Clinical trial NCT04310930: Finding the Optimal Regimen for Mycobacterium Abscessus Treatment
Official title: Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Pulmonary Disease Due to Mycobacteria (Diagnosis)
Keywords: Mycobacterium abscessus
Pulmonary disease
Microbiological
Regimen
Radiological
Quality of life
Health economics
Biomarkers
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: Australian Government Department of Health and Ageing
name: Children's Hospital Foundation
name: Cystic Fibrosis Foundation
name: Newcastle University
name: Griffith University
name: Erasmus Medical Center
name: Monash University
name: University of Copenhagen
name: Hôpital Cochin
name: South Australian Health and Medical Research Institute
name: University of Melbourne
name: James Cook University, Queensland, Australia
name: Murdoch Childrens Research Institute
First posted: 2020-03-17
Enrollment: 300
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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: 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.

Primary outcomes:
measure: Appendix A1 - MABS clearance from respiratory samples with tolerance at final outcome
timeFrame: 56 weeks for participants who received short intensive therapy and 62 weeks for participants who received prolonged intensive therapy.
measure: Nested Study A1.1 Short Intensive Therapy - MABS Clearance
timeFrame: Samples collected at 4 weeks and culture results determined at 6 weeks
measure: Nested study A1.1.1 Efficacy of inhaled Amikacin during intensive therapy in comparison to intravenous Amikacin in the treatment of MABS-PD
timeFrame: samples collected at 4 weeks and culture results determined at 6 weeks
measure: Nested Study A1.1.2 Efficacy of additional clofazimine during short intensive therapy in comparison to no additional clofazimine for treatment of MABS-PD
timeFrame: samples collected at 4 weeks and culture results determined at 6 weeks
measure: 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.
timeFrame: samples collected at 10 weeks and culture results determined at 12 weeks
measure: 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
timeFrame: 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 outcomes:
measure: The probability of microbiological clearance of MABS at time point final, irrespective of toxicity for participants according to treatment path.
timeFrame: 6 weeks, 12 weeks, at end of consolidation (52 and 58 weeks) and at final outcomes at 56 weeks and 62 weeks
measure: The safety of the treatment combinations in patients with MABS
timeFrame: 6 weeks and 12 weeks and at end of consolidation (52 and 58 weeks) and after trial has been completed
measure: 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.
timeFrame: Day 0, 6 weeks, 12 weeks, at end of consolidation (52 and 58 weeks) and at final outcomes at 56 weeks and 62 weeks
measure: 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
timeFrame: Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path
measure: 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
timeFrame: Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path
measure: 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
timeFrame: Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path
measure: The predictive value of structural abnormalities at Day 0 (screening) CTs for sputum conversion and for progression of structural changes in relation to therapy.
timeFrame: Day 0 and 12 weeks and at final outcome at either 56 weeks or 62 weeks according to treatment path
measure: 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.
timeFrame: 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)
measure: 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.
timeFrame: 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)
measure: 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.
timeFrame: 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)
measure: The cost effectiveness of the proposed treatment combinations across both intensive and consolidation phases of the trial.
timeFrame: 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
measure: 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.
timeFrame: 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
Other outcomes:
measure: Examine the MABS clearance status at twelve (12 months) after time point final
timeFrame: 12 months post trial completion
Locations:
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Chermside
country: Australia
facility: The Prince Charles Hospital
city: Gold Coast
country: Australia
facility: Gold Coast University Hospital
city: Greenslopes
country: Australia
facility: Greenslopes Private Hospital,
city: Nedlands
country: Australia
facility: Sir Charles Gairdiner Hospital
city: New Lambton Heights
country: Australia
facility: John Hunter Children's Hospital
city: New Lambton
country: Australia
facility: John Hunter Hospital
city: Perth
country: Australia
facility: Perth Children's Hospital
city: Prahran
country: Australia
facility: The Alfred
city: Randwick
country: Australia
facility: Sydney Children's Hospital
city: South Brisbane
country: Australia
facility: Mater Adult Hospital
city: Sydney
country: Australia
facility: Macquarie University Hospital
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
city: Westmead
country: Australia
facility: Westmead Hospital
city: København
country: Denmark
facility: Rigshospitalet
city: Beer-Sheeva
country: Israel
facility: Soroka Medical Centre
city: Haifa
country: Israel
facility: Carmel Medical Centre
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Ein Kerem Hospital
city: Peta Tikva
country: Israel
facility: Schneider
city: Ramat Gan Tel Aviv
country: Israel
facility: Sheba Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus MC Sophia Children's Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital Pte Ltd
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Cardiff
country: United Kingdom
facility: Noah's Ark Childrens Hospital for Wales
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Children and Young People, Edinburgh
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital, Glasgow
city: Liverpool
country: United Kingdom
facility: Alder Hey Children NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Brompton Hosptial
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham Children's Hosptial
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
city: Nottingham
country: United Kingdom
facility: Welcome Wolfson Adult CF Centre (City Hospital Campus)
city: Penarth
country: United Kingdom
facility: University Hospital Llandough
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Wythenshawe
country: United Kingdom
facility: Wythenshawe Hospital
Study officials:
References: