Optimal Drug Regimen for Lung Disease

(FORMaT Trial)

Recruiting at 67 trial locations

Overseen By Kara Brady, MPharm

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: The University of Queensland

Disqualifiers: Pregnancy, Breastfeeding, Healthy volunteers, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

300 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests different medicine combinations to find the best way to treat a tough lung infection in children and adults. The goal is to find the safest and most effective treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are receiving active treatment for MABS, you may not be eligible, except if you are taking azithromycin for cystic fibrosis and bronchiectasis.

Is the treatment generally safe for humans?

The treatment regimens, including drugs like amikacin, azithromycin, clarithromycin, and rifabutin, have been studied for safety. Amikacin was well tolerated in a study for pneumonia, but some patients experienced kidney-related side effects. Rifabutin, when used in high doses, caused side effects like reduced white blood cell counts and gastrointestinal issues, requiring dose adjustments in many patients. ^{1 2 3 4 5}

What makes the drug regimen for lung disease unique?

This drug regimen for lung disease is unique because it combines multiple antibiotics and other medications, such as Amikacin, Azithromycin, and Linezolid, which are not typically used together in standard treatments for lung conditions. This combination may offer a novel approach by targeting the disease through different mechanisms, potentially improving effectiveness and addressing cases where standard treatments are not suitable. ^{6 7 8 9 10}

What data supports the effectiveness of the drug regimen for lung disease?

The research indicates that amikacin, one of the drugs in the regimen, is used effectively in treating multidrug-resistant tuberculosis when combined with other drugs. Additionally, imipenem, another component, has shown effectiveness in treating resistant tuberculosis strains when used with clavulanate. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for people with a lung condition caused by Mycobacterium abscessus, who meet specific clinical, radiological, and microbiological criteria. It's open to those with mixed infections if needed for treatment. Participants must be able to follow the trial plan and visit schedule. Those treated for MABS in the last year (except certain cases), pregnant or breastfeeding individuals, or anyone allergic to the drugs tested cannot join.

Inclusion Criteria

I have been diagnosed with M. abscessus lung disease based on clinical, radiological, and microbiological criteria.

I have a mixed NTM infection and may need ethambutol as decided by my doctor.

You have at least one positive culture for bacteria in your respiratory system.

Exclusion Criteria

I haven't taken MABS treatment in the last year, except azithromycin for my cystic fibrosis.

You are allergic to the treatment options available for this study.

Pregnancy or planning to continue breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intensive Therapy

Participants receive intensive drug therapy including IV and inhaled antibiotics to clear MABS infection

6-12 weeks

Weekly visits for drug administration and monitoring

Consolidation Therapy

Participants receive oral and/or inhaled antibiotics to maintain MABS clearance

52-58 weeks

Monthly visits for monitoring and drug adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Quarterly visits for health assessments

Treatment Details

Interventions

• Amikacin
• Azithromycin
• Cefoxitin
• Clarithromycin
• Clofazimine
• Co-trimoxazole
• Doxycycline
• Ethambutol
• Imipenem
• Linezolid
• Moxifloxacin
• Rifabutin
• Tigecycline

Trial Overview The FORMaT trial is testing a combination of antibiotics including Cefoxitin, Linezolid, Bedaquiline and others against MABS pulmonary disease. The goal is to find the best treatment regimen that maximizes health outcomes while minimizing toxicity and burden on patients.

Participant Groups

Group I: Intensive Therapy C Experimental Treatment 7 Interventions

Following Randomisation 1, Participants will receive intensive drug therapy in the form of IV amikacin, IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin.

Group II: Intensive Therapy B Experimental Treatment 8 Interventions

Following Randomisation 1, Participants will receive inhaled amikacin (IA), IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin AND clofazimine.

Group III: Consolidation B Experimental Treatment 11 Interventions

Inhaled amikacin (IA), oral clofazimine + oral azithromycin/oral clarithromycin in combination with one to three of the following oral antibiotics: oral linezolid, oral co-trimoxazole, oral doxycycline, oral moxifloxacin, oral bedaquiline (adults only), oral rifabutin.

Group IV: Consolidation A Active Control 10 Interventions

Oral clofazimine + oral azithromycin/oral clarithromycin in combination with one to three of the following oral antibiotics: oral linezolid, oral co-trimoxazole, oral doxycycline, oral moxifloxacin, oral bedaquiline (adults only), oral rifabutin.

Group V: Intensive Therapy A Active Control 8 Interventions

Following Randomisation 1, Participants will receive intensive drug therapy in the form of IV amikacin, IV tigecycline, IV cefoxitin/imipenem + oral azithromycin AND clofazimine.

Amikacin is already approved in United States, European Union for the following indications:

Approved in United States as Amikin for:

• Serious infections caused by susceptible strains of gram-negative bacteria, including Pseudomonas species, Escherichia coli, Proteus species, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (formerly Mima-Herellea) species.
• Initial empirical therapy, in hospital acquired infections, as part of a regimen, in serious infections where one or more of the following are the known or suspected pathogens: Pseudomonas aeruginosa, Serratia spp., and Providencia stuartii.

Approved in European Union as Amikin for:

• Serious infections caused by susceptible strains of gram-negative bacteria, including Pseudomonas aeruginosa and other Pseudomonas species, Escherichia coli, Klebsiella species, Enterobacter species, Serratia species, Citrobacter freundii, and Staphylococcus aureus (methicillin-resistant strains).

Who Is Running the Clinical Trial?

The University of Queensland

Lead Sponsor

Trials

149

Recruited

71,700+

Monash University

Collaborator

Trials

204

Recruited

10,570,000+

Hôpital Cochin

Collaborator

Trials

30

Recruited

16,500+

Cystic Fibrosis Foundation

Collaborator

Trials

199

Recruited

37,800+

University of Melbourne

Collaborator

Trials

193

Recruited

1,287,000+

South Australian Health and Medical Research Institute

Collaborator

Trials

14

Recruited

6,800+

Australian Government Department of Health and Ageing

Collaborator

Trials

11

Recruited

21,000+

Griffith University

Collaborator

Trials

18

Recruited

22,900+

Children's Hospital Foundation

Collaborator

Trials

4

Recruited

450+

Newcastle University

Collaborator

Trials

172

Recruited

14,120,000+

Findings from Research

In a study of 833 patients with drug-sensitive tuberculosis, all five 6-month treatment regimens showed favorable bacteriological responses, with relapse rates of 2% or less for most regimens, except for one that had an 8% relapse rate due to the absence of pyrazinamide.

The study found low incidence of serious toxicity across all regimens, suggesting that these treatment options are safe, and the daily regimen may be particularly useful for self-administration in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. [2015]

In a study of 180 patients with multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB), meropenem/clavulanate showed significantly better treatment outcomes compared to imipenem/clavulanate, with higher sputum smear and culture conversion rates (94.8% vs 79.7% and 94.8% vs 71.9%, respectively).

The treatment success rate was also higher for meropenem/clavulanate at 77.5% compared to 59.7% for imipenem/clavulanate, indicating that meropenem/clavulanate may be a more effective option for these difficult-to-treat TB cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. Tiberi, S., Sotgiu, G., D'Ambrosio, L., et al.[2018]

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis can be effectively treated with a carefully selected combination of at least four antituberculosis drugs, tailored to the specific susceptibility of the Mycobacterium tuberculosis strain.

The treatment regimen involves a stepwise selection process based on drug efficacy, safety, and cost, utilizing groups of drugs including high-dose isoniazid, fluoroquinolones like levofloxacin, and injectable options such as capreomycin, ensuring a comprehensive approach to combat these resistant strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Caminero, JA., Sotgiu, G., Zumla, A., et al.[2022]

In a study of 75 patients with recurrent pulmonary tuberculosis, a more intensive chemotherapy regimen (2b) was significantly more effective than a standard regimen (2a) in stopping bacterial growth after 3 months, with success rates of 86.1% versus 62.5%.

The intensive regimen (2b) also resulted in a higher rate of cavity closure in the lungs after 6 months (76.7% compared to 48.0%), demonstrating its superior efficacy, especially in cases of drug-resistant tuberculosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficiency of a new standard chemotherapy regimen in the treatment of patients with recurrent pulmonary tuberculosis]. Chukanov, VI., Komissarova, OG., Maishin, VIu., et al.[2006]

In a study of 833 patients with drug-sensitive tuberculosis, various 6-month treatment regimens showed a favorable bacteriological response, with relapse rates as low as 1% for certain combinations of medications.

Regimens containing pyrazinamide were particularly effective, achieving similar results in patients with drug-resistant strains, highlighting the importance of this drug in tuberculosis treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. Hong Kong Chest Service/British Medical Research Council. [2019]

In a study of 84 patients with suspected pneumonia, aztreonam combined with other antibiotics showed a microbiologic cure rate of 75%, compared to 63% in the aminoglycoside control group, indicating aztreonam's effectiveness in treating gram-negative bacterial infections.

The aztreonam regimen was associated with a trend towards shorter treatment duration (10 days vs. 12 days) and a lower need for additional antibiotics (21% vs. 36%), while maintaining a good safety profile with no serious adverse reactions reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of empiric aztreonam and aminoglycoside regimens in the treatment of serious gram-negative lower respiratory infections. Bjornson, HS., Ramirez-Ronda, C., Saavedra, S., et al.[2022]

Beta-lactams are the most commonly used antibiotics for nosocomial pneumonia, but 6% to 25% of patients may experience allergic reactions; however, proper evaluation can potentially de-label up to 90% of these allergies.

Aminoglycosides are generally safe for short-term use, but renal function should be monitored, while fluoroquinolones carry risks of serious side effects like cardiovascular events, highlighting the need for careful selection and monitoring of antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety considerations of current drug treatment strategies for nosocomial pneumonia. Ceccato, A., Di Giannatale, P., Nogas, S., et al.[2021]

In a study of 105 critically ill ICU patients with carbapenem-resistant Klebsiella pneumoniae, the ceftazidime-avibactam (CAZ-AVI) regimen showed significantly higher clinical (51.2% vs. 29.0%) and microbiological cure rates (74.4% vs. 33.9%) compared to the tigecycline (TGC) regimen.

The CAZ-AVI group also had a lower incidence of adverse reactions, suggesting a better safety profile, although both treatments had similar 28-day survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceftazidime-Avibactam-Based Versus Tigecycline-Based Regimen for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae-Induced Pneumonia in Critically Ill Patients. Shi, Y., Hu, J., Liu, P., et al.[2021]

Newly approved antibiotics like ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam are effective against certain multidrug-resistant Gram-negative bacteria, particularly those causing hospital-acquired pneumonia.

Cefiderocol shows promise in treating pneumonia caused by Acinetobacter baumannii and has strong activity against multidrug-resistant Pseudomonas aeruginosa, highlighting its potential as a key treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New antibiotics for Gram-negative pneumonia. Bassetti, M., Magnè, F., Giacobbe, DR., et al.[2023]

In a trial involving 26 patients with pulmonary Mycobacterium avium complex (MAC) disease, high-dose rifabutin (600 mg/d) led to adverse events in 77% of participants, with 58% needing dosage adjustments or discontinuation due to side effects.

The most significant adverse effects included a substantial drop in white blood cell counts and gastrointestinal symptoms, prompting a recommendation to lower the rifabutin dose to 300 mg/d when used with macrolides for safer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. Griffith, DE., Brown, BA., Girard, WM., et al.[2019]

In a series of studies involving patients with lung cancer, low-dose carboplatin combined with escalating doses of paclitaxel was tested to determine the maximum tolerated dose, with a maximum tolerated dose of 135 mg/m2 for paclitaxel in patients who had prior chemotherapy, where febrile neutropenia was the main side effect.

Among 21 evaluable patients treated with paclitaxel doses ranging from 100 to 270 mg/m2, there were two partial responses, one minor response, and ten patients with stable disease, indicating some efficacy of the treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early phase studies with paclitaxel/low-dose carboplatin in patients with solid tumors. Creaven, PJ., Raghavan, D., Perez, RP., et al.[2015]

In a study of 34 advanced non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD), the chemotherapy regimen of carboplatin plus nab-paclitaxel demonstrated a 38.2% overall response rate, indicating its efficacy as a first-line treatment.

The regimen was found to be safe, with only 5.7% of patients experiencing acute exacerbation of ILD and no treatment-related deaths, suggesting it can be a viable option for NSCLC patients with preexisting ILD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evaluation of carboplatin plus a weekly dose of nab-paclitaxel for patients with advanced non-small-cell lung cancer with interstitial lung disease. Igawa, S., Nishinarita, N., Takakura, A., et al.[2022]

Cisplatin-based chemotherapy is preferred for treating advanced nonsmall cell lung cancer, with carboplatin as an alternative for patients with contraindications; nonplatinum regimens are also available for those who cannot tolerate platinum-based treatments.

There is no evidence that higher doses of cisplatin improve survival compared to standard doses, and a minimum of four to six cycles of chemotherapy is recommended for patients who respond well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First- and second-line therapy for advanced nonsmall cell lung cancer. Sculier, JP., Moro-Sibilot, D.[2018]

This phase I study involving patients with advanced non-small cell lung cancer found that the combination of carboplatin and paclitaxel is well tolerated, with neutropenia being the main dose-limiting toxicity observed.

A dose-response relationship was noted, with higher doses leading to a greater percentage of partial responses in patients, suggesting that the maximal tolerated doses are likely at least 200 mg/m2 for paclitaxel and 400 mg/m2 for carboplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of carboplatin and paclitaxel in non-small cell lung cancer: a University of Colorado Cancer Center study. Bunn, PA., Kelly, K.[2015]

Cisplatin-based chemotherapy significantly improves survival and symptom control in stage IV non-small cell lung cancer patients with good performance status, suggesting its effectiveness as a primary treatment option.

Combination regimens including cisplatin and at least one other active drug (like ifosfamide or gemcitabine) are recommended, with four to six cycles proposed for patients who respond well, while non-platinum options can be considered for those unable to tolerate platinum-based treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Stage IV NSCLC. Place of chemotherapy]. Meert, AP.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. [2022]

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Efficiency of a new standard chemotherapy regimen in the treatment of patients with recurrent pulmonary tuberculosis]. [2006]

5. Scotland pubmed.ncbi.nlm.nih.gov

Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. Hong Kong Chest Service/British Medical Research Council. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Comparison of empiric aztreonam and aminoglycoside regimens in the treatment of serious gram-negative lower respiratory infections. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety considerations of current drug treatment strategies for nosocomial pneumonia. [2021]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Ceftazidime-Avibactam-Based Versus Tigecycline-Based Regimen for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae-Induced Pneumonia in Critically Ill Patients. [2021]

9. England pubmed.ncbi.nlm.nih.gov

New antibiotics for Gram-negative pneumonia. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Early phase studies with paclitaxel/low-dose carboplatin in patients with solid tumors. [2015]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Real-world evaluation of carboplatin plus a weekly dose of nab-paclitaxel for patients with advanced non-small-cell lung cancer with interstitial lung disease. [2022]

13. England pubmed.ncbi.nlm.nih.gov

First- and second-line therapy for advanced nonsmall cell lung cancer. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

A phase I study of carboplatin and paclitaxel in non-small cell lung cancer: a University of Colorado Cancer Center study. [2015]

15. France pubmed.ncbi.nlm.nih.gov

[Stage IV NSCLC. Place of chemotherapy]. [2013]