Antibiotics for Cystic Fibrosis Pulmonary Exacerbations

(STOP360AG Trial)

Recruiting at60 trial locations

Overseen by Patrick A Flume, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Chris Goss

Must not be taking: Aminoglycosides, CFTR modulators

Disqualifiers: Pregnancy, Renal impairment, Organ transplant, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing whether using one antibiotic or two different antibiotics together is better for treating lung infections in people with cystic fibrosis. It targets patients with worsening lung symptoms needing IV antibiotics. The antibiotics work by killing or stopping bacteria to improve breathing and reduce symptoms.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, you cannot have used certain treatments like investigational therapies or new CFTR modulators within 4 weeks before starting the trial.

What data supports the effectiveness of the drug combination of aminoglycosides and beta-lactams for treating cystic fibrosis pulmonary exacerbations?

Research shows that using a combination of aminoglycosides (like tobramycin) and beta-lactams can improve lung function and reduce bacteria in the lungs for cystic fibrosis patients. In one study, patients treated with tobramycin showed better lung function and reduced bacterial counts compared to those given a placebo. ^{1 2 3 4 5}

Is the use of antibiotics like aminoglycosides and beta-lactams generally safe for treating cystic fibrosis exacerbations?

Aminoglycosides, such as amikacin and tobramycin, are generally effective in treating lung infections in cystic fibrosis patients, but they can cause side effects like hearing loss. One study noted minimal hearing loss in some patients, and another explored the link between tobramycin exposure and hearing damage. No major safety concerns were reported for beta-lactams in the provided studies. ^{2 6 7 8 9}

How is the drug combination of aminoglycosides and beta-lactam antibiotics unique for treating cystic fibrosis pulmonary exacerbations?

This drug combination is unique because it targets Pseudomonas infections, which are common in cystic fibrosis, by using two types of antibiotics that work together to enhance effectiveness and reduce resistance. Aminoglycosides and beta-lactams are often used together to treat severe infections, making them a mainstay for patients with impaired defenses. ^{10 11 12 13 14}

Research Team

Patrick A Flume, MD

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

This trial is for people with cystic fibrosis aged 6 and above who've had a specific lung infection. They must be planning to start a 14-day IV antibiotic treatment for worsening respiratory symptoms. Those pregnant, with kidney issues, organ transplants, or bad reactions to certain antibiotics can't join.

Inclusion Criteria

You have had a positive culture for a specific bacteria called Pseudomonas aeruginosa within the two years before your first study visit.

Documentation of a CF diagnosis

My doctor plans to treat my cystic fibrosis exacerbation with a 14-day course of IV antibiotics.

Exclusion Criteria

I haven't used experimental drugs or treatments for cystic fibrosis or NTM in the last 4 weeks.

I haven't had IV antibiotics, been in ICU, or had lung-related issues in the last 6 weeks.

I have received IV aminoglycosides for one day or less for my current treatment.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous antibiotics for pulmonary exacerbations in cystic fibrosis, with a planned 14-day course of IV antimicrobials

2 weeks

Multiple visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in lung function and respiratory symptoms

4 weeks

Visit at Day 28 ± 2 days

Extended Follow-up

Participants are monitored for adverse events and long-term outcomes

6 weeks

Visit at Day 44 ± 2 days

Treatment Details

Interventions

• Aminoglycoside (Antibiotic)
• Beta-lactam antibiotic (Antibiotic)

Trial Overview The study compares the effectiveness of two antibiotic treatments for cystic fibrosis-related lung problems: one using only beta-lactam antibiotics versus another combining beta-lactams with an aminoglycoside called tobramycin.

Participant Groups

Group I: β-lactam and Aminoglycoside (AG) Experimental Treatment 2 Interventions

Participants randomized to this arm will be prescribed a standard of care intravenous (IV) β-lactam and aminoglycoside selected by their treating physician.

Group II: β-lactam Only (Non-AG) Experimental Treatment 1 Intervention

Participants randomized to this arm will be prescribed a standard of care intravenous (IV) β-lactam as selected by their treating physician. Treatment must not include an IV aminoglycoside.

Aminoglycoside is already approved in Canada, Japan for the following indications:

Approved in Canada as Gentamicin for:

• Bacterial infections in cystic fibrosis
• Pulmonary exacerbations in cystic fibrosis

Approved in Japan as Amikacin for:

• Bacterial infections in cystic fibrosis
• Pulmonary exacerbations in cystic fibrosis

Who Is Running the Clinical Trial?

Chris Goss

Lead Sponsor

Trials

5

Recruited

2,300+

University of Washington

Collaborator

Trials

1,858

Recruited

2,023,000+

Dr. Timothy H. Dellit

University of Washington

Chief Executive Officer since 2023

MD from University of Washington

Dr. Anneliese Schleyer

University of Washington

Chief Medical Officer since 2023

MD, MHA

Medical University of South Carolina

Collaborator

Trials

994

Recruited

7,408,000+

Dr. Erik Summers

Medical University of South Carolina

Chief Medical Officer

MD from University of Alabama at Birmingham

Dr. Patrick J. Cawley

Medical University of South Carolina

Chief Executive Officer

MD, MBA

Cystic Fibrosis Foundation

Collaborator

Trials

199

Recruited

37,800+

Michael P. Boyle

Cystic Fibrosis Foundation

Chief Executive Officer since 2019

MD from Johns Hopkins University

Albert Faro

Cystic Fibrosis Foundation

Chief Medical Officer since 2023

MD

Findings from Research

In a study of 76 cystic fibrosis patients, the combination of azlocillin (a beta-lactam) and tobramycin (an aminoglycoside) resulted in a longer time to the next pulmonary exacerbation compared to azlocillin alone, indicating improved clinical remission.

While the combination therapy showed a greater reduction in sputum Pseudomonas aeruginosa density, it also led to a higher frequency of tobramycin resistance, suggesting a need for careful consideration of antibiotic use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. Smith, AL., Doershuk, C., Goldmann, D., et al.[2019]

A national survey of pharmacists at Cystic Fibrosis Foundation-accredited centers revealed that 78.6% of pediatric pharmacists and 96% of adult pharmacists use extended-interval tobramycin dosing, typically starting at 10 mg/kg every 24 hours, aiming for a serum concentration of 20 to 40 mg/L.

The survey highlights the need for standardized dosing and monitoring strategies for tobramycin and beta-lactams in cystic fibrosis treatment, as most pharmacists reported using these medications in combination, with a focus on optimizing patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tobramycin and Beta-Lactam Antibiotic Use in Cystic Fibrosis Exacerbations: A Pharmacist Approach. Zobell, JT., Epps, K., Kittell, F., et al.[2020]

In a randomized trial involving 22 children with cystic fibrosis, those treated with tobramycin showed significant clinical improvement, with 11 out of 11 responding positively, compared to only 7 out of 11 in the placebo group.

Tobramycin treatment led to a notable decrease in Pseudomonas sp concentrations in sputum cultures for 6 out of 7 patients, while no improvement was observed in pulmonary function for the placebo group, indicating the potential efficacy of antibiotics in managing acute pulmonary exacerbations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute pulmonary exacerbations in cystic fibrosis. A double-blind trial of tobramycin and placebo therapy. Wientzen, R., Prestidge, CB., Kramer, RI., et al.[2019]

In a randomized controlled trial involving patients with cystic fibrosis, both ceftazidime and the combination of ticarcillin and tobramycin were found to be equally effective in improving clinical symptoms during acute respiratory exacerbations.

Ceftazidime was more effective in reducing Pseudomonas aeruginosa levels in sputum and had a lower incidence of antibiotic resistance compared to the ticarcillin/tobramycin combination, which led to resistance in 50% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis. Gold, R., Overmeyer, A., Knie, B., et al.[2019]

Inhaled antipseudomonal antibiotics are considered the safest and most effective treatment for improving lung function in cystic fibrosis patients with pulmonary infections.

Azithromycin and a 28-day treatment with aztreonam or tobramycin significantly enhance respiratory function, while aztreonam lysine may be more effective than tobramycin for chronic Pseudomonas infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of pseudomonas and Staphylococcus bronchopulmonary infection in patients with cystic fibrosis. Das, RR., Kabra, SK., Singh, M.[2021]

Amikacin, an antibiotic effective against Pseudomonas aeruginosa, was used in 22 treatment courses for 18 cystic fibrosis patients, showing a good clinical response in 19 cases despite not eliminating the bacteria from sputum.

The treatment led to significant improvements in lung function and chest x-rays in many patients, with minimal side effects, including only one case of elevated serum creatinine and two instances of mild hearing loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amikacin therapy of exacerbations of Pseudomonas aeruginosa infections in patients with cystic fibrosis. Lau, WK., Young, LS., Osher, AB., et al.[2013]

Aminoglycosides, particularly tobramycin, are essential for treating Pseudomonas aeruginosa infections during acute pulmonary exacerbations in pediatric cystic fibrosis patients, but there is variability in dosing and monitoring practices across different institutions.

This review highlights the need for standardized pharmacokinetic goals and monitoring strategies for aminoglycosides, especially as new CF treatments become available, which may change how these antibiotics are used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aminoglycoside dosing and monitoring for Pseudomonas aeruginosa during acute pulmonary exacerbations in cystic fibrosis. Ochs, MA., Dillman, NO., Caverly, LJ., et al.[2021]

A study of 106 young patients with cystic fibrosis showed a significant relationship between cumulative exposure to tobramycin and minor changes in hearing acuity, with an average hearing loss of only 3.8 dB, indicating that while there is a connection, the ototoxic effects are not clinically significant.

The research highlights the importance of individual susceptibility to ototoxicity and suggests that ongoing hearing assessments should be conducted into adulthood to better understand the long-term effects of tobramycin exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis. Madaule, J., Valenzuela, F., Mittaine, M., et al.[2023]

A study involving 51 adult cystic fibrosis patients developed a pharmacokinetic model for tobramycin, showing that patient height is a better predictor for dosing than weight.

To achieve effective drug concentrations against Pseudomonas aeruginosa, initial tobramycin doses should be between 3.4 mg/cm and 4.4 mg/cm based on height, which is crucial for optimizing treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis. Koloskoff, K., Thirion, DJG., Matouk, E., et al.[2023]

Despite the introduction of new penicillins and cephalosporins, treatment outcomes for infected patients with weakened immune systems have not significantly improved, with Pseudomonas-active beta-lactam combinations with aminoglycosides remaining the primary treatment approach.

Ceftazidime, among the new cephalosporins, shows potential in clinical trials, particularly in combination with amikacin, but ongoing monitoring for antibiotic resistance is crucial to ensure effective treatment and may require adjustments to the empiric regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro considerations in monotherapy and combination therapy for severe infections. Gaya, H.[2004]

In a multicenter phase II study involving 62 patients with advanced non-small-cell lung cancer (NSCLC), amrubicin demonstrated an overall response rate of 18.3% and a median survival time of 8.2 months, indicating its efficacy as a treatment option.

While amrubicin was generally well-tolerated, it did cause significant myelosuppression, with high rates of grade 3 or 4 neutropenia and leukopenia, but non-hematological side effects were mostly mild.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer: a West Japan Thoracic Oncology Group (WJTOG) study. Takeda, K., Takifuji, N., Negoro, S., et al.[2018]

In a phase II study involving 61 patients with advanced non-small-cell lung cancer (NSCLC), amrubicin demonstrated an overall response rate of 27.9%, with one complete response and 16 partial responses, indicating its efficacy as a treatment option.

While amrubicin was generally well-tolerated, it did cause significant myelosuppression, with high rates of grade 3 or 4 neutropenia and leukopenia, highlighting the need for careful monitoring of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer (Study 1): West Japan Thoracic Oncology Group (WJTOG) trial. Sawa, T., Yana, T., Takada, M., et al.[2018]

In a phase I trial involving 15 patients with advanced non-small cell lung cancer, the maximum tolerated dose (MTD) of amrubicin when combined with cisplatin was determined to be 30 mg/m², with a recommended dose of 25 mg/m² for further studies.

The treatment resulted in a partial response in 27% of patients, indicating some efficacy of the amrubicin and cisplatin combination, while the main dose-limiting toxicities were severe neutropenia, which can be managed effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of amrubicin hydrochloride and cisplatin in patients previously treated for advanced non-small cell lung cancer. Ikeda, J., Maruyama, R., Okamoto, T., et al.[2013]

In a phase II trial involving 25 patients with metastatic non-small-cell lung cancer, the combination of amifostine, cisplatin, and vinblastine resulted in a 64% objective response rate, indicating significant efficacy in treating this type of cancer.

The treatment was associated with manageable and mostly reversible toxicities, including neutropenia and nephrotoxicity, suggesting that amifostine may help protect against long-term kidney damage from cisplatin, warranting further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival. Schiller, JH., Storer, B., Berlin, J., et al.[2017]

References

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

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. [2019]

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

Tobramycin and Beta-Lactam Antibiotic Use in Cystic Fibrosis Exacerbations: A Pharmacist Approach. [2020]

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

Acute pulmonary exacerbations in cystic fibrosis. A double-blind trial of tobramycin and placebo therapy. [2019]

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

Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis. [2019]

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

Treatment of pseudomonas and Staphylococcus bronchopulmonary infection in patients with cystic fibrosis. [2021]

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

Amikacin therapy of exacerbations of Pseudomonas aeruginosa infections in patients with cystic fibrosis. [2013]

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

Aminoglycoside dosing and monitoring for Pseudomonas aeruginosa during acute pulmonary exacerbations in cystic fibrosis. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis. [2023]

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

New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis. [2023]

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

In vitro considerations in monotherapy and combination therapy for severe infections. [2004]

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

Phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer: a West Japan Thoracic Oncology Group (WJTOG) study. [2018]

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

Multicenter phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer (Study 1): West Japan Thoracic Oncology Group (WJTOG) trial. [2018]

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

Phase I study of amrubicin hydrochloride and cisplatin in patients previously treated for advanced non-small cell lung cancer. [2013]

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

Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival. [2017]