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

 
 
 
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RATIONAL Platform Trial 
Role of Antibiotic Therapy or Immunoglobulin  
On iNfections in hAematoLogy  
Domain-Specific Appendix: 
Immunoglobulin Stopping or Extension (Stop 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 
 
 STOP Ig Domain-Specific Appendix Development Protocol History 
Version Number 
Date 
Author 
Change 
1.0 
12-Nov-2023 
Prof Zoe McQuilten 
Original version 
 
Domain Specific Appendix Protocol Development Group: 
Name  
Affiliation 
Authors Contributions 

 
 
 
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A/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 
Ms 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 
 
 

 
 
 
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TABLE OF CONTENTS 
 
DOMAIN SUMMARY ........................................................................................................................ 6 
1.1. Domain Summary......................................................................................................................... 6 
 
PROTOCOL APPENDIX STRUCTURE ................................................................................................. 8 
 
DOMAIN GOVERNANCE .................................................................................................................. 9 
3.1. Domain members ......................................................................................................................... 9 
3.2. Stop 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. Potential benefits of ceasing Ig therapy .......................................................................... 11 
4.2.3. Potential risks of ceasing Ig therapy ................................................................................ 11 
4.2.4. Prophylactic antibiotics as an alternative to continuing Ig therapy ................................... 12 
4.2.5. Potential risks of prophylactic antibiotic therapy........................................................... 12 
4.3. The need for a trial assessing immunoglobulin cessation ......................................................... 12 
4.3.1. Domain hypotheses ............................................................................................................ 13 
 
DOMAIN OBJECTIVES .................................................................................................................... 13 
5.1. Aims ........................................................................................................................................... 13 
 
DOMAIN DESIGN ........................................................................................................................... 13 
 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ....................................................................... 14 
7.1. Population .................................................................................................................................. 14 
7.2. Eligibility criteria......................................................................................................................... 14 
7.2.1. Domain inclusion criteria .................................................................................................... 14 
7.2.2. Domain exclusion criteria ................................................................................................... 15 
7.2.3. Intervention exclusion criteria ............................................................................................ 15 
7.3. Randomisation ........................................................................................................................... 15 
 
TREATMENT OF PARTICIPANTS ..................................................................................................... 15 
8.1. Interventions .............................................................................................................................. 15 
8.1.1. Interventions ....................................................................................................................... 15 
8.1.2. Immunoglobulin cessation and commencement of prophylactic antibiotics (Arm A) ....... 16 
8.1.3. Immunoglobulin cessation without commencement of prophylactic antibiotics (Arm B) . 17 
8.1.4. Continuation of immunoglobulin replacement at current dose and schedule (Arm C) ..... 17 
8.1.5. Restarting Ig ........................................................................................................................ 18 

 
 
 
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8.1.6. Duration of therapy ............................................................................................................ 18 
8.1.7. Discontinuation of study assigned treatment protocol ...................................................... 18 
8.1.8. Concomitant care ................................................................................................................ 19 
 
DOMAIN ENDPOINTS .................................................................................................................... 19 
9.1. Primary Endpoint ....................................................................................................................... 19 
9.2. Secondary Endpoints ................................................................................................................. 19 
 ASSESSMENTS AND FOLLOW-UP .................................................................................................. 21 
10.1. Domain Schedule of Assessments ........................................................................................... 21 
10.2. Domain-specific data collection  .............................................................................................. 22 
10.3. Blinding .................................................................................................................................... 22 
 SAFETY ASSESSMENT .................................................................................................................... 22 
 STATISTICAL CONSIDERATIONS ..................................................................................................... 22 
12.1.1. Domain Sub-groups ........................................................................................................... 22 
 ETHICAL CONSIDERATIONS ........................................................................................................... 22 
13.1. Risks and benefits of participation  .......................................................................................... 22 
 GOVERNANCE ISSUES  ................................................................................................................... 22 
14.1. Funding of the Stop Ig Domain ................................................................................................ 23 
 REFERENCES .................................................................................................................................. 24 
 
 
 

 
 
 
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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 
DSMC 
Data safety monitoring committee 
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 
 
 
 

 
 
 
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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 Ig (IV or subcutaneous - SCIg) 
replacement for prevention of bacterial infections due to 
hypogammaglobulinaemia for at least 6 consecutive months.  
2. Patient is eligible for trial of Ig cessation in the opinion of the 
treating clinician and local investigator.  
3. Patient is willing and able to comply with each of the treatment 
arms. 
Domain-specific 
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. Already receiving  systemic antibiotic prophylaxis for the purpose 
of preventing bacterial infection (NB: patients may receive 
antiviral, antifungal and PJP prophylaxis).  
4. Intolerance of all trial antibiotic options in either arm A or arm B. 
5. Communication, compliance or logistical issues that are likely to 
limit patient’s ability to take prophylactic or emergency 
antibiotics, or to obtain urgent medical attention for symptoms of 
infection. 
6. Pregnant or breastfeeding. 
7. Severe renal impairment (estimated or measured creatinine 
clearance of < 30 mL/min). 
8. Previous splenectomy. 
9. Previous participation in this domain. 
10. Treating team deems enrolment in the domain is not in the best 
interests of the patient.  
Interventions to be 
compared 
 
 
 
 
 
 
 
 
 
Arm A: Stop Ig and commence prophylactic oral antibiotics. Once 
daily trimethoprim-sulfamethoxazole (co-trimoxazole) 160mg/800mg.  
NB: Doxycycline 100mg daily as an alternative for patients with 
hypersensitivity to co-trimoxazole. 
 
Arm B: Stop Ig. Patients will be provided with amoxycillin/clavulanic 
acid 1750-2000mg/250mg and ciprofloxacin 750 mg to keep at home 
for initial use if symptoms of infection develop, with immediate review 
by their treating clinical team, or nearest emergency department or 
medical practitioner with phone contact to treating team if most 
practical.  

 
 
 
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NB: Clindamycin 600 mg is permitted as an alternative to 
amoxycillin/clavulanic acid for patients with hypersensitivity to 
penicillin. Ciprofloxacin is omitted for participants with 
hypersensitivity.  
 
Arm C: Continue Ig. Participants will continue treatment with their 
current Ig replacement schedule. Participants will receive monthly 
(every 4 weeks ± 1 week) intravenous immunoglobulin at a dose of 
0.4g/kg, modified to achieve an IgG trough level of at least lower limit 
of age‐specific serum IgG reference range. For patients who have 
already had their Ig dose titrated to IgG trough level, they may 
continue on their current monthly dose of Ig replacement. SCIg, 
weekly, may be used in patients who meet local criteria for home-
based self-administration in centres with established SCIg programs.  
Dosing is usually given at 100mg/kg/week, modified to achieve an IgG 
steady state level of at least the lower limit of the serum reference 
range.   
 
Planned treatment duration for all arms (A, B and C) is 12 months. 
Trial hypotheses 
1. Prophylactic oral antibiotics are non-inferior to continuation of Ig 
replacement for the prevention of severe, and/or recurrent  
infection in patients with secondary hypogammaglobulinaemia 
due to B-cell malignancies. 
2. A strategy of no antibiotic therapy (with a patient-held emergency 
antibiotic supply) is non-inferior to the continuation of Ig 
replacement 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. 
 
Secondary Domain-Specific Endpoints: 
1. Resumption of Ig treatment over 12 months for patients in Ig 
cessation treatment arms.  

 
  
 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 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 Erica Wood 
The members of the Stop Ig Domain are members of the ITSC. 
3.2. Stop Ig Domain-Specific Working Group Authorisation 
The Stop Ig Domain-Specific Working Group have read this appendix and authorise it as the official 
Stop 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 stopping 
Ig replacement with or without prophylactic antibiotics compare to continuing Ig replacement.  
4.2. Domain-specific background 
4.2.1. Overview 
 Duration of Ig replacement – when to cease therapy? 
Evidence to guide duration of IgRT and when to cease it is limited. From the most recent Cochrane 
review,1  in clinical trials of Ig replacement, the duration of therapy was for a period of between 6 
and 12 months, with follow-up not extending beyond 12 months. A recent single-centre, non-
randomised study showed that regular Ig replacement was able to be safety stopped in a small 
cohort of patients with haematological malignancies who received prophylactic antibiotics and an 
additional emergency-held antibiotic supply to keep at home.2 To date, there have been no 
randomised controlled trials to guide if and when to trial cessation of Ig. 
Substantial variation exists in the approach to duration of IgRT and use of alternative therapies, both 
internationally and within Australia.3,4 For patients receiving Ig for this indication, Australian 
government Criteria state: “Cessation of Ig therapy should be considered at least after each 12 
months” of its use.5 This statement is not evidence-based, and in this group of immunocompromised 
patients who are highly infection prone and vulnerable, and for whom infection is their highest risk 
of mortality, such evidence is essential in order to recommend or mandate such a clinical 
management directive. UK guidelines (2019) advise that it may be appropriate to consider 
temporary cessation of Ig in the summer,6  although at least in Australia from 2009 to 2013, there 
was no significant seasonal change in IgRT utilisation.7 In New Zealand (NZ), Ig approvals are 
reviewed every 12 months.  
There is significant variation in clinical practice with regard to duration of IgRT. In a recent survey of 
Australian and New Zealand haematologists, 21% reported continuing Ig unless an adverse event 
occurred, 24% routinely stop after a fixed duration, 15% stop if the patient is in clinical remission 
with recovery from hypogammaglobulinaemia, 6% stop during summer, and 34% decide on a case-
by-case basis.4  
Our current treatment decisions are not evidence-based because no data exist on optimal duration 
of IgRT or outcomes after stopping: cessation is recommended, but standard of care regarding the 

 
 
 
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timing of cessation is not defined. We do not know when or how to predict when it is safe to stop, or 
what to monitor prior to and after stopping. Therefore, a clinical trial is required to evaluate optimal 
duration of Ig use and/or outcomes after stopping.   
 Predictors of which patients are at higher risk of infection to guide Ig cessation 
The effects of changes in immune function over time and its association with disease status, 
treatment with chemotherapy, immunotherapy and other targeted agents, IgRT, as well as infection 
outcomes is not well understood. Monitoring the immune status in patients with haematological 
malignancies over time receiving various immunomodulatory treatments may provide useful insights 
into the risks of development of infection. Analysis of potential changes in the immune profiles in 
these patients and their association with infection outcomes may provide guidance as to which 
patients may benefit most from Ig or other anti-infective measures such as prophylactic antibiotics, 
and which patients may safely cease these therapies. 
4.2.2. Potential benefits of ceasing Ig therapy 
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, 
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.8 Renal impairment and renal failure have 
also been reported in patients receiving IVIg. For patients receiving subcutaneous Ig (SCIg), there 
may also be injection site irritation and there is a requirement for training and equipment to self-
administer the product.  Reduction in use of Ig may help reduce healthcare expenditure on Ig 
product costs and associated healthcare administration costs.  
4.2.3. Potential risks of ceasing Ig therapy 
The risks of ceasing Ig therapy are unknown, but the main possible risk of ceasing Ig therapy is the 
risk of major or recurrent infections. Major or recurrent infections may lead to increased unplanned 
visits to hospital, admission to hospital and/or intensive care, and treatment with antimicrobial 
agents and other therapies. Within this protocol, patients who are allocated to cease Ig therapy and 
who experience a major infection (see below) will be allowed to recommence Ig replacement 
therapy. 

 
 
 
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4.2.4. Prophylactic antibiotics as an alternative to continuing Ig therapy 
Short-term prophylactic oral antibiotics have been shown to reduce infections by 30-50% in 
neutropenic haematology patients following chemotherapy,9 and in non-haematologic malignancy 
patients with bronchiectasis,10 supporting the rationale for their use in acquired 
hypogammaglobulinaemia. A recent systematic review of prophylactic antibiotics in MM showed 
infection reduction in the first 3 months after diagnosis, but no mortality difference.11  
Some international guidelines recommend a trial of prophylactic antibiotics prior to commencing 
IgRT.12 Potential advantages include reduced total healthcare costs, possible improvements to QoL 
with fewer hospital attendances for infusions, and reduction in Ig adverse effects.  On the other 
hand, antibiotic resistance is a concern with wider use of prophylactic antibiotics.10,13 In addition, for 
patients not receiving IgRT the less frequent clinical interactions due to less frequent attendance at 
day treatment centres have the potential to result in later diagnosis of any infection, which in turn 
could lead to poorer outcomes. Therefore, the use of prophylactic antibiotics should be properly 
evaluated with respect to efficacy, safety, QoL, and healthcare costs. 
In addition, our recently completed phase II feasibility trial – the RATIONAL (Role of antibiotic 
therapy or immunoglobulin on infections in haematology) trial – the first to compare starting Ig vs 
prophylactic oral antibiotics in 63 patients with newly diagnosed CLL, MM and NHL who, as a result 
were newly eligible to commence IgRT– demonstrated recruitment feasibility and tolerability of oral 
antibiotics. Although not powered for clinical outcomes, RATIONAL data suggest no increase in 
infection outcomes in the antibiotic arm (ACTRN12616001723471).14 
4.2.5. Potential risks of prophylactic antibiotic therapy 
Some common adverse events to the prophylactic antibiotics used within this protocol include 
nausea, vomiting, diarrhoea and rash. Other less common adverse reactions include anaphylaxis and 
hypersensitivity reactions. Another possible risk of prophylactic antibiotics is development of 
resistant organisms, but its impact on development of infection is unknown. 
4.3. The need for a trial assessing immunoglobulin cessation 
IgRT is effective at reducing infection in this setting; however: 
• 
There have been significant changes to patient populations, therapeutic agents and 
protocols and consequent effects on immune function and supportive care since clinical 
trials of IVIg were performed. 

 
 
 
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• 
IVIg, SCIg and oral antibiotics all carry risks. 
• 
Effectiveness of Ig compared with other potential options, such as prophylactic antibiotics, 
in terms of compliance with therapy, clinical outcomes, adverse effects, QoL, and healthcare 
costs, is unknown. 
• 
Australian national criteria and New Zealand guidelines recommend that a trial of cessation 
of Ig therapy should be considered at least after each 12 months of treatment, but there are 
few prospective studies indicating how this could be achieved. 
• 
IVIg and SCIg costs continue to increase, and haematological malignancies are a growing 
indication for their use. 
No trials powered for clinical outcomes have compared continuing IgRT with Ig cessation with or 
without prophylactic antibiotics in terms of safety, efficacy and cost-effectiveness. Therefore, a 
clinical trial is required. 
This Domain is designed to assess if Ig therapy for adults with haematological malignancies can be 
stopped if patients are free of major infection after six months of therapy, and after stopping, 
whether oral antibiotics should be used to prevent future infection.  
4.3.1. Domain hypotheses 
• 
Prophylactic oral antibiotics are non-inferior to continuation of Ig replacement for the 
prevention of severe, and/or recurrent infection in patients with secondary 
hypogammaglobulinaemia due to B-cell malignancies. 
• 
A strategy of no antibiotic therapy (with a patient-held emergency antibiotic supply) is non-
inferior to the continuation of Ig replacement 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 whether stopping Ig with prophylactic or antibiotics or 
antibiotics on demand, is as effective as continuing Ig (IVIg or SCIg) in patients with 
haematological malignancies and acquired hypogammaglobulinaemia on event-free survival as 
defined in the Core Protocol. 
 DOMAIN DESIGN 

 
 
 
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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 Stop-Ig domain is randomising participants receiving IgRT to one of 3 study interventions: IgRT 
cessation with prophylactic antibiotics, IgRT cessation with antibiotics for emergency use and 
continuation of IgRT.  
The Stop-Ig domain was initially opened as a standalone trial, RATIONALISE. The RATIONALISE trial 
was amended to a platform trial design during the course of the trial, as described in the Protocol 
History Table. As part of the amendment, the RATIONALISE interventions became the ‘STOP-Ig’ 
domain interventions within the larger platform. 
 SELECTION AND WITHDRAWAL OF PARTICIPANTS 
7.1. Population 
The RATIONAL Platform Trial enrols patients with acquired hypogammaglobulinemia due to  
haematological malignancies, including multiple myeloma [MM], chronic lymphocytic leukaemia 
[CLL] and non-Hodgkin lymphoma [NHL]. This domain is available for patients who are currently 
receiving IgRT for prevention of bacterial infections due to hypogammaglobulinaemia.  
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 Ig (IV or subcutaneous - SCIg) replacement for prevention of 
bacterial infections due to hypogammaglobulinaemia for at least 6 consecutive months.  
2. Patient is eligible for trial of Ig cessation in the opinion of the treating clinician and local 
investigator.  

 
 
 
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3. Willing and able to comply with each of the treatment arms.  
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. Already receiving  systemic antibiotic prophylaxis for the purpose of preventing bacterial 
infection (NB: patients may receive antiviral, antifungal and PJP prophylaxis).  
4. Intolerance of all trial antibiotic options in either arm A or arm B. 
5. Communication, compliance or logistical issues (e.g. living long distance from medical 
facility) that are likely to limit a patient’s ability to take prophylactic or emergency 
antibiotics, or to obtain urgent medical attention for symptoms of infection.  
6. Pregnant or breastfeeding. 
7. Severe renal impairment (estimated or measured creatinine clearance of <30mL/min). 
8. Previous splenectomy. 
9. Previous participation in this domain 
10. Treating team deems enrolment in the domain is not in the best interests of the patient. 
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 Stop-Ig 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 
8.1. Interventions 
8.1.1. Interventions 
This domain has three interventions: 

 
 
 
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• 
Immunoglobulin cessation and commencement of prophylactic antibiotics (Arm A) 
• 
Immunoglobulin cessation without prophylactic antibiotics, with a supply of oral antibiotics 
immediately available (at home) for emergency use (Arm B) 
• 
Continuation of immunoglobulin replacement at current dose and schedule (Arm C) 
8.1.2. Immunoglobulin cessation and commencement of prophylactic antibiotics (Arm A) 
Participants will be treated with once daily trimethoprim‐sulfamethoxazole (co-trimoxazole) 
160mg/800mg, with dose adjustments as listed below, from study day 1. For patients with 
hypersensitivity to co‐trimoxazole, or who are taking a medication with potential for a significant 
interaction with co-trimoxazole as outlined below, 100mg doxycycline daily will be permitted as an 
alternative prophylactic antibiotic.  If participants encounter cytopenias which are exacerbated by 
the study antibiotics, participants can be switched to the other antibiotic. Participants must be able 
to tolerate at least one of the study antibiotics to be eligible for entry into the study.  
Medications which cannot be administered with co-trimoxazole include (but are not limited to): 
antiarrhythmics (dofetilide, amiodarone), antivirals (amantadine/memantine, lamivudine), 
antineoplastics (paclitaxel), antibiotics (dapsone). Co-trimoxazole may increase the effect of the 
following agents, and increased monitoring of their drug levels and/or effect is required if co-
administered with co-trimoxazole: digoxin, phenytoin, warfarin, oral hypoglycaemics (repaglinide, 
rosiglitazone, pioglitazone, glipizide), methotrexate, drugs that cause potassium retention (such as 
ACE inhibitors) and cyclosporin (increased monitoring of renal function). 
Medications which cannot be administered with doxycycline include (but are not limited to): 
isotretinoin, etretinate and methoxyflurane.  Doxycycline may increase the effect of the following 
agents, and increased monitoring of drug levels and/or effect is required if co-administered with 
doxycycline: warfarin, cyclosporin, phenytoin.   
 Co-trimoxazole dose adjustments for cytopenias and renal impairment 
For participants with grade 2 or greater anaemia, neutropenia or thrombocytopenia, whether 
attributed to concomitant medications, underlying haematologic disorder or co-trimoxazole itself, 
the dose of co-trimoxazole may be reduced by 50% (to 80/400mg daily) at the discretion of the 
investigator. 
Co-trimoxazole dose will be adjusted for participants with renal impairment, defined by eGFR (or, if 
available, measured creatinine clearance) 

 
 
 
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eGFR or creatinine 
clearance 
Dose 
> 50 mL/Min 
Full dose (160/800mg) 
30 to 50 mL/Min 
50% dose reduction (to 80/400mg) 
< 30 mL/Min 
Consider switching to doxycycline, or discontinue study treatment 
 
8.1.3. Immunoglobulin cessation without commencement of prophylactic antibiotics (Arm B) 
Patients will be provided with amoxycillin/clavulanic acid 1750-2000mg/250mg and ciprofloxacin 
750mg to keep at home for initial use if symptoms of infection develop, with immediate review by 
their treating clinical team, or nearest emergency department or medical practitioner with phone 
contact to treating team if most practical and as clinically required. Diagnosis and management of 
the infection will be determined by the severity of the suspected infection and coordinated by the 
patient’s treating team. 
For patients with hypersensitivity to penicillin, or taking a medication with a significant interaction 
with amoxycillin/clavulanic acid, clindamycin 600mg is permitted as an alternative to 
amoxycillin/clavulanic acid. If the patient has a contraindication to ciprofloxacin, this antibiotic will 
be omitted from the emergency antibiotics. Contraindications to ciprofloxacin include quinolone 
hypersensitivity (including nalidixic acid) and concurrent tizanidine. 
For participants assigned to Arm B, Day 1 of treatment is considered the date of randomisation. 
8.1.4. Continuation of immunoglobulin replacement at current dose and schedule (Arm C) 
Participants will continue treatment with their current Ig replacement schedule. The recommended 
dose of Ig replacement is outline below.  For participants assigned to Arm C, Day 1 of treatment is 
considered the first dose of Ig following randomisation. 
 Intravenous immunoglobulin (IVIg) 
Participants will receive monthly (every 4 weeks ± 1 week) intravenous immunoglobulin at a dose of 
0.4g/kg, modified to achieve an IgG trough level of at least lower limit of age‐specific serum IgG 
reference range. For patients who have already had their Ig dose titrated to IgG trough level, they 
may continue on their current monthly dose of Ig replacement.  

 
 
 
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 Subcutaneous immunoglobulin (SCIg) 
Subcutaneous immunoglobulin weekly may be used in patients who meet local criteria for home-
based self-administration in centres with established SCIg programs.  Dosing is usually given at 
100mg/kg/week, modified to achieve an IgG steady state level of at least the lower limit of the 
serum reference range.   
Study participants may transition from IVIg to SCIg, or vice versa, using a conversion factor of 1:1 for 
total monthly IV to SC dosing.   Where IVIg is used in this protocol, unless explicitly stated, it shall be 
taken to include SCIg. 
8.1.5. Restarting Ig 
If a participant on either of the immunoglobulin cessation intervention arms (Arm A or Arm B) 
experiences a Grade 3 or higher infectious complication, they may recommence 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 reinstate 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 continue to follow the 
schedule of assessments until M12, except in the case of patients who also choose to withdraw from 
the study. 
8.1.6. 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 
infection after completion of trial treatment (at 12 months from Day 1 of study) will be managed by 
the participant’s treating clinician. 
8.1.7. 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 

 
 
 
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• 
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 end-of-
treatment (EOT) visit assessments should be completed 4 weeks (+/- 7 days) after the final 
administration of the participant’s assigned treatment. Trial participation will not end and the 
participant will follow  the schedule of assessments until M12.  
8.1.8. 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, if necessary with a dose increase 
if allocated to Arm A. Higher doses of PJP prophylaxis are not permitted in the immunoglobulin 
treatment arm.  
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 Stop Ig domain aims to demonstrate the non-inferiority of immunoglobulin cessation in adults 
with a diagnosis of MM, CLL or NHL who are currently receiving immunoglobulin replacement for 
recurrent or severe infections or an IgG <4g/L (excluding paraprotein).   
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. 

 
 
 
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Domain-specific secondary endpoints are: 
1. Resumption of Ig treatment over 12 months for patients in Ig cessation treatment arms.

 
  
 
 ASSESSMENTS AND FOLLOW-UP 
10.1. Domain Schedule of Assessments  
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 for participants on Arm A and Arm C. D1 is day of randomisation for participants on Arm B. 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 

 
  
 
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 Stop-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 
• 
Patients on IgRT for less than 12 months prior to randomization 
• 
Country 
 
 ETHICAL CONSIDERATIONS 
13.1. Risks and benefits of participation  
There are no specific benefits for patients from participation in this domain. All of the treatment 
arms in this domain are within normal standard of care.  
 
 GOVERNANCE ISSUES  

 
 
 
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14.1. Funding of the Stop Ig Domain 
The RATIONAL Platform Trial funding sources are specified in the Core Protocol. This domain is also 
supported by a grant from the National Health and Medical Research Council (NHMRC). 

 
 
 
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Paxton L, Hawkins C, Crispin P. Selecting haematological malignancy patients for 
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