Pulmonary Disease Due to Mycobacteria (Diagnosis) Clinical Trial
— FORMaTOfficial title:
Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT)
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.
| Status | Recruiting |
| Enrollment | 300 |
| Est. completion date | August 31, 2024 |
| Est. primary completion date | June 30, 2024 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | N/A and older |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Royal Adelaide Hospital | Adelaide | |
| Australia | Sunshine Coast University Hospital | Birtinya | |
| Australia | Cairns Base Hospital | Cairns | |
| Australia | Royal Prince Alfred Hospital | Camperdown | |
| Australia | The Prince Charles Hospital | Chermside | |
| Australia | Monash Children's Hospital | Clayton | |
| Australia | Monash Medical Centre | Clayton | |
| Australia | Concord Repatriation Hospital | Concord | |
| Australia | Gladstone Hospital | Gladstone | |
| Australia | Gold Coast University Hospital | Gold Coast | |
| Australia | Greenslopes Private Hospital, | Greenslopes | |
| Australia | Royal Brisbane & Women's Hospital | Herston | |
| Australia | Royal Hobart Hospital | Hobart | |
| Australia | Mackay base Hospital | Mackay | |
| Australia | Sir Charles Gardiner Hospital | Nedlands | |
| Australia | John Hunter Hospital | New Lambton | |
| Australia | Perth Children's Hospital | Perth | |
| Australia | The Alfred | Prahran | |
| Australia | Sydney Children's Hospital | Randwick | |
| Australia | Rockhampton Hospital | Rockhampton | |
| Australia | Mater Adult Hospital | South Brisbane | |
| Australia | Queensland Children's Hospital | South Brisbane | Queensland |
| Australia | Townsville Hospital | Townsville | |
| Australia | The Children's Hospital at Westmead | Westmead | |
| Australia | Westmead Hospital | Westmead | |
| Australia | Princess Alexandra Hospital | Woolloongabba | Queensland |
| Canada | St Michaels Hospital | Toronto | |
| Canada | The Hospital for Sick Kids | Toronto | |
| Denmark | Skejby University Hospital | Aarhus | |
| Denmark | Rigshospitalet | København | |
| France | Hospital Cochin | Paris | |
| Ireland | St Vincent's University Hospital | Dublin | |
| Netherlands | Erasmus MC Sophia Children's Hospital | Rotterdam | |
| New Zealand | Starship Children's Hosptial | Auckland | |
| New Zealand | St George's Hospital | Christchurch | |
| Singapore | Tan Tock Seng Hospital Pte Ltd | Singapore | |
| United Kingdom | Royal Brompton Hosptial | London | |
| United Kingdom | Nottingham Children's Hosptial | Nottingham |
| Lead Sponsor | Collaborator |
|---|---|
| The University of Queensland | Australian Government Department of Health and Ageing, Children's Hospital Foundation, Cystic Fibrosis Foundation, Erasmus Medical Center, Griffith University, Hôpital Cochin, James Cook University, Queensland, Australia, Monash University, Murdoch Childrens Research Institute, Newcastle University, South Australian Health and Medical Research Institute, University of Copenhagen, University of Melbourne |
Australia, Canada, Denmark, France, Ireland, Netherlands, New Zealand, Singapore, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Examine the MABS clearance status at twelve (12 months) after time point final | To examine whether MABS has been cleared after 12 months completion of the trial using the 12 month follow up site Principal Investigator Questionnaire. | 12 months post trial completion | |
| Primary | 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. | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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) | |
| Secondary | 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) | |
| Secondary | 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) | |
| Secondary | 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 | |
| Secondary | 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 |