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Testing a Novel Combination Treatment (Arm D) Versus Standard of Care for Intensive Phase 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

ConditionsMycobacterium Abscessus Pulmonary DiseaseMycobacterium Abscessus InfectionNon-Tuberculous Mycobacterial (NTM) InfectionsNon-Tuberculous Mycobacteria Pulmonary Disease
Trial statusNot yet recruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age12+
SponsorThe University of Queensland

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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.

Sulbactam/durlobactam

Trial design

Design model

Parallel

Treatments tested in this trial

  • Sulbactam 25mg/kg -Durlobactam 25mg/kg (Every 6 hours)

    Drug

    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.

  • Ceftriaxone for Injection

    Drug

    Adults and Children 12 years and older: IV ceftriaxone 1g Every TWELVE (12) hourly

  • Amoxicillin

    Drug

    Adults and Children 12 years and older: Oral amoxicillin 1000mg Three times daily

  • Azithromcyin

    Drug

    Adults and Children 12 years and older: Oral Azithromycin 250 - 500mg Once daily If \<40kg or poorly tolerated 250mg Once daily

  • clarithromycin

    Drug

    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

  • Clofazimine

    Drug

    Adults and Children 12 years and older: Oral clofazimine 100mg to 300mg Once daily

  • Ethambutol

    Drug

    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

  • Amikacin Injection

    Drug

    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

  • tigecycline

    Drug

    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

  • Imipenem + Cilastatin

    Drug

    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).

  • Cefoxitin

    Drug

    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.

  • Amikacin (Inhalation)

    Drug

    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.

  • linezolid

    Drug

    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.

  • Trimethoprim / Sulfamethoxazole

    Drug

    Adults and children 12 years and older: Oral Co-trimoxazole (Trimethoprim / Sulfamethoxazole) 160/800mg twice daily.

  • Doxycycline

    Drug

    Adults and Children 12 years and older: Oral doxycycline 100mg once daily.

  • moxifloxacin

    Drug

    Adult: Oral moxifloxacin 400mg once daily. Children 12 years and older: Oral moxifloxacin 10-15mg/kg once daily, maximum dose 400mg

  • bedaquiline

    Drug

    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).

  • Rifabutin

    Drug

    Adult: Oral rifabutin: 5mg/kg once daily, maximum 300-450mg. Children 12 years and older: Oral rifabutin 5mg/kg once daily

Treatment groups

300 Participants
are divided into 6 treatment groups

6

Treatment groups

See each treatment group below.

Group A: Intensive Arm D with Sulbactam-Durlobactam in a combination antibiotic regimenExperimental treatment 13 interventions
Group B: Intensive Arm A with IV amikacin, imipenem or cefoxitin, tigecycline, macrolide and clofazimineActive comparator 8 interventions
Group C: Intensive Arm B with Inhaled Amikacin, imipenem or cefoxitin, tigecycline, macrolide and clofazimineExperimental treatment 8 interventions
Group D: Intensive Arm C with IV amikacin, imipenem or cefoxitin, tigecycline and macrolideExperimental treatment 7 interventions
Group E: Consolidation arm a with clofazimine, macrolide and a combination of 1 to 3 oral antibiotic agentsActive comparator 10 interventions
Group F: Consolidation arm b with inhaled amikacin, clofazimine, macrolide and 1 to 3 oral antibiotic agentsExperimental treatment 11 interventions

Trial outcomes

Primary outcomes

1

The primary outcome of the Intervention Program is microbiological clearance of Mycobacterium abscessus (MABS) with good tolerance of the interventions.

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.

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).
2

Nested Study A3.1 Type of Short Intensive Therapy - MABS clearance from respiratory sample(s) with tolerance.

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.

Time frame
Screening (Day 0) to the End of Short Intensive Therapy (Week 6).
3

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.

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.

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).

Secondary outcomes

1

Probability of MABS clearance at Final Outcome irrespective of toxicity according to participant's treatment pathway.

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.

Time frame
Screening (Day 0); at End of Treatment plus 4 weeks off treatment (Final Outcome Visit - either Week 56 or Week 62).
2

Incidence of Treatment emergent adverse events

Safety of treatment combinations based on the reporting of adverse events that are attributed as either "possibly-", "probably-", or "definitely-" related to study drugs.

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).
3

Safety of treatments based on changes in microbiological resistance.

Safety of treatments based on changes to microbiological resistance of the MABS bacteria during the study treatment period.

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).
4

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.

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).

Other outcomes

1

Participant's MABS clearance status 12 months after Final Outcome.

Participant's MABS clearance status 12 months after Final Outcome will be assessed by a 12 month follow up questionnaire that will be completed by the site investigator.

Time frame
12 months after End of Treatment plus 4 weeks off treatment (Final Outcome Visit).

Locations

This trial has no locations.

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

The University of Queensland

Lead sponsor

Innoviva Specialty Therapeutics

Collaborator

Source ClinicalTrials.gov

This trial is not recruiting at the moment. You can still explore other options: