Optimal Drug Regimen for Lung Disease
(FORMaT Trial)
Recruiting in Palo Alto (17 mi)
+67 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: The University of Queensland
Disqualifiers: Pregnancy, Breastfeeding, Healthy volunteers, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.
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.
12345Is 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.
678910What 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.
1112131415Eligibility 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.
+1 more
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
+1 more
Trial 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
Participant Groups
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.
5Treatment groups
Experimental Treatment
Active Control
Group I: Intensive Therapy CExperimental Treatment7 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 BExperimental Treatment8 Interventions
Following Randomisation 1, Participants will receive inhaled amikacin (IA), IV tigecycline, IV cefoxitin/imipenem + oral azithromycin/oral clarithromycin AND clofazimine.
Group III: Consolidation BExperimental Treatment11 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 AActive Control10 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 AActive Control8 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).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The Hospital for Sick KidsToronto, Canada
St Michaels HospitalToronto, Canada
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Who Is Running the Clinical Trial?
The University of QueenslandLead Sponsor
Monash UniversityCollaborator
Hôpital CochinCollaborator
Cystic Fibrosis FoundationCollaborator
University of MelbourneCollaborator
South Australian Health and Medical Research InstituteCollaborator
Australian Government Department of Health and AgeingCollaborator
Griffith UniversityCollaborator
Children's Hospital FoundationCollaborator
Newcastle UniversityCollaborator
References
Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. [2015]Five 6-month antituberculosis regimens, allocated at random to patients with acid-fast bacilli in their sputum on microscopy, were studied. Four, given three times a week from the start, contained isoniazid and rifampicin together with (1) streptomycin, pyrazinamide, and ethambutol, (2) streptomycin and pyrazinamide, (3) streptomycin and ethambutol, or (4) pyrazinamide and ethambutol. The fifth was daily isoniazid, rifampicin, pyrazinamide, and ethambutol. All 833 patients with drug-sensitive strains of bacilli before treatment had a favourable bacteriological response during chemotherapy, and the bacteriological relapse rates during 12 months after stopping chemotherapy were 2% or less for all regimens except thrice-weekly isoniazid, rifampicin, streptomycin, and ethambutol (the only regimen without pyrazinamide), which had a relapse rate of 8%. The results were equally good for the 138 patients with bacilli resistant to isoniazid, streptomycin, or both drugs initially. The incidence of potentially serious toxicity was low. The daily regimen is relevant to programmes in which patients self-administer their drugs, and the 3 pyrazinamide-containing intermittent regimens are relevant to fully supervised outpatient programmes.
Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. [2018]No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p
Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. [2022]Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are generally thought to have high mortality rates. However, many cases can be treated with the right combination and rational use of available antituberculosis drugs. This Review describes the evidence available for each drug and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis. The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Among the first group (the oral first-line drugs) high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis. The second group is the fluoroquinolones, of which the first choice is high-dose levofloxacin. The third group are the injectable drugs, which should be used in the following order: capreomycin, kanamycin, then amikacin. The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid. The fifth group includes drugs that are not very effective or for which there are sparse clinical data. Drugs in group five should be used in the following order: clofazimine, amoxicillin with clavulanate, linezolid, carbapenems, thioacetazone, then clarithromycin.
[Efficiency of a new standard chemotherapy regimen in the treatment of patients with recurrent pulmonary tuberculosis]. [2006]The efficiency of conventional chemotherapy regimens was comparatively studied in 75 patients with recurrent pulmonary tuberculosis. In the patients with recurrent pulmonary tuberculosis, conventional chemotherapy regimen "2b" including isoniazid, rifampicin, pyrazinamide, ethambutol, fluoroquinolone (ofloxacin, ciprofloxacin, and levofloxacin), and canamycin (amikacin) versus conventional chemotherapy regimen "2a" including isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin could cease bacterial isolation after 3-month therapy, as evidenced by sputum microscopy (86.1 and 62.5%, respectively; p
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]Five 6-month antituberculosis regimens, allocated at random to patients with acid-fast bacilli in their sputum on microscopy, were studied. Four, given 3 times a week throughout, contained isoniazid and rifampicin together with 1. streptomycin, pyrazinamide and ethambutol, 2. streptomycin and pyrazinamide, but no ethambutol, 3. streptomycin and ethambutol, but no pyrazinamide, 4. pyrazinamide and ethambutol, but no streptomycin. The fifth was a daily regimen of isoniazid, rifampicin, pyrazinamide and ethambutol. All 833 patients with drug-sensitive strains of tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy, and the bacteriological relapse rate during 18 months after stopping chemotherapy was 1% for the three-times-weekly regimens containing streptomycin and pyrazinamide in addition to isoniazid and rifampicin (regimens 1 and 2, above) and for the daily regimen, 2% for the regimen of isoniazid, rifampicin, pyrazinamide and ethambutol three times a week (regimen 4), but 8% for the only regimen which did not contain pyrazinamide (regimen 3). The results achieved by the 4 pyrazinamide regimens were practically as good for the 110 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment as they were for the patients with drug-sensitive strains.
Comparison of empiric aztreonam and aminoglycoside regimens in the treatment of serious gram-negative lower respiratory infections. [2022]An open-label, controlled, randomized study was performed to assess the efficacy and safety of combination regimens using either aztreonam or an aminoglycoside control regimen as empiric therapy for suspected aerobic gram-negative bacillary pneumonia or purulent bronchitis. Eighty-four patients, 42 in each arm of the study, were randomly assigned to one of two treatment regimens. The combination aztreonam regimen included aztreonam, 2 gm every 8 hours (q8h), plus either clindamycin, 600 to 900 mg q8h, or nafcillin, 1.5 gm to 2 gm every 6 hours (q6h). The control regimen was one of the following depending on the combination therapy that was designated standard at each of the three study institutions: amikacin, 5 mg/kg q8h, plus cefazolin, 1 gm q8h; amikacin, 500 mg every 12 hours plus mezlocillin, 4 gm q6h; or kinetically dosed tobramycin plus ticarcillin, 3 gm to 4 gm q4h. The two groups were well matched in terms of demographics and clinical characteristics. Among the 84 patients, organisms from the Enterobacteriaceae family accounted for the largest proportion of isolates (44%) including Escherichia coli (13%), Klebsiella species (14%), and Serratia species (9%). Other commonly identified organisms were Pseudomonas aeruginosa (19%), Haemophilus influenzae (15%), Streptococcus pneumoniae (12%), and Staphylococcus aureus (8%). Results of this trial included clinical response rates of 83% in both groups (P = 0.951) and a microbiologic cure rate of 75% in the aztreonam group and 63% in the control group (P = 0.291). In the 59 patients with documented aerobic gram-negative pneumonia, microbiologic eradication rates were 72% in the aztreonam group versus 57% in the control group (P = 0.359). Duration of treatment tended to be shorter in the aztreonam group than in the control group, with a median 10 days of therapy versus 12 days of therapy (P = 0.095), respectively. In addition, the percentage of patients requiring nonstudy antimicrobial agents tended to be lower in the aztreonam group than the control group, involving 21% of patients in the aztreonam group compared with 36% of patients in the control group (P = 0.086). All regimens were well tolerated, and no patient was withdrawn because of adverse reactions to the study medications. Two patients, both in the control group, required dose reduction, which was necessitated by possible aminoglycoside-induced nephrotoxicity. This trial shows that aztreonam is an effective agent with an excellent safety profile when used in combination regimens for the empiric treatment of pneumonia. A well-controlled trial is needed to verify the trend toward shorter hospital stays and a reduced need for additional antimicrobial agents seen with the aztreonam regimen when compared with those receiving aminoglycoside-combination regimens.
Safety considerations of current drug treatment strategies for nosocomial pneumonia. [2021]Introduction: Nosocomial pneumonia unfortunately remains a frequent event for which appropriate antibiotic treatment is central to improving outcomes. Physicians must choose an early and appropriate empirical treatment, basing their decision on the safety profile and possible side effects. Areas covered: In this review, we analyzed the safety profiles of the most common antimicrobials for treating nosocomial pneumonia. Beta-lactams are used most often for these infections, with a high percentage (6% to 25%) of patients reporting allergy or hypersensitivity reactions; however, exhaustive evaluation is key because it seems possible to de-label as many as 90% by proper assessment. Combinations including a beta-lactam are recommended in patients with risk factors for drug-resistant microorganisms and septic shock. Although aminoglycosides are safe for 3-5 days of therapy, renal function should be monitored. Fluoroquinolones must also be used with care given the risk of collagen degradation and cardiovascular events, mainly aneurysm or aortic dissection. Linezolid or vancomycin are both viable for the treatment of methicillin-resistant Staphylococcus aureus, but linezolid seems to be the superior option. Antibiotic stewardships programs must be developed for each center. Expert opinion: Choosing the most appropriate antimicrobial based on information from national and international guidelines, local microbiology data, and stewardship programs may reduce the use of broad-spectrum antibiotics. Daily assessment for the emergence of adverse events related to antimicrobial use is essential.
Ceftazidime-Avibactam-Based Versus Tigecycline-Based Regimen for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae-Induced Pneumonia in Critically Ill Patients. [2021]The aim of the present study was to assess the safety profile and outcomes of a ceftazidime-avibactam (CAZ-AVI)-based regimen and compare them with those of a tigecycline (TGC)-based regimen in intensive care unit (ICU) for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP), which is classified into hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).
New antibiotics for Gram-negative pneumonia. [2023]Pneumonia is frequently encountered in clinical practice, and Gram-negative bacilli constitute a significant proportion of its aetiology, especially when it is acquired in a hospital setting. With the alarming global rise in multidrug resistance in Gram-negative bacilli, antibiotic therapy for treating patients with pneumonia is challenging and must be guided by in vitro susceptibility results. In this review, we provide an overview of antibiotics newly approved for the treatment of pneumonia caused by Gram-negative bacilli. Ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam have potent activity against some of the carbapenem-resistant Enterobacterales, especially Klebsiella pneumoniae carbapenemase producers. Several novel antibiotics have potent activity against multidrug-resistant Pseudomonas aeruginosa, such as ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relabactam and cefiderocol. Cefiderocol may also play an important role in the management of pneumonia caused by Acinetobacter baumannii, along with plazomicin and eravacycline.
Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. [2019]We initiated a multidrug trial that included high-dose rifabutin for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. Twenty-six patients received rifabutin (600 mg/d) in combination with ethambutol, streptomycin, and either clarithromycin (500 mg b.i.d.; 15 patients) or azithromycin (600 mg/d; 11 patients). Rifabutin-related adverse events occurred in 77% of patients. Fifty-eight percent of patients required a dosage adjustment or discontinuance of rifabutin therapy. The most common adverse event was a reduction in the mean total white blood cell (WBC) count, which decreased from 8,600 +/- 2,800/mm3 before treatment to 4,500 +/- 2,100/mm3 during treatment (P = .0001). Although all patients had some decrease in WBC count, only three patients (12%) required a dosage adjustment for this reason. Other common adverse events included gastrointestinal symptoms (nausea, vomiting, or diarrhea; 42%) and abnormal liver enzyme levels (12%). Eight of 11 patients (73%) with gastrointestinal symptoms, including one patient with abnormal liver enzyme levels, required a rifabutin-dosage adjustment. The most severe adverse events, always requiring an adjustment of therapy, were a diffuse polyarthralgia syndrome (19%) and anterior uveitis (8%). The latter toxicity has previously been reported to occur only in patients with AIDS and was seen only in patients who also were receiving clarithromycin. On the basis of the current findings, we recommend that rifabutin be used at a dose of 300 mg/d in multidrug regimens that include a macrolide for treatment of MAC lung disease.
Early phase studies with paclitaxel/low-dose carboplatin in patients with solid tumors. [2015]In preparation for the design of phase II studies in lung cancer, low-dose carboplatin, fixed at a target area under the concentration-time curve (AUC) of 4.0 or 4.5 mg x min/mL, has been combined with escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in a series of studies to establish the maximum tolerated dose of the combination. In patients who had received prior chemotherapy, the maximum tolerated paclitaxel dose was 135 mg/m2 (carboplatin target AUC 4.0); the dose-limiting toxicity was febrile neutropenia. Without granulocyte colony-stimulating factor support in chemotherapy-naive patients (carboplatin target AUC 4.5), and with granulocyte colony-stimulating factor in chemotherapy-pretreated patients, the current paclitaxel dose is 290 mg/m2. The maximum tolerated dose has not been defined. In a study in which paclitaxel was given by 1-hour infusion with carboplatin (target AUC 4.5), a 205 mg/m2 dose was poorly tolerated. No evidence of pharmacokinetic interactions between paclitaxel and carboplatin was found. Twenty-one evaluable patients with lung cancer have been treated to date. There have been two partial responses, one minor response, and 10 patients with stable disease at paclitaxel doses of 100 to 270 mg/m2.
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]The optimal chemotherapy regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remains unknown. Therefore, in this study, we investigated the real-world efficacy and safety of carboplatin (CBDCA) plus nab-paclitaxel (nab-PTX) as a first-line regimen for NSCLC patients with ILD.
First- and second-line therapy for advanced nonsmall cell lung cancer. [2018]The objectives for the treatment of advanced nonsmall cell lung cancer are palliative and include improvement of survival, symptom control, quality of life and cost. The level of evidence of these benefits is based on multiple randomised trials and meta-analyses. Cisplatin-based chemotherapy with one of the regimens shown to be effective should be preferred. Carboplatin may be substituted for cisplatin if medical contraindications exist. Nonplatinum-based regimens are indicated as first-line treatment for advanced nonsmall cell lung cancer in patients for whom platinum-based chemotherapy is contraindicated. Single drug chemotherapy may be considered in patients with poor performance status. The choice of the active drugs depends on the patient's medical condition. There is no conclusive evidence that high doses of cisplatin (100-120 mg.m(-2)) provide better results than standard lower doses (50-60 mg.m(-2)) in terms of survival. The optimal duration of chemotherapy is poorly documented in advanced nonsmall cell lung cancer. A minimum of four to six cycles is advised in responding patients. Second-line chemotherapy is now accepted as a standard and should be offered to patients with good performance status and failing platinum-based first-line chemotherapy. Evidence is in favour of docetaxel and in the case of adenocarcinoma and adequate renal function, pemetrexed is recommended.
A phase I study of carboplatin and paclitaxel in non-small cell lung cancer: a University of Colorado Cancer Center study. [2015]This phase I study was designed to determine the maximal tolerated doses of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), as well as the safety and efficacy of these agents, in patients with advanced, nonresectable stages IIIB and IV non-small cell lung cancer. Paclitaxel was given as a 3-hour intravenous infusion followed by a 30-minute infusion of carboplatin. Patients were assigned to one of seven treatment groups in which paclitaxel and carboplatin were given in doses ranging from 135 to 225 mg/m2 and from 250 to 400 mg/m2, respectively. Overall, the two-drug combination has been well tolerated. The major dose-limiting toxicity has not been reached but will likely be neutropenia. There appears to be a dose-response relationship: two partial responses (12%) were observed among 17 patients assigned to the lower-dose groups, whereas six (50%) of 12 evaluable patients in the higher-dose groups achieved partial responses. The maximal tolerated doses have not been reached yet, and will be at least 200 mg/m2 for paclitaxel and 400 mg/m2 for carboplatin.
[Stage IV NSCLC. Place of chemotherapy]. [2013]Cisplatin based chemotherapy for stage IV non small cell lung cancer patients with good performance status is associated with improved survival and better symptom control. Chemotherapeutic regimens should include cisplatin with at least one other active drugs as ifosfamide, mitomycin C, vindesine, vinblastine (second generation drugs) or gemcitabine, paclitaxel, docetaxel, irinotecan and/or vinorelbine (third generation drugs). If the other drug is a new one, there is no evidence for the addition of a third agent. Four to six cycles is proposed in responding patients. Non-platinum-based regimens may be used in cases where platinum-based chemotherapy is contra-indicated. Single agent chemotherapy may be considered in patients with poor performance status.