Finding the Optimal Regimen for Mycobacterium Abscessus Treatment

Official title

Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT)

Overview

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.

Interventions

• Drug Amikacin
  Adults: Intravenous amikacin 5mg/kg once daily or 7.5mg/kg twice daily or 20-25 mg/kg thrice weekly. Children:Intravenous amikacin 15-30 mg/kg once daily, maximum dose 1500mg
• Drug Tigecycline
  Adults: Intravenous Tigecycline 25 mg increasing by 5 mg every two doses until either maximum dose reached (50mg) or until patient is unable to tolerate twice daily. Children (≥8 years of age) intravenous tigecycline: Day 1- 0.6mg/kg twice daily to a maximum of 25mg. Day 2- 0.6mg/kg (maximum 25mg) in the morning, 1.2 mg/kg (maximum 50mg) at night. Day 3- 1.2mg/kg (maximum 50 mg) twice daily
• Drug Imipenem
  Adults: Intravenous Imipenem (≥50kg) 500mg twice daily (\<50kg) 15 mg/kg twice daily. Children: intravenous imipenem Day 1- 2- 25mg/kg (maximum 1g) twice daily. DAY 3- 25mg/kg (maximum 1g) four times daily (drop to 3 if not tolerated).
• Drug Cefoxitin
  Adults: If imipenem is poorly tolerated intravenous cefoxitin 200 mg/kg thrice daily. Children: if imipenem is poorly tolerated intravenous cefoxitin 50mg/kg (maximum 4g) four times daily.
• Drug Azithromycin
  Adults: Oral azithromycin 500mg (≥40kg) once daily, (\<40kg) 250mg once daily.During consolidaiton: 500mg (≥40kg) thrice weekly, (\<40kg) 250mg thrice weekly. Children: Oral azithromycin:10mg/kg (maximum 500mg) once daily. During consolidation 10mg/kg once daily maximum 500mg.
• Drug Clarithromycin
  Adult: If azithromycin is poorly tolerated use oral clarithromycin 500mg twice daily.Children: If azithromycin is poorly tolerated use oral clarithromycin. In children 1 month old- 11years of age the following dosing applies: \<8kg: 7.5mg/kg twice daily, maximum dose 62.5mg, 8-11kg: 62.5mg twice daily, maximum dose 62.5mg, 12-19 kg: 125mg twice daily, maximum dose 125mg, 20-29 kg: 187.5mg twice daily, maximum dose 187.5mg, 30-40 kg: 250mg twice daily, maximum dose 250mg, Children 12-18 years of
• Drug Clofazimine
  Adult: Oral clofazimine 100mg once daily. Children: Oral clofazimine: 3-5mg/kg once daily. Maximum dose of 50mg once daily if \<40kg or 100mg if ≥40kg once daily.
• Drug Ethambutol
  Adults: with confirmed mixed NTM infections (slow growers + MABS) oral ethambutol can be added at either 15 mg/kg once daily or 25mg/kg thrice weekly. Children with confirmed mixed NTM infections (slow growers + MABS) oral ethambutol can be added at 20 mg/kg once daily.
• Drug Amikacin
  adult: Inhaled amikacin 500mg twice daily. Children: Inhaled amikacin 500mg twice daily
• Drug Linezolid
  Adult: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin, bedaquiline or rifabutin) guided by participant susceptibility and tolerance. Oral linezolid 600mg once daily. Children: during consolidation in combination with one to three oral antibiotics (co-trimoxazole, doxycycline, moxifloxacin or rifabutin) guided by participant susceptibility and tolerance. Age 1 week - 9 years 10mg/kg twice daily maximum dose of 300mg. Age 10-12 ye

Primary outcome measures

• The primary outcome of the Intervention Program is microbiological clearance of MABS with good tolerance of the interventions. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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 measures (12)

• Probability of MABS clearance at Final Outcome irrespective of toxicity according to participant's treatment pathway. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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. [Time frame: 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).]

Eligibility criteria

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

• Eligibility into the Intervention Program, or;
• 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:

• Enrol directly into the Intervention Program, or;
• 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

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

• Clinical: Pulmonary symptoms and exclusion of other diagnoses.
• Radiological: Nodular or cavitary opacities on chest radiograph or a chest high-resolution computed tomography (HRCT) scan showing multifocal bronchiectasis with multiple small nodules.
• 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.

• Male or female participants of any age.
• 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)).
• 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.

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:

• Male and female 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 under 18 years of age.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 22 centers

• St George Hospital — Kogarah
• Queensland Children's Hospital — South Brisbane
• Princess Alexandra Hospital — Woolloongabba
• Austin Hospital — Heidelberg
• Royal Melbourne Hospital — Parkville
• Royal Perth Hospital — Perth
• Royal Adelaide Hospital — Adelaide
• Sunshine Coast University Hospital — Birtinya
• … and 14 more centers

United Kingdom · 17 centers

• Belfast City Hospital — Belfast
• Birmingham Children's Hospital — Birmingham
• Birmingham Heartlands Hospital — Birmingham
• Bristol Royal Hospital for Children — Bristol
• Noah's Ark Childrens Hospital for Wales — Cardiff
• Royal Hospital for Children and Young People, Edinburgh — Edinburgh
• Western General Hospital — Edinburgh
• Queen Elizabeth University Hospital, Glasgow — Glasgow
• … and 9 more centers

Israel · 6 centers

• Soroka Medical Centre — Beer-Sheeva
• Carmel Medical Centre — Haifa
• Rambam Health Care Campus — Haifa
• Hadassah Ein Kerem Hospital — Jerusalem
• Schneider — Petah Tikva
• Sheba Medical Centre — Ramat Gan Tel Aviv

Taiwan · 2 centers

• Kaohsiung Medical University Hospital — Kaohsiung City
• National Taiwan University Hospital — Taipei

Denmark · 1 center

• Rigshospitalet — Copenhagen

Netherlands · 1 center

• Erasmus MC Sophia Children's Hospital — Rotterdam

Singapore · 1 center

• Tan Tock Seng Hospital Pte Ltd — Singapore

Publications

• Jong T, Baird T, Barr HL, Bell S, Bigirumurame T, Brady K, Burke A, Byrnes J, Caudri D, Clark JE, Coin LJM, Goh F, Grimwood K, Hicks D, Jayawardana K, Joshi S, Lee K, Qvist T, Reid D, Rice M, Roberts JA, Rogers G, Shackleton C, Sly PD, Smyth AR, Stevens L, Stockwell R, Tarique A, Taylor S, Thomson R, Tiddens HAWM, Wang XF, Wason J, Wainwright C. Finding the optimal regimen for Mycobacteroides absc PMID 40976660

Identifiers

NCT: NCT04310930 · U1111-1209-0672

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗