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Finding the Optimal Regimen for Mycobacterium Abscessus Treatment
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.
Study details:
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
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 0 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2020-03-02
Primary completion: 2024-06-30
Study completion finish: 2024-08-31
Study type
TREATMENT
Phase
PHASE2
PHASE3
Trial ID
NCT04310930
Intervention or treatment
DRUG: Amikacin
DRUG: Tigecycline
DRUG: Imipenem
DRUG: Cefoxitin
DRUG: Azithromycin
DRUG: Clarithromycin
DRUG: Clofazimine
DRUG: Ethambutol
DRUG: Amikacin
DRUG: Linezolid
DRUG: co-trimoxazole
DRUG: Doxycycline
DRUG: Moxifloxacin
DRUG: Bedaquiline
DRUG: Rifabutin
Conditions
- • Pulmonary Disease Due to Mycobacteria (Diagnosis)
Find a site
Closest Location:
Queensland Children's Hospital
Research sites nearby
Select from list below to view details:
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Royal Adelaide Hospital
Adelaide, Not Specified, Australia
The Children's Hospital at Westmead
Westmead, Not Specified, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
ACTIVE_COMPARATOR: Intensive Therapy A
| DRUG: Amikacin
|
EXPERIMENTAL: Intensive Therapy B
| DRUG: Tigecycline
|
EXPERIMENTAL: Intensive Therapy C
| DRUG: Amikacin
|
ACTIVE_COMPARATOR: Consolidation A
| DRUG: Azithromycin
|
EXPERIMENTAL: Consolidation B
| DRUG: Azithromycin
|
What is the study measuring?
Primary outcome
| Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
|---|---|---|
| Appendix A1 - MABS clearance from respiratory samples with tolerance at final outcome | 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. |
| Nested Study A1.1 Short Intensive Therapy - MABS Clearance | 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. | Samples collected at 4 weeks and culture results determined at 6 weeks |
| 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. | samples collected at 4 weeks and culture results determined at 6 weeks |
| 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. | samples collected at 4 weeks and culture results determined at 6 weeks |
| 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. | samples collected at 10 weeks and culture results determined at 12 weeks |
| 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. |
Secondary outcome
| Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
|---|---|---|
| The probability of microbiological clearance of MABS at time point final, irrespective of toxicity for participants according to treatment path. | Probability of microbiological clearance irrespective of adverse event reporting. | 6 weeks, 12 weeks, at end of consolidation (52 and 58 weeks) and at final outcomes at 56 weeks and 62 weeks |
| The safety of the treatment combinations in patients with MABS | 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. | Relative change in FEV1 z score compared between treatment groups | 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 | Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path |
| 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 % Trapped Air using PRAGMA CT between screening Day 0 and at 12 weeks and at final outcome | Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path |
| 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 | Change in % Disease using PRAGMA CT between screening Day 0 and at 12 weeks and at final outcome | Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path |
| 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 | Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path |
| 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. | Change in HRQOL measured using the SF36 | 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. | Change in HRQOL measured using the Peds-QL™ | 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. | Change in 6 minute walk distance using the six minute walk test in adult participants | 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 |
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