 or higher infectious complication, patients will stay on their assigned 
treatment. However, the treating clinician may increase the dose of IgRT if this is deemed in the 
participant’s best interest. This will not be regarded as an event for EFS in the primary analysis, 
however it will be recorded on the relevant eCRF for the purposes of supplementary analyses. 
In these situations, trial participation will not end and the participant will continueto follow the 
schedule of assessments until M12, except in the case of patients who also choose to withdraw from 
the study. 
8.1.5. Duration of therapy 
Participants will remain on assigned treatment for 12 months. Participants do not need to stop their 
trial-assigned treatment at 12 months, but all treatment decisions including for prevention of 

 
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infection after completion of trial treatment (at 12 months from Day 1 of study) will be managed by 
the participant’s treating clinician. 
8.1.6. Discontinuation of study assigned treatment protocol 
Site investigators/clinicians may discontinue a patient from their assigned trial treatment if this is no 
longer in the participant’s best interest. Reasons for treatment discontinuation may include: 
• 
Grade 3 or higher adverse event 
• 
Grade 3 or higher infectious complication 
• 
Unrelated medical illness or clinical condition representing potential risk, such as change to 
therapy for underlying malignancy 
• 
Participant’s request 
• 
Poor compliance 
• 
Participant is no longer deemed eligible to participate 
If a participant is discontinued from the assigned treatment protocol for any reason, the domain 
end-of-treatment (EOT) visit assessments should be completed 4 weeks (+/- 7 days) after the final 
administration of the participant’s assigned treatment. Domain trial participation will not end and 
the participant will continue to follow the schedule of assessments until M12. 
8.1.7. Concomitant care 
All other aspects of care, including other antimicrobial prophylaxis (including antivirals, antifungals) 
and vaccinations, will be according to usual care and local practice. For example, patients already 
taking low‐dose (80mg/400mg) daily or intermittent (three times a week) co‐trimoxazole for 
Pneumocystis jirovecii pneumonia (PJP) prophylaxis may continue.  
It is recommended that all participants receive routine vaccinations, including pneumococcal, 
influenza and COVID-19 vaccines, as part of their usual care, and have measurement of pre‐ and 
post‐vaccination pneumococcal responses, where polysaccharide pneumococcal vaccine is due to be 
given on study. 
Patients who are commenced on therapy to treat underlying malignancy may continue on the study. 
Patients may receive granulocyte colony stimulating factor (G-CSF) for prophylaxis or treatment of 
neutropenia according to local guidelines. 
 DOMAIN ENDPOINTS 
The Dose Ig domain aims to demonstrate the efficacy and safety of low dose IgRT compared to 

 
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standard dose IgRT in adults with a diagnosis of MM, CLL or NHL who are currently receiving 
immunoglobulin replacement.  
9.1. Primary Endpoint 
The primary endpoint for this domain is the primary endpoint specified in the Core Protocol. 
9.2. Secondary Endpoints 
All secondary endpoints specified in the Core Protocol. 
 
 ASSESSMENTS AND FOLLOW-UP 
10.1. Domain Schedule of Assessments 
Please see Domain Schedule of Assessments over page. This is in addition to the Schedule of 
Assessments in the Core Protocol.  

 
 
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All participants enrolled in the platform and any one of the domains are to be followed according to the Schedule of Assessments in the core platform 
protocol. The following additional assessments are to be completed for all participants enrolled in this domain. All visits for the domain must align with the 
core protocol visits and visit windows, for example the Month 1 visit on the domain is the Month 1 visit on the platform schedule of assessments. 
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 
Domain Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment details# 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Domain eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
*D1 is Day 1 of trial treatment. BL and D1 assessment may occur on the same day. D1 must occur no more than 7 days after randomisation. 
#Updated information on treatment for underlying malignancy if this has changed from platform enrolment

 
 
RATIONAL Platform Trial Dose Ig Domain-Specific Appendix Protocol version 1.0, dated 21-Aug-2023 
Page 21 of 23 
  
 
10.2. Domain-specific data collection  
In addition to the data collection specified in the core protocol, the following data will be collected 
for the Dose-Ig domain: 
BL visit – Updated information on treatment for underlying malignancy if this has changed from 
platform enrolment 
10.3. Blinding 
All interventions will be administered on an open-label basis. 
 SAFETY ASSESSMENT 
Refer to the Core Protocol. 
 STATISTICAL CONSIDERATIONS 
For information regarding the statistical analysis of this domain, refer to the Core protocol Master 
Statistical Analysis Appendix and the DSSAP. 
12.1.1. Domain Sub-groups 
Model-based, sub-group analyses, to be detailed in the DSSAP, will include, but are not limited to: 
• 
Patients receiving active therapy for their primary disease at time of randomisation 
• 
Patients with IgM below reference range at randomisation 
• 
Patients in partial or complete remission of their primary disease at time of randomisation 
• 
Country 
 ETHICAL CONSIDERATIONS 
13.1. Risks and benefits of participation  
There are no specific benefits for patients from participation in this domain. Both of the treatment 
arms in this domain are within normal standard of care.  
 GOVERNANCE ISSUES 
14.1. Funding of the Dose Ig Domain 
The RATIONAL Platform Trial funding sources are specified in the Core Protocol. 

 
RATIONAL Platform Trial Dose Ig Domain-Specific Appendix Protocol version 1.0, dated 12-Nov-2023 
Page 22 of 23 
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