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

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APPENDIX A1- INTERVENTION PROGRAM 
Combined Intensive and Consolidation Therapies 
Appendix 
A1 
– 
Intervention 
Program 
Version 1.1 
Appendix 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 
The University of Queensland 
Contact 
FORMaTtrial@uq.edu.au 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................................... II 
TABLE OF TABLES ............................................................................................................................ V 
TABLE OF FIGURES .......................................................................................................................... V 
ABBREVIATIONS ............................................................................................................................... VI 
APPENDIX A: INTERVENTION PROGRAM .................................................................................. 9 
APPENDIX A1 – COMBINED INTENSIVE AND CONSOLIDATION MODULE .................... 10 
1 
INTRODUCTION ......................................................................................................................... 14 
2 
OBJECTIVES ................................................................................................................................ 14 
2.1 
PRIMARY OBJECTIVES ........................................................................................................................... 14 
2.2 
SECONDARY OBJECTIVES ...................................................................................................................... 15 
2.3 
EXPLORATORY OBJECTIVES .................................................................................................................. 15 
3 
DESIGN .......................................................................................................................................... 15 
4 
ELIGIBILITY CRITERIA .......................................................................................................... 17 
4.1 
INCLUSION CRITERIA ............................................................................................................................. 17 
4.2 
EXCLUSION CRITERIA ............................................................................................................................ 18 
4.3 
ADDITIONAL CRITERIA .......................................................................................................................... 19 
4.3.1 Mixed NTM infections........................................................................................................................ 19 
4.3.2 Co-enrolment with other trials .......................................................................................................... 19 
5 
ACCEPTABLE METHODS OF CONTRACEPTION ............................................................. 19 
6 
TRIAL CONDUCT ....................................................................................................................... 20 
6.1 
INFORMED CONSENT.............................................................................................................................. 20 
6.2 
PREGNANCY INFORMATION CONSENT ................................................................................................... 20 
6.3 
METHODS OF ASSIGNING PARTICIPANTS TO TREATMENT ARMS .......................................................... 20 
7 
INTERVENTION PROGRAM PROCEDURES AND SAFETY MONITORING ................ 21 
7.1 
SERUM/URINE PREGNANCY TEST .......................................................................................................... 21 
7.2 
CHEST CT SCAN .................................................................................................................................... 21 
7.3 
RESPIRATORY SAMPLING ....................................................................................................................... 21 
7.4 
AUDIOGRAM .......................................................................................................................................... 21 
7.5 
VESTIBULAR MONITORING .................................................................................................................... 22 
7.5.1 Dynamic Visual Acuity Testing (DVA) .............................................................................................. 22 
7.5.2 Head Impulse Testing (HIT) .............................................................................................................. 22 
7.5.3 Romberg on Foam Test ...................................................................................................................... 22 

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7.6 
PHYSICAL EXAMINATION ...................................................................................................................... 22 
7.7 
ELECTROCARDIOGRAM (ECG) .............................................................................................................. 22 
7.8 
SIX-MINUTE WALK TEST ........................................................................................................................ 23 
7.9 
BLOOD SAMPLING.................................................................................................................................. 23 
7.10 
STUDY MEDICATION REVIEW ................................................................................................................ 23 
7.11 
AMIKACIN ADMINISTRATION AND MONITORING .................................................................................. 23 
7.11.1 Nebuliser Type FOR IA ..................................................................................................................... 23 
7.11.2 Amikacin Therapeutic Drug Monitoring ........................................................................................... 24 
7.12 
HEALTH RELATED QUALITY OF LIFE AND UTILITY MEASURES............................................................ 24 
7.12.1 Cystic Fibrosis Questionnaire-Revised (CFQ-R) .............................................................................. 24 
7.12.2 EQ-5D-5L .......................................................................................................................................... 25 
7.12.3 EQ-5D-Y ............................................................................................................................................ 25 
7.12.4 St. George Respiratory Questionnaire (SGRQ) ................................................................................. 25 
7.12.5 Short Form- 36 Health Survey ........................................................................................................... 25 
7.12.6 Pediatric Quality of Life Inventory (PedsQL™) ............................................................................... 25 
7.12.7 Child Health Utility 9D (CHU9D) .................................................................................................... 26 
7.13 
MABS CLEARANCE FOLLOW-UP QUESTIONNAIRE ............................................................................... 26 
8 
SITE REIMBURSEMENT ........................................................................................................... 26 
9 
INTENSIVE THERAPY NESTED STUDIES ........................................................................... 27 
9.1 
NESTED STUDY A1.1: SHORT INTENSIVE THERAPY ................................................................. 27 
9.1.1 Primary Objective .............................................................................................................................. 27 
9.2 
NESTED STUDY A1.2: DURATION OF INTENSIVE THERAPY FOR PATIENTS WITH ONGOING 
POSITIVE MABS CULTURES AFTER 4 WEEKS OF INTENSIVE THERAPY. ............................................................. 32 
9.2.1 Introduction ....................................................................................................................................... 32 
9.2.2 Eligibility Criteria ............................................................................................................................. 32 
9.2.3 Objectives .......................................................................................................................................... 32 
9.2.4 Statistical Analysis ............................................................................................................................. 33 
9.3 
INTENSIVE THERAPY DOSING REGIMEN ................................................................................................ 34 
9.3.1 Drug Supply, Storage and Distribution during Intensive Therapy .................................................... 41 
9.3.2 Options for Reducing Nausea During Intensive Therapy .................................................................. 41 
10 NESTED STUDY A1.3: CONSOLIDATION THERAPY ........................................................ 42 
10.1 
INTRODUCTION ...................................................................................................................................... 42 
10.2 
OBJECTIVES ........................................................................................................................................... 42 
10.2.1 Primary Objective .............................................................................................................................. 42 
10.2.2 Secondary Objectives......................................................................................................................... 43 
10.3 
ELIGIBILITY CRITERIA ........................................................................................................................... 43 
10.4 
STATISTICAL ANALYSIS ......................................................................................................................... 43 
10.5 
CONSOLIDATION THERAPY DOSING REGIMEN ...................................................................................... 44 

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10.5.1 Drug Supply, Storage and Distribution during Consolidation Therapy ............................................ 49 
10.5.2 Drug Compliance during Consolidation Therapy ............................................................................. 49 
11 SCHEDULE OF ASSESSMENTS ............................................................................................... 50 
12 RANDOMISATION ...................................................................................................................... 57 
13 APPLICABLE DISCOVERY STUDIES AND REGISTRY LINKAGE FOR APPENDIX A158 
14 REFERENCES .............................................................................................................................. 59 
 
 
 

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TABLE OF TABLES 
Table 1 Intensive therapy dosing regimen for Intensive Arm A in adults .................................................................. 35 
Table 2 Intensive therapy dosing regimen for Intensive Arm B in adults .................................................................. 36 
Table 3 Intensive therapy dosing regimen for Intensive Arm C in adults .................................................................. 37 
Table 4 Intensive therapy dosing regimen for Intensive Arm A in paediatrics .......................................................... 38 
Table 5 Intensive therapy dosing regimen for Intensive Arm B in paediatrics .......................................................... 39 
Table 6 Intensive therapy dosing regimen for Intensive Arm C in paediatrics .......................................................... 40 
Table 7 Consolidation therapy dosing regimen for Consolidation Arm a in adults ................................................... 45 
Table 8 Consolidation therapy dosing regimen for Consolidation Arm b in adults ................................................... 46 
Table 9 Consolidation therapy dosing regimen for Consolidation Arm a in paediatrics ............................................ 47 
Table 10 Consolidation therapy dosing regimen for Consolidation Arm b in paediatrics ......................................... 48 
Table 11 Special considerations for Schedule of Assessments .................................................................................. 50 
Table 12 Schedule of Assessments for Intervention Program Participants: Intensive Therapy ................................. 52 
Table 13 Schedule of Assessments for Intervention Program Participants: Prolonged Intensive Therapy ................ 54 
Table 14 Schedule of Assessments for Consolidation Therapy and Final Outcome .................................................. 56 
 
TABLE OF FIGURES 
Figure 1 Flow Diagram for Appendix A1, Intervention Program .............................................................................. 17 
 
 

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ABBREVIATIONS  
 
AE 
 
 
Adverse Event 
AFB 
 
 
Acid-Fast Bacilli 
ATS 
 
 
American Thoracic Society 
AUC 
 
 
Area Under the Curve 
BAL 
 
 
Bronchoalveolar Lavage 
BAR 
 
 
Bayesian Adaptive Randomisation 
BTS 
 
 
British Thoracic Society 
CEACS 
 
Cost-effectiveness acceptability curves 
CF 
 
 
Cystic Fibrosis 
CFQ-R  
 
Cystic Fibrosis Questionnaire-Revised 
CHU9D 
 
Child Health Utility 9D 
Cmax  
 
Maximum serum concentration 
Cmin  
 
Minimum serum concentration 
CRF 
 
 
Case Report Form 
CT 
 
 
Computed Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
DVA 
 
 
Dynamic Visual Acuity 
ECG 
 
 
Electrocardiogram 
eCRF  
 
electronic Case Report Form 
FEV1  
 
Forced Expiratory Volume in one second 
FORMaT 
 
Finding the Optimal Regimen for Mycobacterium abscessus Treatment 
HIT 
 
 
Head Impulse Test  
HRCT  
 
High-Resolution Computed Tomography 
HRQoL 
 
Health Related Quality of Life 
IA 
 
 
Inhaled Amikacin 
ICD 
 
 
International Statistical Classification of Diseases 

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ICERS  
 
Incremental cost-effectiveness ratios 
IV 
 
 
Intravenous 
IVA 
 
 
Intravenous Amikacin 
MABS  
 
Mycobacterium abscessus 
MABS-PD 
 
MABS Pulmonary Disease 
MAC  
 
Mycobacterium avium Complex 
MARS-5 
 
5-item Medication Adherence Rating Scale 
MIC 
 
 
Minimum Inhibitory Concentration 
MoOP  
 
Manual of Operating Procedures 
MPR 
 
 
Medication Possession Ratio 
NMB  
 
Net Monetary Benefit 
NTM  
 
Non-Tuberculous Mycobacteria 
PedsQL™ 
 
Pediatric Quality of Life Inventory  
QALY  
 
Quality-Life Adjusted Years 
QoL 
 
 
Quality of Life 
RCT 
 
 
Randomised Control Trial 
REDCap 
 
Research Electronic Data Capture 
R-Con  
 
Randomisation – Consolidation  
R-PI/IC  
 
Randomisation – Prolonged Intensive/Immediate Consolidation 
R-SI 
 
 
Randomisation – Short Intensive  
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SF-36  
 
Short form-36 
SGRQ  
 
St George Respiratory Questionnaire 
SOP 
 
 
Standard Operating Procedure 
TDM  
 
Therapeutic Drug Monitoring 
TPF 
 
 
Time Point Final 
TPF-PI  
 
Time Point Final – Prolonged Intensive 

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TPF-SI  
 
Time Point Final – Short Intensive  
TPF-WK12 
 
Time Point Final – at Week 12 Visit 
TPST  
 
Time Point Start Treatment 
TPST-Con 
 
Time Point Start Treatment – Consolidation  
TPST-SI 
 
Time Point Start Treatment – Short Intensive  
VAS 
 
 
Visual Analogue Scale 
vHIT 
 
 
Video Head Impulse Test 
VOR 
 
 
Vestibulo-ocular Reflex 
WTP   
 
Willingness To Pay 
6MWD  
 
Six Minute Walk Distance 
6MWT  
 
Six Minute Walk Test 

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

 
 
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APPENDIX A1 – COMBINED INTENSIVE AND CONSOLIDATION MODULE 
Appendix A1 describes the initial Mycobacterium abscessus Pulmonary Disease (MABS-PD) intervention platform 
for the FORMaT trial.  Within Appendix A1 there are intensive and consolidation therapy nested studies which are 
governed by the trial design and conduct described below.  
FORMaT Appendix A1 Summary 
Treatment 
combinations: 
Intensive therapy arms: 
Arm A  
Arm B  
Arm C  
 
1. IV amikacin, and; 
1. Inhaled amikacin, and; 
1. IV amikacin, and; 
 
2. IV tigecycline, and; 
2. IV tigecycline, and; 
2. IV tigecycline, and; 
 
3. IV imipenem or IV 
cefoxitin, and; 
3. IV imipenem or IV 
cefoxitin, and; 
3. IV imipenem or IV 
cefoxitin, and; 
 
4. Oral azithromycin or 
oral clarithromycin, and; 
4. Oral azithromycin or 
oral clarithromycin, and; 
4. Oral azithromycin or 
oral clarithromycin. 
 
5. Oral clofazimine. 
5. Oral clofazimine. 
 
 
Consolidation therapy arms: 
 
Arm a  
Arm b  
 
1. Oral clofazimine, and; 
2. Oral azithromycin or clarithromycin, 
and; 
3. In combination with one to three of the 
following oral antibiotics: 
• 
Linezolid, 
• 
Trimethoprim / sulfamethoxazole 
(co-trimoxazole), 
• 
Bedaquiline, 
• 
Rifabutin. 
• 
Doxycycline 
• 
Moxifloxacin 
1. 
Inhaled amikacin 
2. 
Oral clofazimine, and 
3. 
Oral azithromycin or clarithromycin, 
and; 
4. 
In combination with one to three of the 
following oral antibiotics: 
• 
Linezolid, 
• 
Trimethoprim / sulfamethoxazole 
(co-trimoxazole), 
• 
Bedaquiline, 
• 
Rifabutin. 
• 
Doxycycline 
• 
Moxifloxacin 
 
 
 
 
 
 
 
 
A mixed Non-Tuberculous Mycobacteria (NTM) infection (slow grower + Mycobacterium 
abscessus (MABS)) can include the use of ethambutol in either/both the intensive or 
consolidation phase/s of treatment. 
Appendix 
A1-
specific eligibility: 
Inclusion and exclusion criteria as per Master Protocol section 4.1 and below. 
Appendix 
A1-
specific inclusions: 
1. Positive MABS-PD diagnosis meeting all three American Thoracic Society (ATS) 
clinical, radiological and microbiological diagnostic criteria for MABS-PD.  Defined as; 
Clinical: Pulmonary symptoms and exclusion of other diagnoses. 
Radiological: Nodular or cavitary opacities on chest radiograph or a chest high-
resolution computed tomography (HRCT) scan showing multifocal bronchiectasis with 
multiple small nodules. 
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; 

 
 
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FORMaT Appendix A1 Summary 
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. 
2. Male or female participants of any age. 
3. Informed consent signed by participant or parent/legal guardian if participant is under 
18 years of age.  For those participating in both the intensive and consolidation modules 
a combined consent form may be used. 
4. Participant has not received MABS-PD treatment in the 12 months preceding assessment 
of eligibility (this includes drugs prescribed for treatment of other mycobacteria and/or 
other indications that may have activity against MABS as specified in FORMaT 
Prohibited Drug List SOP). 
5. Ability to comply with study visits, therapies and study procedures as judged by the site 
investigator. 
Appendix 
A1-
specific 
exclusions: 
1. Participants receiving current treatment for MABS within the previous 12 months (this 
includes drugs prescribed for treatment of other mycobacteria and/or other indications 
that may have activity against MABS, as specified in FORMaT Prohibited Drug List 
SOP), except for participants taking azithromycin as part of routine treatment for Cystic 
Fibrosis (CF) or chronic infection-related pulmonary disease). 
2. Positive pregnancy test at screening or any time during the FORMaT trial for females 
of childbearing potential. 
3. Breast-feeding. 
4. An unwillingness to comply with the acceptable methods of contraception defined in the 
relevant section of Appendix A1. 
5. QTc>500 milliseconds (QT interval to be corrected based on Fridericia method). 
6. Known hypersensitivity to any of the therapies for which no alternative option(s) have 
been provided. 
Target recruitment: 300 participants 
Outcome 
measures: 
Primary outcome: MABS clearance from respiratory sample(s) with tolerance at the Final 
Outcome. 
Secondary outcomes: 
1. Probability of MABS clearance at Final Outcome irrespective of toxicity according to 
participant’s treatment pathway. 
2. Safety of treatment combinations, including changes in microbiological resistance. 
3. Change in FEV1 z-score at Final Outcome compared with Screening in participants who 
do and do not clear MABS at Final Outcome. 
4. Phenotype of the structural abnormalities of chest CTs and changes in chest CT scores 
between Screening and Final Outcome between participants who clear or do not clear 
MABS at Final Outcome. 
5. Predictive value of structural abnormalities on Screening CT scans for sputum 
conversion and for progression of structural changes in relation to treatment. 
6. Change in 6-minute walk distance (6MWD) for adult participants from Screening to 
Final Outcome according to treatment pathway and in participants who do and do not 
clear MABS at Final Outcome. 
7. Change in HRQoL for participants from Screening to Final Outcome according to 
treatment pathway and in participants who do and do not clear MABS at Final Outcome. 
8. Cost effectiveness of the treatment combinations across intensive and consolidation 
phases of the trial. 

 
 
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FORMaT Appendix A1 Summary 
9. Causes for early withdrawal from MABS-PD treatment due to reasons other than poor 
tolerance as defined in the primary objectives. 
Exploratory outcomes: 
1. Participant’s MABS clearance status 12 months after Final Outcome.  
 
Timepoints: 
Screening: 
Up to Minus 42 days from Date of Randomisation-Short 
Intensive (R-SI). 
Time Point Start Treatment-
Short Intensive (TPST-SI): 
R-SI. 
Time Point Final (TPF): 
End of treatment plus four weeks off-treatment (Final 
Outcome Visit date). 
Nested studies 
Intensive Therapy Modules: 
Nested study A1.1: 
Nested study A1.2: 
Type of Short intensive Therapy 
Duration of intensive therapy for patients completing short 
intensive treatment with ongoing positive MABS cultures 
collected at 4 weeks and randomised to either a further 6 
weeks intensive therapy or immediate consolidation. 
Consolidation Therapy Module: 
Nested study A1.3: 
The use of oral therapy only or oral therapy and inhaled 
amikacin for consolidation therapy. 
 
Intensive Therapy Module Nested Studies 
Nested study A1.1: Type of Short Intensive Therapy 
Timepoints: 
Screening: 
Up to Minus 42 days from Date of R-SI. 
TPST-SI: 
R-SI 
Time Point Final-Short 
Intensive (TPF-SI)*: 
Date of Randomisation Prolonged Intensive or Immediate 
Consolidation (R-PI/IC) minus 1 day for those allocated 
prolonged intensive or Randomisation-Consolidation (R-
Con) minus 1 day for those allocated to immediate 
consolidation.  
*The most accurate method of determining TPF for this trial phase is calculating the time immediately 
preceding randomisation to the next treatment phase i.e. date of next randomisation minus 1 day. 
Nested study A1.2: Duration of intensive therapy for patients with ongoing positive MABS cultures 
Timepoints: 
Screening: 
TPST-SI: 
Up to Minus 42 days from R-SI. 
Date of R-SI 
 
TPF-PI* 
or 
TPF-WK12: 
Date of R-Con minus 1 day (for those allocated to prolonged intensive) 
or Week 12 visit date (for those allocated to immediate consolidation). 
 
*The most accurate method of determining TPF for this trial phase is calculating the time immediately 
preceding randomisation to the next treatment phase i.e. date of next randomisation minus 1 day. 
 
 

 
 
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Consolidation Therapy Module Nested Study 
 
Nested study A1.3: Use of oral therapy +/- inhaled amikacin for consolidation therapy 
Timepoints: 
Time Point Start Treatment-
Consolidation (TPST-Con): 
Date of R-Con 
TPF: 
End of treatment plus 4 weeks off treatment (Final 
Outcome Visit date). 
 

 
 
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1 INTRODUCTION 
The probability of microbiological clearance with acceptable toxicity for treatment combinations tested in FORMaT, 
inclusive of both Appendix A1 intensive and Appendix A1 consolidation for patients with Mycobacterium abscessus 
pulmonary disease (MABS-PD) will be determined. 
The probability of microbiological clearance with acceptable toxicity of treatment combinations will also be 
examined in different patient subpopulations (CF and non-CF, those infected with different MABS subspecies (M. 
a. abscessus/ M. a. bolletii [inducible macrolide resistance] and M. a. massiliense) and those with constitutive 
macrolide resistance and those with mixed NTM infections). 
The best therapy combinations may then form the control arms for new intervention studies which can be added as 
new arms within Appendix A. 
Sites may undertake both intensive and consolidation modules or if they are unable to conduct the intensive therapy 
module, then they can partner with a FORMaT site that is able to manage the intensive therapy module, and only 
undertake the consolidation module themselves. Sites that are unable to undertake the intensive therapy module 
themselves and are unable to partner with a site that is able to manage the intensive therapy module, can choose to 
only undertake the consolidation module (see Appendix A2 for detailed information). 
 
2 OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective for Appendix A1 is to determine the optimal treatment for MABS-PD. Optimal treatment is 
defined by MABS clearance from respiratory samples with tolerance at 56 weeks (denoted Final Outcome) for 
participants who received short intensive therapy or at 62 weeks (denoted Final Outcome) for participants who 
received prolonged intensive therapy. 
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. 
MABS clearance at final outcome will be 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 (either week 56 or 62, depending on treatment arm 
randomisation). Or, a MABS negative Bronchoalveolar Lavage (BAL) collected four weeks after completion of 
consolidation (either week 56 or 62, depending on treatment arm randomisation). 

 
 
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2.2 
SECONDARY OBJECTIVES 
1. To examine the probability of microbiological clearance at Final Outcome (irrespective of toxicity) for 
participants according to treatment path. 
2. To describe the safety of the treatment combinations in patients with MABS. 
3. To examine the change in Forced Expiratory Volume in one second (FEV1) z-score at Final Outcome compared 
with Screening in patients who do and who do not clear MABS at Final Outcome. 
4. To phenotype the structural abnormalities of chest Computed Tomography (CT)s of MABS patients and examine 
changes in chest CT scores (bronchiectasis, trapped air, % disease) between Screening and Final Outcome 
between those who clear and those who do not clear MABS at Final Outcome. 
5. To examine the predictive value of structural abnormalities on Screening CTs for sputum conversion and for 
progression of structural changes in relation to therapy. 
6. To examine change in 6MWD for adult participants from Screening to Final Outcome according to treatment 
pathway and in participants who do and do not clear MABS at Final Outcome. 
7. To examine the change in Health-Related Quality of Life (HRQoL) for participants with CF (using the Cystic 
Fibrosis Questionnaire-Revised (CFQ-R)) at Final Outcome compared with Screening according to treatment path 
and in those that do and those that do not clear MABS at Final Outcome. 
8. To examine general HRQoL at Final Outcome compared with Screening according to treatment path and in those 
who do and who do not clear MABS at Final Outcome. 
9. To examine the cost effectiveness of the proposed treatment combinations across both intensive and consolidation 
phases of the trial. 
10. To examine causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance as 
defined in the primary objectives. 
2.3 
EXPLORATORY OBJECTIVES 
• 
To examine MABS clearance status at twelve (12) months after Final Outcome. 
3 DESIGN 
Appendix A1 describes the intensive and consolidation modules (Figure A1.1) and will test therapies that are 
currently used and are the basis for the current treatment guidelines. 
The intensive and consolidation modules function as nested studies within the trial. 
Sites that are unable to participate in intensive therapy (nested A1 studies A1.1 and A1.2) but are able to undertake 
consolidation (nested study A1.3) may still be included as a trial site and partner with other trial sites that are able to 
undertake intensive therapy to facilitate trial participation (see FORMaT Shared Trial Sites SOP for further 
information on management of shared trial sites). 
 

 
 
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Intensive Therapy Module 
Appendix A1.1: Short Intensive Therapy: 
A1.1.1: Use of Inhaled Amikacin (IA) During Intensive Therapy to Replace Intravenous 
Amikacin (IVA) in the Treatment of MABS-PD. 
A1.1.2: The Use of Additional Clofazimine to Standard Intravenous Therapies during 
Intensive Therapy in the Treatment of MABS-PD. 
Appendix A1.2: Duration of Intensive Therapy for Patients with Ongoing Positive MABS cultures after 
completing 4 weeks vs 10 weeks of Intensive Therapy. 
Consolidation Therapy Module 
Appendix A1.3: The use of oral therapy only or oral therapy and inhaled amikacin for Consolidation 
Therapy.  Note, participants recruited as part of Appendix A2 will also be included in the analysis of the 
objectives of this nested study. 

 
 
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Figure 1 Flow Diagram for Appendix A1, Intervention Program Eligibility into the Intervention Program is 
determined at screening. At Randomisation-Short Intensive (R-SI) (▲); participants are randomised between the 
different intensive therapy arms (Intensive A, Intensive B and Intensive C) for a period of 6 weeks. At the end of 
intensive therapy, it will be determined if participants are still MABS positive, or MABS negative (cleared). 
Randomisation-Prolonged Intensive or Immediate Consolidation (R-PI/IC) (★) will ONLY be for participants who 
are still MABS positive based on respiratory samples taken at 4 weeks and will allocate participants to either 1) 
continue intensive therapy or 2) immediately commence consolidation therapy. Randomisation-Consolidation (R-
Con) (✢) allocates participants to the consolidation therapy arms either at week 6 (for those allocated to immediate 
consolidation) or at week 12 (for those allocated to prolonged intensive therapy). Refer to Appendix A2 for 
information regarding Consolidation Only intervention program module where participants receive physician 
directed intensive therapy prior to enrolment into Consolidation Only program. 
 
4 ELIGIBILITY CRITERIA 
Participants are eligible for Appendix A1 if the following criteria are met: 
4.1 
INCLUSION CRITERIA  
1. Positive MABS-PD diagnosis meeting all three American Thoracic Society clinical, radiological and 
microbiological diagnostic criteria for MABS-PD.  Defined as: 
 
Clinical: Pulmonary symptoms and exclusion of other diagnoses. 
 
Radiological: Nodular or cavitary opacities on chest radiograph or a chest high-resolution computed 
tomography (HRCT) scan showing multifocal bronchiectasis with multiple small nodules. 
 
Microbiological: MABS positive culture results from at least two separate expectorated sputum samples. 

 
 
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or 
Positive culture results from at least one bronchial wash or lavage. 
or 
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. 
2. Male or female participants of any age. 
3. Informed consent signed by participant or parent/legal guardian if participant is under 18 years of age.  For 
those participating in both the intensive and consolidation modules at the same site a combined consent may 
be used.  For those sites only participating in the consolidation module, a specific consolidation consent may 
be required.  
4. Participant has not received MABS-PD treatment in the 12 months preceding assessment of eligibility (this 
includes drugs prescribed for the treatment of other mycobacteria and/or other indications that may have 
activity against MABS, as specified in FORMaT Prohibited Drug List SOP). 
5. Ability to comply with study visits, therapies and study procedures as judged by the site investigator. 
 
4.2 
EXCLUSION CRITERIA 
• 
Participants receiving treatment for MABS within the previous 12 months (this includes drugs prescribed for 
treatment of other mycobacteria and/or other indications that may have activity against MABS, as specified in 
FORMaT Prohibited Drug List SOP), except for participants taking azithromycin as part of routine treatment for 
CF or chronic infection-related pulmonary disease. 
• 
Positive pregnancy test at any time during the FORMaT trial for females of childbearing potential.  
• 
Breast-feeding. 
• 
An unwillingness to comply with the acceptable methods of contraception, as described in Section 5 of this 
appendix. 
• 
Participants with a QTc interval >500 milliseconds (QT interval corrected based on Fridericia method). 
• 
Known hypersensitivity to any of the therapies for which no alternative option(s) have been provided.  This 
includes: 
o Amikacin, 
o Tigecycline, 
o Macrolide antibiotics, and 
o Clofazimine. 

 
 
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4.3 
ADDITIONAL CRITERIA 
4.3.1 
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.  If the participant meets all other inclusion criteria and no exclusion criteria they 
will be eligible for participation.  Ethambutol may be used in addition to trial therapies to cover mixed infections 
considered to require treatment by their clinician. 
4.3.2 
CO-ENROLMENT WITH OTHER TRIALS  
Co-enrolment is not permitted when there is a potential interaction between trial interventions, any compromise to 
the validity of either trial or impact on participants’ rights and/or safety.  However, co-enrolment may be permitted 
in the instance where all trials that the participant is enrolled or to be enrolled in have mutually agreed to the co-
enrolment arrangement. 
 
5 ACCEPTABLE METHODS OF CONTRACEPTION 
The effects of some drugs used during the Intervention Program on the unborn child and on the newborn baby are 
not known.  Because of this, it is important that participants are not pregnant or breast-feeding and do not become 
pregnant during the course of the research project. 
It is therefore important that highly effective birth control is used while in this study.  Site investigators should discuss 
effective methods of contraception with participants.  Both male and female participants are to use effective 
contraception, used correctly with every act of sexual intercourse, from at least 14 days before the first dose of 
MABS-PD therapy, during the course of the trial and for a period of 90 days after the last dose of MABS-PD therapy.  
Acceptable methods of contraception for participants enrolled in Appendix A1 include: 
1) Male vasectomy 6 months or more previously, with a documented negative post-vasectomy semen analysis 
for sperm. 
2) Female bilateral tubal ligation performed at least 6 months previously. 
3) Female continuous use of an intrauterine device (non-hormone releasing or hormone releasing) for at least 
90 days before the first dose of MABS-PD therapy. 
4) Female combined (estrogen and progestogen-containing) or progestogen-only oral, injected, implanted or 
vaginal hormonal contraception associated with inhibition of ovulation. 
The barrier contraception methods listed below are not acceptable and are only to be used in special circumstances 
where the investigator determines that barrier contraception is appropriate. 
1) Male and female condom with spermicide (either as a single product if commercially available and/or as 
allowed according to local regulations; otherwise condom and spermicide as separate products). 
2) Male condom with female diaphragm, cervical cap, or vaginal sponge, each with spermicide. 
For female participants using birth control pills 

 
 
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The use of birth control pills for contraception must be discussed and approved by the local site investigator at the 
start of each phase of the trial and when any changes in therapy occur, as some therapies used during the trial may 
interact with the effectiveness of birth control pills.  Birth control pills should be in successful use from at least 60 
days before the first dose of MABS-PD therapy (unless otherwise noted) and until 90 days following the last dose of 
MABS-PD therapy. 
Female participants who change their method of contraception to birth control pills during the trial must continue to 
use a second form of approved contraception for at least 60 days after starting the use of birth control pills. 
For female participants using hormonal injected, implanted or vaginal contraception 
Injected, implanted or vaginal hormonal contraception should be used successfully from at least 60 days before the 
first dose of MABS-PD therapy (unless otherwise noted) and until 90 days following the last dose of MABS-PD 
therapy. 
 
6 TRIAL CONDUCT 
6.1 
INFORMED CONSENT 
In addition to providing consent to the FORMaT Master Protocol, participants enrolling in the Intervention Program 
are required to sign and date the relevant Appendix A1 consent.  Consent to Appendix A1 includes consent to all 
Appendix A1 nested studies.  Consent will be obtained from participants or their parent/guardian in accordance with 
the policies described in section 5.4 of the FORMaT Master Protocol. 
6.2 
PREGNANCY INFORMATION CONSENT 
If a FORMaT trial participant becomes pregnant or is the biological father of a child conceived while enrolled in this 
Intervention Program the site investigators are requested to provide the participant with the FORMaT pregnancy 
information and consent form.  The FORMaT pregnancy and consent form requests to follow the participant and the 
child for 12 months after conception.  Please refer to FORMaT Safety Monitoring and Reporting SOP for further 
detail for safety monitoring and reporting of pregnancies and pregnancy outcomes in female trial participants or 
female partners who are pregnant to male participants in the Intervention Program. 
6.3 
METHODS OF ASSIGNING PARTICIPANTS TO TREATMENT ARMS 
Participants will be randomised into different treatment arms for both the intensive and consolidation phase of 
treatment as described in the Master Protocol section 6.2 using the randomisation technique minimisation, initially 
in a 1:1:1 ratio for R-SI and 1:1 ratio for R-PI and R-Con.  As described in the Master Protocol, all randomisations 
will be conducted via Research Electronic Data Capture (REDCap) at each FORMaT trial site.  At each stage, study 
staff will enter the subject demographic data and the stratification factors (see section 6.3 in the Master Protocol) into 
REDCap, which will then inform them of the participant’s treatment allocation for that stage. 

 
 
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Following interim analysis, after 60 participants have completed 6 weeks of intensive therapy, if appropriate, 
Bayesian Adaptive Randomisation (BAR) will be implemented for R-SI to implement the allocation probabilities 
which will be used until the data support either early stopping for futility, or a maximum sample size is attained.  
Refer to Appendix F: General Statistical Principles for detailed information regarding randomisation and statistical 
principles for Appendix A1. 
 
7 INTERVENTION PROGRAM PROCEDURES AND SAFETY MONITORING  
In addition to the core trial procedures described in the Master Protocol, participants enrolled in the Intervention 
Program are required to undertake procedures and regular toxicology monitoring.  The type of toxicology monitoring 
procedure required will be determined by the treatment arm the participant is allocated to, and in accordance with 
the schedule of assessments outlined in tables 12 to 14.  Toxicology thresholds will be defined in accordance with 
CTCAE criteria as outlined in the Master Protocol, section 5.9.2.  The outcome of all the assessments below will be 
documented in the corresponding Case Report Form (CRF) and entered into REDCap. 
7.1 
SERUM/URINE PREGNANCY TEST 
All female participants of childbearing potential are required to undergo regular pregnancy testing while enrolled in 
the Intervention Program.  Childbearing potential is defined as a premenopausal female capable of becoming 
pregnant, and includes females on oral, injectable, or mechanical contraception; females who are single and females 
whose male partners have been vasectomised or are using mechanical contraception (1).  A serum pregnancy test 
will be performed at screening and at the final study visit (either week 56 or 62 depending on treatment arm 
allocation) and if applicable, at the early withdrawal visit.  A urine β-hCG test or serum pregnancy is acceptable for 
regular pregnancy monitoring from day 1 in accordance with the schedule of assessments outlined in tables 12 to 14.  
Both urine and serum pregnancy tests are to be performed in accordance with site specific procedures. 
7.2 
CHEST CT SCAN 
The chest CT scan for screening is to be performed ideally within the three months prior to screening for Intervention 
Program participants (maximum of six months earlier). 
7.3 
RESPIRATORY SAMPLING 
For screening a minimum of 2 sputum samples (with at least 1 collected within 6 months prior to screening and other 
samples collected within 12 months prior to screening) or 1 BAL collected within 6 months prior to screening is 
required for Intervention Program participants.  Tables 12 to 14 outline the minimum respiratory sample collection 
timepoints during the trial; however, monthly sputum sample collections are recommended. 
7.4 
AUDIOGRAM 
To monitor aminoglycoside induced ototoxicity, regular audiometry assessments will be undertaken in accordance 
with the schedule of assessments outlined in tables 12 to 14.  The battery of assessments to be completed should 
comply with the site-specific requirements. Assessments can be conducted in either a hospital or community setting. 

 
 
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7.5 
VESTIBULAR MONITORING 
Vestibular toxicity monitoring will document any vestibular symptoms (motion-induced oscillopsia, postural 
instability and gait unsteadiness) associated with prolonged aminoglycoside use.  Assessments will take place in 
accordance with the schedule of assessments outlined in tables 12 to 14.  Testing can be completed either by the 
treating physician or a physiotherapist.  Additional vestibular monitoring may be required if deemed necessary by 
the Site investigator.   
7.5.1 
DYNAMIC VISUAL ACUITY TESTING (DVA) 
Ask the patient to read a visual acuity chart (e.g., Snellen) while sitting still at recommended distance.  This result is 
their static visual acuity.  Repeat task while oscillating the patient’s head horizontally or vertically at 1 to 2 Hz.  An 
abnormal DVA is defined as loss of at least three lines of visual acuity compared with static condition (horizontal 
and/or vertical). 
7.5.2 
HEAD IMPULSE TESTING (HIT) 
Stand in front of the seated patient, facing them, and ask the patient to focus on a target directly in front of them.  
Briskly rotate the patient’s head horizontally approximately 10 to 20° amplitude, watching the patient’s eyes closely.  
In normal subjects, the patient’s eyes remain still as they remain on target.  However, in a patient with impaired 
vestibulo-ocular reflex (VOR), the patient’s eyes drift off the target and require a corrective ‘catch-up’ saccade to re-
fixate on the target and stabilise vision.  This catch-up saccade is a small amplitude horizontal eye movement in the 
opposite direction of the head turn and should occur with every head impulse (repeatable). 
If available, Video Head Impulse Test (vHIT) is recommended as this has a higher sensitivity than the traditional 
bedside head impulse test at detecting impaired VOR.  M=The main benefits include detecting covert (hidden) catch 
up saccades and peer review. 
7.5.3 
ROMBERG ON FOAM TEST 
On a foam surface, ask the participant to stand still with two feet together.  The participant should be able to stand 
steady with their eyes open.  If the participant is not able to perform this task, ask them to separate their feet to 
minimal distance that allows them to do so.  Repeat the task this time with their eyes closed.  Record if the participant 
falls (positive Romberg test) or does not (negative Romberg test). 
Document vestibular test results and any further actions (if results indicate significant vestibular impairment) in the 
CRF. 
7.6 
PHYSICAL EXAMINATION 
The physical examination will be performed in accordance with the procedures outlined in the FORMaT Master 
Protocol, section 5.5.5. in accordance with the schedule of assessments outlined in tables 12 to 14. 
7.7 
ELECTROCARDIOGRAM (ECG) 
A standard 12 lead ECG will be performed in accordance with the relevant tables and site-specific procedures after 
the participant has been supine for at least 5 minutes.  A site investigator will interpret, sign and date the ECG.  The 

 
 
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QTc interval and the clinical interpretation will be recorded in the electronic case report form (eCRF) and ECGs will 
be required to be scanned and stored in the CRF.  The QT interval at Screening is to be corrected using the Fridericia 
method.  For any subsequent QTc intervals which are ‘abnormal’ the Fridericia method is to be used to confirm the 
QTc value. 
7.8 
SIX-MINUTE WALK TEST 
A 6-minute walk test (6MWT) will be performed in adult participants only, at the time points outlined in tables 12 
to 14 if the testing is available at the trial site.  The 6MWT will be performed according to the protocol in the ATS 
Statement: Guidelines for the Six Minute Walk Test (2) and/or local standard procedures.  Results of the 6MWT will 
be recorded in the relevant eCRF in the FORMaT database by the end of the Final Outcome visit. 
7.9 
BLOOD SAMPLING 
Blood samples will be collected in accordance with tables 12 to 14.  Liver function, full blood count and chemistry 
and renal function tests (refer to FORMaT Monitoring Blood Parameters SOP for specific blood parameters to be 
measured) are to be performed in accordance with the local pathology requirements.  All relevant de-identified blood 
pathology reports are to be uploaded in the appropriate eCRFs in the FORMaT database by the end of the Week 6, 
Week 12 and Final Outcome Visits.  Any blood abnormalities that meet Adverse Event (AE) or Serious Adverse 
Event (SAE) criteria are to be reported as an AE/SAE within the specified timeframes. 
7.10 STUDY MEDICATION REVIEW 
Participant adherence to MABS-PD treatment in the intervention cohort will be measured via two indirect methods.  
Self-reported adherence will be assessed using a questionnaire, the 5-item Medication Adherence Rating Scale 
(MARS-5)(3, 4) at the timepoints outlined in tables 12 to 14 and results recorded in the Medication Adherence 
Questionnaire CRF.  Data from pharmacy prescription refill records and prescription claims databases will be 
obtained (where possible) and used to calculate the refill adherence measure, Medication Possession Ratio (MPR) 
(5-8). 
7.11 AMIKACIN ADMINISTRATION AND MONITORING 
7.11.1 NEBULISER TYPE FOR IA 
Amikacin for injection preparation (not liposomal amikacin) is to be used for inhalation in participants randomised 
to inhaled amikacin. A low preservative preparation, if available, is advised to reduce the risks of bronchospasm.  
The brand of amikacin preparation, if known, is to be recorded in the study drug CRF.  Five hundred milligrams of 
amikacin should be administered according to local standard practices.  Prior to administration the patient should 
receive a bronchodilator, for example salbutamol, to reduce the risk of coughing and bronchospasm.  This can be 
given nebulised or by metered dose inhaler.  Amikacin for injection may only be mixed with sodium chloride 0.9%.  
It must not be nebulised as a mixture with other nebulised drugs (e.g. salbutamol, dornase alfa or other nebulised 
antibiotics). 
High efficiency nebulisers are required to nebulise amikacin (IV formulation).  A suitable nebuliser with a filter 
attachment (e.g., SideStream Plus with filter attachment, or Pari LC Plus with filter attachment) are to be used to 

 
 
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prevent environmental deposition of nebulised antibiotics and to reduce the risk of developing antibiotic resistant 
organisms.  Air flow of 6-10 L/min is required to achieve effective nebulisation of amikacin. 
7.11.2 AMIKACIN THERAPEUTIC DRUG MONITORING 
TDM of intravenous amikacin will be required to reduce and monitor toxicity.  There is currently variation across 
trial sites surrounding amikacin TDM methods.  To reflect this, acceptable amikacin TDM strategies that can be used 
in this trial include; 
1) Trough amikacin levels (independent of minimum inhibitory concentration (MIC) using nomogram for next 
dose); 
2) Maximum serum concentration (Cmax)/MIC target; 
3) Area under the curve (AUC) target; 
4) Cmax/MIC and minimum serum concentration (Cmin); 
5) AUC/MIC and Cmin. 
The chosen amikacin TDM strategy used must be recorded in the CRF and adhered to consistently for that participant. 
For subjects randomised to Intensive Therapy Arm B, an amikacin level should be collected at week one, 90 minutes 
(range 60 to 120 minutes) post completion of the inhaled dose.  The time of starting and completing the inhaled 
therapy and time of blood collection should be documented.  No adjustment of the inhaled amikacin dose should be 
undertaken. 
7.12 HEALTH RELATED QUALITY OF LIFE AND UTILITY MEASURES 
HRQoL will be assessed in all participants (where possible) according to the schedule of assessments in the relevant 
appendix.  The questionnaires are required to be completed prior to any clinical assessment and are dependent on the 
participant’s age and whether they have CF.  The age appropriate HRQoL questionnaire issued to the participant at 
the start of the study will continue to be used throughout the study even if the participant progresses to a different 
age range.  HRQoL questionnaires will be made available to study sites.  All questionnaires will be made available 
in English or if available the local language version will be sourced.  Questionnaires can be completed by the 
participant and/or their parent/carer via an online link to the questionnaire(s) on the trial database or if unable to 
access the electronic form these may be completed using a paper-based questionnaire.  Responses from paper-based 
questionnaires are to be entered into the trial database by trial site staff. 
7.12.1 CYSTIC FIBROSIS QUESTIONNAIRE-REVISED (CFQ-R) 
The CFQ-R has been developed specifically for use in people with CF.  This questionnaire measures the impact of 
CF on overall health, daily life, perceived well-being and symptoms.  Age-appropriate questionnaires have been 
developed; CFQ-R teen/adult for adolescents and adults 14 years of age and older, the CFQ-R child for those 6-13 
years of age, and the CFQ-R parent for the parents of those aged 6-13. 
In children ≤16 years of age, the CFQ-R should be administered after the PedsQL™. 

 
 
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7.12.2 EQ-5D-5L 
The EQ-5D-5L questionnaire is a standardised measure of health status in adults 18 years of age and older.  This 
questionnaire can be applied as a generic measure of health for clinical and economic appraisal, including the 
calculation of quality-life adjusted years (QALYs).  The EQ-5D-5L measures five dimensions: 
1. Mobility; 
2. Self-care; 
3. Usual activities; 
4. Pain/discomfort; 
5. Anxiety/depression. 
Each dimension has five possible answers: no problems, slight problems, moderate problems, severe problems and 
extreme problems.  The respondent is asked to indicate his/her health state by selecting the most appropriate statement 
from a list. 
7.12.3 EQ-5D-Y 
The EQ-5D-Y is the child friendly version of the EQ-5D-5L questionnaire.  The EQ-5D-Y has been developed for 
use in children 8 to 17 years of age.  The dimensions and the visual analogue scale (VAS) measured are the same as 
the EQ-5D-5L questionnaire, but with child friendly wording.  For children 4 to 7 years of age the proxy 1 version 
of the EQ-5D-Y can be utilised allowing the respondent (parent/carer) to evaluate participants quality of life (QoL) 
from respondents’ own view. 
7.12.4 ST. GEORGE RESPIRATORY QUESTIONNAIRE (SGRQ) 
The SGRQ is to be completed by all non-CF participants 18 years of age and older. The SGRQ is a supervised self-
administered 50-item questionnaire measuring health status across three domains: symptoms, activity and impacts 
(psycho-social) in people with airway obstruction. 
7.12.5 SHORT FORM- 36 HEALTH SURVEY 
The SF-36 health survey is a self-reported questionnaire applicable in all participants 16 years and older.  Covering 
eight health concepts the SF-36 health survey is a generic outcome measure designed to examine a person’s perceived 
health status. 
7.12.6 PEDIATRIC QUALITY OF LIFE INVENTORY (PEDSQL™) 
The PedsQL™ child health questionnaire is a non-preference-based measure to assess HRQoL for children and 
adolescents from 2 years up to 16 years of age.  Children less than 16 years of age at screening will continue to use 
the PedsQLTM up until the end of the trial, rather than change to using the SF-36 if they turn 16 years of age during 
the study. 
Developmentally appropriate child self-report questionnaires are available (ages 5-7, 8-12, 13-18) together with 
parent/carer proxy-reports (ages 2-4, 5-7, 8-12 and 13-18).  If feasible, the PedsQL™ should be completed before 
the respondents complete any other health data forms and before they see their physician or healthcare provider. 

 
 
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Parents/carers, children (aged 8-12) and young people (aged >12 years) may self-administer the PedsQL™ after the 
FORMaT site researcher has provided instructions.  If it is determined by the FORMaT site researcher that the child, 
young person or parent/carer is unable to self-administer the PedsQL™ the questionnaire should be administered, 
word for word by the FORMaT site researcher.  If the child has difficulty understanding the age appropriate 
PedsQL™ the preceding age questionnaire may be used.  The parent and the child must complete the questionnaires 
independently of each other and in accordance with the PedsQL™ administration guidelines (available via hyperlink 
or refer to relevant section in FORMaT Trial Site Manual of Operating Procedures (MoOP)). 
7.12.7 CHILD HEALTH UTILITY 9D (CHU9D) 
The CHU9D is a generic preference-based measure of paediatric HRQoL for use in children 7 to 17 years of age.  
The use of a descriptive system and a set of preference weights allows for the calculation of quality adjusted life 
years (QALYs) for use in economic evaluation. 
7.13 MABS CLEARANCE FOLLOW-UP QUESTIONNAIRE 
Site investigators will be requested to complete a follow up questionnaire for eligible intervention participants to 
assess microbiological clearance of MABS at 12 months after final outcome. 
 
8 SITE REIMBURSEMENT 
For participants enrolled in Appendix A1, trial sites will be reimbursed on a per participant basis at each of the 
following time points;  
1. Screening; 
2. End of intensive; 
3. End of consolidation; 
4. Final study visit. 
Sites will be reimbursed according to their contract. Payments will be paid for each time point once the data is entered 
into the trial database and all queries finalised. Invoices should be prepared at a minimum of every 6 months. 
 
 
 

 
 
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9 INTENSIVE THERAPY NESTED STUDIES 
9.1 
NESTED STUDY A1.1: SHORT INTENSIVE THERAPY 
9.1.1 
PRIMARY OBJECTIVE 
To compare the efficacy of intensive therapies on microbiological clearance of MABS with good tolerance at end of 
short intensive.  Respiratory samples will be collected at 4 weeks to allow microbiological outcomes to be available 
at end of short intensive and tolerance will be assessed at the end of short intensive.  Treatment will continue up until 
the end of short intensive (6 weeks).  Specifically, the effects of inhaled amikacin (IA) versus intravenous amikacin 
(IVA) will be examined (A1.1.1) and the efficacy of additional oral clofazimine to standard intravenous therapy will 
be examined (A1.1.2). 
Investigation of the efficacy of intensive therapy on microbiological clearance with acceptable toxicity of treatment 
combinations will also be examined in different patient subpopulations (CF and non-CF, those infected with different 
MABS subspecies M. a. abscessus/ M. a. bolletii [inducible macrolide resistance] and M. a. massiliense) and those 
with constitutive macrolide resistance). 
MABS clearance at the end of the short intensive therapy will be defined as negative MABS cultures from all 3 
sputum samples or from one BAL sample collected at week 4. 
 
Additional studies nested within Appendix A1.1 are: 
A1.1.1: Use of IA During Intensive Therapy to Replace IVA in the Treatment of MABS-PD; 
A1.1.2: The use of Additional Clofazimine to Standard IV Therapies During Intensive Therapy in the 
Treatment of MABS-PD. 
 
 

 
 
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9.1.1.1. 
Study A1.1.1: Use of Inhaled Amikacin (IA) During Intensive Therapy to Replace 
Intravenous Amikacin (IVA) in the Treatment of MABS-PD 
Introduction 
Amikacin is an aminoglycoside recommended in guideline-based therapy for the treatment of MABS-PD.  It can be 
administered either intravenously or nebulised for inhalation (using the IV formulation).  Inhaled aminoglycosides 
have the potential advantages of achieving higher airway concentrations, while reducing the risk of systemic toxicity.  
However, amikacin for inhalation is not currently available commercially for the indication of treating MABS and 
clinicians have used an “off-label” IV form of amikacin (delivered via a nebuliser).  A Phase II Randomised Control 
Trial (RCT) (9) of amikacin liposome inhalation suspension (Arikayce) sponsored by Insmed Inc., investigated the 
safety and efficacy of Arikayce to treat NTM infection (36% MABS) in addition to highly variable multi-drug therapy 
in 89 patients with (19%) and without (81%) CF in patients who had failed to clear infection using their current 
treatment.  The trial did not meet the primary endpoint of decreased mycobacterial load, but the treatment group had 
a higher proportion of subjects with >1 negative sputum (32% vs 9%, p=0.006) and improved 6- minute walk 
distance, suggesting a potential benefit from adding Arikayce to consolidation therapy.  Arikayce has now been 
approved for the treatment of patients infected with Mycobacterium avium complex (MAC) who do not respond to 
conventional treatment.  This trial highlighted the difficulties and inefficiencies of undertaking conventional clinical 
trials using the “one population, one drug, one disease” in a disease where there are relatively small patient numbers, 
a heterogeneous population and complex, inconsistent drug combinations.  These factors greatly limit the clinical 
information obtained and contribute to making conventional trials in this patient population difficult to interpret.  
This contrasts with innovative platform trials, which have advantages for efficiently evaluating multiple treatment 
combinations (e.g. multi-drug resistant TB (10)) requiring complex drug regimens in a heterogeneous population. 
Eligibility Criteria 
No additional eligibility criteria are required for participation in A1.1.1 from those described in Appendix A1, Section 
4. 
Objectives 
Primary Objective 
To compare the microbiological clearance of MABS from respiratory samples collected at 4 weeks with good 
tolerability assessed at the end of short intensive therapy between the use of IA (Arm B) and the use of IVA (Arm 
A) given during intensive phase. 
Secondary Objectives 
1. Microbiological clearance at 4 weeks (irrespective of toxicity) with use of IA (Arm B) compared with use of 
IVA (Arm A) in different patient subpopulations (CF and non-CF, those infected with different MABS 
subspecies M. a. abscessus/ M. a. bolletii [inducible macrolide resistance] and M. a. massiliense and those 
with constitutive macrolide resistance).  
2. Safety of using IA to replace IVA in the short intensive therapy phase. 

 
 
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3. Change in FEV1 z-score at end of short intensive therapy versus at Screening  with use of IA (Arm B) 
compared with use of IVA (Arm A). 
4. Change in HRQoL (CFQ-R) for participants at end of short intensive therapy versus at Screening with use 
of IA (Arm B) compared with use of IVA (Arm A). 
5. To examine general HRQoL between Screening and end of short intensive therapy in participants with use 
of IA (Arm B) compared with use of IVA (Arm A). 
6. To examine the cost effectiveness of IA compared with IVA during short intensive therapy. 
7. To examine causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance 
as defined in the primary objectives with use of IA (Arm B) compared with use of IVA (Arm A). 
Statistical Analysis 
Details of the simulations (sample size calculation) for Appendix A1 are outlined in Section 6 of the Master Protocol 
and the relevant section of Appendix F: General Statistical Principles and the Statistical Analysis Plan (SAP). 
 
 

 
 
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9.1.1.2. 
Study A1.1.2: The Use of Additional Clofazimine to Standard Intravenous 
Therapies During Intensive Therapy in the Treatment of MABS-PD 
Introduction 
Clofazimine is approved for use in leprosy.  It has recognised antibacterial and anti-inflammatory effects in the 
management of leprosy and has been used to treat erythema nodosum related to leprosy.  There is no current clinical 
trial evidence to support the use of clofazimine in the treatment of MABS-PD.  Clofazimine use has however 
increased clinically, potentially driven by the difficulty in achieving microbiological clearance and reports of in vitro 
synergy between combinations of clofazimine and amikacin (11, 12). 
Eligibility Criteria 
No additional eligibility criteria are required for participation in nested study A1.1.2 from those described in 
Appendix A1, Eligibility Criteria. 
Objectives 
Primary Objective 
To compare the microbiological clearance of MABS from respiratory samples collected at 4 weeks with good 
tolerability assessed at the end of short intensive therapy between standard IV therapy without clofazimine (Arm C) 
and with clofazimine (Arm A) given during intensive phase. 
Secondary Objectives 
1. 
Microbiological clearance from respiratory samples collected at 4 weeks with acceptable toxicity of intensive 
therapy at the end of short intensive therapy without (Arm C) and with the addition of clofazimine (Arm A) 
to standard IV treatment will be examined in different patient subpopulations (CF and non-CF, those infected 
with different MABS subspecies M. a. abscessus/ M. a. bolletii [inducible macrolide resistance] and M. a. 
massiliense) and those with constitutive macrolide resistance). 
2. 
Microbiological clearance (irrespective of toxicity) at 4 weeks without (Arm C) and with the addition of 
clofazimine (Arm A) to standard IV treatment. 
3. 
Microbiological clearance (irrespective of toxicity) at 4 weeks without (Arm C) and with the addition of 
clofazimine (Arm A) to standard IV treatment will be examined in different patient subpopulations (CF and 
non-CF, those infected with different MABS subspecies M. a. abscessus/ M. a. bolletii [inducible macrolide 
resistance] and M. a. massiliense) and those with constitutive macrolide resistance). 
4. 
Safety of treatment without (Arm C) and with the addition of clofazimine (Arm A) in the short intensive 
therapy phase. 
5. 
Change in FEV1 z-score between Screening and end of short intensive therapy in participants treated without 
(Arm C) and with the addition of clofazimine (Arm A). 
6. 
Changes in HRQoL (CFQ-R) for participants with CF between Screening and end of short intensive therapy 
in participants treated without (Arm C) and with the addition of clofazimine (Arm A). 
7. 
To examine general HRQoL between Screening and end of short intensive therapy in participants treated 
without (Arm C) and with the addition of clofazimine (Arm A). 

 
 
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8. 
To examine the cost effectiveness of treatment without (Arm C) and with the addition of clofazimine (Arm 
A) during short intensive therapy in addition to standard IV treatment. 
9. 
To examine causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance 
as defined in the primary objectives without (Arm C) and with the addition of clofazimine (Arm A) to 
standard IV treatment. 
Statistical Analysis 
Details of the sample size calculation for this study are presented in Section 6.0 of the Master Protocol and the 
relevant section of Appendix F: General Statistical Principles and in the SAP.

 
 
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9.2 
NESTED STUDY A1.2: DURATION OF INTENSIVE THERAPY FOR PATIENTS 
WITH ONGOING POSITIVE MABS CULTURES AFTER 4 WEEKS OF 
INTENSIVE THERAPY. 
9.2.1 
INTRODUCTION 
Current published guidelines for the treatment of MABS-PD (13-15) are based on expert opinion, and in practice 
treatments vary considerably (16).  Suggested regimens include an intensive phase of 4-12 weeks of IV antibiotics 
with duration based on clinical and microbiological response.  Whether extending the length of intensive therapy 
improves microbiological clearance of MABS is not known but the strategy is used clinically in patients with ongoing 
positive cultures.  Toxicity and costs are thought to be related to length of treatment and need to be balanced against 
the potential for better microbiological outcomes. 
9.2.2 
ELIGIBILITY CRITERIA 
Participants are required to have completed 6 weeks of intensive therapy and will have at least one out of 3 sputum 
cultures or one BAL culture positive for MABS collected at week 4 (± 3 days). 
No other additional eligibility criteria are required for participation in nested study A1.2 from those described in 
Section 4 of Appendix A1. 
9.2.3 
OBJECTIVES 
9.2.3.1. 
Primary Objective 
To compare the microbiological clearance from samples collected at 10 weeks with good tolerability between those 
who are allocated to prolonged intensive therapy and those allocated to immediate consolidation following short 
intensive therapy. 
MABS clearance, assessed at the end of prolonged intensive therapy (for those allocated to prolonged intensive) or 
at 12 weeks (for those allocated to immediate consolidation) will be defined as negative MABS cultures from all 3 
sputum samples or from one BAL sample collected at 10 weeks. 
9.2.3.2. 
Secondary Objectives 
1. To compare microbiological clearance from samples collected at 10 weeks (irrespective of toxicity) in 
prolonged intensive therapy compared with short intensive and immediate consolidation therapy in patients 
who had MABS positive cultures from samples collected at 4 weeks. 
2. Safety of prolonged intensive therapy compared with short intensive + immediate consolidation therapy. 
3. Change in FEV1 z-score between Screening and end of prolonged intensive therapy or 12 weeks in 
participants that received prolonged intensive compared with short intensive and immediate consolidation 
who had MABS positive cultures from samples collected  at 4 weeks. 
4. Change in FEV1 z-score between Screening and end of prolonged intensive therapy or 12 weeks between 
those participants still culture positive for MABS at 10 weeks compared with those who have cleared MABS 
at 10 weeks. 

 
 
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5. Change in 6MWD between Screening and end of prolonged intensive therapy or 12 weeks in adult 
participants who receive prolonged intensive compared with short intensive and immediate consolidation 
therapy who had MABS positive cultures from samples collected at 4 weeks. 
6. Change in HRQoL (CFQ-R) for participants with CF between Screening and end of prolonged intensive 
therapy or 12 weeks in participants who received prolonged intensive compared with short intensive and 
immediate consolidation therapy who had MABS positive cultures from samples collected at 4 weeks.  
7. Changes in general HRQoL in prolonged intensive therapy compared with short intensive and immediate 
consolidation therapy in patients who had MABS positive cultures at 4 weeks. 
8. Change in CT scan parameters (bronchiectasis, mucus plugging, airway wall thickening, --atelectasis, % 
disease and air trapping), between Screening and end of prolonged intensive therapy (for those allocated to 
prolonged intensive) or 12 weeks (for those allocated to immediate consolidation) taking into account 
microbiological clearance based on samples collected at 4 and at 10 weeks. 
9. To examine the cost effectiveness of prolonged intensive compared with short intensive and immediate 
consolidation for those who remain MABS positive based on samples collected at 4 weeks. 
10. To examine causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance 
as defined in the primary objectives in prolonged intensive compared with short intensive and immediate 
consolidation in patients who had MABS positive cultures based on samples collected at 4 weeks. 
 
9.2.4 
STATISTICAL ANALYSIS  
Details of the sample size calculation for this study are presented in Section 6.0 of the Master Protocol and the 
relevant section of Appendix F: General Statistical Principles and in the SAP.  

 
 
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9.3 
INTENSIVE THERAPY DOSING REGIMEN 
At R-SI, participants will be randomised to one of three treatment arms during the intensive phase and will receive 
drug therapy in accordance with the dosing tables below.  Drug therapy, administration and duration is dependent on 
the treatment arm (Intensive A, Intensive B, Intensive C) the participant is randomised to.  Drug dosing is based on 
the participants age (<18 or ≥18 years of age).  The start and end points of each drug therapy, the dose of each drug 
therapy used, any changes in dosing and all concomitant medications used will be required to be entered into the 
CRF. 
There are currently three proposed treatment arms in the intensive therapy phase.  Randomisation – Short Intensive 
dictates the drug therapy that participants will be randomised to.  Treatment Arm A is the reference arm (i.e., control). 
 
Intensive Arm A 
Intensive Arm B 
Intensive Arm C 
1. IV amikacin, and; 
1. Inhaled amikacin, and; 
1. IV amikacin, and; 
2. IV tigecycline, and; 
2. IV tigecycline, and; 
2. IV tigecycline, and; 
3. IV imipenem/cilastatin or IV 
cefoxitin, and; 
3. IV imipenem/cilastatin or IV 
cefoxitin, and; 
3. IV imipenem/cilastatin or IV 
cefoxitin, and; 
4. Oral 
azithromycin 
or 
oral 
clarithromycin, and; 
4. Oral 
azithromycin 
or 
oral 
clarithromycin, and; 
4. Oral 
azithromycin 
or 
oral 
clarithromycin. 
5. Oral clofazimine. 
5. Oral clofazimine. 
 
 
For participants with confirmed mixed NTM infections (slow growers + MABS), ethambutol can be added to the 
treatment arms (in accordance with the dosing tables below) if required by the treating physician. 
The intensive therapy dosing regimen tables outlined below are separated by age (adult, paediatric) and by intensive 
treatment arm (Arm A, Arm B, Arm C).  The recommended doses and frequencies are a guideline and participant 
dosing must also take into account clinical judgement and relevant prescribing information. 

 
 
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Table 1 Intensive therapy dosing regimen for Intensive Arm A in adults 
Intensive Arm A: Adult Dosing A 
Drug 
Recommended Dose (per dose) 
Frequency 
IV amikacin 
15mg/kg 
 
OR 
 
Once daily 
 
20-25mg/kg 
Thrice weekly 
Dosing will be made in accordance with British Thoracic Society (BTS) guidelines (13) and is dependent on the physiology, 
site and therapeutic drug monitoring (TDM) outcomes of each participant.  In overweight participants use the ideal body 
weight calculator or in cases of extremes of actual body weight where body weight is greater than 20% above ideal use the 
adjusted body weight calculator available in the MoOP.  To determine ideal body weight for amputees, refer to for the table 
in the MoOP describing the percentage of total weight contributed by individual body parts. 
IV tigecycline 
25mg increasing by 5mg every two 
doses until either 50mg reached or until 
patient is unable to tolerate. 
Twice daily or same total daily dose 
over a 24-hour infusion 
IV imipenem/cilastatin  
IV imipenem/cilastatin is preferred but if 
not tolerated, use IV cefoxitin. 
≥50kg 
1g (dose based on imipenem 
component) 
 
Twice – four times daily infused over 
1-4 hours as tolerated 
 
<50kg 
15 – 25mg/kg (dose based on 
imipenem component).  Maximum 1g. 
 
Twice – four times daily infused over 
1-4 hours as tolerated 
IV cefoxitin 
Cefoxitin only for use if 
imipenem/cilastatin not tolerated. 
2 – 4g 
Thrice daily infused over 1-4 hours as 
tolerated, or same total daily dose 
over a 24-hour infusion. 
Oral azithromycin 
250 – 500mg 
Once daily 
 
If azithromycin not tolerated, use oral 
clarithromycin. 
<40kg or poorly tolerated 
250mg 
 
Once daily 
Oral clarithromycin 
Clarithromycin only for use if 
azithromycin not tolerated. 
500mg 
Twice daily 
Oral clofazimine 
100 – 300mg 
Once daily 
 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below.  
Oral ethambutol 
Ethambutol should be dosed on ideal 
body weight. 
15mg/kg  
(rounded to account for tablet strength) 
OR 
Once daily 
25mg/kg  
(rounded to account for tablet strength) 
Thrice weekly 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
 
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Table 2 Intensive therapy dosing regimen for Intensive Arm B in adults 
Intensive Arm B: Adult Dosing A 
Drug 
Recommended Dose (per dose) 
Frequency 
Inhaled amikacin (IA) 
(IV formulation) 
500mg 
Twice daily 
IV tigecycline 
25mg increasing by 5mg every two 
doses until either 50mg reached or until 
patient is unable to tolerate. 
Twice daily or same total daily dose 
over a 24-hour infusion 
IV imipenem/cilastatin  
IV imipenem/cilastatin is preferred but if 
not tolerated, use IV cefoxitin. 
≥50kg 
1g (dose based on imipenem 
component) 
 
Twice – four times daily infused over 
1-4 hours as tolerated 
 
<50kg 
15 – 25mg/kg (dose based on imipenem 
component).  Maximum 1g. 
 
Twice – four times daily infused over 
1-4 hours as tolerated 
IV cefoxitin 
Cefoxitin only for use if 
imipenem/cilastatin not tolerated. 
2 – 4g 
Thrice daily infused over 1-4 hours as 
tolerated, or same total daily dose over 
a 24-hour infusion. 
Oral azithromycin 
250 – 500mg 
Once daily 
 
If azithromycin not tolerated, use oral 
clarithromycin. 
<40kg or poorly tolerated 
250mg 
 
Once daily 
Oral clarithromycin 
Clarithromycin only for use if 
azithromycin not tolerated. 
500mg 
Twice daily 
Oral clofazimine 
100 – 300mg 
Once daily 
 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below.  
Oral ethambutol 
Ethambutol should be dosed on ideal 
body weight. 
15mg/kg  
(round to account for tablet strength) 
OR 
Once daily 
25mg/kg  
(round to account for tablet strength) 
Thrice weekly 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information. 
 
 

 
 
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Table 3 Intensive therapy dosing regimen for Intensive Arm C in adults 
Intensive Arm C: Adult Dosing A 
Drug 
 Recommended Dose (per dose) 
Frequency  
IV amikacin 
15 mg/kg 
 
OR 
 
Once daily 
 
20-25mg/kg 
Thrice weekly 
Dosing will be made in accordance with British Thoracic Society (BTS) guidelines (13) and is dependent on the physiology, 
site and therapeutic drug monitoring (TDM) outcomes of each participant.  In overweight participants use the ideal body 
weight calculator or in cases of extremes of actual body weight where body weight is greater than 20% above ideal use the 
adjusted body weight calculator available in the MoOP.  To determine ideal body weight for amputees, refer to for the table 
in the MoOP describing the percentage of total weight contributed by individual body parts. 
IV tigecycline 
25mg increasing by 5mg every two 
doses until either 50mg reached or until 
patient is unable to tolerate. 
Twice daily or same total daily dose 
over a 24-hour infusion 
IV imipenem/cilastatin 
≥50kg  
1g (dose based on imipenem 
component) 
 
Twice – four times daily infused over 
1-4 hours as tolerated 
 
IV imipenem/cilastatin is preferred but if 
not tolerated, use IV cefoxitin. 
<50kg 
15 – 25mg/kg (dose based on imipenem 
component).  Maximum 1g. 
 
Twice – four times daily infused over 
1-4 hours as tolerated 
IV cefoxitin 
Cefoxitin only for use if 
imipenem/cilastatin not tolerated. 
2 – 4g 
Thrice daily infused over 1-4 hours as 
tolerated, or same total daily dose over 
a 24-hour infusion. 
Oral azithromycin 
 
250 – 500mg 
Once daily 
If azithromycin not tolerated, use oral 
clarithromycin. 
<40kg or poorly tolerated 
250mg 
 
Once daily 
Oral clarithromycin 
Clarithromycin only for use if 
azithromycin not tolerated. 
500mg 
Twice daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below.  
Oral ethambutol 
Ethambutol should be dosed on ideal 
body weight. 
15mg/kg  
(round to account for tablet strength) 
OR 
Once daily 
25mg/kg  
(round to account for tablet strength) 
Thrice weekly 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
 
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Table 4 Intensive therapy dosing regimen for Intensive Arm A in paediatrics 
Intensive Arm A: Paediatric Dosing A 
Drug 
 Recommended Dose  
(per dose) 
Frequency 
IV amikacin 
15-30mg/kg,  
max 1500mg initial dose 
Once daily 
 
Dosing will be made in accordance with BTS guidelines (13) and is dependent on the physiology, site and TDM outcomes 
of each participant. In obese participants, use the ideal body weight calculator or in cases of extremes of actual body weight 
where body weight is greater than 20% above ideal body weight use the adjusted body weight calculator available in the 
MoOP. To determine ideal body weight or adjusted body weight for amputees, refer to for the table in the MoOP describing 
the percentage of total weight contributed by individual body parts. 
IV tigecycline 
(ages ≥8 years) 
Day 1: 
(50% of optimal dose) 
0.6mg/kg, max 25mg 
Twice daily (12 hourly) 
Day 2: 
(75% of optimal dose) 
0.6mg/kg, max 25mg 
In the morning 
1.2mg/kg, max 50mg 
At night 
Day 3: 
(100% of optimal dose) 
1.2mg/kg, max 50mg 
Twice daily (12 hourly) 
IV imipenem/cilastatin 
IV imipenem/cilastatin is 
preferred but if not 
tolerated, use IV cefoxitin. 
Day 1-2 
15 - 25mg/kg, max 1g 
(dose based on imipenem 
component) 
Twice daily (12 hourly) 
Day 3 
15 - 25mg/kg, max 1g 
(dose based on imipenem 
component) 
Four times daily (reduce to 3 
times daily if not tolerated) 
(6 or 8 hourly) 
IV cefoxitin 
Only for use if imipenem/cilastatin not tolerated. 
40mg/kg, max 2g 
Four times daily (6 hourly) 
Oral azithromycin 
If azithromycin not tolerated, use oral clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if 
azithromycin not tolerated. 
Children 1 month – 11 years of age 
<8 kg 
7.5mg/kg  
Twice daily 
8-11 kg 
62.5mg 
12-19 kg 
125mg 
20-29 kg 
187.5mg 
30-40 kg 
250mg 
Children 12-18 years of age 
Dosing independent of 
weight 
500mg 
Twice daily 
Oral clofazimine 
Dosing may be rounded to account for capsule strength. 
<40kg 
3-5mg/kg, max 100mg 
Once daily 
≥40kg 
100mg 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg 
(round to account for tablet 
strength) 
Once daily 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
 
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Table 5 Intensive therapy dosing regimen for Intensive Arm B in paediatrics 
Intensive Arm B: Paediatric Dosing A 
Drug 
 Recommended Dose  
(per dose) 
Frequency 
Inhaled amikacin (IA) (IV formulation) 
 
500mg 
Twice daily 
IV tigecycline 
(ages ≥8 years) 
Day 1: 
(50% of optimal dose) 
0.6mg/kg, max 25mg 
Twice daily (12 hourly) 
Day 2: 
(75% of optimal dose) 
0.6mg/kg, max 25mg 
In the morning 
1.2mg/kg, max 50mg 
At night 
Day 3: 
(100% of optimal dose) 
1.2mg/kg, max 50mg 
Twice daily (12 hourly) 
IV imipenem/cilastatin 
IV imipenem/cilastatin is 
preferred but if not 
tolerated, use IV cefoxitin. 
Day 1-2 
15 - 25mg/kg, max 1g. 
(dose based on imipenem 
component) 
Twice daily (12 hourly) 
Day 3 
15 - 25mg/kg, max 1g 
(dose based on imipenem 
component) 
Four times daily (reduce to 3 
times daily if not tolerated) 
(6 or 8 hourly) 
IV cefoxitin 
Only for use if imipenem/cilastatin not tolerated. 
40mg/kg, max 2g 
Four times daily (6 hourly) 
Oral azithromycin 
If azithromycin not tolerated, use oral clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if azithromycin 
not tolerated. 
Children 1 month – 11 years of age 
<8 kg 
7.5mg/kg  
Twice daily 
8-11 kg 
62.5mg 
12-19 kg 
125mg 
20-29 kg 
187.5mg 
30-40 kg 
250mg 
Children 12-18 years of age 
Dosing independent of 
weight 
500mg 
Twice daily 
Oral clofazimine 
Dosing may be rounded to account for capsules strength. 
<40kg 
3-5mg/kg, max 100mg 
Once daily 
≥40kg 
100mg 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg 
(round to account for tablet 
strength) 
Once daily 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
 
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Table 6 Intensive therapy dosing regimen for Intensive Arm C in paediatrics 
 
Intensive Arm C: Paediatric Dosing A 
Drug 
Recommended Dose  
(per dose) 
Frequency 
IV amikacin 
 
15-30mg/kg,  
max 1500mg initial dose 
Once daily 
Dosing will be made in accordance with BTS guidelines (13) and is dependent on the physiology, site and TDM outcomes 
of each participant. In obese participants, use the ideal body weight calculator or in cases of extremes of actual body weight 
where body weight is greater than 20% above ideal body weight use the adjusted body weight calculator available in the 
MoOP. To determine ideal body weight or adjusted body weight for amputees, refer to for the table in the MoOP describing 
the percentage of total weight contributed by individual body parts. 
IV tigecycline 
(ages ≥8 years) 
Day 1: 
(50% of optimal dose) 
0.6mg/kg, max 25mg 
Twice daily (12 hourly) 
Day 2: 
(75% of optimal dose) 
0.6mg/kg, max 25mg 
In the morning 
1.2mg/kg, max 50mg 
At night 
Day 3: 
(100% of optimal dose) 
1.2mg/kg, max 50mg 
Twice daily (12 hourly) 
IV imipenem/cilastatin 
IV imipenem/cilastatin is 
preferred but if not tolerated, 
use IV cefoxitin. 
Day 1-2 
15 - 25mg/kg, max 1g. 
(dose based on imipenem 
component) 
Twice daily (12 hourly) 
Day 3 
15 - 25mg/kg, max 1g 
(dose based on imipenem 
component) 
Four times daily (reduce to 
3 times daily if not 
tolerated) 
(6 or 8 hourly) 
IV cefoxitin 
Only for use if imipenem/cilastatin not tolerated. 
40mg/kg, max 2g 
Four times daily (6 hourly) 
Oral azithromycin 
If azithromycin not tolerated, use oral clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if azithromycin 
not tolerated. 
Children 1 month – 11 years of age 
<8 kg 
7.5mg/kg  
Twice daily 
8-11 kg 
62.5mg 
12-19 kg 
125mg 
20-29 kg 
187.5mg 
30-40 kg 
250mg 
Children 12-18 years of age 
Dosing independent of 
weight 
500mg 
Twice daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg  
(round to account for tablet 
strength) 
Once daily 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.

 
 
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9.3.1 
DRUG SUPPLY, STORAGE AND DISTRIBUTION DURING INTENSIVE THERAPY 
Supply, distribution and storage of drugs will be the responsibility of the site coming from site/institution pharmacy 
stocks as per standard of care and in accordance with site specific guidelines and requirements. 
 
9.3.2 
OPTIONS FOR REDUCING NAUSEA DURING INTENSIVE THERAPY 
Titration of dosing for imipenem and tigecycline is described in tables 1 to 6.  Imipenem should also be given over 
2-3 hours (where possible) to reduce nausea.  Suggested pharmacological treatment options that could be considered 
to manage nausea are provided in the FORMaT Trial Site MoOP. 

 
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10 NESTED STUDY A1.3: CONSOLIDATION THERAPY 
10.1 INTRODUCTION 
Currently, the guidelines for consolidation therapy (13) suggest that patients with isolates that are sensitive to 
macrolides or that have inducible resistance should be managed with a combination of between one and three oral 
antibiotics based on drug susceptibility of the isolate and tolerance in combination with IA.  Those with isolates that 
have constitutive resistance should use a combination of between two and four oral drugs based on susceptibility and 
tolerance in combination with IA.  In addition, guidelines suggest that patients with isolates that have amikacin 
resistance could substitute IA for an alternative oral antibiotic.  It is suggested that treatment should continue for 12 
months after culture conversion. 
There is currently no evidence for any of these guidelines.  IA is costly and requires time and effort for maintenance 
of hygienic practice and drug delivery.  Furthermore, adherence to inhaled therapies over the longer term is variable 
(17-19).  This study will examine the effects of IA in addition to the oral only thus providing some evidence regarding 
the use of additional IA during consolidation.  The timing of consolidation therapy is only 46 weeks for this trial.  
Microbiological clearance will be determined from culture of respiratory samples (sputum (expectorated or induced)) 
collected at least one week apart or BAL as follows: 
Participants who continue to produce sputum samples during the consolidation phase are requested to provide 
additional sputum samples monthly.  Three consecutive sputum samples will be collected at least one week apart 
over the last 6 weeks of consolidation therapy.  A final sputum sample collected four weeks after cessation of 
consolidation therapy will together determine the final outcome of microbiological clearance.  All four samples will 
need to be clear to determine clearance. 
For participants who continue to have positive sputum cultures at the end of consolidation, a gap in therapy to 
complete final outcomes may not be required if ongoing treatment is clinically required as microbiological clearance 
will not have occurred. 
Participants  must cease treatment for 4 weeks at the end of consolidation prior to  the final outcome measures to 
enable assessment of microbiological clearance without antibiotic suppression. 
For participants who are unproductive of sputum and/or induced sputum during the consolidation phase, or who 
become unproductive of sputum and/or induced sputum during the course of consolidation therapy,  a BAL is to be 
performed at final outcome (4 weeks after completing consolidation therapy). 
10.2 OBJECTIVES 
10.2.1 PRIMARY OBJECTIVE 
To compare the microbiological clearance with good tolerability of MABS between those allocated to consolidation 
therapy with oral treatment and those allocated to consolidation therapy with oral treatment and additional IA at Final 
Outcome. 

 
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10.2.2 SECONDARY OBJECTIVES 
1. To compare microbiological clearance (irrespective of toxicity) at Final Outcome between those allocated to 
consolidation therapy with oral treatment and those allocated to consolidation therapy with oral treatment 
and additional IA taking into account microbiological status at the start of consolidation. 
2. Difference in safety between those allocated to consolidation therapy with oral treatment and those allocated 
to consolidation therapy with oral therapy and additional IA. 
3. Change in FEV1 z-score between start of consolidation therapy and Final Outcome between those allocated 
to consolidation therapy with oral treatment and those allocated to consolidation therapy with oral therapy 
and additional IA taking into account microbiological clearance at Final Outcome. 
4. Change in 6MWD between Week 12 of the trial and Final Outcome between adult participants allocated to 
consolidation therapy with oral treatment and those allocated to consolidation therapy with oral therapy and 
additional IA taking into account microbiological clearance at Final Outcome. 
5. Change in CT scan parameters (bronchiectasis, mucus plugging, airway wall thickening, atelectasis, % 
disease and air trapping), between 12 weeks and Final Outcome taking into account microbiological 
clearance at start of consolidation therapy between those allocated to consolidation therapy with oral 
treatment and those allocated to consolidation therapy with oral therapy and additional IA. 
6. Changes in HRQoL (CFQ-R) for participants with CF between start of consolidation therapy and Final 
Outcome between those allocated to consolidation therapy with oral treatment and those allocated to 
consolidation therapy with oral therapy and additional IA. 
7. To examine general HRQoL between start of consolidation therapy and Final Outcome in adults (CF and 
non-CF) between those allocated to consolidation therapy with oral treatment and those allocated to 
consolidation therapy with oral therapy and additional IA. 
8. To compare the cost effectiveness of consolidation between those allocated to consolidation therapy with 
oral treatment and those allocated to consolidation therapy with oral therapy and additional IA. 
9. To examine causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance 
as defined in the primary objectives between those allocated to consolidation therapy with oral treatment and 
those allocated to consolidation therapy with oral therapy and additional IA. 
 
10.3 ELIGIBILITY CRITERIA 
Participants who have been randomised to intensive therapy in Appendix A1 and have either completed intensive 
therapy or who are unable to complete Intensive therapy due to a lack of tolerance.  
. 
10.4 STATISTICAL ANALYSIS 
Details of the sample size calculation for this study are presented in Section 6.0 of the Master Protocol and the 
relevant section of Appendix F: General Statistical Principles and in the SAP. 
 

 
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10.5 CONSOLIDATION THERAPY DOSING REGIMEN 
Following R-Con, participants will receive consolidation treatment in accordance with the dosing tables below. Drug 
therapy, administration and duration is dependent on the treatment arm (Consolidation Arm a and Consolidation Arm 
b), age, and/or weight of the participant.  The start and end points of each drug therapy, the dose of each drug therapy 
used, any changes in dosing, and all concomitant medications used will be required to be entered into the CRF. 
There are currently two proposed treatment arms that participants will be randomised to during consolidation therapy. 
 
Consolidation Arm a 
Consolidation Arm b 
1. Oral clofazimine, and; 
1. Inhaled amikacin 
2. Oral azithromycin or oral clarithromycin, and; 
2. Oral clofazimine, and; 
 
3. Oral azithromycin or oral clarithromycin, and; 
 In combination with one to three of the following oral 
antibiotics: 
 In combination with one to three of the following oral 
antibiotics: 
• 
Oral linezolid, 
• 
Oral linezolid, 
• 
Oral trimethoprim / sulfamethoxazole, 
• 
Oral trimethoprim / sulfamethoxazole, 
• 
Oral bedaquiline, 
• 
Oral bedaquiline, 
• 
Oral rifabutin, 
• 
Oral doxycycline, 
• 
Oral moxifloxacin. 
• 
Oral rifabutin, 
• 
Oral doxycycline, 
• 
Oral moxifloxacin. 
 
For participants with confirmed mixed NTM infections (slow growers + MABS), ethambutol can be added to the 
treatment arms (in accordance with the dosing tables below) if required by the treating physician. 
The consolidation therapy dosing regimen tables outlined below are separated by age (adult, paediatric) and by 
consolidation treatment arm (Arm a and Arm b). The recommended doses and frequencies are a guideline and 
participant dosing must also take into account clinical judgement and relevant prescribing information.  
 
 

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

 
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Table 8 Consolidation therapy dosing regimen for Consolidation Arm b in adults 
Consolidation Arm b: Adult Dosing A 
Drug 
 Recommended Dose (per dose) 
Frequency  
Inhaled amikacin (IA) 
(IV formulation) 
500mg 
Twice daily 
Oral clofazimine 
100 – 300mg 
Once daily 
Oral azithromycin 
250 – 500mg 
OR 
500mg 
Once daily 
 
Thrice weekly 
If azithromycin not tolerated, use oral 
clarithromycin. 
<40kg or poorly tolerated 
250mg 
 
Thrice weekly 
Oral clarithromycin 
Clarithromycin only for use if 
azithromycin not tolerated. 
500mg 
Twice daily 
In combination with one to three of the following oral antibiotics guided by participant susceptibility and tolerance. 
Oral linezolid 
600mg 
Once daily 
Oral trimethoprim with 
sulfamethoxazole 
160mg/800mg  
Twice daily 
Oral bedaquiline 
(Weighing at least 30kg) 
First 2 weeks 400mg 
Once daily 
For remaining 22 weeks 200mg 
Max duration 6 months 
Thrice weekly 
At least 48 hours between doses 
Oral rifabutin 
5mg/kg, max 450mg 
Once daily 
Oral doxycycline 
100mg 
Once daily 
Oral moxifloxacin 
400mg 
Once daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below.  
Oral ethambutol 
Ethambutol should be dosed on ideal 
body weight. 
15mg/kg  
(round to account for tablet strength) 
OR 
Once daily 
25mg/kg  
(round to account for tablet strength) 
Thrice weekly 
 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
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Table 9 Consolidation therapy dosing regimen for Consolidation Arm a in paediatrics 
Consolidation Arm a: Paediatric Dosing A 
Drug 
Recommended Dose  
(per dose) 
Frequency 
Oral clofazimine 
Dosing may be rounded to account for capsules. 
<40kg 
3-5mg/kg, max 100mg 
Once daily 
≥40kg 
100mg 
Oral azithromycin 
If azithromycin not tolerated, use oral clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if azithromycin 
not tolerated. 
Children 1 month – 11 years of age 
<8 kg 
7.5mg/kg  
Twice daily 
8-11 kg 
62.5mg 
12-19 kg 
125mg 
20-29 kg 
187.5mg 
30-40 kg 
250mg 
Children 12-18 years of age 
Dosing independent of 
weight 
500mg 
Twice daily 
In combination with one to three of the following oral antibiotics guided by participant susceptibility and tolerance. 
Oral linezolid 
1 month – 9 years 
10mg/kg, max 450mg 
Twice daily 
10 – 12 years 
10mg/kg, max 600mg 
Daily 
>12 years 
600mg 
Daily 
Oral trimethoprim with sulfamethoxazole  
5mg/kg trimethoprim 
max 160mg trimethoprim 
Twice daily 
Oral bedaquiline 
(age ≥5 years) 
Weeks 1 and 2 
≥15kg - <20kg 
160mg 
Once daily 
≥20kg - <30kg 
200mg 
≥30kg 
400mg 
Weeks 3-24 - Max Duration 6 Months 
≥15kg - <20kg 
80mg 
Thrice weekly. 
At least 48 hours between 
doses 
≥20kg - <30kg 
100mg 
≥30kg 
200mg 
Oral rifabutin 
5mg/kg, max 300mg 
Once daily 
Oral doxycycline 
(ages ≥8 years) 
2mg/kg, max 100mg 
Once daily 
Oral moxifloxacin  
Dosing may be rounded to account for capsules. 
10-15mg/kg, max 400mg 
Once daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg 
(round to account for tablet 
strength) 
Once daily 
 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
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Table 10 Consolidation therapy dosing regimen for Consolidation Arm b in paediatrics 
Consolidation Arm b: Paediatric Dosing A 
Drug 
Recommended Dose  
(per dose) 
Frequency 
Inhaled amikacin (IA) 
(IV formulation) 
500mg 
Twice daily 
Oral clofazimine 
Dosing may be rounded to account for capsules. 
<40kg 
3-5mg/kg, max 100mg 
Once daily 
≥40kg 
100mg 
Oral azithromycin 
If azithromycin not tolerated, use oral clarithromycin. 
10mg/kg, max 500mg 
Once daily 
Oral clarithromycin 
Only for use if azithromycin 
not tolerated. 
Children 1 month – 11 years of age 
<8 kg 
7.5mg/kg  
Twice daily 
8-11 kg 
62.5mg 
12-19 kg 
125mg 
20-29 kg 
187.5mg 
30-40 kg 
250mg 
Children 12-18 years of age 
Dosing independent of 
weight 
500mg 
Twice daily 
In combination with one to three of the following oral antibiotics guided by participant susceptibility and tolerance. 
Oral linezolid 
1 month – 9 years 
10mg/kg, max 450mg 
Twice daily 
10 – 12 years 
10mg/kg, max 600mg 
Daily 
>12 years 
600mg 
Daily 
Oral trimethoprim with sulfamethoxazole  
5mg/kg trimethoprim 
max 160mg trimethoprim 
Twice daily 
Oral bedaquiline 
(age ≥5 years) 
Weeks 1 and 2 
≥15kg - <20kg 
160mg 
Once daily 
≥20kg - <30kg 
200mg 
≥30kg 
400mg 
Weeks 3-24 - Max Duration 6 Months 
≥15kg - <20kg 
80mg 
Thrice weekly. 
At least 48 hours between 
doses 
≥20kg - <30kg 
100mg 
≥30kg 
200mg 
Oral rifabutin 
5mg/kg, max 300mg 
Once daily 
Oral doxycycline 
(ages ≥8 years) 
2mg/kg, max 100mg 
Once daily 
Oral moxifloxacin  
Dosing may be rounded to account for capsules. 
10-15mg/kg, max 400mg 
Once daily 
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral 
ethambutol to the treatment arm in accordance with the dosing below. 
Oral ethambutol 
Ethambutol should be dosed on ideal body weight. 
15mg/kg, max 1200mg 
(round to account for tablet 
strength) 
Once daily 
 
A The recommended doses and frequencies are a guideline and participant dosing must also consider clinical 
judgement and relevant prescribing information.  
 

 
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10.5.1 DRUG SUPPLY, STORAGE AND DISTRIBUTION DURING CONSOLIDATION 
THERAPY 
Supply, distribution and storage of drugs will be the responsibility of the site coming from site/institution pharmacy 
stocks as per standard of care and made in accordance with site-specific guidelines and requirements. 
10.5.2 DRUG COMPLIANCE DURING CONSOLIDATION THERAPY 
The procedures for distribution of consolidation therapy are site dependent.  Drug compliance during consolidation 
therapy will be captured from pharmacy records of drugs dispensed to the participant while enrolled in FORMaT 
Appendix A1. 
 
 

 
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11 SCHEDULE OF ASSESSMENTS 
Table 11 lists the special considerations that are applicable to all Schedule of Assessment tables.  Table 11 must be 
used in conjunction with Tables 12 to 14.  Tables 12 to 14 show the schedules of assessment tables for participants 
enrolled in Appendix A1.  Table 12 shows the schedule of assessments for all participants from Screening to end of 
Week 6, Table 13 shows the schedule of assessments from Week 7 to Week 12 for participants randomised to 
Prolonged Intensive and Table 14 shows the schedule of assessments for all participants during the Consolidation 
therapy phase and at the Final Outcome.  Acceptable stud[08yy visit windows are also outlined in tables 12 to 14. 
Table 11 Special considerations for Schedule of Assessments 
Symbol Definition 
A 
Participant reconsent is required with IRB/ IED/HREC approved changes to the protocol that affect the 
participants rights and/or safety and/or if a child turns 18 years old during the trial and must reconsent 
as an adult participant. 
B 
Visits may be conducted while an inpatient or at home if participant is receiving home-based care. 
C 
To be eligible to enrol in the Intervention Program, the participant is required to have either two (2) 
MABS-positive sputum samples or one (1) MABS-positive BAL sample.  Refer to section 7.3 for further 
information.  
D 
To determine MABS clearance following four (4) weeks of intensive therapy, three sputum samples or 
one BAL sample are required to be collected in Week 4 (±3 days) to ensure results are available by week 
6 of intensive therapy to inform randomisation. 
E 
Adult height is to be recorded once (preferably at the screening visit).  Paediatric height must be 
measured at least every six weeks. 
F 
Only required if the screening assessments were reviewed more than two (2) weeks earlier than Day 1. 
G 
Refer to section 7.2 for eligibility criteria for the screening visit chest CT. 
H 
Only required in female participants of childbearing potential.  A serum pregnancy test is required at 
screening and final study visit.  A urine or serum pregnancy test is acceptable at all other times. 
I 
Screening audiology and screening vestibular assessment can be performed if a participant has 
commenced intensive therapy but must be performed within three (3) days of first receiving treatment. 
J 
QT interval at screening is to be corrected using the Fridericia method. Any subsequent abnormal QTc 
intervals are to be confirmed using the Fridericia method. 
K 
Six-minute walk test to be performed in participants ≥18 years of age only. 
L 
Plasma levels post inhaled amikacin are to be collected 90 minutes post dose (range 60 to 120 minutes).  
Please record inhaled amikacin start and stop times.  
M 
IV Amikacin Therapeutic Drug Monitoring to be completed within 48 hours of dosing according to site 
protocol. 
N 
The EQ-5D-5L is to be administered to participants ≥18 years of age whereas the EQ-5D-Y is to be 
administered to participants 8 to 17 years of age.  The EQ-5D-Y Proxy is to be administered to 
parents/carers of participants 4 to 7 years of age. 
O 
The SF-36 is to be administered to participants ≥16 years of age at time of Screening.  For participants 
aged <16 years at Screening, the PedsQLTM is to be used for entire duration of trial. 
P 
The PedsQL™ is only to be assessed in participants <16 years of age at time of Screening.  If both the 
PedsQL™ and the CFQ-R are administered where possible, the PedsQL™ should be administered prior 
to the CFQ-R. 
Q 
The CFQ-R is only to be completed in participants with CF.  The age appropriate CFQ-R assessment 
should be selected; CFQ-R adult/teen (≥14 years of age), CFQ-R child (6 to 13 years of age) and CFQ-
R parent (parent/carer of participant 6 to 13 years of age). 
R 
The Child Health Utility is only to be assessed in participants 7 to 17 years of age. 

 
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S 
The SGRQ is only to be assessed in non-CF participants 18 years of age and older. 
T 
Costs questionnaire only required for participants that are randomised to immediate consolidation.  
U 
MARS-5 is only to be completed in participants in the intervention cohort on outpatient based MABS-
PD treatment. 
V 
Week 12 chest CT scan is optional and requires participant to consent to FORMaT Sub-Study C3: 
Imaging.  The site must have approval to conduct this additional scan, be certified to perform the scan 
using the scanner specific protocol and the participant must provide additional consent. 
W 
To determine MABS clearance following ten (10) weeks of intensive therapy, three sputum samples or 
one BAL sample are required to be collected in Week 10 (±3 days). 
X 
Participants unable to produce a sputum sample (expectorated or induced) to be marked as unproductive 
on the CRF. 
Y 
Participants who have produced sputum samples during Weeks 18, 28, and 38 are requested to provide 
three additional sputum samples collected at least one week apart nearer to the end of Weeks 52.  For 
participants who were unproductive (intermittent or continual) during Weeks 18, 28, 38 and 52, a BAL 
sample is to be collected during Week 56. 
Z 
Clinic visit and some assessments at Week 10 can be completed at any time between Week 10 and Week 
12.  
1 
Chest CT scan at early withdrawal visit will only be requested if clinically indicated. 

 
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Table 12 Schedule of Assessments for Intervention Program Participants: Intensive Therapy (Screening and first six weeks of intensive therapy) 
ASSESSMENT 
SCREENING 
VISIT 
INTENSIVE THERAPY 
Week 1 - Week 6 
Day 0 
Day 1 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
-42 Days 
 +24 hours 
+3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
Informed consent for Appendix A1A 
✓ 
 
 
 
 
 
 
 
Clinic visit B 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Review eligibility 
✓ 
 
 
 
 
 
 
 
Randomisation 
 
✓ 
 
 
 
 
 
✓ 
Adverse event monitoring 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Respiratory 
sample 
Sputum (expectorated or induced) or; 
✓C 
 
 
 
 
✓ 
x3D 
 
 
BAL 
✓C 
 
 
 
 
✓D 
 
 
Height E and Weight 
✓ 
 
 
 
 
 
 
✓ 
Medication Review 
✓ 
✓F 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Spirometry 
✓ 
 
 
 
 
 
 
✓ 
Chest CT 
✓G 
 
 
 
 
 
 
 
Pregnancy Test and Breastfeeding Status H 
✓ 
✓ 
 
✓ 
 
✓ 
 
✓ 
Audiogram 
✓I 
 
 
 
 
✓ 
 
 
Vestibular Monitoring 
✓I 
 
 
 
 
✓ 
 
 
ECG J 
✓ 
 
 
✓ 
 
 
 
✓ 
6-minute walk test K 
✓ 
 
 
 
 
 
 
 
Blood collection: 
 
 
 
 
 
 
 
 
1. Chemistry and Renal Function 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
2. Liver Function Tests 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
3. Full Blood Count 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Physical examination 
✓ 
✓F 
 
 
 
 
 
✓ 
Amikacin 
monitoring 
Therapeutic Drug Monitoring, or; 
 
✓M 
Arm A & C 
 
✓ 
Arm A & C 
 
 
 
✓ 
Arm A & C 
Post dose levels L 
 
 
✓ 
Arm B only 
 
 
 
 
 
Health-related quality of life questionnaires: 
 
 
 
 
 
 
 
 
1. EQ-5D-5L or -Y N 
✓ 
 
 
 
 
 
 
✓ 
2. SF36  O 
✓ 
 
 
 
 
 
 
✓ 
3. PedsQL™ P 
✓ 
 
 
 
 
 
 
✓ 
4. CFQ-R Q 
✓ 
 
 
 
 
 
 
✓ 

 
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ASSESSMENT 
SCREENING 
VISIT 
INTENSIVE THERAPY 
Week 1 - Week 6 
Day 0 
Day 1 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
-42 Days 
 +24 hours 
+3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
5. Child Health Utility 9D R 
✓ 
 
 
 
 
 
 
✓ 
6. SGRQ S 
✓ 
 
 
 
 
 
 
✓ 
Costs Questionnaire 
✓ 
 
 
 
 
 
 
✓ 
Medication Adherence Questionnaire U 
 
 
 
 
 
 
 
✓ 

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

 
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ASSESSMENT 
PROLONGED INTENSIVE THERAPY  
Week 7- Week 12 
Week 7 
Week 8 
Week 9 
Week 10 
Week 11 
Week 12 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
±3 Days 
13. CFQ-R Q 
 
 
 
 
 
✓ 
14. Child Health Utility 9D R 
 
 
 
 
 
✓ 
15. SGRQ S 
 
 
 
 
 
✓ 
Costs Questionnaire 
 
 
 
 
 
✓ 
Medication Adherence Questionnaire U 
 
 
 
 
 
✓ 

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

 
 
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57 
12 RANDOMISATION 
There will be three stages of randomisation in the Intervention Program Appendix A, dictating the treatment the 
participant will receive: 
Randomisation to Short Intensive (R-SI): The first randomisation will be at the start of the intensive phase, with all 
participants randomised between the different intensive therapy arms according to the study specific Appendix. 
Randomisation to Prolonged Intensive or Immediate Consolidation (R-PI/IC): The second randomisation will 
ONLY be for participants who are still MABS positive at the end of short intensive therapy (based on respiratory 
sampling collected at 4 weeks) and are able to continue with intensive therapy.  Randomisation will occur at the end 
of short intensive therapy and will allocate participants to either; 
Continue intensive therapy which will be followed by consolidation (participants remain on the same 
intensive therapy drug regimen if randomised to prolonged intensive therapy),  
or immediately commence consolidation therapy. 
Randomisation to Consolidation (R-Con): This randomisation will allocate participants to the consolidation therapy 
arms.  Each randomisation will function as a ‘quasi-separate’ trial (as described in the relevant sections of Appendix 
A), as well as being considered in combination (intensive + consolidation).  Randomisation at each level will be 
conducted using the method of minimisation (described in the relevant sections of the Master Protocol and Appendix 
F: General Statistical Principles).  Each randomisation level will be planned to enable flexibility via pre-planned 
adaptations as described above. 
 
 

 
 
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58 
13 APPLICABLE DISCOVERY STUDIES AND REGISTRY LINKAGE FOR 
APPENDIX A1 
Intervention Program participants may be eligible to enrol in the following FORMaT Sub-Studies and Integrated 
Studies: 
1) Appendix C Discovery 
i. 
C1: Pharmacokinetics 
i) C1.1 Steady state pharmacokinetics of Amikacin 
ii) C1.2 Microsampling and non-blood matrix validation for amikacin TDM 
iii) C1.3 Pharmacokinetics of MABS-PD therapies 
iv) C1.4 Pharmacokinetics of CFTR modulator therapy in persons with CF on MABS therapy 
ii. 
C2: Immune factors and biomarkers 
i) C2.1 Macrophage function 
ii) C2.2 Mitochondrial stress 
iii) C2.3 T-cell function  
iv) C2.4 Gene expression  
v) C2.5 Serology 
iii. 
C3: Imaging 
2) Appendix D Registry Linkage 
i. 
D1: Australian cystic fibrosis data registry 
3) Appendix E Health Economics 
i. 
E1: Cost effectiveness and Resource utilisation 
Please see the relevant sections of the applicable appendix for further information, including additional eligibility 
criteria. 
 

 
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59 
14 REFERENCES 
1. 
Food US, Drug A. Guideline for the study and evaluation of gender differences in the clinical evaluation of 
drugs; notice. Fed Regist. 1993;58(139):39406-16. 
2. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care 
Med. 2002;166(1):111-7. 
3. 
Kwan YH, Weng SD, Loh DHF, Phang JK, Oo LJY, Blalock DV, et al. Measurement Properties of Existing 
Patient-Reported Outcome Measures on Medication Adherence: Systematic Review. J Med Internet Res. 
2020;22(10):e19179. 
4. 
Chan AHY, Horne R, Hankins M, Chisari C. The Medication Adherence Report Scale: A measurement tool 
for eliciting patients' reports of nonadherence. Br J Clin Pharmacol. 2020;86(7):1281-8. 
5. 
Lam WY, Fresco P. Medication Adherence Measures: An Overview. Biomed Res Int. 2015;2015:217047. 
6. 
Vrijens B, Urquhart J. Methods for measuring, enhancing, and accounting for medication adherence in 
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7. 
Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and 
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8. 
Al-Hassany L, Kloosterboer SM, Dierckx B, Koch BC. Assessing methods of measuring medication 
adherence in chronically ill children-a narrative review. Patient Prefer Adherence. 2019;13:1175-89. 
9. 
Olivier KN, Griffith DE, Eagle G, McGinnis Ii JP, Micioni L, Liu K, et al. Randomized Trial of Liposomal 
Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease. Am J Respir Crit Care Med. 2016. 
10. 
Prevots DR, Marras TK. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a 
review. Clin Chest Med. 2015;36(1):13-34. 
11. 
van Ingen J, Totten SE, Helstrom NK, Heifets LB, Boeree MJ, Daley CL. <em>In Vitro</em> Synergy 
between Clofazimine and Amikacin in Treatment of Nontuberculous Mycobacterial Disease. Antimicrobial 
Agents and Chemotherapy. 2012;56(12):6324-7. 
12. 
Shen G-H, Wu B-D, Hu S-T, Lin C-F, Wu K-M, Chen J-H. High efficacy of clofazimine and its synergistic 
effect with amikacin against rapidly growing mycobacteria. International Journal of Antimicrobial Agents. 
2010;35(4):400-4. 
13. 
Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, et al. British Thoracic Society 
guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax. 
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14. 
Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA 
statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit 
Care Med. 2007;175(4):367-416. 
15. 
Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation 
and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous 
mycobacteria in individuals with cystic fibrosis: executive summary. Thorax. 2016;71(1):88-90. 
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Novosad SA, Beekmann SE, Polgreen PM, Mackey K, Winthrop KL, Team MaS. Treatment of 
Mycobacterium abscessus Infection. Emerg Infect Dis. 2016;22(3):511-4. 

 
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17. 
Harrison MJ, McCarthy M, Fleming C, Hickey C, Shortt C, Eustace JA, et al. Inhaled versus nebulised 
tobramycin: A real world comparison in adult cystic fibrosis (CF). Journal of Cystic Fibrosis. 
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18. 
Nasr SZ, Chou W, Villa KF, Chang E, Broder MS. Adherence to dornase alfa treatment among commercially 
insured patients with cystic fibrosis. Journal of Medical Economics. 2013;16(6):801-8. 
19. 
Bakker EM, Volpi S, Salonini E, van Der Wiel-Kooij EC, Sintnicolaas CJJCM, Hop WCJ, et al. Improved 
treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation. European 
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