Overview Study details Eligibility Things to know Research Study plan

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Overview Study details Eligibility Things to know Research Study plan

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Finding the Optimal Regimen for Mycobacterium Abscessus Treatment

PHASE2PHASE3RECRUITING

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

Positive MABS-PD diagnosis meeting all three American Thoracic Society clinical, radiological and microbiological diagnostic criteria for MABS-PD.
Male or female participants of any age.
Participant has not received treatment for MABS-PD in the 12 months preceding assessment of eligibility.
Informed consent signed by participant or parent/legal guardian if participant is under 18 years of age.
Ability to comply with study visits, therapies and study procedures as judged by the site investigator.

Exclusion criteria

Participants receiving current treatment for MABS, except for participants taking azithromycin as part of routine treatment for CF or chronic infection-related pulmonary disease.
Participants who have a QTc interval of >500 milliseconds.
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.

Eligibility

Age eligible for study : NA

Healthy volunteers accepted : No

Gender eligible for study: ALL

Things to know

Study dates

Study start:

Primary completion:

Study completion finish:

Study type

TREATMENT

Phase

PHASE2PHASE3

Study 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)

Condition: Pulmonary Disease Due to Mycobacteria (Diagnosis)
DRUG: Amikacin and other drugs
Kogarah, New South Wales, Australia and more
Sponsor: The University of Queensland

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Research sites nearby

Closest Location:

St George Hospital

Select from list below to view details:

St George Hospital
Kogarah, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Austin Hospital
Heidelberg, Victoria, Australia

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Who is running the clinical trial?

TUoQ

The University of Queensland

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 Following Randomisation 1, Participants will receive intensive drug therapy in the form of IV amikacin, IV tigecycline, IV cefoxitin/imipenem + oral azithromycin AND clofazimine.	Drug: Amikacin, Drug: Tigecycline, Drug: Imipenem, Drug: Cefoxitin, Drug: Azithromycin, Drug: Clarithromycin, Drug: Clofazimine, Drug: Ethambutol
EXPERIMENTAL: Intensive Therapy B Following Randomisation 1, Participants will receive inhaled amikacin (IA), IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin AND clofazimine.	Drug: Tigecycline, Drug: Imipenem, Drug: Cefoxitin, Drug: Azithromycin, Drug: Clarithromycin, Drug: Clofazimine, Drug: Ethambutol, Drug: Amikacin
EXPERIMENTAL: Intensive Therapy C Following Randomisation 1, Participants will receive intensive drug therapy in the form of IV amikacin, IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin.	Drug: Amikacin, Drug: Tigecycline, Drug: Imipenem, Drug: Cefoxitin, Drug: Azithromycin, Drug: Clarithromycin, Drug: Ethambutol
ACTIVE_COMPARATOR: Consolidation A 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.	Drug: Azithromycin, Drug: Clarithromycin, Drug: Clofazimine, Drug: Ethambutol, Drug: Linezolid, Drug: co-trimoxazole, Drug: Doxycycline, Drug: Moxifloxacin, Drug: Bedaquiline, Drug: Rifabutin
EXPERIMENTAL: Consolidation B 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.	Drug: Azithromycin, Drug: Clarithromycin, Drug: Clofazimine, Drug: Ethambutol, Drug: Amikacin, Drug: Linezolid, Drug: co-trimoxazole, Drug: Doxycycline, Drug: Moxifloxacin, Drug: Bedaquiline, Drug: Rifabutin

What is the study measuring?

Primary Outcome

Measure	Description	Time Frame
The primary outcome of the Intervention Program is microbiological clearance of MABS with good tolerance of the interventions.	The primary outcome of the Intervention Program is microbiological clearance of MABS with good tolerance of the interventions. Definition of MABS clearance at final outcome: Negative MABS cultures from four consecutive sputum samples with one of those sputum specimens collected four weeks after the completion of consolidation therapy, or a MABS negative Bronchoalveolar Lavage (BAL) collected four weeks after completion of consolidation. 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.	Screening (Day 0) to End of treatment plus four weeks off-treatment (Final Outcome Visit (Week 56 for those allocated to Immediate Consolidation or Week 62 for those allocated to Prolonged Intensive).
Nested Study A1.1 Type of Short Intensive Therapy - MABS clearance from respiratory sample(s) with tolerance.	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 Inhaled Amikacin (Arm B) and the use of Intravenous Amikacin (Arm A) given during intensive phase. Definition of MABS clearance is 3 MABS negative sputum samples or ONE MABS negative Bronchoalveolar Lavage (BAL) at end of Short Intensive Therapy. "Good" tolerance is defined as no adverse events occurring or only adverse events that are attributed as either "possibly-", "probably-", or "definitely-" related to study drug coded as CTCAE grades 1 and 2.	Screening (Day 0) to the End of Short Intensive Therapy (Week 6).
Nested Study A1.2 - 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.	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. "Good" tolerance is defined as no adverse events occurring or only adverse events that are attributed as either "possibly-", "probably-", or "definitely-" related to study drug coded as CTCAE grades 1 and 2.	Screening (Day 0) to EITHER the End of Prolonged Intensive Therapy (for those allocated to Prolonged Intensive) OR Week 12 Visit (for those allocated to immediate consolidation therapy).
Nested Study 1.3 Consolidation Therapy - The use of oral therapy only or oral therapy and inhaled amikacin for consolidation therapy.	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 Inhaled Amikacin at Final Outcome. Definition of MABS clearance at final outcome: Negative MABS cultures from four consecutive sputum samples with one of those sputum specimens collected four weeks after the completion of consolidation therapy, or a MABS negative Bronchoalveolar Lavage (BAL) collected four weeks after completion of consolidation. "Good" tolerance is defined as no adverse events occurring or only adverse events that are attributed as either "possibly-", "probably-", or "definitely-" related to study drug coded as CTCAE grades 1 and 2.	Start of Consolidation Therapy (Date of Randomisation to Consolidation Therapy) to End of Treatment plus 4 weeks off treatment (Final Outcome Visit - Week 56 for those randomised to Immediate Consolidation or Week 62 for those in Prolonged Intensive).

Secondary Outcome

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References

Clinical Trials Gov: Finding the Optimal Regimen for Mycobacterium Abscessus Treatment

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Measure	Description	Time Frame
Probability of MABS clearance at Final Outcome irrespective of toxicity according to participant's treatment pathway.	Probability of MABS clearance at Final Outcome irrespective of toxicity according to participant's treatment pathway. Definition of MABS clearance at final outcome: Negative MABS cultures from four consecutive sputum samples with one of those sputum specimens collected four weeks after the completion of consolidation therapy, or a MABS negative Bronchoalveolar Lavage (BAL) collected four weeks after completion of consolidation.	Screening (Day 0); at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Safety of treatment combinations based on adverse event reporting.	Safety of treatment combinations based on the reporting of adverse events that are attributed as either "possibly-", "probably-", or "definitely-" related to study drugs.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Safety of treatments based on changes in microbiological resistance.	Safety of treatments based on changes to microbiological resistance of the MABS bacteria during the study treatment period.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in FEV1 z-score at Final Outcome compared with Screening in participants who do and do not clear MABS at Final Outcome.	Change in FEV1 z-score at Final Outcome compared with Screening in participants who do and do not clear MABS at Final Outcome.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
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.	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.	Screening (Day 0); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Predictive value of structural abnormalities on Screening CT scans for sputum conversion and for progression of structural changes in relation to treatment.	Predictive value of structural abnormalities on Screening CT scans for sputum conversion and for progression of structural changes in relation to treatment.	Screening (Day 0); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
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.	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.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in HRQoL (measured using the CFQ-R) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome.	Change in HRQoL (measured using the CFQ-R) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome. CFQ-R is the Cystic Fibrosis Questionnaire Revised and will be completed by all CF participants.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in HRQoL (measured using the EQ-5D) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome.	Change in HRQoL (measured using the EQ-5D) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome. EQ-5D is the EuroQol 5 Dimensions and will be completed by all participants.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in HRQoL (measured using the SGRQ) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome.	Change in HRQoL (measured using the SGRQ) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome. SGRQ is the St George's Respiratory Questionnaire and will be completed by all non-CF participants who are 18 years and older.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in HRQoL (measured using the SF-36) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome.	Change in HRQoL (measured using the SF-36) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome. The SF-36 is the Short-Form 36 questionnaire and will be completed by all participants 16 years and older.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in HRQoL (measured using the PedsQL) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome.	Change in HRQoL (measured using the PedsQL) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome. The PedsQL is the Pediatric Quality of Life Inventory questionnaire and will be completed by participants 2 years old to 16 years old.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Change in HRQoL (measured using the CHU-9D) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome.	Change in HRQoL (measured using the CHU-9D) for participants from Screening to Final Outcome according to treatment pathway and in participants who do and do not clear MABS at Final Outcome. CHU-9D is the Child Health Utility 9D and will be completed by all children aged 7 to 17 years of age.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Cost effectiveness of the treatment combinations (measured using the Costs Questionnaire and Linked Administrative Healthcare Utilisation Data (for applicable jurisdictions)) across intensive and consolidation phases of the trial.	Cost effectiveness of the treatment combinations across intensive and consolidation phases of the trial. Cost effectiveness of the treatments will be assessed using the unvalidated "Costs Questionnaire" and where applicable and available, the linked administrative healthcare utilisation data e.g. in Australian participants.	Screening (Day 0); At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
Causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance as defined in the primary objectives.	Causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance as defined in the primary objectives.	At End of Short Intensive Therapy (Week 6); At End of Prolonged Intensive Therapy OR at Week 12 visit; at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).