Mycobacterium Abscessus Pulmonary Disease, Mycobacterium Abscessus Infection, Non-Tuberculous Mycobacterial (NTM) Infections, Non-Tuberculous Mycobacteria Pulmonary Disease
Conditions
Keywords
adaptive platform trial, dual beta lactam, sulbactam-durlobactam
Brief summary
The goal of this clinical trial is to learn if a new combination antibiotic treatment (Arm D) works to treat a rare lung condition called mycobacterium abscessus pulmonary disease in people of any age and sex, when compared to the standard treatments. It will also learn about the safety of this new combination antibiotic treatment when compared to the standard treatments. The main questions it aims to answer are: * How well does Arm D treat mycobacterium abscessus pulmonary disease? * What side effects does Arm D cause when used to treat mycobacterium abscessus pulmonary disease? Researchers will compare Arm D to the current standard of care treatments to see if Arm D treats mycobacterium abscessus pulmonary disease better and if it will cause less side effects. Participants will: * Be screened and recruited to the FORMaT adaptive platform trial (NCT04310930) * Be given Arm D for 4 weeks or standard of care treatments for 6 weeks. * Be reviewed by the study doctors weekly for checkups and tests. * Provide respiratory samples (sample coughed up from the chest), respond to quality-of-life questionnaires, have CT lung scans and blood tests.
Detailed description
Mycobacterium abscessus pulmonary disease (MABS-PD) is a rare and serious lung infection that affects people who already have lung problems such as bronchiectasis, cystic fibrosis, past tuberculosis, or weakened immune systems, as well as people who do not have pre-existing lung problems. This infection is becoming more common worldwide and is difficult to treat because it is highly resistant to many antibiotics. Current treatment usually lasts 12-18 months, is hard for patients to tolerate, and often causes significant side effects. This study will test a new combination of antibiotics given during the first four weeks of treatment-the "intensive phase." The new regimen includes intravenous sulbactam-durlobactam and intravenous ceftriaxone, along with oral amoxicillin, oral azithromycin, and oral clofazimine. The trial will compare this new approach to the current standard-of-care therapy using the existing FORMaT adaptive platform trial, which was created to identify better treatments for MABS-PD. The main goal of the study is to find out whether the new combination can clear the infection while also being easier for patients to tolerate. Additional study measures will look at lung function, chest imaging, quality of life, and health-care use. The trial also includes several research components that will examine how the drugs behave in the body, immune responses, mycobacterial genetics, and antibiotic resistance. This innovative study aims to provide the first high-quality clinical evidence for a potentially more effective and less toxic treatment option for people living with this challenging and severe lung infection.
Interventions
Adults and Children 12 years and older: IV sulbactam/durlobactam Greater than or equal to 130ml/min Every FOUR (4) hourly. Administered by intravenous infusion over 3 hours. For CrCL 45 to 129ml/min 1g sulbactam/ 1g durlobactam Every SIX (6) hourly. Administer by intravenous infusion over 3 hours. For CrCL 30 to 44ml/min 1g sulbactam/ 1g durlobactam Every EIGHT (8) hourly. Administer by intravenous infusion over 3 hours. For CrCL 15 to 29ml/min 1g sulbactam/ 1g durlobactam Every TWELVE (12) hourly. Administer by intravenous infusion over 3 hours. For CrCL\<15ml/min 1g sulbactam/ 1g durlobactam Every TWELVE (12) hourly for first 3 doses then reduce to every 24 hourly thereafter. Administer by intravenous infusion over 3 hours.
Adults and Children 12 years and older: IV ceftriaxone 1g Every TWELVE (12) hourly
DRUGAmoxicillin
Adults and Children 12 years and older: Oral amoxicillin 1000mg Three times daily
DRUGAzithromcyin
Adults and Children 12 years and older: Oral Azithromycin 250 - 500mg Once daily If \<40kg or poorly tolerated 250mg Once daily
DRUGclarithromycin
Oral clarithromycin. Only for use if azithromycin not tolerated. Adults: 500mg twice daily. Children: 12-18 years of age: Dosing independent of weight 500mg twice daily
DRUGClofazimine
Adults and Children 12 years and older: Oral clofazimine 100mg to 300mg Once daily
DRUGEthambutol
For participants with confirmed mixed NTM (slow growers + MABS) infections, there is an option to add oral ethambutol to the treatment arm in accordance with the dosing below. Oral ethambutol 15mg/kg (rounded to account for tablet strength) OR Once daily 25mg/kg (rounded to account for tablet strength) Thrice weekly
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
DRUGtigecycline
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
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).
DRUGCefoxitin
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.
Adult: Inhaled amikacin 500mg twice daily. Children: Inhaled amikacin 500mg twice daily. PLEASE NOTE: low preservative intravenous amikacin preparation to be used as inhalation, NOT liposomal amikacin.
DRUGlinezolid
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: \>12 years 600mg once daily.
Adults and children 12 years and older: Oral Co-trimoxazole (Trimethoprim / Sulfamethoxazole) 160/800mg twice daily.
DRUGDoxycycline
Adults and Children 12 years and older: Oral doxycycline 100mg once daily.
DRUGmoxifloxacin
Adult: Oral moxifloxacin 400mg once daily. Children 12 years and older: Oral moxifloxacin 10-15mg/kg once daily, maximum dose 400mg
DRUGbedaquiline
Adult: Oral bedaquiline (18-64 years of age) 400mg once daily for the first two weeks followed by 400mg thrice weekly for 22 weeks (maximum duration of 6 months).
DRUGRifabutin
Adult: Oral rifabutin: 5mg/kg once daily, maximum 300-450mg. Children 12 years and older: Oral rifabutin 5mg/kg once daily
Sponsors
The University of Queensland
Innoviva Specialty Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must meet eligibility criteria as per the FORMaT Master Protocol and Appendix A1 Inclusion Criteria (NCT04310930). 2. Male or female participants aged 12 years and older.
Exclusion criteria
1. Must not have any
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary outcome of the Intervention Program is microbiological clearance of Mycobacterium abscessus (MABS) with good tolerance of the interventions. | 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). | 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. |
| Nested Study A3.1 Type of Short Intensive Therapy - MABS clearance from respiratory sample(s) with tolerance. | Screening (Day 0) to the End of Short Intensive Therapy (Week 6). | Microbiological clearance of MABS from respiratory samples collected at 4 weeks with good tolerability assessed at the end of short intensive therapy between Arm D and the standard of care arms 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. Treatment tolerance is defined as no Treatment emergent adverse events and/or Treatment emergent adverse events that are "possibly-", "probably-", or "definitely-" related to study drug and coded as grade 1 or 2 based on the CTCAEv5.0. |
| Nested Study A3.2 - 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. | 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). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of MABS clearance at Final Outcome irrespective of toxicity according to participant's treatment pathway. | Screening (Day 0); at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62). | 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. |
| Incidence of Treatment emergent adverse events | 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 treatment combinations based on the reporting of adverse events that are attributed as either "possibly-", "probably-", or "definitely-" related to study drugs. |
| Safety of treatments based on changes in microbiological resistance. | 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 to microbiological resistance of the MABS bacteria during the study treatment period. |
| Change in Forced Expiratory Volume in 1 second (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). | Change in FEV1 z-score at Final Outcome compared with Screening in participants who do and do not clear MABS at Final Outcome. |
| Phenotype of the structural abnormalities of chest Computer Tomography (CT) 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). | 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. |
| 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). | Predictive value of structural abnormalities on Screening CT scans for sputum conversion and for progression of structural changes in relation to treatment. |
| 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 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 HRQoL (measured using the Cystic Fibrosis Questionnaire - Respiratory domain (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. | 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. CFQ-R is the Cystic Fibrosis Questionnaire Revised and will be completed by all CF participants. The CFQ-R has a score from 0 to 100. With 0 indicating the lowest quality of life and 100 indicating the highest. |
| Change in HRQoL (measured using the EuroQol 5-Dimension (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. | 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. EQ-5D is the EuroQol 5 Dimensions and will be completed by all participants. |
| Change in HRQoL (measured using the St George's Respiratory Questionnaire (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. | 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. SGRQ is the St George's Respiratory Questionnaire and will be completed by all non-CF participants who are 18 years and older. |
| Change in HRQoL (measured using the Short Form (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. | 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. The SF-36 is the Short-Form 36 questionnaire and will be completed by all participants 16 years and older. The SF-36 operates on a transformed scoring system ranging from 0 (lowest/worst health) to 100 (highest/best health). Lowest Score (0): Represents maximum disability, poor health, or significant limitation. Highest Score (100): Represents no disability, optimal health, and no limitations. |
| Change in HRQoL (measured using the Pediatric Quality of Life Inventory (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. | 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. The PedsQL is the Pediatric Quality of Life Inventory questionnaire and will be completed by participants 2 years old to 16 years old. The PedsQL responses are transformed onto a 0 to 100 scale, where a higher score indicates a better Health-Related Quality of Life (HRQOL). Lowest Score: 0 (indicates poorest quality of life/most problems). Highest Score: 100 (indicates best quality of life/no problems). |
| Change in HRQoL (measured using the Child Health Utility 9 Dimensions (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. | 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. CHU-9D is the Child Health Utility 9D and will be completed by all children aged 7 to 17 years of age. |
| Cost effectiveness of the treatment combinations (measured using the Costs Questionnaire across intensive and consolidation phases of the trial. | 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 across intensive and consolidation phases of the trial. Cost effectiveness of the treatments will be assessed using the unvalidated "Costs Questionnaire". |
| Cost effectiveness of the treatment combinations (measured using Linked Administrative Healthcare Utilisation Data (for applicable jurisdictions)) across intensive and consolidation phases of the trial. | 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 across intensive and consolidation phases of the trial. Cost effectiveness of the treatments will be assessed the linked administrative healthcare utilisation data e.g. in Australian participants. |
| 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). | Causes for early withdrawal from MABS-PD treatment due to reasons other than poor tolerance as defined in the primary objectives. |
Contacts
CONTACTClaire Wainwright Chief Investigator, MD
CONTACTTiffany Jong Project Manager, BPharm
Outcome results
None listed