Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT)

Australian Government Department of Health and Ageing, Children's Hospital Foundation, Cystic Fibrosis Foundation, Newcastle University, Griffith University, Erasmus Medical Center, Monash University, University of Copenhagen, Hôpital Cochin, South Australian Health and Medical Research Institute, University of Melbourne, James Cook University, Queensland, Australia, Murdoch Childrens Research Institute

Mycobacterium abscessus (MABS) is a group of rapid-growing, multi-drug resistant non-tuberculous mycobacteria (NTM) causing infections in humans. MABS pulmonary disease (MABS-PD) can result in significant morbidity, increased healthcare utilisation, accelerated lung function decline, impaired quality of life, more challenging lung transplantation, and increased mortality. While the overall numbers affected is small, the prevalence of infections is increasing worldwide. The Finding the Optimal Regimen for Mycobacterium abscessus Treatment (FORMaT) trial aims to produce high quality evidence for the best treatment regimens to maximise health outcomes and minimise toxicity and treatment burden, as well as developing biomarkers (serology, gene expression signatures, and radiology) to guide decisions for starting treatment and measuring disease severity in patients with MABS PD.

Mycobacterium abscessus (MABS) are a group of non-tuberculous mycobacteria (NTM) found in water and soil habitats that exhibit high levels of intrinsic multi-drug resistance. They are recognised opportunistic human pathogens capable of causing chronic pulmonary disease (MABS-PD), predominantly in individuals with underlying inflammatory lung diseases. Finding the Optimal Regimen for Mycobacterium abscessus Treatment (FORMaT) is an iterative, standing, platform trial with innovative and adaptive properties that evaluate and develop the optimal combinations of therapies for children and adults with MABS-PD to clear MABS infection with acceptable tolerance. We will use these opportunities afforded by the clinical trial platform to establish discovery studies to: (i) understand the effects of disease and treatment on health-related quality of life, (ii) determine cost effectiveness of interventions, (iii) optimise pharmacokinetic drug dosing, (iv) understand susceptibility to MABs-PD, (v) develop biomarkers of clinical disease, (vi) investigate genomics of MABs strains causing MABs-PD and development of antimicrobial resistance. FORMaT provides a pragmatic design to address challenges to develop an evidence base for the first time for MABS-PD. Initially, the trial has been designed to test therapies that are currently the basis for treatment guidelines for MABS-PD. The trial has the capacity to add new treatments and to eliminate therapies because of futility as they either lack efficacy or cause unacceptable toxicity. Novel therapeutic approaches are then tested against the previously determined optimal approaches, thus leading in an iterative fashion to improve microbiological clearance, and health outcomes associated with MABS-PD. The trial is designed as a series of trials within the main trial to enable investigation of the different phases of treatment; intensive (intravenous treatment phase) and consolidation (oral and or inhaled treatment phase) based on clinical guidelines. The primary outcome for each trial is microbiological clearance with clinical tolerance (Grade 1 or 2) based on Common Terminology Criteria for Adverse Events (version 5). This enables subjects to continue in the trial even if tolerance is poor or they change treatments in a specific phase of the trial as those events contribute to the primary outcome determination.

Mycobacterium abscessus, Pulmonary disease, Microbiological, Regimen, Radiological, Quality of life, Health economics, Biomarkers

There are 2 different phases of treatment; intensive therapy (IT) followed by consolidation therapy (CT). Intervention cohort participants will be randomised to 1 of 3 treatment arms for 6 weeks of IT. After the first 6 weeks of IT participants who are culture positive for MABS are randomised to either prolonged IT (additional 6 weeks of IT) then CT, or to commence CT. If, at week 6 participants are MABS culture-negative they will commence CT. Participants commencing CT are randomised to one of two treatment arms for 50 weeks. There are 12 possible paths through the trial. This standing platform trial design enables assessment of short IT, prolonged IT, and CT components individually as well as the overall combination of IT and CT. After 100 patients have completed short IT an interim analysis will be conducted, and Bayesian adaptive randomisation (BAR) will be implemented. New interventions may be added or stopped in the future due to lack of benefit at interim analyses.

The FORMAT trial may include placebo controlled double blind randomised interventions in the future, but the initial intervention program is randomised but open label. There will be three stages of randomisation in the intervention program of this study, dictating the treatment the participant will receive. Randomisation at each level will be conducted using the method of minimisation. Each randomisation level will be planned to enable flexibility via pre-planned adaptations.

Following Randomisation 1, Participants will receive intensive drug therapy in the form of IV amikacin, IV tigecycline, IV cefoxitin/imipenem + oral azithromycin AND clofazimine.

Following Randomisation 1, Participants will receive inhaled amikacin (IA), IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin AND clofazimine.

Following Randomisation 1, Participants will receive intensive drug therapy in the form of IV amikacin, IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin.

Oral clofazimine + oral azithromycin/oral clarithromycin in combination with one to three of the following oral antibiotics: oral linezolid, oral co-trimoxazole, oral doxycycline, oral moxifloxacin, oral bedaquiline (adults only), oral rifabutin.

Inhaled amikacin (IA), oral clofazimine + oral azithromycin/oral clarithromycin in combination with one to three of the following oral antibiotics: oral linezolid, oral co-trimoxazole, oral doxycycline, oral moxifloxacin, oral bedaquiline (adults only), oral rifabutin.

Adults: Intravenous amikacin 5mg/kg once daily or 7.5mg/kg twice daily or 20-25 mg/kg thrice weekly. Children:Intravenous amikacin 15-30 mg/kg once daily, maximum dose 1500mg

Adults: Intravenous Tigecycline 25 mg increasing by 5 mg every two doses until either maximum dose reached (50mg) or until patient is unable to tolerate twice daily. Children (≥8 years of age) intravenous tigecycline: Day 1- 0.6mg/kg twice daily to a maximum of 25mg. Day 2- 0.6mg/kg (maximum 25mg) in the morning, 1.2 mg/kg (maximum 50mg) at night. Day 3- 1.2mg/kg (maximum 50 mg) twice daily

Adults: Intravenous Imipenem (≥50kg) 500mg twice daily (<50kg) 15 mg/kg twice daily. Children: intravenous imipenem Day 1- 2- 25mg/kg (maximum 1g) twice daily. DAY 3- 25mg/kg (maximum 1g) four times daily (drop to 3 if not tolerated).

Adults: If imipenem is poorly tolerated intravenous cefoxitin 200 mg/kg thrice daily. Children: if imipenem is poorly tolerated intravenous cefoxitin 50mg/kg (maximum 4g) four times daily.

Adults: Oral azithromycin 500mg (≥40kg) once daily, (<40kg) 250mg once daily.During consolidaiton: 500mg (≥40kg) thrice weekly, (<40kg) 250mg thrice weekly. Children: Oral azithromycin:10mg/kg (maximum 500mg) once daily. During consolidation 10mg/kg once daily maximum 500mg.

Adult: If azithromycin is poorly tolerated use oral clarithromycin 500mg twice daily.Children: If azithromycin is poorly tolerated use oral clarithromycin. In children 1 month old- 11years of age the following dosing applies: <8kg: 7.5mg/kg twice daily, maximum dose 62.5mg, 8-11kg: 62.5mg twice daily, maximum dose 62.5mg, 12-19 kg: 125mg twice daily, maximum dose 125mg, 20-29 kg: 187.5mg twice daily, maximum dose 187.5mg, 30-40 kg: 250mg twice daily, maximum dose 250mg, Children 12-18 years of age: 500 mg twice daily

Adult: Oral clofazimine 100mg once daily. Children: Oral clofazimine: 3-5mg/kg once daily. Maximum dose of 50mg once daily if <40kg or 100mg if ≥40kg once daily.

Adults: with confirmed mixed NTM infections (slow growers + MABS) oral ethambutol can be added at either 15 mg/kg once daily or 25mg/kg thrice weekly. Children with confirmed mixed NTM infections (slow growers + MABS) oral ethambutol can be added at 20 mg/kg once daily.

Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral linezolid 600mg once daily. Children: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin or rifabutin) guided by participant susceptibility and tolerance. Age 1 week - 9 years 10mg/kg twice daily maximum dose of 300mg. Age 10-12 years 10mg/kg twice daily maximum dose of 600mg. >12 years 600mg once daily.

Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral Co-trimoxazole (TMP-SMX) 160/800mg twice daily. Children: During consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin or rifabutin) guided by participant susceptibility and tolerance. Oral co-trimoxazole 5mg TMP/kg maximum dose of 160mg TMP/ 800mg SMX twice daily.

Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral doxycycline 100mg once daily. Children: During consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin or rifabutin) guided by participant susceptibility and tolerance. Oral doxycycline (ages ≥ 8 years) 2mg/kg once daily maximum dose 100mg.

Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral moxifloxacin 400mg once daily. Children: During consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin or rifabutin) guided by participant susceptibility and tolerance. Oral moxifloxacin 10-15mg/kg once daily, maximum dose 400mg

Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral bedaquiline (18-64 years of age) 400mg once daily for the first two weeks followed by 400mg thrice weekly for 22 weeks (maximum duration of 6 months).

Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral rifabutin: 5mg/kg once daily, maximum 300-450mg. Children: During consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin or rifabutin) guided by participant susceptibility and tolerance. Oral rifabutin 5mg/kg once daily

The probability of MABS clearance with good tolerance at final outcome. MABS clearance defined as: Negative MABS cultures from 4 consecutive sputum samples with one of those sputum specimens collected four weeks after the completion of consolidation therapy or a MABS negative BAL collected four weeks after completion of consolidation. Tolerance will be defined using 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 defined as no adverse events occurring or only adverse events coded as CTCAE grades 1 and 2. "Poor" as any adverse events coded as CTCAE grades 3, 4, or 5.

56 weeks for participants who received short intensive therapy and 62 weeks for participants who received prolonged intensive therapy.

The number of patients in each group with microbiological clearance of MABS with good tolerance (in accordance with CTCAE). MABs clearance based on results from 3 sputum specimens or one BAL. Tolerance will be defined using 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 defined as no adverse events occurring or only adverse events coded as CTCAE grades 1 and 2. "Poor" as any adverse events coded as CTCAE grades 3, 4, or 5.

Nested study A1.1.1 Efficacy of inhaled Amikacin during intensive therapy in comparison to intravenous Amikacin in the treatment of MABS-PD

The number of patients in each group with microbiological clearance of MABS with good tolerability at completion of short intensive therapy with the use of inhaled amikacin (Arm B) and with the use of IV amikacin (Arm A) given during intensive phase. Clearance will be based on results from 3 consecutive sputum or 1 BAL sample.Tolerance will be defined using 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 defined as no adverse events occurring or only adverse events coded as CTCAE grades 1 and 2. "Poor" as any adverse events coded as CTCAE grades 3, 4, or 5.

Nested Study A1.1.2 Efficacy of additional clofazimine during short intensive therapy in comparison to no additional clofazimine for treatment of MABS-PD

The number of patients in each group with microbiological clearance of MABS with good tolerability at completion of short intensive therapy with the use of additional clofazimine (Arm A) and without the use of additional clofazimine (Arm C) given during intensive phase. Clearance will be based on results from 3 consecutive sputum or 1 BAL sample.Tolerance will be defined using 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 defined as no adverse events occurring or only adverse events coded as CTCAE grades 1 and 2. "Poor" as any adverse events coded as CTCAE grades 3, 4, or 5.

Nested Study A1.2 - Comparison of microbiological clearance of MABS with good tolerability at 12 weeks in patients with MABS positive cultures at 6 weeks and allocated to prolonged intensive therapy and those allocated to consolidation therapy.

The number of patients in each group with clearance of MABS at 12 weeks with good tolerance. Clearance will be based on the results of 3 consecutive sputum samples or 1 BAL sample.Tolerance will be defined using 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 defined as no adverse events occurring or only adverse events coded as CTCAE grades 1 and 2. "Poor" as any adverse events coded as CTCAE grades 3, 4, or 5.

Nested Study 1.3 Consolidation Therapy - Comparison of MABS clearance between those allocated to consolidation therapy with oral treatment and those allocated to consolidation with oral therapy and additional inhaled amikacin

The number of patients with microbiological clearance of MABS with good tolerability between those allocated to consolidation therapy with oral treatment and those allocated to consolidation therapy with oral therapy and additional inhaled amikacin. MABS clearance based on 3 consecutive sputum samples or 1 BAL sample.Tolerance will be defined using 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 defined as no adverse events occurring or only adverse events coded as CTCAE grades 1 and 2. "Poor" as any adverse events coded as CTCAE grades 3, 4, or 5.

52 weeks or 58 weeks depending on clearance of MABS at 4 weeks, with those allocated to short IT completing at 52 weeks and those allocated to prolonged IT completing at 58 weeks.

The probability of microbiological clearance of MABS at time point final, irrespective of toxicity for participants according to treatment path.

6 weeks, 12 weeks, at end of consolidation (52 and 58 weeks) and at final outcomes at 56 weeks and 62 weeks

The number of participants with treatment-related adverse events as assessed by CTCAE version 5 at completion of short IT, at completion of prolonged IT, at completion of CT and at final outcomes.

6 weeks and 12 weeks and at end of consolidation (52 and 58 weeks) and after trial has been completed

The relative change in FEV1 z-score between treatment groups for time point final compared with time point start in patients who do and who do not clear MABS at time point final.

Day 0, 6 weeks, 12 weeks, at end of consolidation (52 and 58 weeks) and at final outcomes at 56 weeks and 62 weeks

Change in % Bronchiectasis scored using PRAGMA in chest CTs between Day 0 (screening) and at 12 weeks and at final outcome and between those who clear and those who do not clear MABS

Change in % Bronchiectasis using PRAGMA CT between screening Day 0 and at 12 weeks and at final outcome

Change in % Air Trapping scored using PRAGMA in chest CTs between Day 0 (screening) and at 12 weeks and at final outcome and between those who clear and those who do not clear MABS

Change in % Disease scored using PRAGMA in chest CTs between Day 0 (screening) and at 12 weeks and at final outcome and between those who clear and those who do not clear MABS

The predictive value of structural abnormalities at Day 0 (screening) CTs for sputum conversion and for progression of structural changes in relation to therapy.

Association between structural abnormalities (%Bronchiectasis, %Air trapping and %Disease) at screening Day 0 and clearance of MABs at 12 weeks and at final outcome and with change in %Bronchiectasis, %Air trapping and %Disease between screening day 0 and at 12 weeks and at final outcome

The change in CFQ-R respiratory domain for those with CF between treatment groups for short intensive, prolonged intensive and consolidation phases as well as between Day 0 and final outcome and between participants with and without MABS clearance.

The change in CFQ-R respiratory domain for patients with CF between baseline and at 6 weeks, 12 weeks and 56 weeks for those that had short intensive therapy and 62 weeks for those who received prolonged intensive therapy

Day 0 and 6 weeks and 12 weeks, and at completion consolidation (at 52 and 58 weeks for those who completed short or prolonged IT) and at final outcome (at 56 and 62 weeks for those who completed short or prolonged IT)

The change in HRQOL in adults, between treatment groups for short intensive, prolonged intensive and consolidation phases as well as between Day 0 and final outcome and between participants with and without MABS clearance.

Day 0 and 6 weeks and 12 weeks, and at completion consolidation (at 52 and 58 weeks for those who completed short or prolonged IT) and at final outcome (at 56 and 62 weeks for those who completed short or prolonged IT)

The change in HRQoL in Children between treatment groups for short intensive, prolonged intensive and consolidation phases as well as between Day 0 and final outcome and between participants with and without MABS clearance.

Day 0 and 6 weeks and 12 weeks, and at completion consolidation (at 52 and 58 weeks for those who completed short or prolonged IT) and at final outcome (at 56 and 62 weeks for those who completed short or prolonged IT)

The cost effectiveness of the proposed treatment combinations across both intensive and consolidation phases of the trial.

Total cost between treatments calculated as the sum product of health resource utilisation and resource unit price during treatment period.

from date of randomization for the duration of treatment up to 56 weeks for those allocated to short IT and up to 62 weeks for those allocated to prolonged IT

The change in six minute walk distance for adult participants from the date of randomization to up to 62 weeks according to treatment path and in participants who do and do not clear MABS at time point final.

from date of randomization for the duration of treatment up to 56 weeks for those allocated to short IT and up to 62 weeks for those allocated to prolonged IT

To examine whether MABS has been cleared after 12 months completion of the trial using the 12 month follow up site Principal Investigator Questionnaire.

Intervention Cohort Inclusion Criteria: Subjects with respiratory cultures positive for M. abscessus (MABS) (sub species abscessus, sub species bolletii, or subspecies massiliense) are required to meet all 3 American Thoracic Society criteria (clinical, radiological and microbiological) for MABS pulmonary disease (PD). Subjects with mixed NTM infections (slow growers + MABS) (adding ethambutol will be permitted if required by the treating physician). Willingness and ability to comply with trial regimens and the study visit requirements. Intervention cohort Exclusion Criteria: Receiving active treatment for MABS within the previous 12 months, except azithromycin for participants with cystic fibrosis and bronchiectasis. Healthy volunteers may not participate. Pregnancy or planning to continue breastfeeding Known hypersensitivity to any of the therapies for which no alternate options(s) have been provided. Observation Cohort Inclusion Criteria: At least one positive respiratory MABS culture Willingness and ability to comply with the study visit requirements. Observation cohort Exclusion Criteria for: Receiving active treatment for MABS within the previous 12 months, except azithromycin for participants with cystic fibrosis and bronchiectasis. Healthy volunteers may not participate.

Data will be made available to recognised academic institutes and clinical teams upon written request with a proposal for data usage to Chief Investigator, Professor Claire Wainwright