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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A multi-centre, randomised, multi-arm, adaptive platform trial in 
people with or without cystic fibrosis Finding the Optimal 
Regimen for Mycobacterium abscessus Treatment (FORMaT) 
MASTER PROTOCOL 
Protocol Version 
Version 4.1 
Protocol Date 
20 February 2024 
Protocol Number  
FORMaT001 
Funding 
 
1- Medical Research Future Fund, Australian Government 
Department of Health 
2- Cystic Fibrosis Foundation 
3- Anonymous Donor 
4- Thoracic Society of Australia and New Zealand 
5- The University of Queensland 
6- Children’s Hospital Foundation 
Australian and New Zealand  
Clinical Trials Registry Number 
ACTRN12618001831279 
ClinicalTrials.gov Identifier  
NCT04310930 
EudraCT Number 
2020-000050-10 
EU-CT Number 
2023-506575-99-00-EU CT 
Sponsor 
Contact  
The University of Queensland 
FORMaTtrial@uq.edu.au 
 
 

 
 
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TABLE OF CONTENTS 
1.1 
SYNOPSIS ................................................................................................................................................... 2 
1.2 
PROTOCOL STRUCTURE .............................................................................................................................. 4 
1.3 
FORMAT MASTER PROTOCOL................................................................................................................... 5 
1.3.1 FORMaT Appendices and Supplements ................................................................................................ 5 
2.1 
MICROBIOLOGY OF MABS ........................................................................................................................ 7 
2.2 
EPIDEMIOLOGY .......................................................................................................................................... 7 
2.2.1 High-risk Patient Populations ............................................................................................................... 7 
2.3 
CLINICAL PRESENTATION AND DIAGNOSTIC CHALLENGES ...................................................................... 8 
2.4 
TREATMENT REGIMENS GUIDELINES AND CHALLENGES .......................................................................... 8 
2.5 
HEALTH RELATED QUALITY OF LIFE ........................................................................................................ 8 
2.6 
THE PATIENT VOICE .................................................................................................................................. 9 
2.7 
GENERATING EVIDENCE USING A RANDOMISED PLATFORM TRIAL DESIGN ............................................ 9 
2.8 
SUMMARY ................................................................................................................................................ 10 
3.1 
PRIMARY OBJECTIVE ............................................................................................................................... 10 
3.2 
SECONDARY OBJECTIVES ........................................................................................................................ 10 
4.1 
ELIGIBILITY CRITERIA ............................................................................................................................. 10 
4.2 
INTERVENTION PROGRAM ELIGIBILITY (APPENDIX A) ........................................................................... 11 
4.2.1 Intervention Program Inclusion Criteria ............................................................................................. 11 
4.2.2 Intervention Program Exclusion Criteria ............................................................................................ 12 
4.3 
OBSERVATIONAL COHORT (APPENDIX B) ............................................................................................... 12 
4.3.1 Observational Cohort Inclusion Criteria ............................................................................................ 12 
4.3.2 Observational Cohort Exclusion Criteria............................................................................................ 12 
4.4 
ADDITIONAL ELIGIBILITY CRITERIA........................................................................................................ 13 
4.5 
TRIAL SETTING AND PARTICIPATING REGIONS ........................................................................................ 13 
4.6 
TRIAL ENDPOINTS .................................................................................................................................... 13 

 
 
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5.1 
SITE INITIATION ....................................................................................................................................... 14 
5.2 
TRIAL DURATION ..................................................................................................................................... 14 
5.3 
RECRUITMENT OF POTENTIAL PARTICIPANTS ......................................................................................... 14 
5.4 
INFORMED CONSENT................................................................................................................................ 14 
5.4.1 Consent to the FORMaT Master Protocol ........................................................................................... 14 
5.4.2 Consent to Specific Appendix Intervention Program(s), Observation, Discovery Sub-Studies and 
Integrated studies ............................................................................................................................................ 15 
5.5 
CORE TRIAL PROCEDURES ....................................................................................................................... 15 
5.5.1 Respiratory Samples for Microbiology Assessment ............................................................................. 18 
5.5.2 Whole Genome Sequencing ................................................................................................................. 19 
5.5.3 Chest Computed Tomography ............................................................................................................. 19 
5.5.4 Spirometry ........................................................................................................................................... 19 
5.5.5 Physical Examination and Vital Signs ................................................................................................. 19 
5.5.6 Six Minute Walk Test ........................................................................................................................... 20 
5.5.7 Medication Review............................................................................................................................... 20 
5.6 
QUALITY ASSURANCE (QA) .................................................................................................................... 20 
5.6.1 Microbiology and DNA Extraction QA ............................................................................................... 20 
5.7 
NOTES ON SPECIFIC TRIAL VISITS ........................................................................................................... 21 
5.7.1 Screening ............................................................................................................................................. 21 
5.7.2 Time Point Start treatment (TPST) ...................................................................................................... 21 
5.7.3 Time Point Final (TPF) ....................................................................................................................... 21 
5.7.4 Early Withdrawal Visit ........................................................................................................................ 21 
5.7.5 Unscheduled Visit ................................................................................................................................ 21 
5.8 
SAFETY MONITORING .............................................................................................................................. 22 
5.8.1 Definition of Adverse Events ............................................................................................................... 22 
5.8.2 Attribution of Adverse Events in the FORMaT Trial ........................................................................... 22 
5.8.3 Definition of Serious Adverse Events .................................................................................................. 22 
5.8.4 Reporting of Safety Events ................................................................................................................... 23 
5.8.5 Coding of Adverse Events for Analysis ................................................................................................ 24 
5.8.6 Toxicology Thresholds ......................................................................................................................... 24 
5.9 
PARTICIPANT WITHDRAWAL AND DISCONTINUATION OF TREATMENT .................................................. 24 
5.9.1 Withdrawal of Consent ........................................................................................................................ 24 
5.9.2 Discontinuation of Treatment .............................................................................................................. 24 
5.10 
DATA MANAGEMENT............................................................................................................................... 28 
5.10.1 Data Collection, Entry and Storage .................................................................................................... 28 
5.10.2 Data Storage and Retention ................................................................................................................. 29 

 
 
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6.1 
BAYESIAN ANALYSIS AND BAYESIAN ADAPTIVE RANDOMISATION (BAR) ........................................... 29 
6.2 
RANDOMISATION ..................................................................................................................................... 30 
6.2.1 Blinding of Treatment Allocation ........................................................................................................ 30 
6.3 
MINIMISATION ......................................................................................................................................... 30 
6.4 
ADDING AND STOPPING INTERVENTIONS ................................................................................................ 31 
6.5 
SEAMLESS PHASE II TO PHASE III............................................................................................................ 31 
6.6 
SIMULATIONS AND STATISTICAL POWER ................................................................................................ 32 
6.7 
GENERAL ANALYSIS PRINCIPLES ............................................................................................................ 32 
7.1 
OVERVIEW ............................................................................................................................................... 32 
7.2 
TRIAL STEERING COMMITTEE ................................................................................................................. 32 
7.3 
INDEPENDENT DATA SAFETY MONITORING BOARD ............................................................................... 32 
7.4 
TRIAL MANAGEMENT COMMITTEE ......................................................................................................... 34 
7.5 
FORMAT PHARMACOVIGILANCE TEAM .................................................................................................. 34 
7.6 
DRUG AND INTERVENTION SELECTION COMMITTEE (DISC) .................................................................. 35 
7.7 
CONSUMER ADVISORY GROUP (CAG) .................................................................................................... 35 
7.8 
MONITORING ........................................................................................................................................... 35 
8.1 
RESEARCH ETHICS APPROVAL AND SITE-SPECIFIC GOVERNANCE ......................................................... 35 
8.1.1 FORMaT Master Protocol and Trial Document Amendments ............................................................ 36 
8.1.2 Protocol Deviations ............................................................................................................................. 36 
8.2 
CONFIDENTIALITY ................................................................................................................................... 37 
8.3 
SITE REIMBURSEMENT ............................................................................................................................. 37 
8.4 
DATA SHARING ........................................................................................................................................ 37 
8.5 
PUBLICATION POLICY .............................................................................................................................. 37 
 
 
 
 

 
 
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TABLE OF TABLES 
Table 1 Special Considerations for Core Trial Procedures and Schedule .................................................................. 16 
Table 2 Core Trial Procedures and Schedule ............................................................................................................. 17 
Table 3: Safety critical monitoring thresholds ............................................................................................................ 25 
 
TABLE OF FIGURES 
Figure 1 Design of the FORMaT Master Protocol and Appendices ............................................................................. 4 
Figure 2 FORMaT participant flow diagram ................................................................................................................ 6 
Figure 3 Participant enrolment into the FORMaT trial. ............................................................................................. 11 
 
 

 
 
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ABBREVIATIONS  
 
ADL 
 
 
Activities of Daily Living 
AE 
 
 
Adverse Event 
AFB 
 
 
Acid-Fast Bacilli 
ATS 
 
 
American Thoracic Society 
BAL 
 
 
Bronchoalveolar Lavage 
BAR 
 
 
Bayesian Adaptive Randomisation 
BCM  
 
Biased Coin Minimisation 
CAG  
 
Consumer Advisory Group 
CF 
 
 
Cystic Fibrosis 
CFTR  
 
Cystic Fibrosis Transmembrane Conductance Regulator 
CI 
 
 
Chief Investigator 
CRF 
 
 
Case Report Form 
CT 
 
 
Computed Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
DISC  
 
Drug and Intervention Selection Committee 
DNA  
 
Deoxyribonucleic Acid 
eCRF  
 
electronic Case Report Form 
eISF 
 
 
electronic Investigator Site File 
eTMF  
 
electronic Trial Master File 
FDA 
 
 
Food and Drug Administration 
FORMaT 
 
Finding the Optimal Regimen for Mycobacterium abscessus Treatment 
GCP 
 
 
Good Clinical Practice 
GDPR  
 
General Data Protection Regulation 
GLI 
 
 
Global Lung Initiative 

 
 
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HRCT  
 
High-Resolution Computed Tomography 
HREC  
 
Human Research Ethics Committee 
IA 
 
 
Inhaled Amikacin 
ICH-GCP  
 
International Council for Harmonisation Good Clinical Practice Guidelines 
ICMJE  
 
International Committee of Medical Journal Editors 
iDSMB  
 
Independent Data Safety Monitoring Board 
IEC 
 
 
Independent Ethics Committee 
IRB 
 
 
Independent Review Board 
ISO 
 
 
International Organization for Standardization 
IV 
 
 
Intravenous 
IVA 
 
 
Intravenous Amikacin 
LAI 
 
 
Liposomal Amikacin for Inhalation 
LLN 
 
 
Lower Limit of Normal 
MABS  
 
Mycobacterium abscessus 
MABS-PD 
 
MABS Pulmonary Disease 
MBS  
 
Medicare Benefits Scheme 
MCRI  
 
Murdoch Children’s Research Institute 
MoOP  
 
Manual of Operating Procedures 
MRL  
 
Mycobacterial Reference Laboratory 
NTM  
 
Non-Tuberculous Mycobacteria 
PBS 
 
 
Pharmaceutical Benefits Scheme 
PI 
 
 
Principal Investigator 
PICF  
 
Participant Information and Consent Form 
PK 
 
 
Pharmacokinetics 
QA 
 
 
Quality Assurance 
QoL 
 
 
Quality of Life 

 
 
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R-Con  
 
Randomisation – Consolidation 
RCT 
 
 
Randomised Control Trial 
REDCap 
 
Research Electronic Data Capture 
REMAP-CAP  
Randomised, Embedded, Multifactorial Adaptive Platform trial for Community-
Acquired Pneumonia  
R-PI/IC 
 
Randomisation – Prolonged Intensive or Immediate Consolidation 
rRNA  
 
ribosomal ribonucleic acid 
R-SI 
 
 
Randomisation – Short Intensive  
SAEs  
 
Serious Adverse Events 
SAHMRI 
 
South Australian Health and Medical Research Institute 
SIV 
 
 
Site Initiation Visit 
SOP 
 
 
Standard Operating Procedure 
SSI 
 
 
Significant Safety Issues 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TB 
 
 
Tuberculosis 
TDM  
 
Therapeutic Drug Monitoring 
TMC  
 
Trial Management Committee 
TPF 
 
 
Time Point Final 
TPST  
 
Time Point Start Treatment 
TSC 
 
 
Trial Steering Committee 
ULN 
 
 
Upper Limit of Normal 
USMs  
 
Urgent Safety Matters 
UQ 
 
 
University of Queensland 
WGS  
 
Whole Genome Sequencing 
6MWD 
 
Six-minute walk distance  
6MWT  
 
Six-minute walk test  

 
 
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PRINCIPAL INVESTIGATORS STATEMENT 
 
I confirm that I have read the FORMaT Master Protocol Version 4.1, dated 20th February 2024. As the Principal 
Investigator, I understand it, and I agree to adhere to the study conduct requirements and agree to conduct this protocol 
in accordance with International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), the 
Declaration of Helsinki, the United States (US) Food and Drug Administration (FDA), and local regulations and 
guidelines.  I agree to report all information or data in accordance with the protocol, and in particular I agree to report 
any serious adverse events.  I will accept the monitors’, auditors’ and regulatory inspectors’ oversight of the study.  
I will promptly submit the protocol to the applicable ethical review board as required. 
 
………………………………………………………………………………………………...... 
Principal Investigator Signature 
 
………………………………………………………………………………………………….. 
Principal Investigator Name 
 
………………………………………………………………………………………………….. 
Date (dd/mmm/yyyy) 

 
 
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1 
INTRODUCTION 
1.1 
SYNOPSIS 
Background: Mycobacteria in the Mycobacterium abscessus group (MABS) are a species of non-tuberculous 
mycobacteria (NTM) found in water and soil habitats that exhibit high levels of intrinsic multi-drug resistance (1).  
NTM includes more than 160 species that are recognised opportunistic human pathogens, with chronic pulmonary 
infections the most common clinical presentation.  Individuals with underlying inflammatory lung diseases are more 
susceptible to MABS pulmonary disease (MABS-PD), but MABS also affects patients with no underlying condition.  
MABS-PD can result in significant morbidity, increased healthcare utilisation, accelerated lung function decline, 
impaired quality of life (QoL) (2), more challenging lung transplantation (3), and increased mortality (2).  Of 
particular concern is the increasing prevalence of pulmonary infections occurring worldwide in patients with 
bronchiectasis and cystic fibrosis (CF), with prevalence between 5 to 20% (2, 4, 5).  There is real evidence of this in 
Queensland, Australia (where the infection is notifiable) with the prevalence increasing from 0.85/100,000 in 2001 
to 2.35/100,000 in 2016, where now over 100 cases are reported annually, clearly illustrating the emerging threat of 
this infection.  While the increasing prevalence might be reflective of enhanced surveillance and improved 
microbiological detection (6-8) (9) the reasons for this changing epidemiology are poorly understood (2, 4, 10, 11). 
Treatment regimens for MABS are highly variable, not evidence-based and involve complex, expensive, and often 
poorly tolerated drug combinations for prolonged periods (>12 months).  Some individuals will have positive cultures 
that clear spontaneously, some will initially have positive cultures without obvious MABS-PD but go on to develop 
disease at a later stage, and some may present with established MABS-PD.  MABS-PD can be associated with a rapid 
decline in health status, and there is evidence that successfully clearing infection is associated with better health 
outcomes (12, 13).  However, toxicity, poor tolerance and the prolonged and complex nature of therapy may increase 
the reluctance of clinicians to initiate treatment and for patients to accept it.  A recent systematic review and meta-
analysis revealed that such treatment regimens are often ineffective and may even worsen QoL (14).  The costs and 
treatment burden of NTM infection are high, and highest for MABS-PD, estimated at $AUD12-28,000/month (15) 
highlighting the need to assess the healthcare costs and cost-effectiveness of therapies to inform health policy around 
NTM.  Pathogen, host, and treatment factors all likely play a role in clinical and microbiological outcomes. 
 
Aims: 
1. To build an iterative, standing, platform trial with innovative and adaptive properties to evaluate combinations 
of therapies for patients with MABS-PD.  Initially this will test therapies that are currently used and 
recommended in published international consensus guidelines and are the basis for the current treatment 
guidelines for MABS-PD.  Once the best combinations have been established the platform described in the 
Master Protocol will have the capacity to add new treatments and to eliminate therapies because of futility as 
they either lack efficacy or cause unacceptable toxicity.  The data obtained as part of the trial will be used to plan 
for new waves of the platform trial using novel therapeutic approaches that may be tested against the previously 
determined optimal approaches, thus leading in an iterative fashion to improving microbiological clearance and 
health outcomes associated with MABS-PD. 

 
 
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2. To use the opportunities afforded by the clinical trial platform to establish discovery studies to: 
i. 
Understand the effects of MABS-PD and therapeutic interventions on health-related quality of life and 
determine the cost effectiveness of proposed therapy combinations; 
ii. 
 To develop strategies for optimising drug dosing using robust pharmacokinetics; 
iii. 
 Understand susceptibility to MABS-PD and develop biomarkers of clinical disease, disease progression 
and response to therapy; 
iv. 
 Investigate the genomics of human MABS strains and antibiotic resistance genes and impact of 
therapeutic interventions. 
3. To investigate the use of registries to facilitate the long-term monitoring of patient outcomes from MABS-PD 
and treatment. 
 
Methodology: Entry into the Finding the Optimal Regimen for Mycobacterium abscessus Treatment (FORMaT) 
trial can occur at two different levels; 
1 - participants of any age from their first MABS isolate and not receiving current MABS therapy are eligible to enrol 
in the Observational Cohort and; 
2 - participants of any age meeting the American Thoracic Society (ATS) criteria for the diagnosis of MABS-PD and 
are untreated for MABS-PD at the time of starting intensive therapy are eligible to enrol in the Intervention Program.  
Participants initially enrolled into the Observational Cohort who go on to meet the ATS criteria for MABS-PD can 
transition to the Intervention Program at any time.  Intervention Program participants will be randomised to receive 
MABS-PD therapy combinations and additional outcomes will be assessed. 
Participants in both the Observational Cohort and Intervention Programs will contribute the same core data, thus 
providing the opportunity to examine what happens to both treated and untreated patients with positive cultures 
longitudinally as well as the transition to MABS-PD.   
 
Primary Outcome 
The primary outcome of the Intervention Program is microbiological clearance of MABS with good tolerance of the 
interventions. 
Definition of MABS clearance at final outcome: 
Negative MABS cultures from four consecutive sputum samples with one of those sputum specimens collected four 
weeks after the completion of consolidation therapy, or a MABS negative Bronchoalveolar Lavage (BAL) collected 
four weeks after completion of consolidation. 
Definition of tolerance: 
Tolerance is based on the Common Terminology Criteria for Adverse Events (CTCAE version 5.0).  Only adverse 
events that are attributed as either “possibly-“, “probably-“, or “definitely-“ related to study drug will be assessed in 
the determination of tolerance.  “Good” tolerance is defined as no adverse events occurring or only adverse events 
coded as CTCAE grades 1 and 2. “Poor” tolerance is defined as any adverse events attributed as possibly-, probably-
, or definitely-related to study drug coded as CTCAE grades 3, 4, or 5. 

 
 
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The Intervention Program within the FORMaT platform will adopt an adaptive design with Bayesian Adaptive 
Randomisation (BAR) when there is randomisation across three or more interventions and may also include interim 
rules for dropping or adding treatment arms. BAR allows the randomisation probabilities to each of the interventions 
to be updated during the trial to enable more participants to be randomised to more promising interventions. The 
probabilities of allocation to each intervention are based on the posterior probability of the intervention being superior 
to the control (16). The approach used will carry forward the most promising arms that achieve a minimum level of 
efficacy with acceptable toxicity. If a treatment is carried forward until the end it will be tested against the 
control/reference group and recommended if the test statistic is above a certain threshold. The Intervention Program 
will consist of treatment modules specified in Appendix A starting with sequential Phase II trials, including a 
randomised intensive treatment phase, and a randomised consolidation treatment phase. In the future, interventions 
reaching a probability threshold of demonstrating success at the end of the Phase II trial will have the potential to 
seamlessly continue to recruit to a Phase III study to enable the Phase II data to be utilised as part of a Phase III study, 
thus reducing the resources required to achieve high quality evidence on which to base treatments.  
The FORMaT Master Protocol describes the adaptive platform trial to evaluate microbiological, functional, 
radiological, and quality of life outcomes of interventions utilised in the treatment of MABS-PD, in combination 
with the Observational Cohort. 
 
1.2 
PROTOCOL STRUCTURE 
The FORMaT trial is designed as a standing iterative, platform trial with innovative and adaptive properties.  This is 
reflected in the multi component structure of the FORMaT Protocol outlined in Figure 1.  The framework for the 
FORMaT trial is established within the FORMaT Master Protocol.  The Intervention Program(s), the Observational 
Cohort, Discovery, Registry Linkage studies, Health Economics and General Statistical Principles are described in 
specific Appendices. 
 
 
Figure 1 Design of the FORMaT Master Protocol and Appendices
                                                                       
               
          
            
        
          
        
       
       
          
             
      
          
         
       
          
      
         
          
       
           
          

 
 
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1.3 
FORMAT MASTER PROTOCOL 
The FORMaT Master Protocol outlines the core structure, procedures, and processes of the FORMaT trial.  The 
information described in the FORMaT Master Protocol applies to all participants regardless of if they are receiving 
intervention treatment for MABS-PD or are enrolled in the Observational Cohort, unless otherwise stated. 
The Master Protocol has the following structure: 
• 
The background and rationale for determining the optimal treatment regimens for MABS-PD. 
• 
The overarching objectives of the FORMaT trial (including both the Intervention Program and the 
Observational Cohort). 
• 
The design of the FORMaT trial including the two-level approach to assessing eligibility into the trial, the 
trial endpoints and the general statistical principles to be used in the analysis of the trial. 
• 
The conduct of the FORMaT trial detailing recruitment methods and consent processes, the core trial 
timepoints and procedures, safety monitoring processes and data management procedures. 
• 
Details of The FORMaT trial oversight, ethical and administrative considerations. 
 
1.3.1 
FORMAT APPENDICES AND SUPPLEMENTS 
The FORMaT Appendices describe in detail the information specific to the Appendices and the sub-studies and 
integrated studies nested within them. As such, appendix specific information is not described within the FORMaT 
Master Protocol but rather the Master Protocol sets the framework within which the Appendices exist.  As the trial 
progresses, new interventions and methodologies can be added to the FORMaT trial through the addition of a new 
appendix.  Conversely, as interventions and methodologies are found to be futile the corresponding studies in the 
appendix can be removed.  It is not anticipated that these changes will affect the framework of the Master Protocol.  
Any changes to appendix specific studies require ethics approval. 
The FORMaT Supplements are additional documents that expand the scope of the relevant appendices.  They provide 
additional detail and information to supplement the specific appendix they are linked to.  Changes to supplements do 
not require ethical approval as they are not a part of the Master Protocol or appendices but are an additional document 
to elaborate on the specific components contained within an appendix.  FORMaT Appendices are structured as 
follows: 
• 
Each appendix has a theme: for example, Appendix A for Interventions, Appendix B for Observation, 
Appendix C for Discovery studies, Appendix D for Registry Interactions, Appendix E for Health Economics, 
and Appendix F for General Statistical Principles. 
• 
Appendix A describes the details for the Intervention Programs of the FORMaT Trial including intensive 
and consolidation interventions (Figure 2).  For example, Appendix A1 describes the first of such 
Intervention Programs and if new interventions are added to either the intensive or consolidation phases these 
would be added in new Appendices A2, A3 etc.  Data from previous programs using the same intervention 
combinations may be incorporated in the analysis of a new program.  Thus, data from Appendix A1 could 
be combined with data from Appendix A2 for example. 

 
 
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• 
Within some of the Appendices are nested studies that have been designed to investigate specific objective(s). 
The components described within each appendix are variable and dependant on the nature of the appendix and the 
studies nested within it.  Overall, FORMaT Appendices will contain the following components: 
• 
The overall objective specific to that appendix. 
• 
Where relevant, information about the features of the interventions or the study to be investigated. 
• 
Appendix specific eligibility criteria. 
• 
Appendix specific consent requirements. 
• 
Appendix specific procedures and safety measures to be assessed. 
• 
Appendix specific statistical methods and simulations where relevant. 
 
Figure 2 FORMaT participant flow diagram 
Eligibility into the Intervention Program or Observational Cohort is determined at Screening.  For the first iteration 
of the Intervention Program, there will be up to three randomisations between Screening and the Final Outcome Visit.  
Symbols (▲✢) indicate possible randomisation points (see the relevant appendix for further information on 
randomisation). 
 
 
   
                 
              
                         
     
         
 
     
         
 
     
         
 
      
         
    
   
              
              
                        
 
 
 
              
         
        
              
              
                        
 
         
              
              
                        
 
         
         
       
                          
              
              
                        
 
                          
      
     
         
       
 

 
 
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2 
BACKGROUND 
2.1 
MICROBIOLOGY OF MABS 
Of the many pathogenic NTM species, MABS are recognised as causing the most serious pulmonary infections, 
associated with the greatest problems of antibiotic resistance, toxicity and treatment failure (12, 17).  MABS are 
currently divided into 3 subspecies: M. abscessus subspecies abscessus (M. a. abscessus), subs. massiliense (M. a. 
massiliense) and subs. bolletii (M. a. bolletii).  While there is variation in the prevalence of the subspecies in different 
populations, M. a. abscessus is the most common overall (45-68%), followed M. a. massiliense (20-55%) and M. a. 
bolletii (8-25%) (18-20).  Progression of MABS-PD due to the different subspecies (21) appears to be similar, 
although treatment outcomes vary significantly and are partially explained by differential antimicrobial susceptibility 
to macrolide antibiotics.  MABS are intrinsically drug resistant to multiple classes of antibiotics and they can also 
acquire antibiotic resistance genes to macrolides and aminoglycosides, leading to clearance rates of ≈50% following 
intensive therapy (19, 22, 23).  After apparently successful treatment, relapse or recurrences with new strains occur 
in 15-33% of patients (19).  Nevertheless, macrolides provide the therapeutic backbone of guideline-based MABS 
treatment (1, 4).  Furthermore, they are the only antibiotic class where there is some correlation between in vitro 
susceptibility data and clinical response (14).  Macrolide resistance in MABS is either constitutive or inducible (20).  
The less common, constitutive resistance may be acquired during macrolide therapy and results from mutations in 
the 23S rRNA gene (rrl).  Inducible macrolide resistance is related to the MABS ribosomal methyl transferase gene, 
erm(41).  Such isolates appear susceptible at day 3 following infection, but resistant by day 14 using prolonged 
incubation drug susceptibility testing.  M. a. massiliense has a truncated and dysfunctional erm(41) gene, thus making 
it more susceptible to macrolides, whereas M. a. abscessus and M. a. bolletii usually, but not invariably, have 
inducible resistance (20).  It is not surprising then that microbiological cure rates of MABS-PD appear partly related 
to macrolide resistance with clearance rates up to 88% in those with macrolide susceptible isolates, and only 36% in 
the setting of inducible macrolide resistance (19).  Molecular detection of the subspecies, including identifying the 
erm(41) and rrl genes is important in understanding treatment response, and potentially targeting novel treatment 
approaches. 
 
2.2 
EPIDEMIOLOGY 
NTM can cause both asymptomatic and symptomatic infections in humans (1).  Pathogenic strains of MABS have 
been isolated from potable water, and MABS infections are more prevalent in coastal areas and regions with humid 
tropical climates (12, 24, 25).  While most infections are thought to be acquired from environment aerosols (26), in 
patients with CF there is evidence supporting the emergence of worldwide dominant clones (of increased virulence) 
that may be capable of patient-to-patient transmission (18). 
 
2.2.1 
HIGH-RISK PATIENT POPULATIONS 
CF is an autosomal recessive condition caused by mutations in the CF transmembrane conductance regulator (CFTR) 
gene.  Mortality and morbidity of CF patients are predominantly related to chronic suppurative lung disease (27).  CF 

 
 
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is a risk factor for MABS-PD (and NTM more broadly) and even carrier status of disease-causing mutation in CFTR 
(24) may also increase risk.  Other structural lung diseases, bronchiectasis, chronic obstructive pulmonary disease, 
previous mycobacterial disease (including Tuberculosis (TB) and NTM), severe gastro-oesophageal reflux and 
immunosuppression (where dissemination can occur) (11) also increase risk of infection.  The age range of CF and 
non-CF affected patients with MABS-PD overlap, with non-CF patients generally being older than those with CF 
(>55 vs <30 years) (24). 
 
2.3 
CLINICAL PRESENTATION AND DIAGNOSTIC CHALLENGES 
Due to their ubiquitous nature, the clinical significance of positive MABS cultures in respiratory specimens can be 
challenging.  It may appear transiently in sputum cultures, persistently colonise the lower airways or progress to 
MABS-PD.  The radiological and clinical features of underlying chronic respiratory disorders overlap considerably 
with changes attributable to MABS-PD making diagnosis and treatment decisions difficult and care is required to 
follow the ATS criteria in making the diagnosis of MABS-PD.  Inclusion into the intervention program(s) will require 
meeting all the ATS criteria including both microbiological and clinical criteria. 
 
2.4 
TREATMENT REGIMENS GUIDELINES AND CHALLENGES 
MABS treatment outcomes differ according to the etiologic organism.  Recurrence rates for infection are high, despite 
successful treatment completion (28) but these approaches have not been evaluated in any trials.  Differing treatment 
outcomes present multiple therapeutic challenges in the treatment of MABS.  In recognition of these challenges, the 
ATS and the United States CF Foundation/European CF Society have published guidelines on NTM pulmonary 
disease (1, 4).  In agreement with the latest Cochrane Review (29), they note there are no drug regimens of proven or 
predictable efficacy for treating MABS.  Therefore, the guidelines are based on expert opinion only and in practice 
the treatments vary considerably (30).  Suggested regimens include an intensive phase of 4-12 weeks (based on 
microbiological response) of intravenous (IV) antibiotics (usually amikacin, cefoxitin or imipenem + tigecycline) 
plus an oral macrolide.  This is followed by consolidation therapy that includes oral drugs (usually a macrolide, plus 
others based on antibiograms, tolerability and experience) and an inhaled IV formulation of amikacin for 3 to >12 
months.  Dosing by individual pharmacokinetic (PK) data and therapeutic drug monitoring (TDM) may lead to 
optimal drug levels at infection sites and better treatment outcomes, although measuring levels within the lower 
airways frequently and non-invasively is challenging.  Few PK studies involving antibiotics for NTM have been 
performed and few assays are currently available.  Inhaled antibiotics have the potential advantages of achieving 
higher airway concentrations, while reducing the risk of systemic toxicity. 
 
2.5 
HEALTH RELATED QUALITY OF LIFE 
A recent systematic review and meta-analysis revealed that MABS treatments are often ineffective and may even 
worsen QoL (14).  The review strongly recommended that “clinical, functional and QoL parameters should be given 
more emphasis in the evaluation of treatment outcomes” and that “better applications of current antibiotics are 

 
 
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urgently needed” (14, 30).  In addition, the costs and the treatment burden of NTM infection are high, and highest 
for MABS-PD; estimated at $AUD12-28,000/month (15), highlighting the need to assess the healthcare costs and 
cost-effectiveness of therapies to inform health policy around NTM.  Pathogen, host and treatment factors are all 
likely to play a role in clinical and microbiological outcomes.  Consequently, there is an urgent need for evidence to 
support treatment decision-making for patients with MABS lung infection. 
 
2.6 
THE PATIENT VOICE 
In October 2015, the Food and Drug Administration (FDA) held a public meeting on NTM infection with patients 
and carers with the key theme to emerge (31) being the need for better, less toxic treatment with lower therapeutic 
burden.  Participants also prioritised “validating and using tools to measure QoL and developing disease specific 
activity and severity assessment tools” (32).  In January 2017, The James Lind Alliance released their top 10 research 
priorities for people with CF developed by CF patients, their families, and healthcare providers.  The third top priority 
was “What is the best treatment for NTM, including when to start and what medication?” (33).  Patients and 
healthcare providers are asking for evidence to guide the best approaches to manage this challenging infection. 
A consumer representative is a member of the FORMaT Trial Steering Committee and will be involved in the ongoing 
oversight of the trial.  In addition, the FORMaT consumer advisory group will enable a range of consumers to 
participate in the review of the protocol, trial development plans and consumer materials.  The consumer group will 
be able to provide their views and advice which will then be taken on board by the investigators and trial management 
team. 
 
2.7 
GENERATING EVIDENCE USING A RANDOMISED PLATFORM TRIAL 
DESIGN 
Platform trials using Bayesian statistical models, provide the opportunity to efficiently investigate multiple treatments 
for difficult-to-treat infections (e.g. multi-drug resistant TB (34)) requiring complex drug regimens in a 
heterogeneous population and can provide an iterative resource facilitating the translation of findings to improve 
clinical outcomes (35-37).  New adaptive trial approaches are now recognised and accepted by regulatory authorities, 
including the FDA.  Such trials are now being used in infectious diseases (38)  and TB (34), complex chronic diseases 
(36) and rare oncology conditions (39).  MABS-PD is a serious but relatively rare problem which can benefit from 
such methodology.  FORMaT provides a common platform that will enable a broad enrolment of patients who both 
do and do not have cystic fibrosis and across all ages that enables generalisability but also maintains the ability to 
examine the heterogeneity of treatment responses across specific subgroups, while also enabling a comparison with 
non-treated patients through an Observational Cohort who are followed up simultaneously.  The ability to examine 
novel therapeutic approaches using a common platform, along with the option to seamlessly move from phase II to 
phase III if warranted, also reduces the resources and the time required to deliver evidence-based treatments to 
patients who need it compared with conducting a series of independent trials. 

 
 
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2.8 
SUMMARY 
There is no evidence currently to guide therapy for MABS-PD, a complex and increasing health problem.  The 
FORMaT trial seeks to provide answers to key questions by healthcare providers and patients on the timing and 
nature of treatments for the growing number of people infected with MABS, as well as the potential to model the 
progression of this condition in both treated and untreated patients.  Furthermore, the trial will provide a platform for 
improving health outcomes for MABS patients and build a solid foundation for future testing of new therapeutics in 
the treatment of MABS. 
 
3 
OBJECTIVES 
3.1 
PRIMARY OBJECTIVE 
To determine the optimal therapy for the treatment of patients with MABS-PD. 
 
3.2 
SECONDARY OBJECTIVES 
1. To investigate the optimal approaches to antibiotic dosing and therapeutic drug monitoring. 
2. To investigate the health-related quality of life and cost effectiveness of proposed therapy combinations. 
3. To examine changes in clinical markers such as chest imaging and lung function to predict the onset of 
MABS-PD and response to therapies. 
4. To develop biomarkers to predict the onset of MABS-PD and response to therapies. 
5. To understand susceptibility to infection with MABS associated with the development of MABS-PD and host 
immune responses to infection and with treatment. 
6. To characterise the genomics of human MABS strains and antibiotic resistance genes in patients in the 
observation and intervention studies. 
 
4 
TRIAL DESIGN 
4.1 
ELIGIBILITY CRITERIA 
Eligibility criteria for the FORMaT trial can be applied at two levels: 
1. Eligibility into the Intervention Program, or; 
2. Eligibility into the Observational Cohort. 
Potential participants can only be enrolled in either the Intervention Program or the Observational Cohort at any one 
time.  Provided the eligibility criteria are met, potential participants may either: 
1. Enrol directly into the Intervention Program, or; 
2. Enrol into the Observational Cohort and transition into the Intervention Program once they satisfy the 
inclusion criteria for this program which can occur at any time during the trial (see Figure 3). 
 

 
 
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Figure 3 Participant enrolment into the FORMaT trial. 
Eligibility into the FORMaT trial will be assessed at screening. Observational Cohort participants who go on to meet 
the Intervention Program eligibility criteria can transition from the Observational Cohort to the Intervention Program. 
 
4.2 
INTERVENTION PROGRAM ELIGIBILITY (APPENDIX A) 
Potential participants are eligible for the Intervention Program (Appendix A) if the criteria below are met.  Eligible 
participants with mixed NTM infections (slow growers + MABS) or with recurrence of MABS infection following 
completion of previous treatment  will be eligible if they meet the inclusion and exclusion criteria listed below.  For 
eligible participants with mixed NTM infections additional therapy combinations are available as detailed in the 
relevant appendices. 
 
4.2.1 
INTERVENTION PROGRAM INCLUSION CRITERIA 
1. 
Positive MABS-PD diagnosis meeting all three American Thoracic Society clinical, radiological and 
microbiological diagnostic criteria for MABS-PD. Defined as: 
a. 
Clinical: Pulmonary symptoms and exclusion of other diagnoses. 
b. 
Radiological: Nodular or cavitary opacities on chest radiograph or a chest high-resolution computed 
tomography (HRCT) scan showing multifocal bronchiectasis with multiple small nodules. 
c. 
Microbiological: MABS positive culture results from at least two separate expectorated sputum 
samples. 
or 
Positive culture results from at least one bronchial wash or lavage. 
 
or 
F RMAT
Eligibility Criteria
Assessed
Intervention
Program
 bservational
Cohort

 
 
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Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous 
inflammation or acid-fast bacilli (AFB)) and positive culture for NTM or biopsy showing 
mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum 
or bronchial washes that are culture positive for NTM. 
Screening samples must be collected within the timeframes stated in the relevant appendix. 
2. 
Male or female participants of any age. 
3. 
Participant has not received treatment for MABS-PD in the 12 months preceding assessment of eligibility 
or as specified in the relevant appendix (this includes drugs prescribed for the treatment of other 
mycobacteria and/or other indications that may have activity against MABS, as specified in the FORMaT 
Prohibited Drug List Standard Operating Procedure (SOP)). 
4. 
Informed consent signed by participant or parent/legal guardian if participant is under 18 years of age. 
5. 
Ability to comply with study visits, therapies and study procedures as judged by the site investigator. 
 
4.2.2 
INTERVENTION PROGRAM EXCLUSION CRITERIA 
• 
Participants receiving current treatment for MABS (this includes drugs prescribed for the treatment of other 
mycobacteria and/or other indications that may have activity against MABS, as specified in the FORMaT 
Prohibited Drug List SOP), except for participants taking azithromycin as part of routine treatment for CF or 
chronic infection-related pulmonary disease, or as specified in the relevant appendix. 
• 
Participants who have a QTc interval of >500 milliseconds (QT interval corrected based on Fridericia 
method). 
• 
Participants who are pregnant or planning to continue breast feeding. 
• 
Known hypersensitivity to any of the therapies for which no alternative option(s) have been provided. 
 
4.3 
OBSERVATIONAL COHORT (APPENDIX B) 
4.3.1 
OBSERVATIONAL COHORT INCLUSION CRITERIA 
To be eligible to participate in the Observational Cohort the following criteria must be met: 
1. Male and female participants of any age with at least one positive respiratory culture for MABS. 
2. Informed consent signed by participant or parent/legal guardian if participant is under 18 years of age. 
3. Ability to comply with study visits and study procedures as judged by the site investigator. 
 
4.3.2 
OBSERVATIONAL COHORT EXCLUSION CRITERIA 
Potential participants will be ineligible to participate in the Observational Cohort if any of the following criterion are 
met: 

 
 
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• 
Receiving active treatment for MABS within the previous 12 months (this includes drugs prescribed for the 
treatment of other mycobacteria and/or other indications that may have activity against MABS, as specified 
in the FORMaT Prohibited Drug List SOP, except for participants taking azithromycin as part of routine 
treatment for CF or chronic infection-related pulmonary disease). 
 
4.4 
ADDITIONAL ELIGIBILITY CRITERIA 
Mixed NTM infections 
Participants who have cultured slow growing NTM of the same species two or more times in the 24 months prior to 
screening, with one of those cultures within the 6 months prior to screening, will be considered to have mixed NTM 
infection at the time of screening.  The participants must meet all other inclusion criteria and no exclusion criteria to 
be eligible for participation.  Ethambutol may be used in addition to trial therapies to cover mixed NTM infections 
considered to require treatment by their clinician. 
Appendix specific sub-studies and integrated studies  
Appendix specific sub-studies and integrated studies may have additional eligibility criteria which are described in 
each of the relevant appendices. 
 
4.5 
TRIAL SETTING AND PARTICIPATING REGIONS 
The trial will be conducted in multiple regions and trial sites.  There is no limit to the number of countries or 
participating sites.  A list of participating countries and sites are available on the FORMaT trial website 
(www.formattrial.com) and the clinical trial registries and will be updated as required. 
Race and Ethnicity 
Race and ethnicity will be collected as part of the demographic information for each participant. This information 
may be used to determine whether there are any potentially clinically significant racial and/or ethnic differences in 
the effects of any trial interventions. 
 
4.6 
TRIAL ENDPOINTS 
The primary outcome for the FORMaT Trial (Appendix A Intervention Program) is MABS clearance from 
respiratory samples with treatment tolerance.  MABS clearance is defined as negative MABS cultures from four 
consecutive sputum samples with one of those sputum specimens collected four weeks after the completion of 
consolidation therapy or a MABS negative Bronchoalveolar Lavage (BAL) collected four weeks after completion of 
consolidation therapy. 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be applied for the coding of all 
adverse events (AEs) and serious adverse events (SAEs) that occur during the FORMaT trial that are categorised as 
“possibly-”, “probably-,” or “definitely-” related to study medications and/or interactions between study medications 

 
 
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and concomitant medications.  “Good” tolerance will be defined as no adverse events occurring or only adverse 
events coded CTCAE grades 1 or 2. “Poor” tolerance will be defined as any adverse events coded as CTCAE grades 
3, 4, or 5. 
The primary outcome of the FORMaT Trial will be assessed as per the relevant appendices. 
 
5 
TRIAL CONDUCT 
5.1 
SITE INITIATION 
The FORMaT Trial is a multicentre, international clinical trial and the initiation of the FORMaT Master Protocol 
(including the Appendices) will be staggered across trial sites.  This staggered approach will allow the FORMaT 
Trial Management Team to closely examine the effectiveness of the FORMaT Trial Master Protocol.  Any changes 
required to improve the trial processes can be shared and implemented in other trial sites prior to site initiation.  The 
FORMaT Trial will open in Australia, and as feasible expand to other countries including centres in Europe, the 
United Kingdom, the Asia Pacific Region, Canada and North and South America.  Site activation and initiation will 
be performed in accordance with the FORMaT Site Initiation and Activation SOP. 
 
5.2 
TRIAL DURATION 
The FORMaT Master Protocol describes a standing platform trial with an innovative design tailored to the clinical 
setting that will enable new therapies to be tested as they become available.  As such, there is no specific limit to the 
duration of the FORMaT trial while there is clinical need for the trial except for logistic issues which include trial 
funding.  A detailed outline of the trial timeline for participants is described in the relevant appendix. 
 
5.3 
RECRUITMENT OF POTENTIAL PARTICIPANTS 
Potential participants will be identified at study sites by the treating physician.  Once identified, potential participants 
or their parent/guardian will be approached by the FORMaT Trial site-specific research team or treating physician to 
discuss the FORMaT trial and provided with the FORMaT Participant or Parent/Guardian Information and Consent 
Forms (PICFs).  The FORMaT Trial site-specific research team members will allow participants and/or their 
parent/guardian adequate time to read the PICFs and an opportunity to ask any trial related questions and to have 
these questions answered to the satisfaction of the potential participant or their parent/guardian. 
 
5.4 
INFORMED CONSENT 
5.4.1 
CONSENT TO THE FORMAT MASTER PROTOCOL 
In accordance with the International Council for Harmonisation Good Clinical Practice Guidelines (ICH-GCP) and/or 
the Declaration of Helsinki, consent to the FORMaT Master Protocol will be obtained by the FORMaT trial site-
specific research team prior to any study related procedures being performed or study data being collected.  All 

 
 
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participants, regardless of whether they are enrolled in the Observational or Intervention Program are required to 
consent to the FORMaT Master Protocol.  If the participant is under 18 years of age or unable to provide consent 
(due to severe cognitive impairment, an intellectual disability, or a mental illness, including patients with dementia) 
then informed consent will be obtained from the participant’s parent/legal guardian in accordance with FDA guidance 
(40).  Where it is expected that the subject population will not understand English, the written participant information 
and consent forms will be translated into the anticipated specific language that will be understood in accordance with 
FDA guidance (40).  Participants who are enrolled and are under 18 years of age who turn 18 during the study period 
will require re-consent on the adult consent form.  Telephone consent, re-consent, and re-consent via email will be 
acceptable (using the informed consent checklist outlined in the FORMaT Trial Site Manual of Operating Procedures 
(MoOP)) when face-to-face consent is not possible. 
The FORMaT Master Protocol consent form is required to be signed and dated by the individual providing consent 
or the participant’s parent/guardian where appropriate.  A copy of the signed consent form will be given to the 
participant or their parent/guardian for their records with the original signed consent form(s) stored at the site in the 
participant’s medical record and a copy of the signed consent form(s) stored in the participant’s study file.  Any 
Independent Review Board (IRB) / Independent Ethics Committee (IEC) / Human Research Ethics Committee (HREC) 
approved changes to the trial Master Protocol that affect the participant’s rights and/or safety will require the 
participant’s reconsent. 
 
5.4.2 
CONSENT 
TO 
SPECIFIC 
APPENDIX 
INTERVENTION 
PROGRAM(S), 
OBSERVATION, DISCOVERY SUB-STUDIES AND INTEGRATED STUDIES 
If a participant meets the eligibility criteria for the FORMaT Appendices and/or specific sub-studies and integrated 
studies, additional appendix specific consent will be required in accordance with the procedures detailed above in 
section 5.4.1.  Appendix specific consent requirements are detailed in the appendices.  If additional sub-studies and/or 
integrated studies are added or removed from an appendix, or any changes are made to the appendix specific sub-
studies and/or integrated studies, IRB/IEC/HREC approval for these changes will be sought.  Reconsent will be 
required for additional trial specific procedures and changes that affect the participant’s rights and/or safety. 
 
5.5 
CORE TRIAL PROCEDURES 
Table 1 lists the special considerations that are applicable to Table 2 Core Trial Procedures and Schedule.  Scheduling 
of core trial procedures (including collection time points) are detailed in Table 2 and in the Schedule of Assessment 
Tables in the relevant appendix. 

 
 
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Table 1 Special Considerations for Core Trial Procedures and Schedule 
Symbol 
Definition 
A 
Trial phases relate to various stages of treatment, participant cohorts and/or FORMaT substudies as outlined in the relevant appendices. 
B 
Start of trial phase, Interim and End of trial phase visits are required for FORMaT participants as per the Schedule of Assessments in the relevant appendices. 
C 
Participant reconsent is required with IRB/ IEC/HREC approved changes to the protocol that affect participants’ rights and/or safety and/or if a child turns 18 
years old during the trial and must reconsent as an adult participant. 
D 
MABS-PD status reviewed in accordance with the ATS criteria as per the Schedule of Assessments in the relevant appendices. 
E 
Respiratory Samples are required to be collected for FORMaT participants as per the Schedule of Assessments in the relevant appendices. 
F 
Participants unable to produce a sputum sample (expectorated or induced) to be marked as unproductive on the CRF. 
G 
If participants are unable to provide the minimum requested sputum samples as per the Schedule of Assessments in the relevant appendices, then a BAL sample 
is to be collected. 
H 
Adult participants require height to be recorded once only during the study (ideally at the Screening Visit). 
I 
Adult participants do not require weight to be measured at every visit. 
J 
Chest CT Scan at early withdrawal visit will only be requested if clinically indicated. 
K 
Safety/Toxicology Monitoring assessments are to be performed as per the Schedule of Assessments in the relevant appendices. 
L 
Specific Health Related Quality of Life questionnaires are required to be completed by FORMaT participants as per the Schedule of Assessments in the relevant 
appendices. 
M 
Six-minute walk test to be performed in participants ≥ 18 years of age only. 

 
 
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Table 2 Core Trial Procedures and Schedule 
Assessments 
Screening Visit 
Start of Trial 
Phase A 
Interim Visit(s) 
End of Trial 
Phase A 
Final Outcome 
Early 
Withdrawal Visit 
Clinic Visit 
✓ 
✓B 
✓B 
✓B 
✓ 
✓ 
Informed Consent C 
✓ 
 
 
 
 
 
Review Eligibility 
✓ 
 
 
 
 
 
MABS-PD Status 
✓ 
 
✓D 
 
✓D 
✓D 
Randomisation 
 
✓ 
 
 
 
 
Medication Review 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Respiratory Sample 
✓ 
 
✓E/F/G 
✓E/F/G 
✓E/F/G  
✓E/F 
Height H and Weight I 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Spirometry 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Chest Computed Tomography 
✓ 
 
 
 
✓ 
✓J 
Physical Examination 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Safety/Toxicology Monitoring K 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Health Related Quality of Life 
Questionnaires L 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Costs Questionnaire 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Six-minute walk test M 
✓ 
 
✓ 
 
✓ 
✓ 
  

 
 
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5.5.1 
RESPIRATORY SAMPLES FOR MICROBIOLOGY ASSESSMENT 
Respiratory samples are to be collected for participants enrolled in either the Observational Cohort or the Intervention 
Program.  The respiratory samples will be collected as per the relevant appendix. 
Collection of respiratory sample(s) for the identification of MABS at screening may not be required if recent 
sample(s) have been provided by the participant, (within the specified time frames prior to screening stated in the 
relevant appendix) have been stored and are available as per the local laboratory guidelines (standard of care) to 
identify and diagnose MABS.  If the screening sample has been stored, then the sample will be analysed 
retrospectively once consent to participate in the FORMaT trial is given. 
All respiratory samples collected for MABS identification are to be sent to local pathology as per local guidelines. 
Acceptable methods for collecting a respiratory sample for the microbiological assessment of MABS include: 
 
5.5.1.1 
Expectorated Sputum 
Participants able to expectorate sputum are required to provide a 1ml expectorated sputum sample in a specimen jar 
or separate specimen jars if multiple samples are obtained.  Specimen jar(s) are to be labelled and sputum samples 
processed in accordance with site specific pathology requirements for the detection of MABS. 
 
5.5.1.2 
Induced Sputum 
Sputum induction is indicated for participants incapable of expectorating sputum.  Prior to sputum induction a 
bronchodilator can be administered to minimise bronchospasm.  Sputum induction should be conducted as per local 
guidelines. 
 
5.5.1.3 
Bronchoalveolar Lavage (BAL) 
A BAL is indicated if an expectorated or induced sputum sample is unobtainable.  Where possible, a six-lobe lavage 
should be collected.  If six-lobe lavage is not feasible, a minimum two-lobe lavage from the area most affected on 
chest CT scan should be collected.  All BAL samples are to be processed in accordance with site specific procedures. 
 
5.5.1.4 
Lung/Airway Biopsy 
Lung/airway biopsy is only acceptable for the initial MABS diagnosis, but not as a routine method for MABS 
microbiological assessment throughout the trial. 
Please note, cough swabs are not an acceptable respiratory sampling technique for the FORMaT Trial. 
 

 
 
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5.5.2 
WHOLE GENOME SEQUENCING 
All MABS-positive isolates cultured from the respiratory samples collected in the FORMaT Trial will be stored and 
deoxyribonucleic acid (DNA) extracted according to FORMaT DNA Extraction SOP.  The extracted DNA from all 
samples will undergo whole genome sequencing (WGS) according to the FORMaT WGS SOP and/or local laboratory 
standard procedures). The genetic data generated from the WGS of MABS DNA will be stored by the approved 
collaborator in a mycobacterial genomic library. 
 
5.5.3 
CHEST COMPUTED TOMOGRAPHY 
Chest CT will be performed at screening and at final outcome.  If at screening a recent chest CT scan has already 
been performed (within 6 months of screening), as part of the standard of care diagnosis of MABS an additional chest 
CT will not be required.  Any additional chest CT scans performed for clinical purposes at other time points while 
the participant is enrolled in the FORMaT Trial will also be collected as an outcome measure.  Once consent is 
provided for the FORMaT trial these images will be accessed from the participant’s medical records and included in 
trial analysis. 
The site and scanner specific protocols for chest CTs as well as the evaluation of trial CTs are described in the relevant 
appendix.  The site and scanner specific protocols are recommended to be used to perform the core trial chest CT 
scans where feasible at sites that are certified and trained to use the site and scanner specific protocols. 
 
5.5.4 
SPIROMETRY 
Spirometry will be measured in all participants from three years of age in accordance with the American Thoracic 
Society and European Respiratory Society standards (41) and according to the appendix specific schedule of 
assessments where possible. The multi-ethnic global lung initiative (GLI) reference values for all spirometry indices 
will be applied to participants 3-95 years of age (42). 
 
5.5.5 
PHYSICAL EXAMINATION AND VITAL SIGNS 
A physical examination of all body systems and vital signs will be completed in accordance with appendix specific 
schedule of assessments (where possible) and with assessment of any adverse event(s).  A physical examination is to 
be completed by a site investigator or delegate.  The physical examination includes a review of the following systems: 
head/neck/thyroid, eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal 
and neurological systems.  Breast, anorectal, and genital examinations will be performed only when medically 
indicated.  After screening, any new clinically significant abnormal findings in physical examinations will be reported 
as adverse events (AEs), see section 5.8. 
Vital signs include blood pressure (systolic and diastolic), temperature, pulse rate and respiration rate will be assessed 
following a 5-minute rest in the seated or supine position. 

 
 
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5.5.6 
SIX MINUTE WALK TEST 
There are several modalities available for the objective evaluation of functional exercise capacity.  The 6-minute 
walk test (6MWT) is a clinical exercise test that is tolerated by those with chronic respiratory disease and is reflective 
of activities of daily living.  This test measures the distance that a patient can quickly walk on a flat, hard surface in 
a period of 6 minutes (6-minute walk distance (6MWD)).  The strongest indication for the 6MWT is to measure 
response to medical interventions in patients with moderate to severe heart or lung disease.  Most 6MWTs will be 
performed before and after an intervention to determine whether the patient has experienced a clinically significant 
improvement.  The change in 6MWD is expressed as an absolute value. 
The 6MWT is to be conducted in adult participants only and performed according to the protocol in the ATS 
Statement: Guidelines for the Six-Minute Walk Test and/or local standard clinical practice guidelines (43).  The ATS 
guideline includes absolute contraindications, relative contraindications and precautions to completing the test. 
 
5.5.7 
MEDICATION REVIEW 
Current medication use including both prescription, over-the counter medication, herbal remedies and preparations 
will be recorded from time of consent until final outcome visit as per the schedule of assessments in the relevant 
appendix.  Trade drug names, start and stop dates, dose, route, and indications for use should be recorded in the 
relevant Case Report Form (CRF). 
 
5.6 
QUALITY ASSURANCE (QA) 
The FORMaT trial will be conducted in accordance with the current approved Master Protocol and Appendices.  To 
improve Master Protocol adherence as well as ensure complete data entry, the following QA procedures will be 
implemented: 
1. A FORMaT trial start-up meeting for research coordinators and site investigators prior to the submission of 
ethical approval and any other required approvals. 
2. A Site Initiation Visit (SIV) once the FORMaT site has obtained ethics and any other required approvals, but 
prior to participant recruitment. 
3. A CRF Completion Guide detailing all the data to be collected in the CRFs/electronic CRFs (eCRFs). 
4. Regular and timely validation of entered data, queries and corrections by the FORMaT Trial Management Team. 
5. Trial monitoring (onsite, remote, central, and/or local) as described in Section 7.7 Monitoring and according to 
the FORMaT Monitoring SOP and Monitoring Plan. 
 
5.6.1 
MICROBIOLOGY AND DNA EXTRACTION QA 
Microbiology is of key importance and samples are processed in each of the participating countries in the local 
mycobacterial reference laboratories (MRLs). The FORMaT trial management team will work collaboratively with 
each MRL to ensure standard approaches for sample processing are followed where feasible.  

 
 
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5.7 
NOTES ON SPECIFIC TRIAL VISITS 
The timepoint definitions outlined below are overarching concepts that are applicable to each of the intervention 
studies described within the relevant appendices. 
5.7.1 
SCREENING  
Screening is a window of time between the Date of Consent and the date of first randomisation in which a 
participant’s eligibility into the trial is assessed and screening assessment data is collected according to the schedule 
of assessments in the relevant Appendices.   
 
5.7.2 
TIME POINT START TREATMENT (TPST) 
Participants in the Intervention program(s) will commence on the treatment arm allocated by randomisation.  Time 
Point Start Treatment (TPST) is defined as the date the participant undergoes the randomisation allocating a treatment 
arm. Each separate randomisation will have its own TPST as defined in the relevant appendix. 
 
5.7.3 
TIME POINT FINAL (TPF) 
Participants will be reviewed at the end of each trial phase (Time Point Final (TPF)) and assessments will be 
performed as per the appendix specific schedule of assessments.  Each treatment phase that follows a randomisation 
will have its own separate TPF as defined in the relevant appendix. 
 
5.7.4 
EARLY WITHDRAWAL VISIT 
Participants who are withdrawn or who withdraw from the trial will be asked to attend an Early Withdrawal Visit.  
Where practical, all efforts should be made for the participants to complete the early withdrawal trial procedures 
detailed in the appendix specific schedule of assessments.  Where possible, if there are any ongoing AEs these should 
be followed and monitored in accordance with the FORMaT Master Protocol irrespective of withdrawal from study. 
 
5.7.5 
UNSCHEDULED VISIT 
Study visits that are conducted in addition to those listed in the appendix specific assessment schedule are known as 
Unscheduled Visits.  If the Investigator deems that a participant should attend the study site to follow up an AE, 
repeat laboratory testing or any other study-related reason, then this visit should be documented in the FORMaT 
Research Electronic Data Capture (REDCap) database via the Unscheduled Visit CRF. 
 

 
 
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5.8 
SAFETY MONITORING  
Occurrence of AEs due to the underlying MABS infection and treatments used are well recognised and expected 
during the FORMaT trial.  As such, AE monitoring procedures outlined in the relevant appendices will be 
implemented for participants enrolled in the Intervention Program or Observational Cohort. Toxicology monitoring 
procedures will be implemented for Intervention Program participants.  
 
5.8.1 
DEFINITION OF ADVERSE EVENTS 
An AE is any untoward medical occurrence in a clinical investigation of a participant enrolled in FORMaT who 
may or may not be treated with an investigational product. 
The Investigator will probe, via discussion with the participant, for the occurrence of AEs during each participant 
visit and record the information in the participant’s medical record or source documents.  AEs will be recorded in the 
AE or SAE eCRF.  AEs will be described by duration (start and stop dates), severity, outcome, treatment, and 
relationship to study medication (where relevant), or if unrelated, the cause. 
AEs will be collected from the time of informed consent until the final study visit. 
All AEs will be reviewed by the FORMaT trial Pharmacovigilance Team and coded in accordance with the CTCAE 
version 5.  For any AE that is unable to be categorised in accordance with the CTCAE, the independent data safety 
monitoring board (iDSMB) will be required to review and categorise the AE. 
 
5.8.2 
ATTRIBUTION OF ADVERSE EVENTS IN THE FORMAT TRIAL 
The relationship, or attribution, of an AE to the trial therapies will be determined by the Investigator.  The relationship 
of the AE to the investigational product should be coded according to the following definitions: 
Unrelated: The adverse event is clearly not related to the investigational product. 
Unlikely: The adverse event is doubtfully related to the investigational product. 
Possibly: The adverse event may be related to the investigational product. 
Probably: The adverse event is likely related to the investigational product. 
Definitely: The adverse event is clearly related to the investigational product. 
 
5.8.3 
DEFINITION OF SERIOUS ADVERSE EVENTS 
SAEs will be defined as any untoward medical occurrence that: 
1. Results in death. 
2. Is considered life threatening (i.e., in the view of the Investigator the adverse experience places the participant 
at immediate risk of death from the reaction, as it occurred; it does not include a reaction that, had it occurred 
in a more severe form, might have caused death). 

 
 
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3. Requires hospital admission or prolongation of an existing hospitalisation. 
4. Results in persistent or significant disability/incapacity (i.e., a substantial disruption of a person’s ability to 
conduct normal life functions). 
5. Is a congenital anomaly/birth defect. 
6. Is an important medical event (i.e., when based upon appropriate medical judgment, the adverse experience 
may jeopardise the participant and may require medical or surgical intervention to prevent one of the above 
listed outcomes). 
 
5.8.4 
REPORTING OF SAFETY EVENTS 
Study sites will document all SAEs that occur after informed consent is obtained until the final study visit in an SAE 
Report (whether or not related to study treatment).  All SAEs will be reported to the FORMaT Trial Management 
Team within 24 hours of becoming aware of the event.  Exclusions to the expedited SAE reporting include: 
1. Infective exacerbation of an underlying lung condition requiring hospitalisation or home intravenous 
antibiotic treatment does not require expedited reporting to the FORMaT Trial Management Team; 
2. Any planned and/or elective hospital admissions does not require expedited reporting; 
3. Any planned and/or elective medical procedures does not require expedited reporting. 
The site will complete and submit an initial SAE report form via the FORMaT trial database.  Any follow up 
information about the SAE is to be reported on an SAE follow up report form and submitted in the FORMaT trial 
database as soon as relevant information is available. 
All SAEs will be reviewed by the FORMaT trial Pharmacovigilance Team and coded in accordance with the CTCAE 
version 5.  For any SAE that is unable to be categorised in accordance with the CTCAE, the iDSMB will be required 
to review and categorise the SAE. 
Suspected unexpected serious adverse reactions (SUSARs) will be reported on the SAE form via the FORMaT Trial 
database.  Urgent safety measures (USMs) and significant safety issues (SSIs) will be reported via email to the FORMaT 
Trial Management Team and submitted in the FORMaT trial database (if the USM or SSI is also an SAE).  USMs, SSIs, 
and SUSARs are to be reported by the FORMaT Trial Management Team and/or the local site investigator to the relevant 
regulatory bodies within their required timeframes. 
The FORMaT Trial Management Team, as the Sponsor delegate, will notify the Sponsor of all SUSARs, USMs and 
SSIs as required and submit an Annual Safety Report to the Sponsor.  Site investigators are required to report all AEs 
that are related to study intervention(s) and/or interaction with study intervention(s) within 2 weeks of becoming 
aware of the event.  All other AEs and laboratory abnormalities that are not related to study intervention(s) or 
interactions with study intervention(s) are to be reported to the FORMaT Trial Management by the end of specified 
TPF outlined in the relevant appendix. 
Refer to FORMaT Safety Monitoring and Reporting SOP for detailed procedure(s) for safety reporting. 

 
 
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5.8.5 
CODING OF ADVERSE EVENTS FOR ANALYSIS 
CTCAE, version 5.0 will be applied for the database coding of all AEs including SAEs but only those categorised as 
at least “possibly”, “probably”, or “definitely” related to study medications and/or interactions between study 
medications and concomitant medications will be used to assess tolerance.  Coding for analysis will be completed by 
the FORMaT Pharmacovigilance Team.  Refer to section 4.6 for the definition of tolerance. Coding and grading is 
performed in accordance with the FORMaT Coding and Grading Work Instruction.  
If an AE is unable to be coded and/or graded by the pharmacovigilance team or if coding/grading cannot be agreed 
upon, the iDSMB will be consulted to assess and code and/or grade the AE. 
 
5.8.6 
TOXICOLOGY THRESHOLDS 
Toxicology monitoring will use the thresholds that match the grading from CTCAE, Version 5.0 as described in 
Table 3 and toxicity monitoring procedures for trial interventions will be as specified in the relevant intervention 
appendix. New interventions will require a separate toxicity monitoring plan including any requirements for central 
laboratory testing of samples. 
 
5.9 
PARTICIPANT WITHDRAWAL AND DISCONTINUATION OF TREATMENT 
5.9.1 
WITHDRAWAL OF CONSENT 
All participants are free to withdraw from the study at any time, with or without a specified reason and without 
prejudice.  Where possible, the participant or the participant’s parent/legal guardian is required to sign the withdrawal 
of consent form, formally documenting the withdrawal process including the reason for withdrawal if they choose to 
provide this information.  In the event of a participant withdrawing from the trial, an early withdrawal visit should 
be completed within the specified window of time from withdrawal if the participant is agreeable.  If for any reason 
the participant is unable to complete the early withdrawal visit this should be noted on the Study Completion eCRF.   
 
5.9.2 
DISCONTINUATION OF TREATMENT 
Participants enrolled in the Intervention Program can discontinue treatment at any time during the trial if: 
• 
The participant is no longer able to comply with the FORMaT Master Protocol and relevant appendix, 
including completing required study assessments for safety requirements. 
• 
The site investigator believes that treatment is no longer in the participant’s best interests (due to safety or 
tolerance concerns). 
• 
The participant no longer wants to continue treatment. 
Participants discontinuing treatment prematurely but who do not withdraw consent or assent will be encouraged to 
continue with the trial according to the specific appendix intervention study and schedule of assessments in 
accordance with the relevant appendices with the final outcome respiratory sampling assessments to be prioritised. 

 
 
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Table 3: Safety critical monitoring thresholds 
Investigations 
Grade 
CTCAE Term 
1 
2 
3 
4 
5 
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was normal, or; 
1.5 – 3.0 x baseline if 
baseline was abnormal.  
>3.0 - 5.0 x ULN if baseline 
was normal, or; 
>3.0 - 5.0 x baseline if 
baseline was abnormal. 
>5.0 - 20.0 x ULN if 
baseline was normal, or; 
>5.0 - 20.0 x baseline if 
baseline was abnormal. 
>20.0 x ULN if baseline 
was normal, or; 
>20.0 x baseline if baseline 
was abnormal. 
- 
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.  
Anaemia 
 
Haemoglobin (Hgb) <LLN 
- 10.0 g/dL; <LLN – 6.2 
mmol/L; <LLN – 100 g/L. 
Hgb <10.0 – 8.0 g/ dL; <6.2 
– 4.9 mmol/L; <100 - 80 
g/L. 
Hgb 
<8.0 
g/ 
dL;  
<4.9 mmol/L; < 80 g/L; 
transfusion indicated. 
Life-threatening 
consequences; 
urgent 
intervention indicated.  
Death 
Definition: A disorder characterized by a reduction in the amount of haemoglobin in 100 ml of blood. Signs and symptoms of anaemia may include pallor of the 
skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.  
Aspartate aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was normal, or; 
1.5 – 3.0 x baseline if 
baseline was abnormal. 
>3.0 - 5.0 x ULN if baseline 
was normal, or; 
>3.0 – 5.0 x baseline if 
baseline was abnormal. 
>5.0 - 20.0 x ULN if 
baseline was normal, or; 
>5.0 – 20.0 x baseline if 
baseline was abnormal. 
>20.0 x ULN if baseline 
was normal, or; 
>20.0 x baseline if baseline 
was abnormal. 
- 
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in the blood specimen. 
Blood bilirubin increased 
>ULN - 1.5 x ULN if 
baseline was normal, or; 
>1.0 – 1.5 x baseline if 
baseline was abnormal.  
>1.5 - 3.0 x ULN if baseline 
was normal, or; 
>1.5 – 3.0 x baseline if 
baseline was abnormal.  
>3.0 – 10.0 x ULN if 
baseline was normal, or; 
>3.0 – 10.0 x baseline if 
baseline was abnormal. 
>10.0 x ULN if baseline 
was normal, or; 
>10.0 x baseline if baseline 
was abnormal. 
- 
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice. 
Electrocardiogram 
QT 
corrected interval prolonged 
Average QTc 450 - 480 ms 
Average QTc 481 - 500 ms 
Average QTc >= 501 ms; 
>60 
ms 
change 
from 
baseline.  
Torsade 
de 
pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms of serious 
arrhythmia. 
- 
Definition: A disorder characterised by Electrocardiogram T wave amplitude changes.  

 
 
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Investigations 
Grade 
CTCAE Term 
1 
2 
3 
4 
5 
Hearing impaired 
Adults enrolled on a 
Monitoring Program (on a 
1, 2, 4, 3, 6, and 8 kHz 
audiogram): Threshold 
shift of 15 - 25 dB 
averaged at 2 contiguous 
test frequencies in at least 
one ear; 
Adults not enrolled on a 
Monitoring Program: 
Subjective change in 
hearing in the absence of 
documented hearing loss; 
Pediatric (on a 1, 2, 3, 4, 6, 
and 8 kHz audiogram): 
Threshold shift >20 dB 
hearing loss (HL) (i.e., 25 
dB HL or greater); 
sensorineural hearing loss 
(SNHL) above 4 kHz (i.e., 
6 or 8 kHz) in at least one 
ear. 
Adults enrolled on a 
Monitoring Program (on a 
1, 2, 3, 4, 6, and 8 kHz 
audiogram): Threshold 
shift of >25 dB averaged at 
2 contiguous test 
frequencies in at least one 
ear; 
Adults not enrolled on a 
Monitoring Program: 
Hearing loss with hearing 
aid or intervention not 
indicated; limiting 
instrumental ADL; 
Pediatric (on a 1, 2, 3, 4, 6, 
and 8 kHz audiogram): 
Threshold shift >20 dB at 4 
kHz in at least one ear. 
Adults enrolled on a 
Monitoring Program (on a 
1, 2, 3, 4, 6, and 8 kHz 
audiogram): Threshold 
shift of >25 dB averaged at 
3 contiguous test 
frequencies in at least one 
ear; therapeutic 
intervention indicated; 
Adults not enrolled on a 
Monitoring Program: 
Hearing loss with hearing 
aid or intervention 
indicated; limiting self care 
ADL; 
Pediatric (on a 1, 2, 3, 4, 6, 
and 8 kHz audiogram): 
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids; threshold shift 
>20 dB at 2 to < 4 kHz in 
at least one ear. 
Adults: Decrease in hearing 
to profound bilateral loss 
(absolute threshold >80 dB 
HL at 2 kHz and above); 
nonservicable hearing. 
Pediatric: Audiologic 
indication for cochlear 
implant; > 40 dB HL (i.e., 
45 dB HL or more); SNHL 
at 2 kHz and above. 
- 
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures 
Leukocytosis 
- 
- 
>100,000/mm3 
Clinical manifestations of 
leucostasis; 
urgent 
intervention indicated. 
- 
Definition: A disorder characterised by laboratory results that indicate an increased number of white blood cells in the blood.  
Lymphocyte count decreased 
<LLN - 800/mm3; 
 <LLN - 0.8 x 109/L 
<800 – 500/mm3;  
<0.8 - 0.5 x 109/L 
<500 – 200/mm3;  
<0.5 - 0.2 x 109/L 
< 200/mm3;  
< 0.2 x 109/L 
- 

 
 
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Investigations 
Grade 
CTCAE Term 
1 
2 
3 
4 
5 
Definition: A finding based on laboratory test results that indicate a decrease in the number of lymphocytes in a blood specimen. 
Neutrophil count decreased 
<LLN - 1500/mm3; 
<LLN - 1.5 x 109/L 
<1500 - 1000/mm3; 
<1.5 - 1.0 x 109/L 
<1000 - 500/mm3; 
<1.0 - 0.5 x 109/L 
<500/mm3;  
< 0.5 x 109/L 
- 
Definition: A finding based on laboratory test results that indicate a decrease in the number of neutrophils in a blood specimen. 
Platelet count decreased 
<LLN 
- 
75,000/ 
mm3; 
<LLN - 75.0 x 109/L 
<75,000 - 50,000/ mm3; 
<75.0 - 50.0 x 109/L 
<50,000 - 25,000/ mm3; 
<50.0 - 25.0 x 109/L 
<25,000/ mm3;  
<25.0 x 109/L 
- 
Definition: A finding based on laboratory test results that indicate a decrease in the levels of pancreatic enzymes in a biological specimen. 
Tinnitus 
Mild symptoms; 
intervention not indicated. 
Moderate symptoms; 
limiting instrumental ADL. 
Severe symptoms; limiting 
self care ADL. 
- 
- 
Definition: A disorder characterised by noise in the ears, such as ringing, buzzing, roaring or clicking. 
Vertigo 
Mild symptoms. 
Moderate 
symptoms; 
limited instrumental ADL. 
Severe symptoms; limiting 
self care ADL. 
 
- 
- 
Definition: A disorder characterised by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were 
revolving in space (subjective vertigo).  
Vestibular Disorder 
- 
Symptomatic; limiting 
instrumental ADL. 
Severe symptoms; limiting 
self care ADL. 
- 
- 
Definition: A disorder characterised by dizziness, imbalance, nausea and vision problems.  
White blood cell decreased 
<LLN - 3000/ mm3; 
<LLN – 3.0 x 109/L 
<3000 - 2000/ mm3; 
<3.0 – 2.0 x 109/L 
<2000 - 1000/ mm3; 
<2.0 – 1.0 x 109/L 
<1000/ mm3; 
<1.0 x 109/L 
- 
Definition: A finding based on laboratory test results that indicate a decrease in the number of white blood cells in a blood specimen. 
Adapted from CTCAE, version 5.0

 
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5.10 DATA MANAGEMENT 
5.10.1 DATA COLLECTION, ENTRY AND STORAGE 
Trial data will be collected from various sources including, but not limited to, medical records, participant 
questionnaires, output from lab results, study assessments, correspondence and CT scans.  These documents and any 
documents where data is first recorded for a participant will form the source documents.  FORMaT trial site staff will 
be trained in the collection of the required data during the site initiation visit and data collection instructions will be 
stored in the site’s electronic Investigator Site File (eISF). 
The site investigators are responsible for ensuring the accuracy, completeness, legibility, and timeliness of all trial 
data reported.  All source documents are to be viewable in a neat, legible manner to ensure accurate interpretation of 
data.  The site investigators will maintain adequate case histories of trial participants, including source 
documentation.  
Sites will enter the data required for the trial directly into an eCRF located in a study specific Research Electronic 
Data Capture (REDCap) FORMaT database.  Data for the eCRF will be obtained directly from the medical record or 
source documents. 
Due to the adaptive design of the trial all data is to be entered within 14 days from the specified TPF as defined 
in the relevant appendix unless otherwise stated (e.g. expedited AE/SAE reporting)  Data cleaning will be 
performed at regular intervals for the trial to ensure that the data are cleaned and ready for interim analyses. 
The REDCap FORMaT database will be hosted on Murdoch Children’s Research Institute (MCRI) infrastructure 
and is subject to the same security and backup regimen as other systems at the MCRI (e.g. the network file servers).  
Data is backed up nightly to a local backup server, with a monthly backup taken to tape and stored offsite.  All data 
transmissions between users and the REDCap server are encrypted.  Regular data quality checks, such as automatic 
range checks, will be performed to identify data that appear inconsistent, incomplete, or inaccurate. 
Access to REDCap is managed by the system administrator.  The permissions granted to each user within each 
REDCap project is controlled by and is the responsibility of the FORMaT trial management team.  REDCap has 
functionality that makes adding and removing users and managing user permissions straightforward.  REDCap 
maintains an audit trail of data created/updated/deleted that is accessible to project users that are granted permission 
to view it. 
The SiteDocs Portal is an online tool hosted by TrialDocs Clinical Research Document Management and The 
University of Queensland (UQ) that is compliant with FDA requirements and General Data Protection Regulation 
(GDPR) which will securely host and track all key trial documents for the FORMaT Trial, including the electronic 
Trial Master File (eTMF).  SiteDocs includes features such as version control, document protection, temporary 
remote monitoring access, alerts, archiving and a full audit trail of data and users. 
Trial sites will have individual secure access to their site’s eISF via SiteDocs, where protocols, templates, trial 
documents and correspondence will be hosted.  Sites will be able to collaborate with the Sponsor and/or their delegate 
to upload site-specific clinical trial documents or deidentified participant documents to their eISF, receive 
notifications of changes and easily access the most up-to-date document versions. 

 
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Trial sites will have access to their own separate site-specific Portal for SiteDocs where they can upload and manage 
identifiable source documents.  Sites will be responsible for granting access to their site-specific Portal, including 
temporary access to external monitors. 
 
5.10.2 DATA STORAGE AND RETENTION 
Each site is required to maintain source documents for a minimum of 15 years post completion of the trial.  If site 
specific requirements or relevant legislation dictate data retention for periods longer than 15 years, trial sites will be 
required to adhere to these requirements. 
 
6 
STATISTICAL ANALYSIS PRINCIPLES 
This section of the Master Protocol provides an outline and summary of the general statistical methods and principles 
used for FORMaT.  The detailed statistical methods and sample size simulations relevant to each of the Intervention 
Programs and discovery studies are outlined in the relevant appendix. 
 
6.1 
BAYESIAN ANALYSIS AND BAYESIAN ADAPTIVE RANDOMISATION (BAR) 
Interim monitoring for the Intervention Program in the FORMaT trial will use a Bayesian analysis approach (44).  
This approach will calculate the (posterior) probability of an intervention being found to be superior to the reference 
arm during the trial.  As new data is generated the probability will be updated.  This updating will occur at the time 
of the meetings of the iDSMB, who will have access to blinded and unblinded data and will ask the Trial Steering 
Committee (TSC) to ratify the updated blinded probabilities.  Initially there are no plans to stop any arms of the study 
arms due to superiority, but such rules may be established as the trial continues and will be detailed in the relevant 
appendices.  The iDSMB may however make a recommendation to the TSC about stopping current interventions if 
they show poor promise or futility.  Stopping rules will be defined to guide the use of the posterior probabilities. 
Adaptive randomisation allows intervention arm allocation ratios to be adapted based on interim analyses undertaken 
during the trial to favour the intervention arm with the highest posterior probability of success (45).  This approach 
can lead to increased efficiency of the trial and reduce patient exposures to less promising or more toxic therapies 
compared with non-adaptive randomisation.  In the FORMaT trial, BAR will be used for updating allocation 
probabilities in randomisations when there are more than two interventions being compared at any one of the 
randomisation stages.  BAR will be implemented after every 60 participants have been randomised so that there is 
sufficient information available to determine the adaptation.  Success of an intervention (and hence the adaptations) 
will be determined by the primary outcome; microbiological clearance with tolerability (refer to sections 1.1 Synopsis 
and 4.6 Trial Endpoints for definitions of clearance and tolerance). 
 

 
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6.2 
RANDOMISATION 
6.2.1 
BLINDING OF TREATMENT ALLOCATION 
The FORMaT trial may include placebo controlled double blind randomised interventions in the future, but the initial 
Intervention Program detailed in Appendix A1 is randomised and open label. 
Each stage of the FORMaT intervention program(s) requires randomisation and is detailed in the relevant appendix. 
The allocated treatment must start on the same day as the randomisation where feasible, or as soon as possible after 
the randomisation has been performed. Any delays to starting an allocated treatment after randomisation has occurred 
must be reported to the FORMaT Trial Management Team. 
 
6.3 
MINIMISATION 
To ensure balance between arms in important patient characteristics, randomisation at the different stages of the trial 
will use minimisation with a random element.  Minimisation is a dynamic randomisation approach used in clinical 
trials to balance allocation to treatment arms with respect to a number of important stratification factors.  In 
minimisation, the first participant is allocated to their treatment arm at random.  Subsequent participants are assigned 
to a treatment arm by first selecting the preferred arm that would best improve the balance of participants across the 
arms based on the stratification variables of interest in terms of the numerical difference in the sample size in each 
of the treatment arms across all of the stratification factors (46, 47).  The preferred arm is then selected with a 
probability of 0.7, with rest of the probability split between the alternative arms. 
Following updating the randomisation allocations through BAR, minimisation will be conducted using Biased Coin 
Minimisation (BCM) (48).  Under this method, the same methodology as standard minimisation will be used to 
determine the preferred intervention, but the randomisation probabilities will be altered to reflect the minimisation 
probabilities and the updated allocation ratios from the BAR as detailed in Han et al (48). 
Randomisation will be conducted electronically through the trial database following completion of all the specific 
required data entry by the study team at each site.  Participants will be randomised according to the stratification 
criteria described below using to the weights specified for each factor: 
1.  Macrolide resistance*: Yes or no (weight = 50% in randomisations 1 and 2 (Randomisation-Short Intensive 
(R-SI) and Randomisation-Prolonged Intensive or Immediate Consolidation (R-PI/IC), respectively), 25% 
in randomisation 3 (Randomisation-Consolidation (R-Con))). 
Any of these measurement methods are acceptable for defining macrolide resistance (in order of preference): 
a. Inducible at 14 days or constitutive at 3 days, and/or; 
b. Erm(41) status: Functional or dysfunctional, and/or; 
c. MABS subspecies: M. a. abscessus & M. a. bolletii combined or M. a. massiliense. 
2. Age: <12 years, 12-30 years and >30 years of age (weight = 20%). 
3. Sex: Male or Female (weight = 7.5%). 
4. Location: Asia Pacific as one stratum (includes Australia, New Zealand, Singapore and other Asian Pacific 
countries), United Kingdom and Republic of Ireland as one stratum, Europe as another stratum (includes 

 
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Denmark, France, Netherlands), and Canada and the Americas as one stratum (weight = 7.5%). Parts of the 
world not listed above can be added into the regions based on closest proximity to the regions longitudinally. 
5. Cystic Fibrosis Status: Yes or no (weight = 7.5%). 
6. Mixed NTM infections at enrolment: Yes or no (weight =7.5%). 
7. MABS positive culture (at initial randomisation to intensive therapy (R-SI) and for R-PI/IC all participants 
will have a positive culture, so this factor will not be required. However, it will be required for R-Con): Yes 
or no (weight = 25%). 
 
6.4 
ADDING AND STOPPING INTERVENTIONS 
New interventions, which may include new therapeutics or new timelines either during the intensive or consolidation 
phase, may be added as a treatment arm either for the intensive or for the consolidation phase as determined by the 
trial Drug and Intervention Selection committee (DISC) with approval of the TSC.  No new therapies will be added 
until at least 60 subjects have completed the trial phase associated with the proposed new intervention. 
Interventions may be stopped early due to a lack of benefit at interim analyses.  Interim analyses will be conducted 
after every 60 participants have completed the trial phase.  The statistical team, acting in confidence, will present the 
results from such analyses only to the iDSMB who will provide guidance around stopping particular interventions.  
Pre-defined triggers for stopping an intervention will be specified for both intensive and consolidation interventions 
separately, and for the combination of intensive and consolidation.  If a single intervention, or combination of 
interventions, has less than a 0.01 posterior probability of being an optimal intervention in that phase then that 
intervention will be regarded as inferior and should be recommended to be discontinued. 
For new interventions in the future, if an intervention has a high posterior probability (to be pre-specified prior to the 
new intervention being added) of being an optimal therapy this invention will be considered as superior, in which 
case the iDSMB might recommend that the randomisation stage be stopped for superiority.  Stopping rules for 
superiority will be detailed in the relevant section of the appendices.  Following the iDSMB meeting, the 
recommendations from the iDSMB will be notified to the Trial Management Committee (TMC) and TSC.  The TSC 
will consider the recommendations and make a decision regarding the potential to stop the randomisation stage for 
superiority.  If any interventions are stopped, the TMC will have the responsibility of developing a public disclosure 
as is practical through presentation of results and publications. 
 
6.5 
SEAMLESS PHASE II TO PHASE III 
The FORMaT platform trial provides a resource to enable promising therapies to be more rapidly evaluated and has 
the potential to facilitate seamless transition from Phase II to a Phase III study.  Initially the platform will support a 
phase II study, but new interventions being evaluated in the future may be considered for the potential to move 
seamlessly from this Phase II study to a Phase III (49).  The principles guiding this move will include planning for 
the potential of Phase III in the design of the Phase II study and with agreement between the Platform trial team and 
sponsors of the new therapy around management and access to data.  The move to a Phase III trial will be guided by 
a pre-defined threshold for the probability of a successful intervention during phase III, which would need to be 

 
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established in planning the Phase II trial and agreed to by regulatory authorities for pivotal studies.  If a seamless 
transition to Phase III is considered feasible, the TMC along with the trial statistics team will provide the iDSMB 
and TSC with a Phase III proposal, and if this is approved by the iDSMB and TSC then further recruitment to the 
target number determined would be undertaken. 
 
6.6 
SIMULATIONS AND STATISTICAL POWER 
The design (including stopping rules) and sample size of each intervention program will be informed by simulations 
using Monte Carlo methods to give a range of power according to different scenarios and taking into account the 
probabilities of variable responses to intensive and/or consolidation interventions.  Simulations will be updated with 
the addition of any new interventions.  The details of these simulations can be found in the relevant appendix. 
 
6.7 
GENERAL ANALYSIS PRINCIPLES 
The analyses will be conducted according to the statistical analysis methods described in the relevant appendices, 
statistical principles appendix and the statistical analysis plan. 
 
7 
STUDY OVERSIGHT 
7.1 
OVERVIEW 
The FORMaT Trial will have several committees established to provide oversight of the FORMaT Trial. 
 
7.2 
TRIAL STEERING COMMITTEE 
The TSC is the executive decision-making group and provides overall supervision of the FORMaT trial.  The Terms 
of Reference (available on request) outlines the roles and responsibilities of the TSC members.  Membership to the 
TSC will consist of independent and non-independent members from a variety of backgrounds including clinical and 
statistical as well as a member from the general community.  The Chair of the TSC will be independent of the 
FORMaT Trial. 
 
7.3 
INDEPENDENT DATA SAFETY MONITORING BOARD 
The iDSMB will review interim analyses, monitor for effectiveness and safety, along with trial conduct.  They will 
meet prior to the commencement of the trial at least annually and at the time of interim analysis after every 60 
participants have completed each stage of the trial.  The iDSMB will provide advice to the TSC and the Trial 
Management Committee (TMC).  The iDSMB Charter (available on request) outlines the roles and responsibilities 
of the iDSMB members.  Membership to the iDSMB will consist of clinicians and statisticians who are independent 
of the FORMaT Trial. 
The iDSMB will be responsible for defining its deliberative processes, including event triggers that would call for an 
unscheduled review and voting procedures prior to initiating any data review.  The iDSMB will be responsible for 

 
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maintaining the confidentiality of its internal discussions and activities as well as the contents of reports provided to 
it. 
The iDSMB will review each version of the FORMaT Master Protocol (including any new or updated appendices). 
During the trial, the iDSMB will review cumulative study data to evaluate safety, study conduct, and scientific 
validity and integrity of the trial. As part of this responsibility, iDSMB members must be satisfied that the timeliness, 
completeness, and accuracy of the data submitted to them for review are sufficient for evaluation of the safety and 
welfare of study participants.  The iDSMB will also assess the performance of overall study operations and any other 
relevant issues, as necessary. 
Items to be reviewed by the iDSMB may include: 
• 
Interim/cumulative data for evidence of study-related AEs. 
• 
Interim/cumulative data for evidence of efficacy and futility according to pre-established statistical 
guidelines. 
• 
Data quality, completeness and timeliness. 
• 
Performance of individual centres/countries. 
• 
Adequacy of compliance with goals for recruitment and retention, including those related to the participation 
of women and minorities. 
• 
Adherence to the protocol. 
• 
Factors that might affect the study outcome or compromise the confidentiality of the trial data (such as 
protocol deviations, unmasking, etc.). 
• 
Factors external to the study such as scientific or therapeutic developments that may impact participant safety 
or the ethics of the study. 
• 
AEs that are unable to be categorised by the FORMaT Pharmacovigilance Team in accordance with the 
CTCAE. 
The iDSMB will conclude each review with their recommendations to the TSC and the FORMaT Chief Investigator 
(CI) as to whether the study should continue without change, be modified, or terminated.  Recommendations 
regarding modification of the design and conduct of the study could include: 
• 
Modifications of the Master Protocol (including appendices) based upon the review of the safety data. 
• 
Suspension or early termination of the study or of one or more study arms because of serious concerns about 
subjects’ safety, inadequate performance or rate of enrolment. 
• 
Suspension or early termination of the study or of one or more study arms because study objectives have 
been obtained according to pre-established statistical guidelines. 
• 
Corrective actions regarding a study centre whose performance appears unsatisfactory or suspicious. 
Confidentiality must always be maintained during all phases of iDSMB review and deliberations. 
Meeting sessions can be either open or closed at the request of the iDSMB Chair or may involve periods of each. The 
lead investigators of FORMaT can attend the open session along with other investigators as requested. 

 
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The closed session will only include the iDSMB members who have voting rights and they will formulate 
recommendations regarding the study to the TSC.  The FORMaT CI may be invited to the closed session to present 
an update of the trial but will not be present for any other agenda items. 
Reports will be provided to iDSMB that include an open report and a closed report.  Reports for the iDSMB will be 
prepared by the Clinical Epidemiology and Biostatistics Unit at MCRI. 
Open reports will include information on the study conduct such as accrual data, demographics and baseline 
characteristics, site performance and protocol compliance and quality control issues along with general toxicity and 
safety data presented across the study as a whole with no reference to treatment arm. 
Closed reports will include the same data as the open reports as well as data on efficacy outcomes at the time of each 
interim analysis (every 60 patients in randomisation levels with more than two interventions) and will be presented 
by (masked) treatment arm. 
Reports from the iDSMB will provide details of any items that require urgent action as well as any 
recommendations made by the iDSMB and will be provided to the FORMaT CI and the TSC and notified to other 
participating organisations as well as to the IRB/IEC/HRECs involved. 
 
7.4 
TRIAL MANAGEMENT COMMITTEE 
The Trial Management Committee (TMC) is responsible for reviewing the day-to-day management of the trial and 
assist the FORMaT project team with any issues that arise during the study, as well as provide advice to the TSC and 
iDSMB where relevant. The TMC will include the FORMaT Trial CI, the Senior Trial Project Managers, appropriate 
representatives across all the key areas (Statistics, Database, Pharmacovigilance, Drug and Intervention Selection 
Committee (DISC), and Microbiology), and a representative from each participating country or region.  To facilitate 
and ensure adequate communication across the large number of team members and a wide geographic spread, 
information from the TMC may be shared on the FORMaT trial website and SiteDocs.  The TMC will report to the 
TSC.  Day-to-day management will be overseen by the FORMaT CI, the senior trial project managers and the core 
trial clinical lead physicians.  A Terms of Reference (available on request) outlines the roles and responsibilities of 
the TMC. 
 
7.5 
FORMAT PHARMACOVIGILANCE TEAM 
All AEs and SAEs will be reviewed by the FORMaT Pharmacovigilance Team and coded in accordance with the 
CTCAE, version 5.0. Members of the FORMaT Pharmacovigilance Team include: 
• 
Senior Clinical Pharmacist (Lead). 
• 
Non-independent senior paediatric physician. 
• 
Non-independent senior adult physician. 
• 
FORMaT Trial database representative (if required). 
• 
Statistician (If required). 
For further detail refer to the Pharmacovigilance Team Terms of Reference (available on request). 
 

 
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7.6 
DRUG AND INTERVENTION SELECTION COMMITTEE (DISC) 
The DISC includes the DISC chair, FORMaT CI, FORMaT Trial Management Team, a representative from each 
participating country and experts external to the trial. The role of the DISC includes assessment of new intervention 
or therapies to be considered for inclusion in a new Intervention Program. The DISC will provide a report supported 
by the Statistical Analysis Team and reviewed by the trial management team, for consideration by the TSC and if 
approved will lead to a new therapy program being included.  For further detail refer to the DISC Terms of Reference 
(available on request). 
 
7.7 
CONSUMER ADVISORY GROUP (CAG) 
The purpose of the FORMaT consumer advisory group (CAG) is to provide a consumer and community perspective 
to various aspects of the FORMaT trial. This includes advice on participant facing documents such as consent forms, 
future research plans including proposals for new treatments to be added to the study, grant applications requesting 
funding support for the study, and lay summaries of the study and any study results. Members of the CAG may also 
be invited to join various trial committee meetings to provide their perspective. 
 
7.8 
MONITORING 
The Sponsor and its delegates will have overall responsibility for monitoring.  An SIV will occur prior to sites 
commencing the recruitment of trial participants.  The purpose of the SIV is to train site investigators and local study 
coordinators with regards to the Master Protocol, the Appendices, data entry, management of trial documentation, 
and safety monitoring and reporting.  The site will be activated once the SIV has been presented and all the essential 
documentation from the local site has been collected according to FORMaT Site Initiation and Activation SOP.  
Monitoring visits will ensure that the study is being conducted according to good clinical practice (GCP), the Master 
Protocol and relevant appendices, that study participants’ safety, rights and well-being are being protected and that 
data entry is accurate and verifiable from source documentation.  These will be conducted via central, remote, local 
or on-site monitoring.  Visits may be conducted either face-to-face or through on-site electronic facilities, at intervals 
specified in the FORMaT Trial Monitoring SOP and Trial Monitoring Plan.  The FORMaT trial will accommodate 
any requests to be audited by ethical, regulatory and/or other relevant authorities. 
 
8 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
The trial will be conducted according to the Declaration of Helsinki, the International Conference on 
Harmonization - Good Clinical Practice E6 (ICH-GCP) and with the laws and regulations of the country in which 
the research is conducted, whichever represents the greater protection of the individual. 
 
8.1 
RESEARCH ETHICS APPROVAL AND SITE-SPECIFIC GOVERNANCE 
Prior to trial initiation the FORMaT Master Protocol, appendices, information sheets and consent forms, trial 
questionnaires and any other patient facing material will be reviewed and approved by the relevant IRB/IEC/HREC 

 
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for each participating country and/or site.  Approved delegates will keep the IRB/IEC/HREC informed as to the 
progress of the trial and comply with annual reporting requirements. 
The IRB/IEC/HREC must approve any revisions to FORMaT trial documents and be informed of any serious and/or 
unexpected AEs occurring during the trial as required and of any new information that may adversely affect the safety 
of the participants or the conduct of the trial.  Reporting requirements are to be adhered to in accordance with local 
IRB/IEC/HREC and additional site-specific requirements. 
 
8.1.1 
FORMAT MASTER PROTOCOL AND TRIAL DOCUMENT AMENDMENTS 
Any amendments to the approved IRB/IEC/HREC FORMaT trial documents may not be initiated without prior 
written IRB/IEC/HREC approval except when necessary to eliminate immediate hazards to the participants.   
Amendments will be submitted in writing to relevant IRB/IEC/HRECs and written approval will be obtained before 
the updated version is implemented. 
 
8.1.2 
PROTOCOL DEVIATIONS 
A protocol deviation occurs when there is any deviation from the study procedures or treatment plans as specified in 
the IRB/IEB/HREC approved protocol.  Examples of protocol deviations may include non-compliance with GCP, 
study visits outside of set windows and missing assessments outlined in the protocol.  Participants enrolled in the 
intervention cohort where protocol deviations have occurred involving modifications to the study drug regimen are 
able to continue to be enrolled and assessed for the remainder of the study. 
Protocol deviations may be minor or major. Minor protocol deviations do not carry significant ethical or 
administrative consequences.  Major protocol deviations are those that affect participant’s rights, safety or wellbeing 
and/or accuracy and reliability of the study data. An example of a minor protocol deviation is visit non-compliance 
(i.e. study visit and assessments are conducted outside of the required timeframe, or a procedure is missed) and there 
are no participant safety concerns. 
Examples of major protocol deviations include: 
a. Randomisation of an ineligible participant. 
b. Visit non-compliance (e.g., study visit and assessments are conducted outside of the required timeframe, or 
visit or assessment is missed) and there are participant safety concerns. 
c. Dispensing or dosing error of IMP. 
d. Not reporting SAEs. 
When a major protocol deviation occurs, it will be discussed with the site investigator(s) and site PI and a Protocol 
Deviation Form detailing the deviation will be generated.  This form, outlining the major protocol deviation, will be 
signed by the site investigator.  A copy of the form will be filed in the investigator site file and details of the deviation 
will be entered onto the study database. 
 

 
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8.1.2.1 
Reporting Requirements 
Minor protocol deviations do not need to be reported to the lead IRB/IEB/HREC at the time they occur. All minor 
deviations must be recorded in the protocol deviation log and reported to the Sponsor (if applicable). 
Major protocol deviations may need to be reported to the lead IRB/IEC/HREC and to the Sponsor (if applicable) as 
per local requirements and a protocol deviation form detailing the event completed.  The protocol deviation CRF is 
to be completed, signed by the site investigator, and entered in the database. 
All protocol deviations (major or minor) must be recorded in a protocol deviation log and reported as per local ethical 
and regulatory requirements. 
 
8.2 
CONFIDENTIALITY 
The Investigator must ensure that a participant’s anonymity will be respected throughout the study and that their 
identities are protected from unauthorised parties.  A participant’s privacy and confidentiality will be maintained by 
the assignment of a unique identification number.  On CRFs and other documents submitted to review committees 
and the Sponsor participants will not be identified by their names, rather their unique identification number.  These 
numbers will be used to collect, store and report participant information, including in the trial database.  The local 
site should keep a Subject Identification Log showing codes, names and dates of birth of the participants.  
Confidentiality and protection of data will be maintained according to local regulatory requirements.  All information 
disclosed or obtained during the trial is confidential.  The site PI and any person under his/her authority must maintain 
this confidentiality and must not disclose the information to any third party without the prior written approval of the 
CI. 
 
8.3 
SITE REIMBURSEMENT 
Sites will be reimbursed according to each participating site’s contract.  Please see the relevant appendix for further 
information. 
 
8.4 
DATA SHARING 
All de-identified raw data measured during the trial will be made available on request to relevant regulatory authorities, 
recognised academic institutions and clinical teams.  Deidentified, aggregated data sets will be hosted on an approved 
public research data platform. Data requests must be made in writing with a proposal for data usage to the CI.  Upon 
the approval for data sharing by the CI, the requester will be required to sign a data agreement.    
 
8.5 
PUBLICATION POLICY 
The results of this trial (positive, negative and/or inconclusive) will be published and/or presented at scientific 
meetings.  The preparation and submission for publication of manuscripts containing the trial results shall only be 
done if prior consent is obtained by the CI.  Any manuscript requests can be submitted to the FORMaT Trial 

 
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Management Team.  Authorship will be granted according to the recommendations from the International Committee 
of Medical Journal Editors (ICMJE)(50). 
 
 
 
 
 
 
 
 
 
 

 
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