A Multi-centre, Randomised Trial Comparing a Novel Combination Treatment (Arm D - Intravenous Sulbactam-durlobactam in Combination With Intravenous Ceftriaxone, Oral Amoxicillin, Oral Azithromycin and Oral Clofazimine) Versus Standard of Care Treatments for the Intensive Phase of Treatment for Mycobacterium Abscessus Pulmonary Disease in People With or Without Cystic Fibrosis in the Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT) Adaptive Platform Trial
Phase: PHASE2
Conditions: Mycobacterium Abscessus Pulmonary Disease, Mycobacterium Abscessus Infection, Non-Tuberculous Mycobacterial (NTM) Infections, Non-Tuberculous Mycobacteria Pulmonary Disease
Sponsor: The University of Queensland

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APPENDIX A3 - INTERVENTION PROGRAM 
Intensive Treatment Phase – Arm D 
Appendix A3 – Intervention 
Program 
Version 1.0 
Appendix Date 
11th November 2025 
Protocol Number  
FORMaT002 
Australian and New Zealand  
Clinical Trials Registry Number 
TBC 
ClinicalTrials.gov Identifier  
TBC 
EudraCT Number 
2020-000050-10 
EU-CT Number 
2023-506575-99-00-EU CT 
Sponsor 
The University of Queensland 
Contact 
FORMaTtrial@uq.edu.au 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS.................................................................................................................. II 
TABLE OF TABLES ...................................................................................................................... III 
TABLE OF FIGURES .................................................................................................................... III 
ABBREVIATIONS .......................................................................................................................... IV 
APPENDIX A: INTERVENTION PROGRAM ............................................................................. 7 
APPENDIX A3 – INTENSIVE TREATMENT PHASE – ARM D ............................................... 8 
1 
INTRODUCTION .................................................................................................................... 11 
2 
PRIMARY OBJECTIVE ARM D .......................................................................................... 13 
3 
DESIGN ..................................................................................................................................... 13 
4 
ELIGIBILITY CRITERIA ...................................................................................................... 15 
4.1 
INCLUSION CRITERIA ........................................................................................................................ 15 
4.2 
EXCLUSION CRITERIA ....................................................................................................................... 15 
4.3 
ADDITIONAL CRITERIA ..................................................................................................................... 15 
5 
ACCEPTABLE METHODS OF CONTRACEPTION ........................................................ 15 
6 
TRIAL CONDUCT .................................................................................................................. 15 
6.1 
INFORMED CONSENT ........................................................................................................................ 15 
6.2 
PREGNANCY INFORMATION CONSENT ............................................................................................. 15 
6.3 
METHODS OF ASSIGNING PARTICIPANTS TO TREATMENT ARMS ..................................................... 16 
7 
INTERVENTION PROGRAM PROCEDURES AND SAFETY MONITORING ........... 16 
8 
SITE REIMBURSEMENT ...................................................................................................... 16 
9 
INTENSIVE THERAPY NESTED STUDIES ....................................................................... 18 
9.1 
NESTED STUDY A3.1: SHORT INTENSIVE THERAPY: THE USE OF INTRAVENOUS SULBACTAM 
– DURLOBACTAM IN COMBINATION WITH IV CEFTRIAXONE + ORAL AMOXICILLIN + ORAL MACROLIDE + 
ORAL CLOFAZIMINE DURING INTENSIVE THERAPY IN THE TREATMENT OF MABS-PD ............................... 18 
10 INTENSIVE THERAPY DOSING REGIMEN .................................................................... 22 
10.1.1 Drug Supply, Storage and Distribution during Intensive Therapy ............................................... 27 
10.1.2 Options for Reducing Nausea During Intensive Therapy ............................................................. 27 
11 SCHEDULE OF ASSESSMENTS .......................................................................................... 28 

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12 APPLICABLE DISCOVERY STUDIES AND REGISTRY LINKAGE FOR APPENDIX 
A3 33 
13 REFERENCES ......................................................................................................................... 34 
 
TABLE OF TABLES 
Table 1 Intensive therapy dosing regimen for Intensive Arm D in adults – WEEKS 1 to 4 (and WEEKS 7 to 
10 if randomised to prolonged intensive therapy) ........................................................................................... 23 
Table 2 Intensive therapy dosing regimen for Intensive Arm D in paediatrics (aged 12 years and older) – 
WEEKS 1 to 4 (and WEEKS 7 to 10 if randomised to prolonged intensive therapy) .................................... 24 
Table 3 Intensive therapy dosing regimen in adults – WEEKS 5 to 6 (and WEEKS 7 to 10 if randomised to 
prolonged intensive therapy) ........................................................................................................................... 25 
Table 4 Intensive therapy dosing regimen in paediatrics – WEEKS 5 to 6 (and WEEKS 7 to 10 if randomised 
to prolonged intensive therapy) ....................................................................................................................... 26 
Table 5 Special considerations for Schedule of Assessments ......................................................................... 28 
Table 6 Schedule of Assessments for Intervention Program Participants in Appendix A3: Intensive Therapy
 ......................................................................................................................................................................... 30 
Table 7 Schedule of Assessments for Intervention Program Participants: Prolonged Intensive Therapy ....... 31 
Table 8 Schedule of Assessments for Consolidation Therapy and Final Outcome ......................................... 32 
 
TABLE OF FIGURES 
Figure 1 Flow Diagram for Appendix A1 and A3, Intervention Program ...................................................... 14 
 
 

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ABBREVIATIONS  
 
AMOX 
 
Amoxycillin 
BAL 
 
 
Bronchoalveolar Lavage 
BAR 
 
 
Bayesian Adaptive Randomisation 
BlaMab 
 
 
MABS major β-lactamase 
BLI 
 
 
β-lactamase inhibitors 
CF 
 
 
Cystic Fibrosis 
CFTR  
 
Cystic Fibrosis Transmembrane Conductance Regulator  
CFQ-R  
 
Cystic Fibrosis Questionnaire-Revised 
CHU9D 
 
Child Health Utility 9D 
CRF 
 
 
Case Report Form 
CT 
 
 
Computed Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CXM  
 
Cefuroxime 
DBOs  
 
diazabicyclooctanes 
D,D-c  
 
D,D-carboxypeptidases 
Ddts 
 
 
D,D-transpeptidases 
DUR 
 
 
Durlobactam 
FDA 
 
 
Food and Drug Administration 
FEV1  
 
Forced Expiratory Volume in one second 
FORMaT 
 
Finding the Optimal Regimen for Mycobacterium abscessus Treatment 
HMW PBPs 
 
high-molecular weight penicillin-binding proteins 
HRQoL 
 
Health Related Quality of Life 
iDSMB  
 
independent data safety monitoring board  
IPM 
 
 
Imipenem 

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IRB/IEC/HREC 
Independent Research Board/Independent Ethics Committee/Human Research Ethics 
Committee 
IST 
 
 
Innoviva Specialty Therapeutics  
IV 
 
 
Intravenous 
Ldts 
 
 
L,D-transpeptidases 
Ldtmab2,4 
 
L,D-transpeptidases from MABS 
LMW PBP 
 
low-molecular weight penicillin-binding protein  
MABS  
 
Mycobacterium abscessus 
MABS-PD 
 
MABS Pulmonary Disease 
MARS-5 
 
5-item Medication Adherence Rating Scale 
MIC 
 
 
Minimum Inhibitory Concentration 
NTM  
 
Non-Tuberculous Mycobacteria 
PedsQL™ 
 
Pediatric Quality of Life Inventory  
REDCap 
 
Research Electronic Data Capture 
R-Con  
 
Randomisation – Consolidation  
R-PI/IC  
 
Randomisation – Prolonged Intensive/Immediate Consolidation 
R-SI 
 
 
Randomisation – Short Intensive  
SF-36  
 
Short form-36 
SGRQ  
 
St George Respiratory Questionnaire 
SOC 
 
 
Standard of Care 
SUL 
 
 
Sulbactam 
SUL-DUR 
 
Sulbactam-Durlobactam 
TPF 
 
 
Time Point Final 
TPF-PI  
 
Time Point Final – Prolonged Intensive 
TPF-SI  
 
Time Point Final – Short Intensive  
TPF-WK12 
 
Time Point Final – at Week 12 Visit 
TPST  
 
Time Point Start Treatment 

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TPST-Con 
 
Time Point Start Treatment – Consolidation  
TPST-SI 
 
Time Point Start Treatment – Short Intensive  
6MWT  
 
Six Minute Walk Test 

 
 
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APPENDIX A: INTERVENTION PROGRAM 
Appendix A contains the Intervention Program modules, with new modules created as interventions are added 
to either intensive or consolidation phases of the trial.  The modules are numbered sequentially, A1, A2, A3 
etc, with Appendix A1 describing the first iteration of the Intervention Program.  The relevant detailed 
statistical methods and simulations for each Intervention Program module will be described in Appendix F: 
General Statistical Principles.  Separate consent procedures may be required for each appendix.  Of note, in 
some cases data collected as part of one appendix may be incorporated in the analysis of another appendix, if 
collected to address the same objective.  If this occurs, it will be detailed in the relevant appendices.  Should 
an intervention arm be dropped, or a new intervention arm added either to intensive therapy or consolidation 
therapy this will require a new appendix and a new statistical analysis plan. 
Each program in Appendix A will stipulate which of the Discovery studies and Registry linkages is applicable. 
The Intervention Program modules in Appendix A will include the following: 
• 
A description of the primary and secondary objectives. 
• 
A description of the intervention trial design including any specific inclusion or exclusion criteria 
specific to the Intervention Program modules. 
• 
A description of the interventions and dosing. 
• 
The methods for assigning treatment arms to the Intervention Program participants. 
• 
Consent requirements. 
• 
Specific Intervention Program trial procedures, monitoring and safety requirements and schedule of 
assessments. 
• 
A description of relevant nested studies. 
• 
The Discovery studies applicable to the module (if relevant). 
 
A description of cost effectiveness methodology and analysis as appropriate will be detailed in Appendix E: 
Health Economics. 
A general description of statistical analyses and simulations are detailed in Appendix F: General Statistical 
Principles. 
 
 

 
 
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APPENDIX A3 – INTENSIVE TREATMENT PHASE – ARM D 
Appendix A3 describes Intensive Treatment Arm D, which will be added to the FORMaT Intervention 
Programs (Appendix A) following the first interim analysis of the FORMaT trial. Appendix A3 must be 
reviewed together with Appendix A1. Interim analysis will consider discontinuing one of the short intensive 
arms (either arm B or C) to continue to have 3 intensive treatment arms. Arm A remains as the reference Arm.  
After completion of the Intensive Treatment Arm D, participants will continue onto the Consolidation 
Treatment Phase as outlined in Appendix A1.  
Within Appendix A3 there are nested studies which are governed by the trial design and conduct described 
below.  
FORMaT Appendix A3 Summary 
Treatment 
combinations: 
Intensive therapy Arm D: 
Arm D  
 
Weeks 1 to 4 (and Weeks 7 to 10 if randomised to Prolonged Intensive) 
1. IV sulbactam - durlobactam, and; 
 
2. IV ceftriaxone, and; 
3. Oral amoxicillin, and; 
4. Oral azithromycin or oral clarithromycin, and; 
5. Oral clofazimine. 
 
 
 
 
Weeks 5 to 6 (and Weeks 8 to 12 if randomised to Prolonged Intensive) 
 
1. Oral clofazimine, and; 
2. Oral azithromycin or clarithromycin, and; 
3. In combination with one to three of the following oral antibiotics: 
• 
Linezolid, 
• 
Trimethoprim / sulfamethoxazole (co-trimoxazole), 
• 
Bedaquiline, 
• 
Rifabutin, 
• 
Doxycycline, 
• 
Moxifloxacin. 
 
 
 
 
 
 
 
 
 
 
A mixed Non-Tuberculous Mycobacteria (NTM) infection (slow grower + 
Mycobacterium abscessus (MABS)) can include the use of ethambutol in either/both 
the intensive or consolidation phase/s of treatment. 
Appendix 
A3-
specific 
eligibility: 
Eligibility criteria as per Master Protocol section 4.1, 4.2 and 4.4 and Appendix A1 
section 4.1 and 4.3. 
Appendix 
A3-
specific 
inclusions: 
Inclusion criteria as per Master Protocol section 4.2 and Appendix A1 section 4.1 
AND  
Male or female participants aged 12 years and older. 

 
 
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FORMaT Appendix A3 Summary 
Appendix 
A3-
specific 
exclusions: 
Exclusion criteria as per Master Protocol section 4.2 and Appendix A1 section 4.2 
AND 
Participants aged between 12 and <18years old with clinically significant renal 
impairment as indicated by an age-appropriate estimated creatinine clearance.  
Known hypersensitivity to any of the therapies for which no alternative option(s) have 
been provided.  This includes: 
o 
Sulbactam/durlobactam 
o 
Ceftriaxone, 
o 
Amoxicillin, 
o 
Macrolide antibiotics, and 
o 
Clofazimine. 
Target 
recruitment: 
80 to 100 participants randomised to Arm D.  
Outcome 
measures: 
Primary, Secondary and exploratory outcomes are as per the Master Protocol Section 
4.6 and Appendix A1 Section 2.0.  
Timepoints: 
Screening: 
Up to Minus 42 days from Date of Randomisation-
Short Intensive (R-SI). 
Time 
Point 
Start 
Treatment-Short Intensive 
(TPST-SI): 
R-SI. 
Time Point Final (TPF): 
End of treatment plus four weeks off-treatment (Final 
Outcome Visit date). 
Nested studies 
Intensive Therapy Modules: 
Nested study A3.1: 
Nested study A3.2: 
Type of Short intensive Therapy (Arm D versus all 
other treatment arms detailed in Appendix A1) 
Duration of intensive therapy for patients completing 
short intensive treatment with ongoing positive MABS 
cultures collected at 4 weeks and randomised to either 
a further 6 weeks intensive therapy or immediate 
consolidation. 
 
 
 

 
 
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Intensive Therapy Module Nested Studies 
Nested study A3.1: Short Intensive Therapy 
Timepoints: 
Screening: 
Up to Minus 42 days from Date of R-SI. 
TPST-SI: 
R-SI 
Time Point Final-Short 
Intensive (TPF-SI)*: 
Date of Randomisation Prolonged Intensive or 
Immediate Consolidation (R-PI/IC) minus 1 day for 
those allocated prolonged intensive or Randomisation-
Consolidation (R-Con) minus 1 day for those allocated 
to immediate consolidation.  
*The most accurate method of determining TPF for this trial phase is calculating the time immediately 
preceding randomisation to the next treatment phase i.e. date of next randomisation minus 1 day. 
Nested study A3.2: Duration of intensive therapy for patients with ongoing positive MABS cultures 
Timepoints: 
Screening: 
Up to Minus 42 days from R-SI. 
TPST-SI: 
Date of R-SI 
TPF-PI* 
(Time 
Point 
Final 
– 
Prolonged 
Intensive) or TPF-WK12 
(Time Point Final – Week 
12): 
Date of R-Con minus 1 day (for those allocated to 
prolonged intensive) or Week 12 visit date (for those 
allocated to immediate consolidation). 
*The most accurate method of determining TPF for this trial phase is calculating the time immediately 
preceding randomisation to the next treatment phase i.e. date of next randomisation minus 1 day. 
 
 

 
 
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1 INTRODUCTION 
Appendix A3 describes Intensive Treatment Arm D, which will be added to the FORMaT Intervention 
Programs (Appendix A) following the first interim analysis of the FORMaT trial. Appendix A3 must be 
reviewed together with Appendix A1.  
Sites may undertake intensive treatment detailed in Appendix A1 only.  Alternatively, sites may undertake 
intensive treatment detailed in Appendix A3 and Appendix A1 depending on access to the Appendix A3 study 
drugs. All sites will undertake consolidation treatment according to Appendix A1. 
Background 
There has been increasing interest globally in the role of β lactam/ β lactamase combinations for potential 
treatment of Mycobacterium abscessus (MABS). Evidence for this is currently based on in vitro studies with 
some case reports of clinical outcomes. 
BlaMab is MABS’ major β-lactamase responsible for inactivating several β-lactams and is effectively blocked 
by avibactam but not clavulanate. Genetic inactivation of BlaMab, however, has little impact on the potency of 
imipenem (IPM) or cefoxitin.  The addition of β lactamase inhibitors (BLIs) such as relebactam to imipenem 
has only resulted in a 1 to 2 fold change in imipenem MIC distribution so relying on BLIs is unlikely to deliver 
a drastic potency increase for imipenem and cefoxitin (1). 
Another source of β-lactam resistance in MABS are the L,D-transpeptidases (Ldts). The better-studied D,D-
transpeptidases (Ddts; also referred to as high-molecular weight penicillin-binding proteins or HMW PBPs) 
form 4,3-cross-links between adjacent peptidoglycan stem peptides. In contrast, Ldts form 3,3-cross-links, and 
in MABS, this linkage predominates. Ldts in MABS are resistant to penicillins but are inhibited by 
carbapenems and some cephalosporins. Important to the function of Ldts are the D,D-carboxypeptidases (D,D-
c), a group of low-molecular-weight penicillin-binding proteins (LMW PBPs) that convert pentapeptides of 
peptidoglycan subunits to tetrapeptides that can subsequently be used by Ldts; these enzymes also appear to 
be inhibited by β-lactams. 
It is believed that the synergy exhibited by dual β-lactams in susceptibility studies may be driven by inhibition 
of multiple enzymes in the peptidoglycan synthesis pathway (i.e., “target redundancy”). This “target 
redundancy” may lead to an unanticipated synergistic effect using β-lactam combinations. This hypothesis is 
supported by the finding that combinations of certain β-lactams and β-lactamase inhibitors inhibit more than 
one critical enzyme in the cell wall synthesis process. In addition to inhibition of Ldts, select cephalosporins 
and carbapenems are known to inhibit the traditionally recognized targets of β-lactams (Ddts) (2). 
Dousa and colleagues have shown that durlobactam (DUR), a diazabicyclooctane (DBO) BLI, is an inhibitor 
of BlaMab and protects BlaMab substrates against hydrolysis but also exhibits intrinsic activity through inhibition 
of Ldts. Little is known about the potential role of sulbactam (SUL) against MABS, which does not inhibit 
BlaMab (2). 

 
 
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Dousa et al. suggest that DUR is a very potent inhibitor of BlaMab with an on rate kinetic constant 30-fold and 
17,000-fold higher than was observed for the BLIs avibactam and relebactam, respectively. In cell-based 
assays, susceptibility of MABS isolates to amoxicillin (AMOX), IPM, and cefuroxime (CXM) was 
significantly enhanced with the addition of DUR. DUR combined with AMOX or CXM and IPM can inactivate 
multiple cell wall targets such as D,D-carboxypeptidase and two of the L,D-transpeptidases in MABS 
(LdtMab2,4). The triple drug combinations of CXM-DUR-AMOX and IPM-DUR-AMOX were most potent, 
with Minimum Inhibitory Concentration (MIC) ranges of ≤0.06 to 1 μg/mL and an MIC50/MIC90 of ≤0.06/0.25 
μg/mL, respectively (2). Shin et al (2025), performed time kill and enzyme kinetic studies using mass 
spectrometry which showed that DUR alone resulted in a ~2 log10 reduction in cell numbers, and when 
combined with IPM or two β-lactams, DUR achieved near-eradication of MABS (3). Enzyme kinetics were 
also favourable towards DUR. 
Sulbactam-Durlobactam (SUL-DUR) 
In vitro data support the efficacy of SUL-DUR against MABS in combination with orally available β-lactams 
(2, 4), and susceptibility testing of 50 clinical MABS strains from Australian patients with and without cystic 
fibrosis (CF) demonstrated similar results (unpublished data). β-Lactams are bactericidal, display overall 
excellent tolerability profiles and have been in use for decades. However, BlaMab contributes to β-lactam 
resistance. DUR is a novel BLI that inactivates BlaMab allowing β-lactams to destroy the bacterial cell wall. 
Other BLIs such as clavulanic acid and tazobactam are not active against BlaMab.  Importantly, DUR has an 
advantage over other BLIs such as avibactam in that it has dual actions: a direct antibacterial effect on MABS 
in vitro (i.e. acts similarly to a β-lactam) plus inactivation of the β-lactamase that confers β-lactam resistance 
(2). The presence of DUR markedly decreases the MICs of AMOX and CXM against β-lactam-resistant MABS 
to levels which may render them effective at currently used doses. The addition of SUL-DUR to other β-
lactams has been shown to enhance bacterial killing compared to the β-lactam alone (3, 5).  Singh et al. have 
shown with a MABS hollow fibre infection model system that the SUL-DUR plus ceftriaxone combination 
was particularly potent, with a 3.85 log10 reduction in bacterial burden without regrowth (5, 6). Ceftriaxone is 
widely available, generally well tolerated and achieves high lung concentrations. The biochemical rationale 
for including oral AMOX in the proposed treatment combination is to combine the β-lactam components to 
provide the best potential impact on MABS killing, as ceftriaxone and AMOX target different cell wall 
synthesis proteins thus, in combination with SUL-DUR achieving target redundancy and potentially significant 
synergy. 
Arm D is also appealing as it will allow a reduction from three intravenous (IV) antibiotics to two IV antibiotics 
combined with oral agents with a potential reduction in toxicity. 
Clinical use and tolerance of SUL-DUR 
SUL-DUR has been approved by the U.S. Food and Drug Administration (FDA) for treatment of hospital-
acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in patients 18 years of age and 
older caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus (A. baumannii) complex (7, 8). 

 
 
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The recommended duration of SUL-DUR is 7 to 14 days given by IV infusion over 3 hours, 4 times daily in 
adults with normal renal function. A preapproval expanded access program documented tolerability in a limited 
number of patients who received SUL-DUR for up to 42 days (9). The safety profile of SUL-DUR is based on 
a relatively small clinical development program in which the pivotal trial included only patients with serious 
hospital acquired bacterial pneumonia or ventilator associated bacterial pneumonia caused by A. baumannii 
(8). Adverse reactions occurring in the pivotal trial at a frequency of >5% were liver test abnormalities, 
diarrhea, anaemia, hypokalaemia, arrhythmia, acute kidney injury, thrombocytopenia, and constipation (8).  
Advantages of SUL-DUR include: 
• 
In vitro studies from different laboratories and different methodologies support the rationale 
of SUL-DUR. 
• 
It is already FDA approved for serious respiratory infections. 
• 
The pharmacokinetics of SUL-DUR is well described in the listed indication (Gram-negative 
pneumonia in critical care).  
• 
It will reduce current intensive phase regimen from three IV agents to one or two IV agents 
with other companion drugs. 
• 
Drug-drug interactions are unlikely to be problematic for most patients; there are no known 
drug-drug interactions with cystic fibrosis transmembrane conductance regulator (CFTR) 
modulators. 
• 
It has a good safety profile observed in a highly vulnerable population with ventilator 
associated bacterial pneumonia and hospital acquired bacterial pneumonia making it likely to 
be better tolerated than the current standard of care (SOC) MABS treatment regimens.   
2 PRIMARY OBJECTIVE ARM D 
The primary objective of Appendix A3 is to determine if the β lactam/ β lactamase antimicrobial combination 
(Arm D) in the intensive phase of the trial will result in a greater proportion with MABS clearance with 
tolerance compared with 1) reference Arm A and 2) either of the remaining treatment arms detailed in 
Appendix A1 following the first interim analysis. 
The primary outcome definitions, and secondary and exploratory objectives and outcomes are as per Appendix 
A1 Section 2.  
3 DESIGN 
Appendix A3 describes the intensive phase Arm D compared with each of the intensive treatment arms 
described in Appendix A1 (Figure 1). 
 
 

 
 
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Intensive Therapy Module 
Appendix A3.1: Short Intensive Therapy: Arm D versus treatment arms detailed in Appendix A1 
updated following the first interim analysis.  
Appendix A3.2: Duration of Intensive Therapy for Patients with Ongoing Positive MABS cultures 
after completing 4 weeks vs 10 weeks of Intensive Therapy. 
 
Figure 1 Flow Diagram for Appendix A1 and A3, Intervention Program Eligibility into the Intervention 
Program is determined at screening. At Randomisation-Short Intensive (R-SI) (▲); participants are 
randomised between the different intensive therapy arms (Intensive A, Intensive B, Intensive C or Intensive 
D) for a period of 6 weeks. At the end of intensive therapy, it will be determined if participants are still MABS 
positive, or MABS negative (cleared). Randomisation-Prolonged Intensive or Immediate Consolidation (R-
PI/IC) (★) will ONLY be for participants who are still MABS positive based on respiratory samples taken at 
4 weeks and will allocate participants to either 1) continue intensive therapy or 2) immediately commence 
consolidation therapy. Randomisation-Consolidation (R-Con) (✢) allocates participants to the consolidation 
therapy arms either at week 6 (for those allocated to immediate consolidation) or at week 12 (for those allocated 
to prolonged intensive therapy). Refer to Appendix A2 for information regarding Consolidation Only 

 
 
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intervention program module where participants receive physician directed intensive therapy prior to 
enrolment into Consolidation Only program. 
4 ELIGIBILITY CRITERIA 
Eligibility criteria for Appendix A3 are the eligibility criteria described in Master Protocol section 4.1, 4.2 and 
4.4 and Appendix A1 section 4.1 and 4.3 with the additional inclusion and exclusion criteria detailed below.  
4.1 
INCLUSION CRITERIA  
1. Inclusion criteria as described in Master Protocol section 4.2 and Appendix A1 section 4.1. 
2. Male or female participants aged 12 years and older.  
 
4.2 
EXCLUSION CRITERIA 
• 
Exclusion criteria as per Master Protocol section 4.2 and Appendix A1 section 4.2. 
• 
Participants aged <12 years old.  
• 
Participants aged between 12 and <18years old with clinically significant renal impairment as 
indicated by an age-appropriate estimated creatinine clearance.  
• 
Known hypersensitivity or contraindications to any of the therapies for which no alternative option(s) 
have been provided.  This includes: 
o Sulbactam/durlobactam 
o Ceftriaxone, 
o Amoxicillin, 
o Macrolide antibiotics, and 
o Clofazimine. 
4.3 
ADDITIONAL CRITERIA 
Additional criteria as per Master Protocol section 4.4 and Appendix A1 section 4.3. 
5 ACCEPTABLE METHODS OF CONTRACEPTION 
Acceptable methods of contraception for Appendix A3 are as described in Appendix A1 Section 5.  
6 TRIAL CONDUCT 
6.1 
INFORMED CONSENT 
Participants enrolling in Appendix A3 are required to sign and date the relevant Master Protocol and Appendix 
A consent(s).  Consent will be obtained from participants or their parent/guardian in accordance with the 
policies described in section 5.4 of the FORMaT Master Protocol. 
6.2 
PREGNANCY INFORMATION CONSENT 
Pregnancy Information Consent for Appendix A3 is as described in Appendix A1 Section 6.2.  

 
 
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6.3 
METHODS OF ASSIGNING PARTICIPANTS TO TREATMENT ARMS 
Participants will be randomised among different treatment arms for both the intensive and consolidation phase 
of treatment as described in the Master Protocol section 6.2 using the randomisation technique minimisation. 
In this appendix, randomisation in the intensive phase (R-SI) will initially be in a 2:1:1 ratio between Arm D, 
the control Arm A, and the remaining intervention arm in Appendix A1 until the numbers of participants in 
each Arm have equalised (+/- 2), after which time the first interim analysis with Arm D will take place.  
Following the first interim analysis with Arm D, after a total of 100 participants have completed 6 weeks of 
intensive therapy, if appropriate, Bayesian Adaptive Randomisation (BAR) will be implemented for R-SI to 
adjust the allocation probabilities to favour the more promising intervention(s). BAR will then be used until 
the data support either early stopping for futility, or a maximum sample size is attained.  R-PI between short 
or prolonged intensive for participants who remain culture positive at week 6 will be unchanged in a 1:1 ratio 
between short and prolonged intensive. As described in the Master Protocol, all randomisations will be 
conducted via Research Electronic Data Capture (REDCap) at each FORMaT trial site.  At each stage, study 
staff will enter the subject demographic data and the stratification factors (see section 6.3 in the Master 
Protocol) into REDCap, which will then inform them of the participant’s treatment allocation for that stage. 
Refer to Statistical Considerations in Appendix A3 and Appendix F: General Statistical Principles for detailed 
information regarding randomisation and statistical principles for Appendix A3. 
7 INTERVENTION PROGRAM PROCEDURES AND SAFETY 
MONITORING  
In addition to the core trial procedures described in the Master Protocol, participants enrolled in the 
Intervention Program are required to undertake procedures and regular toxicology monitoring as described in 
Appendix A1.  The type of toxicology monitoring procedure required will be determined by the treatment arm 
the participant is allocated to, and in accordance with the schedule of assessments outlined in tables 6 to 8.  
Toxicology thresholds will be defined in accordance with the Common Terminology Criteria for Adverse 
Events (CTCAE) criteria as outlined in the Master Protocol, section 5.9.2.  The outcome of all the assessments 
below will be documented in the corresponding Case Report Form (CRF) and entered into REDCap. All 
Intervention Program Procedures and Safety Monitoring for Appendix A3 are as described in detail in 
Appendix A1 Section 7. 
8 SITE REIMBURSEMENT 
For participants enrolled in Appendix A3, trial sites will be reimbursed on a per participant basis at each of the 
following time points;  
1. Screening; 
2. End of intensive; 
3. End of consolidation; 
4. Final study visit. 

 
 
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Sites will be reimbursed according to their contract. Payments will be paid for each time point once the data is 
entered into the trial database and all queries finalised. Invoices should be prepared at a minimum of every 6 
months. 
 
 
 

 
 
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9 INTENSIVE THERAPY NESTED STUDIES 
9.1 
NESTED STUDY A3.1: SHORT INTENSIVE THERAPY: THE USE OF 
INTRAVENOUS SULBACTAM – DURLOBACTAM IN COMBINATION 
WITH IV CEFTRIAXONE + ORAL AMOXICILLIN + ORAL MACROLIDE 
+ ORAL CLOFAZIMINE DURING INTENSIVE THERAPY IN THE 
TREATMENT OF MABS-PD 
Introduction 
IV SUL-DUR, supplied in kind by Innoviva Specialty Therapeutics (IST), will be administered in combination 
with IV ceftriaxone, oral high dose amoxicillin, azithromycin and clofazimine for the treatment of MABS 
pulmonary disease (MABS-PD). This combination therapy will be delivered over a 4-week intensive period. 
During this respiratory samples will be collected according to the Schedule of Assessments.  Following the 4-
week intensive phase and while awaiting results and further randomisation at 6 weeks, participants will 
commence an oral only regimen. This treatment arm will be trialled in FORMaT participants aged ≥12 years, 
who are considered as adults for drug dosing purposes. IST are currently undertaking a paediatric study from 
birth to <18 years. Upon availability of safety data for the younger paediatric cohort, <12 years, FORMaT 
aims to extend the SUL-DUR containing arm to include these paediatric participants. Pharmacokinetic and 
pharmacodynamic studies will be required for both adult and paediatric participants for feasible sites able to 
participate in these studies.  
At 6 weeks: 
1. 
If respiratory samples remain culture positive for MABS they are randomised to either 
prolonged intensive (continuation of their previous intensive treatment regimen) or transition 
to consolidation therapy, with further randomisation to an oral only treatment or oral plus 
inhaled treatment.  
2. 
If respiratory samples are negative for MABS, participants will continue on oral consolidation 
treatment and will be randomised to receive either, additional inhaled treatment or no inhaled 
treatment.    
Eligibility Criteria 
No additional eligibility criteria are required for participation in A3.1 from those described in Appendix A3, 
Section 4. 
Objectives 
Primary Objective 
To compare the efficacy of Arm D against 1) reference Arm A and 2) either of the remaining treatment arms 
detailed in in Appendix A1 following the first interim analysis based on microbiological clearance of MABS 
with good tolerance at end of short intensive.  Respiratory samples will be collected at 4 weeks to allow 

 
 
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microbiological outcomes to be available at end of short intensive and tolerance will be assessed at the end of 
short intensive.  Treatment will continue up until the end of short intensive (6 weeks).   
Investigation of the efficacy of intensive therapy on microbiological clearance with acceptable toxicity of 
treatment combinations will also be examined in different patient subpopulations (CF and non-CF, those 
infected with different MABS subspecies M. a. abscessus/ M. a. bolletii [inducible macrolide resistance] and 
M. a. massiliense and those with constitutive macrolide resistance). 
MABS clearance at the end of the short intensive therapy will be defined as negative MABS cultures from all 
3 sputum samples or from one bronchoalveolar lavage (BAL) sample collected at week 4. 
Secondary Objectives 
1. Microbiological clearance at 4 weeks (irrespective of toxicity) between Arm D and each of the 
treatment arms described in Appendix A1 in different patient subpopulations (CF and non-CF, those 
infected with different MABS subspecies M. a. abscessus/ M. a. bolletii [inducible macrolide 
resistance] and M. a. massiliense and those with constitutive macrolide resistance).  
2. Safety of using Arm D compared to each of the treatment arms described in Appendix A1 in the short 
intensive therapy phase. 
3. Change in FEV1 z-score at end of short intensive therapy versus at Screening with use of Arm D 
compared to each of the treatment arms described in Appendix A1. 
4. Change in health-related quality of life (HRQoL) CF questionnaire – Revised (CFQ-R) for participants 
at end of short intensive therapy versus at Screening with use of Arm D compared to each of the 
treatment arms described in Appendix A1. 
5. To examine general HRQoL between Screening and end of short intensive therapy in participants with 
use of Arm D compared to each of the treatment arms described in Appendix A1. 
6. To examine the cost effectiveness of Arm D compared to each of the treatment arms described in 
Appendix A1 during short intensive therapy. 
7. To examine causes for early withdrawal from MABS-PD treatment due to reasons other than poor 
tolerance as defined in the primary objectives with use of Arm D compared to each of the treatment 
arms described in Appendix A1. 
Statistical Considerations 
Sample size considerations: The schedule for interim analyses and stopping rules used in the trial and sample 
size for each research question was informed by simulations using Monte Carlo methods to give a range of 
power according to different plausible scenarios for responses to intensive  interventions.  
A simulation study was conducted to determine the study design and explore the statistical properties of adding 
Arm D into the intensive phase randomisation. While we cannot provide data on the primary outcomes by 
treatment arm, we have noted that approximately 30% of all participants have experienced poor tolerance 
during intensive therapy in the trial to date. We plan to drop one of the current treatment arms from the 
intensive phase at the first interim analysis due to feasibility, as guided by the independent data safety 

 
 
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monitoring board (iDSMB). Following this the new Arm D will be added. In the simulations, it is assumed 
that Arm-A (reference arm) will remain and either Arm B or Arm C will be dropped. For the purposes of the 
simulation, we assume Arm B continues, and Arm C is ceased. We simulated trials where 300 new participants 
are enrolled, along with 20 participants in Arm A and 20 participants from Arm B recruited (total 60 
participants completed short intensive) prior to the new arm being added and assumed that interim analyses 
will be conducted after a total of 100 and subsequently after a total of 200 participants have been recruited and 
completed each phase (intensive and consolidation) of the trial. At these interim analyses the allocation ratio 
was updated using BAR based on the posterior probability of each intervention arm being better than control 
in terms of the primary outcome. The simulations allowed early stopping of an intervention arm for efficacy if 
the posterior probability of it being better than control is >99%, and for futility if the same posterior probability 
is <2% (these thresholds were chosen to provide desirable statistical properties in initial simulations). An 
intervention arm will be recommended if it stops early for efficacy or if there is evidence that the intervention 
is better than the control arm at the final analysis of 300 with a 1-sided p-value of 0.025. Simulations were 
repeated 100,000 times to estimate the type 1 error and power for 5 scenarios that varied: 
1) 
The probability of clearance at R-SI for each of the 3 arms. 
2) 
The probability of toxicity (lack of tolerability) at the R-SI for each of the 3 arms.  
In all cases it was assumed that 10 participants per month were enrolled to the intensive phase and that the 
probability of toxicity and clearance are independent. The below table shows the outcomes and operating 
characteristics for the five scenarios (*Represents false positive rate rather than power): 
Scenario Probability of 
clearance at intensive 
phase (Arm A, B, D) 
Probability of toxicity 
at intensive phase 
(Arm A, B, D) 
Power to conclude 
intervention Arm D 
better than A 
Proportion of 
replicates where Arm 
D stops early for 
efficacy 
1 
(0.66,0.66,0.66)  
(0.3,0.3,0.3) 
 
0.033*  
0.017 
2 
(0.66,0.66,0.75)  
(0.3,0.3,0.1) 
 
0.93 
 
0.64 
3 
(0.66,0.7,0.75)  
(0.3,0.2,0.1) 
 
0.90 
 
0.61 
4 
(0.66,0.66,0.8)  
(0.3,0.3,0.1) 
 
0.99 
 
0.83 
5 
(0.66,0.66,0.9)  
(0.3,0.3,0.1) 
 
>0.99  
0.99 
 
 
Scenario 1 represents the ‘null scenario’ where no intervention makes a difference to outcomes. 
Scenario 2 assumes that Arm D makes a small difference to clearance and a larger difference to toxicity. 
Scenario 3 is the same as scenario 2 other than Arm B is assumed to have modest effect on toxicity and 
clearance (thus meaning the BAR procedure will allocate fewer individuals to Arm D on average). Scenario 4 
is the same as scenario 2 but it assumes a larger effect of Arm D on clearance. Scenario 5 is the same as 
scenario 4 other than it assumes an even larger effect of Arm D on clearance. The sample size of 300 with 

 
 
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interim analyses at 100 and 200 participants provides 99% power if the new intensive arm provides an 
improvement in the probability of clearance with tolerance from 66% in the control arm to 80% in Arm D. 
With this scenario, there is an 83% chance that the new intensive arm would stop early for efficacy.  
Statistical methods: The interim and final analyses will be conducted using a Bayesian logistic regression 
model for the primary outcome adjusted for stratification factors. Once an arm is stopped (either at an interim 
analysis or at 300 participants) a frequentist analysis will also be conducted and reported along with data on 
the secondary outcomes. All analyses will be conducted using the intention to treat/treatment policy principle. 
The statistical analysis will also explore the best treatment strategies (linking intensive phase with 
consolidation phase) using methodology for analysing Sequential Multi Assignment Randomised Trials (10) 
as detailed in Appendix F General Statistical Principles. 
 

 
 
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10 INTENSIVE THERAPY DOSING REGIMEN 
At R-SI, participants will be randomised to either Arm D or the treatment arms outlined in Appendix A1 during 
the intensive phase. Participants randomised to Arm D will receive drug therapy in accordance with the dosing 
tables below.  Drug therapy, administration and duration is dependent on the treatment arm the participant is 
randomised to.  The start and end points of each drug therapy, the dose of each drug therapy used, any changes 
in dosing and all concomitant medications used will be required to be entered into the CRF. 
R-SI dictates the drug therapy that participants will be randomised to.   
Intensive Arm D 
 Weeks 1 to 4 (and Weeks 7 to 10 if 
randomised to prolonged intensive therapy) 
Weeks 5 to 6 (and Weeks 10 to 12 if 
randomised to prolonged intensive therapy) 
1. IV sulbactam-durlobactam 
2. IV ceftriaxone 
3. Oral amoxicillin 
4. Oral azithromycin or clarithromycin 
5. Oral clofazimine 
1. Oral clofazimine, and; 
2. Oral azithromycin or clarithromycin, and; 
3. In combination with one to three of the 
following oral antibiotics: 
• 
Linezolid, 
• 
Trimethoprim / sulfamethoxazole 
(co-trimoxazole), 
• 
Bedaquiline, 
• 
Rifabutin. 
• 
Doxycycline  
• 
Moxifloxacin 
 
For participants with confirmed mixed NTM infections (slow growers + MABS), ethambutol can be added to 
the treatment arms (in accordance with the dosing tables below) if required by the treating physician. 
The Arm D intensive therapy dosing regimen tables outlined below are separated by age (adult, paediatric).  
The recommended doses and frequencies are a guideline and participant dosing must also take into account 
clinical judgement, the Investigator’s Brochure (for SUL-DUR) and relevant prescribing information for the 
non-SUL-DUR drugs in Arm D.   
The medications in Arm D have the potential for drug-drug interactions. The clinician should consider drug 
and non-drug interactions, special warnings and precautions for use prior to prescribing these medications 
according to the Investigator’s Brochure (for SUL-DUR) and relevant prescribing information for the non-
SUL-DUR drugs in Arm D.  

 
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Table 1 Intensive therapy dosing regimen for Intensive Arm D in adults – WEEKS 1 to 4 (and WEEKS 
7 to 10 if randomised to prolonged intensive therapy) 
WEEKS 1 to 4 Intensive Arm A: Adult Dosing A 
Drug 
Recommended Dose (per dose) 
Frequency 
IV sulbactam-durlobactam 
Greater than or equal to 130ml/min 
Every FOUR (4) hourly. 
Administered by intravenous 
infusion over 3 hours.  
 
For CrCL 45 to 129ml/min  
1g sulbactam/ 1g durlobactam 
Every SIX (6) hourly. Administer 
by intravenous infusion over 3 
hours.  
For CrCL 30 to 44ml/min  
1g sulbactam/ 1g durlobactam 
Every EIGHT (8) hourly. 
Administer by intravenous infusion 
over 3 hours. 
For CrCL 15 to 29ml/min 
1g sulbactam/ 1g durlobactam 
Every TWELVE (12) hourly. 
Administer by intravenous infusion 
over 3 hours. 
For CrCL<15ml/min 
1g sulbactam/ 1g durlobactam 
Every TWELVE (12) hourly for 
first 3 doses then reduce to every 
24 hourly thereafter. Administer by 
intravenous infusion over 3 hours. 
IV ceftriaxone 
1g  
Every TWELVE (12) hourly 
 
Oral amoxicillin  
1000mg 
Three times daily 
 
Oral azithromycin 
250 – 500mg 
Once daily 
 
If azithromycin not tolerated, use oral 
clarithromycin. 
<40kg or poorly tolerated 
250mg 
Once daily 
Oral clarithromycin 
Clarithromycin only for use if 
azithromycin not tolerated. 
500mg 
Twice daily 
Oral clofazimine 
100 – 300mg 
Once daily 
 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below.  
Oral ethambutol 
Ethambutol should be dosed on ideal 
body weight. 
15mg/kg  
(rounded to account for tablet 
strength) 
OR 
Once daily 
25mg/kg  
(rounded to account for tablet 
strength) 
Thrice weekly 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement, the Investigator’s Brochure (for SUL-DUR) and relevant prescribing information for the non-SUL-
DUR drugs.  
 

 
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Table 2 Intensive therapy dosing regimen for Intensive Arm D in paediatrics (aged 12 years and older) 
– WEEKS 1 to 4 (and WEEKS 7 to 10 if randomised to prolonged intensive therapy) 
WEEKS 1 to 4 Intensive Arm D: Paediatric Dosing A 
Drug 
 Recommended Dose  
(per dose) 
Frequency 
IV sulbactam/durlobactam 
 
 
 
Sulbactam 25mg/kg  
Durlobactam 25mg/kg 
Do not to exceed 1g 
sulbactam - 1g durlobactam  
Every SIX hourly. 
Administer by intravenous 
infusion over 3 hours.  
IV ceftriaxone 
 
1g  
Every TWELVE (12) hourly 
Oral amoxicillin  
 
1000mg  
Three times daily 
Oral azithromycin 
If azithromycin not tolerated, use oral 
clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if azithromycin 
not tolerated. 
Children 1 month – 11 years of age 
Twice daily 
<8 kg 
7.5mg/kg  
8-11 kg 
62.5mg 
12-19 kg 
125mg 
20-29 kg 
187.5mg 
30-40 kg 
250mg 
Children 12-18 years of age 
Twice daily 
Dosing independent 
of weight 
500mg 
Oral clofazimine 
Dosing may be rounded to account for capsule 
strength. 
<40kg 
3-5mg/kg, max 100mg 
Once daily 
≥40kg 
100mg 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg 
(round to account for tablet 
strength) 
Once daily 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement, the Investigator’s Brochure (for Sul-Dur) and relevant prescribing information for the non-Sul-
Dur drugs.  
 
 

 
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Table 3 Intensive therapy dosing regimen in adults – WEEKS 5 to 6 (and WEEKS 7 to 10 if randomised 
to prolonged intensive therapy) 
WEEKS 5 to 6 Intensive Therapy Arm-D: Adult DosingA 
Drug 
 Recommended Dose (per dose) 
Frequency  
Oral clofazimine 
100 – 300mg 
Once daily 
Oral azithromycin  
250 – 500mg 
OR 
500mg  
Once daily 
 
Thrice weekly 
If azithromycin not tolerated, use oral 
clarithromycin. 
<40kg or poorly tolerated 
250mg 
 
Thrice weekly 
Oral clarithromycin 
Clarithromycin only for use if 
azithromycin not tolerated. 
500mg 
Twice daily 
In combination with one to three of the following oral antibiotics guided by participant susceptibility and 
tolerance. 
Oral linezolid 
600mg 
Once daily 
Oral trimethoprim with 
sulfamethoxazole  
160mg/800mg 
Twice daily 
Oral bedaquiline  
(Weighing at least 30kg) 
First 2 weeks 400mg 
Once daily 
For remaining 22 weeks 200mg 
Max duration 6 months 
Thrice weekly 
At least 48 hours between doses 
Oral rifabutin 
5mg/kg, max 450mg 
Once daily 
Oral doxycycline 
100mg 
Once daily 
Oral moxifloxacin 
400mg 
Once daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below.  
Oral ethambutol 
Ethambutol should be dosed on ideal 
body weight. 
15mg/kg 
(round to account for tablet strength) 
OR 
Once daily 
25mg/kg 
(round to account for tablet strength) 
Thrice weekly 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information. 

 
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Table 4 Intensive therapy dosing regimen in paediatrics – WEEKS 5 to 6 (and WEEKS 7 to 10 if 
randomised to prolonged intensive therapy) 
WEEKS 5 to 6 Intensive Therapy Arm-D: Paediatric Dosing A 
Drug 
Recommended Dose  
(per dose) 
Frequency 
Oral clofazimine 
Dosing may be rounded to account for capsules. 
<40kg 
3-5mg/kg, max 100mg 
Once daily 
≥40kg 
100mg 
Oral azithromycin 
If azithromycin not tolerated, use oral clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if 
azithromycin not tolerated 
Children 12 to <18 years of age 
 
Dosing independent of 
weight 
500mg 
Twice daily 
In combination with one to three of the following oral antibiotics guided by participant susceptibility and 
tolerance. 
Oral linezolid 
1 month – 9 years 
10mg/kg, max 450mg 
Twice daily 
10 – 12 years 
10mg/kg, max 600mg 
Daily 
>12 years 
600mg 
Daily 
Oral trimethoprim with 
sulfamethoxazole  
 
5mg/kg trimethoprim 
max 160mg trimethoprim 
Twice daily 
Oral bedaquiline 
(age ≥5 years) 
Weeks 1 and 2 
 
Once daily 
≥15kg - <20kg 
160mg 
≥20kg - <30kg 
200mg 
≥30kg 
400mg 
Weeks 3-24 - Max Duration 6 Months 
Thrice weekly. 
At least 48 hours between 
doses 
≥15kg - <20kg 
80mg 
≥20kg - <30kg 
100mg 
≥30kg 
200mg 
Oral rifabutin 
5mg/kg, max 300mg 
Once daily 
Oral doxycycline 
(ages ≥8 years) 
2mg/kg, max 100mg 
Once daily 
Oral moxifloxacin  
Dosing may be rounded to account for capsules. 
10-15mg/kg, max 400mg 
Once daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg 
(round to account for 
tablet strength) 
Once daily 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information. 

 
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10.1.1 DRUG SUPPLY, STORAGE AND DISTRIBUTION DURING INTENSIVE 
THERAPY 
Sulbactam-Durlobactam 
Shipping, clinical trial drug labelling, storage prior to delivery to trial sites and distribution to trial sites will 
be the responsibility of the FORMaT Sponsor and their contracted vendor(s). The supply of SUL-DUR will 
be provided in-kind by the industry partner IST. Trial sites will be responsible for the storage, accountability, 
dispensing and administration of SUL-DUR at their respective trial site. Trial sites will be responsible for the 
destruction of SUL-DUR at the Sponsor’s request.  
Other non-SUL-DUR drugs in Arm D 
Supply, distribution and storage of the non-SUL-DUR drugs within Arm D will be the responsibility of the 
investigational site, utilising site/institutional pharmacy stock. These activities will be conducted as per 
standard of care and in accordance with site specific policies and regulatory requirements. 
Any medication the participant is prescribed which are not investigational products, including adjunctive 
treatments, for example, medication to treat nausea, will be commercially available products and are to be 
sourced and supplied locally by study sites according to local standard practices. 
10.1.2 OPTIONS FOR REDUCING NAUSEA DURING INTENSIVE THERAPY 
Study drugs used in the intensive phases of the FORMaT Trial may cause nausea. Pharmacological treatment 
options to manage nausea are at the discretion of the clinician and are to be prescribed according to local 
guidelines.  
 

 
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11 SCHEDULE OF ASSESSMENTS 
Table 5 lists the special considerations that are applicable to all Schedule of Assessment tables.  Table 5 must 
be used in conjunction with Tables 6 to 8.  Tables 6 to 8 show the schedules of assessment tables for participants 
enrolled in Appendix A3.  Table 6 shows the schedule of assessments for all participants from Screening to 
end of Week 6, Table 7 shows the schedule of assessments from Week 7 to Week 12 for participants 
randomised to Prolonged Intensive and Table 8 shows the schedule of assessments for all participants during 
the Consolidation therapy phase and at the Final Outcome.  Acceptable study visit windows are also outlined 
in tables 6 to 8. 
Table 5 Special considerations for Schedule of Assessments 
Symbol Definition 
A 
Participant reconsent is required with Institutional Review Board/ Independent Ethics Committee 
/Human Research Ethics Committee (IRB/ IEC/HREC) approved changes to the protocol that 
affect the participants rights and/or safety and/or if a child turns 18 years old during the trial and 
must reconsent as an adult participant. 
B 
Visits may be conducted while an inpatient or at home if participant is receiving home-based care. 
C 
To be eligible to enrol in the Intervention Program, the participant is required to have either two 
(2) MABS-positive sputum samples or one (1) MABS-positive BAL sample.  Refer to Appendix 
A1 section 7.3 for further information.  
D 
To determine MABS clearance following four (4) weeks of intensive therapy, three sputum 
samples or one BAL sample are required to be collected in Week 4 (±3 days) to ensure results are 
available by week 6 of intensive therapy to inform randomisation. 
E 
Adult height is to be recorded once (preferably at the screening visit).  Paediatric height must be 
measured at least every six weeks. 
F 
Only required if the screening assessments were reviewed more than two (2) weeks earlier than 
Day 1. 
G 
Refer to Appendix A1 section 7.2 for eligibility criteria for the screening visit chest CT. 
H 
Only required in female participants of childbearing potential.  A serum pregnancy test is required 
at screening and final study visit.  A urine or serum pregnancy test is acceptable at all other times. 
I 
Screening audiology and screening vestibular assessment can be performed if a participant has 
commenced intensive therapy but must be performed within three (3) days of first receiving 
treatment. 
J 
QT interval at screening is to be corrected using the Fridericia method. Any subsequent 
abnormal QTc intervals are to be confirmed using the Fridericia method. 
K 
Six-minute walk test to be performed in participants ≥18 years of age only. 
N 
The EQ-5D-5L is to be administered to participants ≥18 years of age whereas the EQ-5D-Y is to 
be administered to participants 8 to 17 years of age.  The EQ-5D-Y Proxy is to be administered 
to parents/carers of participants 4 to 7 years of age. 
O 
The Short Form-36 (SF-36) health survey is to be administered to participants ≥16 years of age 
at time of Screening.  For participants aged <16 years at Screening, the PedsQLTM is to be used 
for entire duration of trial. 
P 
The Pediatric Quality of Life Inventory (PedsQL™) is only to be assessed in participants <16 
years of age at time of Screening.  If both the PedsQL™ and the CFQ-R are administered where 
possible, the PedsQL™ should be administered prior to the CFQ-R. 

 
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Q 
The CFQ-R is only to be completed in participants with CF.  The age appropriate CFQ-R 
assessment should be selected; CFQ-R adult/teen (≥14 years of age), CFQ-R child (6 to 13 years 
of age) and CFQ-R parent (parent/carer of participant 6 to 13 years of age). 
R 
The Child Health Utility is only to be assessed in participants 7 to 17 years of age. 
S 
The St George Respiratory Questionnaire (SGRQ) is only to be assessed in non-CF participants 
18 years of age and older. 
T 
Costs questionnaire only required for participants that are randomised to immediate consolidation.  
U 
5-item Medication Adherence Rating Scale (MARS-5) is only to be completed in participants in 
the intervention cohort on outpatient based MABS-PD treatment. 
V 
Week 12 chest CT scan is optional and requires participant to consent to FORMaT Sub-Study C3: 
Imaging.  The site must have approval to conduct this additional scan, be certified to perform the 
scan using the scanner specific protocol and the participant must provide additional consent. 
W 
To determine MABS clearance following ten (10) weeks of intensive therapy, three sputum 
samples or one BAL sample are required to be collected in Week 10 (±3 days). 
X 
Participants unable to produce a sputum sample (expectorated or induced) to be marked as 
unproductive on the CRF. 
Y 
Participants who have produced sputum samples during Weeks 18, 28, and 38 are requested to 
provide three additional sputum samples collected at least one week apart nearer to the end of 
Weeks 52.  For participants who were unproductive (intermittent or continual) during Weeks 18, 
28, 38 and 52, a BAL sample is to be collected during Week 56. 
Z 
Clinic visit and some assessments at Week 10 can be completed at any time between Week 10 
and Week 12.  
1 
Chest CT scan at early withdrawal visit will only be requested if clinically indicated. 
2 
Vital signs to be performed: Heart rate (pulse), blood pressure, respiratory rate and body 
temperature. 

 
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Appendix A3-Intervention Program – Arm D, Version 1.0,  Date 11 November 2025 
30 
Table 6 Schedule of Assessments for Intervention Program Participants in Appendix A3: Intensive Therapy (Screening and first six weeks of intensive therapy) 
ASSESSMENT 
SCREENING 
VISIT 
INTENSIVE THERAPY 
Week 1 - Week 6 
Day 0 
Day 1 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
-42 Days 
 +24 hours 
+3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
Informed consent for Appendix A3A 
✓ 
 
 
 
 
 
 
Clinic visit B 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Review eligibility 
✓ 
 
 
 
 
 
 
Randomisation 
 
✓ 
 
 
 
 
✓ 
Adverse event monitoring 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Respiratory 
sample 
Sputum (expectorated or induced) or; 
✓C 
 
 
 
 
✓x3D 
 
BAL 
✓C 
 
 
 
 
✓D 
 
Height E and Weight 
✓ 
 
 
 
 
 
✓ 
Medication Review 
✓ 
✓F 
✓ 
✓ 
✓ 
✓ 
✓ 
Spirometry 
✓ 
 
 
 
 
 
✓ 
Chest CT 
✓G 
 
 
 
 
 
 
Pregnancy Test and Breastfeeding Status H 
✓ 
✓ 
 
✓ 
 
✓ 
✓ 
Audiogram 
✓I 
 
 
 
 
 
 
ECG J 
✓ 
 
 
✓ 
 
 
✓ 
6-minute walk test K 
✓ 
 
 
 
 
 
 
Blood collection: 
 
 
 
 
 
 
 
1. Chemistry and Renal Function 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
2. Liver Function Tests 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
3. Full Blood Count 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination 
✓ 
✓F 
 
 
 
 
✓ 
Vital signs2 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
Health-related quality of life questionnaires: 
 
 
 
 
 
 
 
1. EQ-5D-5L or -Y N 
✓ 
 
 
 
 
 
✓ 
2. SF36  O 
✓ 
 
 
 
 
 
✓ 
3. PedsQL™ P 
✓ 
 
 
 
 
 
✓ 
4. CFQ-R Q 
✓ 
 
 
 
 
 
✓ 
5. Child Health Utility 9D R 
✓ 
 
 
 
 
 
✓ 
6. SGRQ S 
✓ 
 
 
 
 
 
✓ 
Costs Questionnaire 
✓ 
 
 
 
 
 
✓ 
Medication Adherence Questionnaire U 
 
 
 
 
 
 
✓ 

 
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Table 7 Schedule of Assessments for Intervention Program Participants: Prolonged Intensive Therapy(Total of 12 weeks of intensive therapy) 
ASSESSMENT 
PROLONGED INTENSIVE THERAPY  
Week 7- Week 12 
Week 7 
Week 8 
Week 9 
Week 10 
Week 12 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
Clinic visit B 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomisation 
 
 
 
 
✓ 
Adverse event monitoring 
✓ 
✓ 
✓ 
✓ 
✓ 
Respiratory 
sample 
Sputum (expectorated or induced) or; 
 
 
 
✓x3W 
 
BAL 
 
 
 
✓W 
 
Height E and Weight 
 
 
 
 
✓ 
Medication Review 
✓ 
✓ 
✓ 
✓ 
✓ 
Spirometry 
 
 
 
 
✓ 
Chest CT 
 
 
 
 
Optional V 
Pregnancy Test and Breastfeeding Status H 
 
 
✓ 
 
✓ 
ECGJ 
 
 
 
 
✓ 
6-minute walk test K 
 
 
 
 
✓ 
Blood collection: 
 
 
 
 
 
7. Chemistry and Renal Function 
✓ 
✓ 
✓ 
✓ 
✓ 
8. Liver Function Tests 
✓ 
✓ 
✓ 
✓ 
✓ 
9. Full Blood Count 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination 
 
 
 
 
✓ 
Vital Signs2 
✓ 
✓ 
✓ 
✓ 
 
Health-related quality of life questionnaires: 
 
 
 
 
 
10. EQ-5D-5L or -Y N 
 
 
 
 
✓ 
11. SF36  O 
 
 
 
 
✓ 
12. PedsQL™  P 
 
 
 
 
✓ 
13. CFQ-R Q 
 
 
 
 
✓ 
14. Child Health Utility 9D R 
 
 
 
 
✓ 
15. SGRQ S 
 
 
 
 
✓ 
Costs Questionnaire 
 
 
 
 
✓ 
Medication Adherence Questionnaire U 
 
 
 
 
✓ 

 
 
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32 
Table 8 Schedule of Assessments for Consolidation Therapy and Final Outcome 
ASSESSMENT 
CONSOLIDATION THERAPY 
FINAL 
STUDY 
VISIT 
Early 
Withdrawal 
Visit 
Immediate consolidation 
After completing six weeks (short) intensive therapy 
Delayed consolidation 
After completing 12 weeks (prolonged) 
intensive therapy 
Week 
10 
Week 
12 
Week 
18 
Week 
28 
Week 
38 
End of 
consolidatio
n (Week 52) 
Week 
18 
Week 
28 
Week 
38 
End of 
consolidatio
n (Week 58) 
+4 weeks 
post End of 
consolidation 
+30 days 
±3 days 
±3 days 
±30 
days 
±30 
days 
±30 
days 
+5 days 
±30 
days 
±30 
days 
±30 
days 
+5 days 
+14 days 
 
Clinic visit B 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse event monitoring 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Respiratory 
sample 
Sputum 
(expectorated 
or 
induced) or; 
✓ 
x3W 
 
✓X 
✓X 
✓X 
✓X 
✓X 
✓X 
✓X 
✓X 
✓Y 
✓ 
Broncho-alveolar lavage (BAL) 
✓W 
 
Height E and Weight 
✓Z 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
Medication Review 
✓Z 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Spirometry 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
Chest CT 
 
Optional 
V 
 
 
 
 
 
 
 
 
✓ 
✓1 
Pregnancy Test and Breastfeeding Status H 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Audiogram 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
ECG J 
 
✓ 
 
✓ 
 
 
 
✓ 
 
 
✓ 
✓ 
6-minute walk test K 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
Blood collections: 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Chemistry and Renal Function 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
2. 
Liver Function Tests 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
3. 
Full Blood Count 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
Health-related quality of life questionnaires: 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
EQ-5D-5L or -Y N 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
5. 
SF-36 O 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
6. 
PedsQL™  P 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
7. 
CFQ-R Q 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
8. 
Child Health Utility 9D R  
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
9. 
SGRQ S 
 
✓ 
 
 
 
 
 
 
 
 
✓ 
✓ 
Costs Questionnaire 
 
✓ 
 
✓ 
 
 
 
✓ 
 
 
✓ 
✓ 
Medication Adherence Questionnaire U 
 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
✓ 
 
 

 
 
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Appendix A3-Intervention Program – Arm D, Version 1.0,  Date 11 November 2025 
33 
12 APPLICABLE DISCOVERY STUDIES AND REGISTRY LINKAGE FOR 
APPENDIX A3 
Intervention Program participants in Appendix A3 may be eligible to enrol in the following FORMaT Sub-
Studies and Integrated Studies: 
1) Appendix C Discovery 
i. 
C1: Pharmacokinetics 
i) C1.3 Pharmacokinetics of MABS-PD therapies 
ii) C1.4 Pharmacokinetics of CFTR modulator therapy in persons with CF on MABS therapy 
iii) C1.5 Pharmacokinetics of SUL-DUR 
ii. 
C2: Immune factors and biomarkers 
i) C2.1 Macrophage function 
ii) C2.2 Mitochondrial stress 
iii) C2.3 T-cell function  
iv) C2.4 Gene expression  
v) C2.5 Serology 
iii. 
C3: Imaging 
2) Appendix D Registry Linkage 
i. 
D1: Australian cystic fibrosis data registry 
3) Appendix E Health Economics 
i. 
E1: Cost effectiveness and Resource utilisation 
Please see the relevant sections of the applicable appendix for further information, including additional 
eligibility criteria. 
 

 
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Appendix A3-Intervention Program – Arm D, Version 1.0,  Date 11 November 2025 
34 
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1. 
Negatu DA, Aragaw WW, Gebresilase TT, Paruchuri S, Kaya F, Shin SJ, et al. Durlobactam to boost 
the clinical utility of standard of care beta-lactams against Mycobacterium abscessus lung disease. 
Antimicrob Agents Chemother. 2025;69(1):e0104624. 
2. 
Dousa KM, Nguyen DC, Kurz SG, Taracila MA, Bethel CR, Schinabeck W, et al. Inhibiting 
Mycobacterium abscessus Cell Wall Synthesis: Using a Novel Diazabicyclooctane beta-Lactamase 
Inhibitor To Augment beta-Lactam Action. mBio. 2022;13(1):e0352921. 
3. 
Shin E, Dousa KM, Taracila MA, Bethel CR, Nantongo M, Nguyen DC, et al. Durlobactam in 
combination with beta-lactams to combat Mycobacterium abscessus. Antimicrob Agents Chemother. 
2025;69(2):e0117424. 
4. 
Dousa KM, Shin E, Kurz SG, Plummer M, Nantongo M, Bethel CR, et al. Synergistic effects of 
sulopenem in combination with cefuroxime or durlobactam against Mycobacterium abscessus. mBio. 
2024;15(6):e0060924. 
5. 
Singh S, Shrivastava A, Boorgula GD, Long MC, Robbins B, McShane PJ, et al. Sulbactam-
Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens for Mycobacterium abscessus 
Lung Disease. bioRxiv. 2025. 
6. 
Shrivastava A, Boorgula GD, Singh S, Stiles D, McShane PJ, Devine M, et al. Sulbactam-durlobactam 
improves cephalosporin and carbapenem susceptibility and time-kill effect against Mycobacterium 
abscessus. Microbiol Spectr. 2025:e0149225. 
7. 
XACDURO® (sulbactam for injection; durlobactam for injection), co-packaged for intravenous use  
Initial U.S. Approval: 2023 FULL PRESCRIBING INFORMATION. 2023. 
8. 
Kaye KS, Shorr AF, Wunderink RG, Du B, Poirier GE, Rana K, et al. Efficacy and safety of sulbactam-
durlobactam versus colistin for the treatment of patients with serious infections caused by 
Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 
3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023;23(9):1072-84. 
9. 
Sulbactam-durlobactam for the treatment of hospital-acquired bacterial pneumonia and ventilator-
associated bacterial pneumonia caused by susceptible strains of acinetobacter baumannii calcoaceticus 
complex - Sponsor Briefing Document - Antimicrobial Drugs Advisory Committee: Entasis 
Therapeutics 2023. 
10. 
Bigirumurame T, Uwimpuhwe G, Wason J. Sequential multiple assignment randomized trial studies 
should report all key components: a systematic review. J Clin Epidemiol. 2022;142:152-60.