A Multi-centre, Randomised Trial Comparing a Novel Combination Treatment (Arm D - Intravenous Sulbactam-durlobactam in Combination With Intravenous Ceftriaxone, Oral Amoxicillin, Oral Azithromycin and Oral Clofazimine) Versus Standard of Care Treatments for the Intensive Phase of Treatment for Mycobacterium Abscessus Pulmonary Disease in People With or Without Cystic Fibrosis in the Finding the Optimal Regimen for Mycobacterium Abscessus Treatment (FORMaT) Adaptive Platform Trial
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 300
- 主要终点
- The primary outcome of the Intervention Program is microbiological clearance of Mycobacterium abscessus (MABS) with good tolerance of the interventions.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must meet eligibility criteria as per the FORMaT Master Protocol and Appendix A1 Inclusion Criteria (NCT04310930).
- •Male or female participants aged 12 years and older.
排除标准
- •Must not have any exclusion criteria as per the FORMaT Master Protocol and Appendix A1 Exclusion Criteria (NCT04310930).
- •Participants aged <12 years old.
- •Participants aged between 12 and <18years old with clinically significant renal impairment as indicated by an age-appropriate estimated creatinine clearance.
- •Known hypersensitivity to any of the therapies for which no alternative option(s) have been provided. This includes:
- •Sulbactam/durlobactam
- •Ceftriaxone,
- •Amoxicillin,
- •Macrolide antibiotics, and
- •Clofazimine.
结局指标
主要结局
The primary outcome of the Intervention Program is microbiological clearance of Mycobacterium abscessus (MABS) with good tolerance of the interventions.
时间窗: 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.
时间窗: 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.
时间窗: 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.
次要结局
- 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).)
- 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 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).)
- 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).)
- 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).)
- 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.(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 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 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 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 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 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 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).)
- 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 (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).)
- 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).)