Finding the Optimal Regimen for Mycobacterium Abscessus Treatment

Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT)

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.

Eligibility criteria for the FORMaT trial can be applied at two levels:

1. Eligibility into the Intervention Program, or;
2. Eligibility into the Observational Cohort.

Potential participants can only be enrolled in either the Intervention Program or the Observational Cohort at any one time. Provided the eligibility criteria are met, potential participants may either:

1. Enrol directly into the Intervention Program, or;
2. Enrol into the Observational Cohort and transition into the Intervention Program once they satisfy the inclusion criteria for this program which can occur at any time during the trial.

Eligibility into the FORMaT trial will be assessed at screening. Observational Cohort participants who go on to meet the Intervention Program eligibility criteria can transition from the Observational Cohort to the Intervention Program.

INTERVENTION PROGRAM ELIGIBILITY (APPENDIX A) Potential participants are eligible for the Intervention Program (Appendix A) if the criteria below are met. Eligible participants with mixed NTM infections (slow growers + MABS) or with recurrence of MABS infection following completion of previous treatment will be eligible if they meet the inclusion and exclusion criteria listed below. For eligible participants with mixed NTM infections additional therapy combinations are available as detailed in the relevant appendices.

INTERVENTION PROGRAM INCLUSION CRITERIA

1. Positive MABS-PD diagnosis meeting all three American Thoracic Society clinical, radiological and microbiological diagnostic criteria for MABS-PD. Defined as:

   1. Clinical: Pulmonary symptoms and exclusion of other diagnoses.
   2. Radiological: Nodular or cavitary opacities on chest radiograph or a chest high-resolution computed tomography (HRCT) scan showing multifocal bronchiectasis with multiple small nodules.
   3. 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 Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or acid-fast bacilli (AFB)) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washes that are culture positive for NTM.

   Screening samples must be collected within the timeframes stated in the relevant appendix.

2. Male or female participants of any age.

3. Participant has not received treatment for MABS-PD in the 12 months preceding assessment of eligibility or as specified in the relevant appendix (this includes drugs prescribed for the treatment of other mycobacteria and/or other indications that may have activity against MABS, as specified in the FORMaT Prohibited Drug List Standard Operating Procedure (SOP)).

4. Informed consent signed by participant or parent/legal guardian if participant is under 18 years of age.

5. Ability to comply with study visits, therapies and study procedures as judged by the site investigator.

INTERVENTION PROGRAM EXCLUSION CRITERIA

• Participants receiving current treatment for MABS (this includes drugs prescribed for the treatment of other mycobacteria and/or other indications that may have activity against MABS, as specified in the FORMaT Prohibited Drug List SOP), except for participants taking azithromycin as part of routine treatment for CF or chronic infection-related pulmonary disease, or as specified in the relevant appendix.
• Participants who have a QTc interval of >500 milliseconds (QT interval corrected based on Fridericia method).
• Participants who are pregnant or planning to continue breast feeding.
• Known hypersensitivity or contraindication to any of the therapies for which no alternative option(s) have been provided.

OBSERVATIONAL COHORT INCLUSION CRITERIA

To be eligible to participate in the Observational Cohort the following criteria must be met:

1. Male and female participants of any age with at least one positive respiratory culture for MABS.
2. Informed consent signed by participant or parent/legal guardian if participant is under 18 years of age.
3. Ability to comply with study visits and study procedures as judged by the site investigator.

OBSERVATIONAL COHORT EXCLUSION CRITERIA

Potential participants will be ineligible to participate in the Observational Cohort if any of the following criterion are met:

• Receiving active treatment for MABS within the previous 12 months (this includes drugs prescribed for the treatment of other mycobacteria and/or other indications that may have activity against MABS, as specified in the FORMaT Prohibited Drug List SOP, except for participants taking azithromycin as part of routine treatment for CF or chronic infection-related pulmonary disease).

ADDITIONAL ELIGIBILITY CRITERIA Mixed NTM infections Participants who have cultured slow growing NTM of the same species two or more times in the 24 months prior to screening, with one of those cultures within the 6 months prior to screening, will be considered to have mixed NTM infection at the time of screening. The participants must meet all other inclusion criteria and no exclusion criteria to be eligible for participation. Ethambutol may be used in addition to trial therapies to cover mixed NTM infections considered to require treatment by their clinician.

Appendix specific sub-studies and integrated studies Appendix specific sub-studies and integrated studies may have additional eligibility criteria which are described in each of the relevant appendices.