Finding the Optimal Regimen for Mycobacteroides abscessus Treatment (FORMaT) in people with Mycobacteroides abscessus pulmonary disease: a multi-centre, randomised, multi-arm, adaptive platform trial.
Finding the Optimal Regimen for Mycobacterium abscessus Treatment (FORMaT)
The University of Queensland
300 participants
Mar 2, 2020
Interventional
Conditions
Summary
Mycobacterium abscessus (MABS) is a group of rapid-growing, multi-drug resistant non-tuberculous mycobacteria causing infections in humans. While the overall numbers affected is small, the prevalence of infections is increasing. Individuals with cystic fibrosis (CF) and bronchiectasis are at particular risk of MABS becoming established within their lungs, resulting in a clinical spectrum ranging from simple colonisation to severe infection with increased healthcare utilisation and mortality. There is no evidence for either the timing of starting therapy, or for the currently used treatment regimens, which are complex, often poorly tolerated, and involve multiple expensive and toxic drug combinations given for at least 1-2 years. These considerable challenges have resulted in very few clinical trials being performed leaving an urgent clinical management evidence vacuum. Population: Those with MABS positive respiratory samples. Intervention: We aim to build an iterative, experimental clinical trial platform with adaptive properties and an observation arm to enable multiple treatment combinations to be evaluated in patients with and without CF, in those infected with different MABS subspecies, and strains with macrolide resistance. The platform will enable future novel treatments to efficiently enter the trial as they become available. Comparison: The trial platform will include the current standard of care as a comparator arm; as evidence is accumulated new comparators may be incorporated. Outcome: The trial platform will facilitate the evolution of optimal management for MABS lung disease with primary outcome of microbial clearance and include pharmacokinetic and health economic evaluation. Biomarkers will be developed to guide when to initiate treatment, and enable the monitoring of treatment responses. This will reduce unnecessary treatment associated toxicity and costs and enable targeted therapeutic approaches to maximise clinical benefit.
Eligibility
Inclusion Criteria23
- Eligibility criteria
- Entry into the study can occur at two different levels:
- Participants of any age meeting the ATS criteria1 for MABS-PD and not receiving treatment are eligible to enrol in the Intervention program, and;
- Participants of any age from their first MABS isolate who do not require treatment or who have elected not to receive MABS therapy can enrol in the Observational cohort. Participants enrolled into the Observational cohort who proceed to meet the ATS criteria for MABS-PD can transition to the Intervention Program at any time.
- Intervention program participants are randomised to receive MABS-PD therapy combinations.
- ATS diagnostic criteria for MABS-PD are fulfilled (clinical, radiographic and microbiological).
- a. Clinical: Pulmonary symptoms and exclusion of other causes.
- b. Radiographic: Nodular or cavitary opacities on chest radiograph or a chest high-resolution computed tomography (HRCT) scan showing multifocal bronchiectasis with multiple small nodules.
- c. Microbiological: MABS positive culture results from at least two separate expectorated sputum samples.
- or
- Positive culture results from one bronchial wash or bronchoalveolar lavage (BAL).
- or
- One lung biopsy with histology consistent with NTM and the biopsy or sputum culture positive for MABS.
- Screening samples must be collected within the timeframes stated in the relevant appendix.
- Participants of any age and sex.
- Not received treatment for MABS-PD in the preceding 12-months, 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).
- Informed consent signed by participant or parent/legal guardian (if participant is aged
- <18-years).
- Ability to comply with study visits, therapies and study procedures as judged by the site investigator.
- Participants meeting the following criteria are eligible to be recruited into the Observational Cohort:
- Participants of any age with at least one positive respiratory culture for MABS.
- Informed consent signed by participant or parent/legal guardian if participant is aged <18-years.
- Ability to comply with study visits and study procedures as judged by the site investigator.
Exclusion Criteria5
- Receiving current treatment for MABS (including drugs prescribed for other mycobacteria and/or other indications that may have activity against MABS, except for azithromycin as part of routine treatment for CF or chronic infection-related pulmonary disease).
- QTc interval >500 milliseconds.
- Pregnancy or breast feeding.
- Known hypersensitivity to any of the therapies for which there are no alternative option(s).
- Receiving current treatment for MABS (including drugs prescribed for other mycobacteria and/or other indications that may have activity against MABS, except for azithromycin as part of routine treatment for CF or chronic infection-related pulmonary disease).
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Interventions
This study is a standing platform trial to evaluate the efficacy of antibiotic therapy combinations in clearing Mycobacterium abscessus pulmonary disease (MABS-PD). The study will provide a pipeline for new therapies to be evaluated for treating MABS-PD in all age groups. There are two different phases of treatment; intensive therapy followed by consolidation therapy. Intervention cohort participants will be randomised to 1 of 3 treatment arms for 6 weeks of intensive therapy. After the first 6 weeks of intensive therapy participants who are culture positive for MABS are randomised to either prolonged intensive therapy (additional 6 weeks of intensive therapy) then consolidation therapy, or to commence consolidation therapy. If, at week 6 participants are MABS culture-negative they will commence consolidation therapy. Participants commencing consolidation therapy are randomised to one of two treatment arms for 50 weeks. There are 12 possible paths through the trial and they are detailed below: 1. Intensive Arm A for 6 weeks, Consolidation arm b for 46 weeks, 2. Intensive Arm A for 12 weeks, Consolidation arm b for 46 weeks, 3. Intensive Arm A for 6 weeks, “Consolidation: arm a” for 46 weeks, 4. Intensive Arm A for 12 weeks, “Consolidation: arm a” for 46 weeks, 5. Intensive Arm B for 6 weeks, Consolidation arm b for 46 weeks, 6. Intensive Arm B for 12 weeks, Consolidation arm b for 46 weeks, 7. Intensive Arm B for 6 weeks, “Consolidation: arm a” for 46 weeks, 8. Intensive Arm B for 12 weeks, “Consolidation: arm a” for 46 weeks, 9. Intensive Arm C for 6 weeks, Consolidation arm b for 46 weeks, 10. Intensive Arm C for 12 weeks, Consolidation arm b for 46 weeks, 11. Intensive Arm C for 6 weeks, “Consolidation: arm a” for 46 weeks, 12. Intensive Arm C for 12 weeks, “Consolidation: arm a” for 46 weeks, Where Intensive Arm A is IV amikacin, and; IV tigecycline, and; IV imipenem/cilastatin or IV cefoxitin, and; Oral azithromycin or oral clarithromycin, and; Oral clofazimine. Intensive Arm B is Inhaled amikacin, and; IV tigecycline, and; IV imipenem/cilastatin or IV cefoxitin, and; Oral azithromycin or oral clarithromycin, and; Oral clofazimine. Intensive Arm C is IV amikacin, and; IV tigecycline, and; IV imipenem/cilastatin or IV cefoxitin, and; Oral azithromycin or oral clarithromycin. Consolidation arm a is Oral clofazimine, and; Oral azithromycin or oral clarithromycin, and; In combination with one to three of the following oral antibiotics: Oral linezolid, Oral trimethoprim / sulfamethoxazole, Oral bedaquiline, Oral rifabutin, Oral doxycycline, Oral moxifloxacin. Consolidation arm b is Inhaled amikacin, and; Oral clofazimine, and; Oral azithromycin or oral clarithromycin, and; In combination with one to three of the following oral antibiotics: Oral linezolid, Oral trimethoprim / sulfamethoxazole, Oral bedaquiline, Oral rifabutin, Oral doxycycline, Oral moxifloxacin. Dosing recommendations for each drug is outlined in the Drug dosing Regimen Tables contained in the relevant sections of the FORMaT Intervention Program Appendix A1 and Appendix A2 modules. This standing platform trial design enables assessment of short intensive therapy, prolonged intensive therapy, and consolidation therapy components individually as well as the overall combination of intensive therapy and consolidation therapy. After 100 patients have completed short intensive therapy 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. Those participants that have a positive respiratory specimen but do not meet all three ATS criteria or those who are MABS-PD positive but are not commencing drug therapy can be recruited into the observation cohort where they will undergo all the same monitoring and outcomes collection but will not receive treatment. If they meet ATS criteria at a later stage during the trial they may be randomised into the active treatment phases (intensive and consolidation) of the trial. The FORMaT trial has several substudies that are conducted alongside the main trial. These substudies are registered on a separate trial registration.
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ACTRN12618001831279