Antibiotics for Cystic Fibrosis Pulmonary Exacerbations

(STOP360AG Trial)

Recruiting at 64 trial locations

Overseen By Barbra Fogarty

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: Chris Goss

Must not be taking: Aminoglycosides, CFTR modulators

Disqualifiers: Pregnancy, Renal impairment, Organ transplant, 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

Compensation: Varies

Number of Visits: 72

Duration: 2 weeks

730 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the best way to treat lung flare-ups in people with cystic fibrosis (CF) using antibiotics. Researchers aim to determine if one antibiotic (beta-lactams) is as effective as two types (beta-lactams plus tobramycin, an aminoglycoside antibiotic). People with CF who have experienced worsening breathing problems requiring IV antibiotics might be suitable for this study. Participants should have a recent history of a specific lung infection (a positive culture for Pa bacteria) and need a planned 14-day IV antibiotic treatment. As a Phase 4 trial, this research involves an FDA-approved treatment and seeks to understand its benefits for more patients.

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 is the safety track record for these treatments?

Research has shown that two types of antibiotics, aminoglycosides and beta-lactams, are often used to treat lung infections in people with cystic fibrosis. Studies have found that administering aminoglycosides at specific intervals is safe and effective for these patients. The Cystic Fibrosis Foundation supports this method.

For beta-lactam antibiotics, research indicates that the correct dosage can improve lung function by effectively fighting infections. These antibiotics are generally safe when carefully monitored.

Overall, both treatments are considered safe for people with cystic fibrosis when used as recommended. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for cystic fibrosis pulmonary exacerbations because they explore different combinations of antibiotics to tackle infections more effectively. Unlike standard treatments that often rely on a single type of antibiotic, this approach combines a β-lactam antibiotic with or without an aminoglycoside. The use of a dual therapy with β-lactam and aminoglycoside can potentially enhance bacterial eradication and improve lung function more rapidly. This strategy might offer a more potent and tailored approach to managing the complex infections seen in cystic fibrosis patients.

What evidence suggests that this trial's treatments could be effective for cystic fibrosis?

Research has shown that certain antibiotics called beta-lactams effectively treat lung infections in people with cystic fibrosis. Studies indicate that continuous administration of beta-lactams can improve symptoms during lung flare-ups. In this trial, participants will receive either beta-lactams alone or in combination with aminoglycosides. Using these antibiotics together might enhance treatment effectiveness, as aminoglycosides target specific bacteria causing these infections. Evidence supports using beta-lactams alone or with aminoglycosides to manage lung flare-ups in cystic fibrosis patients. ^{5 6 7 8 9}

Who Is on the Research Team?

Patrick A Flume, MD

Principal Investigator

Medical University of South Carolina

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Aminoglycoside
• Beta-lactam 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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Tobramycin for:

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

Approved in United States as Tobramycin for:

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

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+

Medical University of South Carolina

Collaborator

Trials

994

Recruited

7,408,000+

Cystic Fibrosis Foundation

Collaborator

Trials

199

Recruited

37,800+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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]

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 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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4905153/

Extended-Interval Aminoglycoside Use in Cystic Fibrosis ... On the other hand, higher aminoglycoside clearance may indicate a lower risk of antibiotic accumulation and toxicity. In addition, a prolonged drug-free ...

2. withpower.com withpower.com/trial/phase-4-pulmonary-fibrosis-1-2023-7dd50

Antibiotics for Cystic Fibrosis Pulmonary Exacerbations This trial is testing whether using one antibiotic or two different antibiotics together is better for treating lung infections in people with cystic ...

3. resmedjournal.com resmedjournal.com/article/S0954-6111(23)00125-7/fulltext

Therapeutic drug monitoring in cystic fibrosis and ... All patients received 14 days of intravenous beta-lactam antibiotics while inpatient (either piperacillin-tazobactam or cefepime).

4. experts.llu.edu experts.llu.edu/en/publications/pharmacokinetics-of-continuous-infusion-beta-lactams-in-the-treat-4/

Pharmacokinetics of Continuous Infusion Beta-lactams in ... Background: Several clinical trials have shown the efficacy of continuous infusion beta-lactam (BL) antibiotics in patients with cystic fibrosis (CF); ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S156919932400047X

Update on the diagnosis and management of cystic fibrosis ... Characteristics and outcomes of oral antibiotic treated pulmonary exacerbations in children with cystic fibrosis ... beta-lactam antibiotics: endorsed by ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3385040/

National Survey of Extended-Interval Aminoglycoside ... The Cystic Fibrosis Foundation recently deemed the use of extended-interval dosing (EID) of aminoglycosides acceptable for the treatment of cystic fibrosis ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9514759/

Impact of Patient-Specific Aminoglycoside Monitoring for ... Aminoglycosides are frequently used for empiric and definitive treatment of cystic fibrosis (CF) pulmonary exacerbations.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05548283

Study Details | NCT05548283 | Standardizing Treatments ... The purpose of this study is to look at pulmonary exacerbations in people with cystic fibrosis (CF) that need to be treated with antibiotics given through a ...

9. med.stanford.edu med.stanford.edu/content/dam/sm/bugsanddrugs/documents/antimicrobial-dosing-protocols/SHC-Aminoglycoside-Dosing-Guide.pdf

Stanford Health Care Aminoglycoside Dosing Guideline For patients with cystic fibrosis exacerbation the Cystic Fibrosis consensus guidelines recommend extended interval dosing with 10 mg/kg once daily. Exclusion ...