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

 
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RATIONAL Platform Trial 
Role of Antibiotic Therapy or Immunoglobulin  
On iNfections in hAematoLogy  
Domain-Specific Appendix: 
Starting Immunoglobulin  (Start 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 
 
 START Ig Domain-Specific Appendix Development Protocol History 
Version Number 
Date 
Author 
Change 
1.0 
12-Nov-2023 
Prof Zoe McQuilten 
Original version 
 
 
 

 
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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 
 
 

 
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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. Start 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. Prophylactic antibiotics as an alternative to immunoglobulin replacement ...................... 11 
4.2.4. Comparison of IgRT with prophylactic antibiotics .............................................................. 12 
4.2.5. Potential risks of Ig therapy.............................................................................................. 12 
4.2.6. Potential risks of prophylactic antibiotic therapy........................................................... 13 
4.2.7. Summary ............................................................................................................................. 13 
4.3. The need for a trial comparing IgRT with prophylactic antibiotics ............................................ 13 
4.3.1. Domain hypothesis ............................................................................................................. 14 
 
DOMAIN OBJECTIVES .................................................................................................................... 14 
5.1. Aims ........................................................................................................................................... 14 
 
DOMAIN DESIGN ........................................................................................................................... 14 
 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ....................................................................... 14 
7.1. Population .................................................................................................................................. 14 
7.2. Eligibility criteria......................................................................................................................... 15 
7.2.1. Domain inclusion criteria .................................................................................................... 15 
7.2.2. Domain exclusion criteria ................................................................................................... 15 
7.2.3. Intervention exclusion criteria ............................................................................................ 15 
7.3. Randomisation ........................................................................................................................... 15 
 
TREATMENT OF PARTICIPANTS ..................................................................................................... 16 
8.1. Interventions .............................................................................................................................. 16 
8.1.1. Interventions ....................................................................................................................... 16 
8.1.2. Commencement of prophylactic antibiotics (Arm A) ......................................................... 16 

 
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8.1.3. Commencement of immunoglobulin replacement (Arm B) ............................................... 17 
8.1.4. Cross-over ........................................................................................................................... 17 
8.1.5. Duration of therapy ............................................................................................................ 18 
8.1.6. Discontinuation of study assigned treatment protocol ...................................................... 18 
8.1.7. Concomitant care ................................................................................................................ 19 
 
DOMAIN ENDPOINTS .................................................................................................................... 19 
9.1. Primary Endpoint ....................................................................................................................... 19 
9.2. Secondary Endpoints ................................................................................................................. 19 
 ASSESSMENTS AND FOLLOW-UP .................................................................................................. 20 
10.1. Domain Schedule of Assessments ........................................................................................... 20 
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 Start Ig Domain ................................................................................................ 22 
 REFERENCES .................................................................................................................................. 23 
 
 

 
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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 
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 
None. 
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. Already receiving  systemic antibiotic prophylaxis for the purpose 
of preventing bacterial infection (NB: patients may receive 
antiviral, antifungal and PJP prophylaxis).  
3. Received immunoglobulin replacement in the preceding three 
months. 
4. Objection to receiving immunoglobulin products. 
5. Known history of IgA deficiency with anti-IgA. 
6. History of severe allergy to immunoglobulin products. 
7. Current active infection requiring systemic antibiotics. 
8. Allergy or intolerance of all domain antibiotic options. 
9. Pregnant or breastfeeding. 
10. Severe renal impairment (estimated or measured creatinine 
clearance of < 30 mL/min). 
11. Previous splenectomy. 
12. Previous participation in this domain. 
13. Treating team deems enrolment in the domain is not in the best 
interest of the patient.  
Interventions to be 
compared 
 
 
 
 
 
 
 
 
 
 
Arm A: Start 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: Start immunoglobulin replacement IVIg 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; or 
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.  A loading IVIg dose may be given in the first 
month if required. 
Planned treatment duration for all arms (A and B) is 12 months. 

 
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Trial hypotheses 
1. Prophylactic oral antibiotics are non-inferior to 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. 

 
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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 Start Ig Domain are members of the ITSC. 
3.2. Start Ig Domain-Specific Working Group Authorisation 
The Start Ig Domain-Specific Working Group have read this appendix and authorise it as the official 
Start 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 
prophylactic antibiotics as an alternative Ig replacement in patients who have not yet commenced Ig 
replacement therapy.   
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. IgRT used to prevent recurrent bacterial infections for patients with MM, 
NHL & CLL is provided under Australian Criteria for government-funded Ig – with the caveat of 
“Evidence of probable benefit – more research needed”.1 This recommendation is based on outdated 
data. Whilst the most recent Cochrane review which showed IgRT reduced infections in patients 
with secondary hypogammaglobulinemia due to blood cancers, it only included only 3 trials 
published between 1988 and 1995 with a total of only 205 patients.2-5 In our recently completed 
systematic review of interventions to prevent infections in CLL, MM and NHL we did not identify any 
new evidence to guide Ig use.6  We found no difference in risk of all-cause mortality in patients 
allocated to IgRT compared to standard of care (relative risk 1.35, 95% CI 0.57-3.18), however a 
reduction in risk of clinically documented infections (RR 0.70, 95% CI 0.54-0.96, see figure 1). 
However, our certainty in the evidence was low due to small sample size of included trials, 
classification of infection outcomes, high risk of bias in the included studies and lack of 
contemporary data applicable to the current standard of care.6 These trials did not specify if routine 
prophylactic antibiotics were administered. 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. We 
have no current data to inform which patients should receive IgRT. This lack of evidence has led to 
substantial variation to the use of IgRT, both internationally and within Australia.7 
 
 

 
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Figure 1. Immunoglobulin replacement vs standard of care on one or more clinically documented 
infection 
 
 
4.2.3. Prophylactic antibiotics as an alternative to immunoglobulin replacement 
Short-term prophylactic oral antibiotics have been shown to reduce infections by 30-50% in 
neutropenic haematology patients following chemotherapy,8 and in non-haematologic patients with 
bronchiectasis,9 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.10 Our systematic review identified 4 trials of 
prophylactic antibiotics in patients with MM, and although antibiotics did not reduce all-cause 
mortality (RR 1.11, 95% CI 0.85-1.45) or infection in our review (RR 0.84, 95% CI 0.34-2.09, Figure 2), 
the included studies did not specify whether patients had hypogammaglobulinaemia or whether 
they were also receiving IgRT.  
Figure 2. Prophylactic antibiotics vs standard care on one or more clinically documented infections 
 

 
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Despite the limited evidence for their use, some international guidelines recommend a trial of 
prophylactic antibiotics prior to commencing IgRT,11 but this is not required in Australia or other 
jurisdictions. Potential advantages of antibiotics 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.9,12 Antibiotics also have different safety profiles to IgRT. Therefore, the use of 
prophylactic antibiotics should be properly evaluated with respect to efficacy, safety, QoL, and 
healthcare costs.  
4.2.4. Comparison of IgRT with prophylactic antibiotics 
In our systematic review, the only 
trial that we identified that 
directly compared starting 
prophylactic antibiotics with 
starting IgRT in patients with 
acquired hypogammaglobulinemia 
was our recently completed the 
RATIONAL phase II feasibility trial 
(ACTRN12616001723471). This 
trial compared the use of IgRT vs 
prophylactic oral antibiotics in 63 
patients with CLL, MM & NHL. 
RATIONAL demonstrated recruitment feasibility and tolerability of oral antibiotics. Although not 
powered for clinical outcomes, RATIONAL data suggested that infection rates were not increased in 
the antibiotic arm (the lower quartile for time to first major infection was 11.1 months in the 
immunoglobulin and 9.7 months in the antibiotic arm Figure 3).13 Clinically documented infections 
averaged 1.86 per participant in the immunoglobulin treatment arm and 1.33 per participant in the 
prophylactic antibiotic treatment arm.  As this was a feasibility study, our results need to be 
confirmed in a larger trial. 
4.2.5. Potential risks of 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 
Figure 3: Time to first major (grade 3+) infection 

 
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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.14 Renal impairment and renal failure have 
also been reported in patients receiving IVIg. In 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.   
4.2.6. 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. 
4.2.7. Summary 
Secondary hypogammaglobulinemia is common in patients with haematological malignancies and 
associated with infections (approximately 25% of participants in our pilot trial experienced at least 
one grade 3 or higher infection). Substantial variation exists in the approach to use of IgRT and 
alternative therapies such as prophylactic antibiotics in patients with acquired 
hypogammaglobulinaemia secondary to haematological malignancies, both internationally and 
within Australia.7,15  
4.3. The need for a trial comparing IgRT with prophylactic antibiotics 
Our current treatment decisions on whether to use IgRT or prophylactic antibiotics in patients with 
acquired hypogammaglobulinaemia secondary to haematological malignancies are not evidence-
based because there is limited data on efficacy of IgRT or prophylactic antibiotics, and the available 
trial evidence is limited by small patient numbers, risk of bias and lack of contemporaneous and 
comparative data. These have been identified as priority evidence gaps in the recent Australian 
Medical Services Advisory Committee review of the cost-effectiveness of IgRT, specifically:  
-Consideration for eligibility criteria used in Europe (trial of antibiotics before starting Ig therapy)  
-Cost effectiveness of Ig in NHL (the largest patient group), as there are no Ig studies in these 
patients. 
Therefore, a clinical trial is required to evaluate the comparative efficacy, safety and cost-
effectiveness of prophylactic antibiotics compared with IgRT.   

 
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4.3.1. Domain hypothesis 
Prophylactic oral antibiotics are non-inferior to IgRT 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 the effectiveness of prophylactic antibiotics compared to 
IgRT in patients with haematological malignancies and acquired 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 Start Ig DSA is one of multiple domains in the RATIONAL Platform trial. This domain is testing  
whether commencing prophylactic antibiotics 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 multiple myeloma [MM], chronic lymphocytic leukaemia 
[CLL] and non-Hodgkin lymphoma [NHL]. This domain is available for patients who are not currently 
receiving IgRT for prevention of bacterial infections due to hypogammaglobulinaemia.  

 
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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 
None. 
7.2.2. Domain exclusion criteria 
1. Prior or planned allogeneic haematopoietic stem cell transplantation.  
2. Already receiving  systemic antibiotic prophylaxis for the purpose of preventing bacterial 
infection (NB: patients may receive antiviral, antifungal and PJP prophylaxis).  
3. Received immunoglobulin replacement in the preceding three months. 
4. Objection to receiving immunoglobulin products. 
5. Known history of IgA deficiency with anti-IgA. 
6. History of severe allergy to immunoglobulin products. 
7. Current active infection requiring systemic antibiotics. 
8. Allergy or intolerance of all domain antibiotic options. 
9. Pregnant or breastfeeding. 
10. Severe renal impairment (estimated or measured creatinine clearance of < 30 mL/min). 
11. Previous splenectomy. 
12. Previous participation in this domain. 
13. 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 Start 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. 

 
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 TREATMENT OF PARTICIPANTS 
8.1. Interventions 
8.1.1. Interventions 
This domain has two interventions: 
• 
Commencement of prophylactic antibiotics (Arm A) 
• 
Commencement of immunoglobulin replacement (Arm B) 
8.1.2. 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, 

 
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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) 
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. Commencement of immunoglobulin replacement (Arm B) 
 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. In the first month of therapy, if IgG <4g/L then an additional (loading) dose of 
0.4g/kg may be given at the clinician’s discretion. 
 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.  A loading IVIg dose may be given in the first month if required. 
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. 
8.1.4. Cross-over 
If a participant on the prophylactic antibiotic intervention arm (Arm A) experiences a Grade 3 or 
higher infectious complication, they may commence IgRT, as directed by their treating clinician.  

 
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In the absence of a Grade 3 or higher infectious complication, patients will stay on their assigned 
treatment. However, the treating clinician may start 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.  
For participants on the immunoglobulin replacement (Arm B) who develop a grade 3 or higher 
infection, their subsequent treatment will be according to standard care as directed by their treating 
clinician.  
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. 
8.1.5. 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 
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 (e.g. if they develop a contraindication 
to treatment allocation) 
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 continue  to follow the schedule of assessments until M12.  

 
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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, 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 Start Ig domain aims to demonstrate the efficacy and safety of prophylactic antibiotics 
compared to IgRT in adults with a diagnosis of MM, CLL or NHL who are eligible to receive 
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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 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

 
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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 Start-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 Start Ig Domain 
The RATIONAL Platform Trial funding sources are specified in the Core Protocol. 

 
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