Diabetes Mellitus and Tuberculosis
Amikacin Safe, Improves Respiratory Symptoms In M. Avium Complex Lung ...
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Key takeaways:SAN DIEGO — Amikacin for 6 months improved respiratory symptoms in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease, according to a presentation at the American Thoracic Society International Conference.
Healio previously reported on the findings from the phase 3 ARISE trial investigating the efficacy of amikacin liposome inhalation suspension (ALIS; Arikayce, Insmed) for treatment of MAC lung disease among newly diagnosed patients in September 2023.
Data were derived from Daley CL. Scientific symposium. B13. Breaking news: Clinical trial results in pulmonary medicine. Presented at: American Thoracic Society International Conference; May 17-22, 2024; San Diego.In this randomized, double-blind, multi-region trial, researchers assessed 99 adults with newly diagnosed or recurrent MAC lung disease who had not started antibiotics to validate the quality of life-bronchiectasis (QOL-B) respiratory domain, a patient-reported outcome instrument, as well as determine how respiratory symptoms and microbiologic outcomes differ between those receiving once-daily ALIS and those receiving once-daily placebo for 6 months.
"There is no currently validated fit-for-purpose [patient-reported outcome] instrument for people with MAC lung disease," Charles L. Daley, MD, chief of the division of mycobacterial and respiratory infections and professor in the department of medicine at National Jewish Health, said during his presentation.
"[The QOL-B respiratory domain] has been validated in those with non-CF bronchiectasis but not in those with MAC," he added.
Notably, after the 6-month treatment period, researchers waited 1 month to evaluate QOL-B patient-reported outcomes.
In terms of microbiologic outcomes, researchers cultured two sputum samples in agar and broth from each patient each month and looked for culture conversion, or "no MAC growth on agar and broth media in all sputum cultures at two consecutive visits," Daley said.
Of the total cohort, 48 patients (median age, 71.5 years; 66.7% women; 85.4% white; 72.9% first diagnosis of MAC) received ALIS plus macrolide-based background regimen, and 51 patients (median age, 67 years; 88.2% women; 76.5% white; 72.5% first diagnosis of MAC) received placebo plus macrolide-based background regimen.
At baseline, both groups had a mean QOL-B respiratory domain score within the 60-to-70-point range out of 100 (ALIS, 63.04 points vs. Placebo, 66.9 points). With this tool, Daley noted that a higher score signaled fewer respiratory symptoms and better health-related quality of life.
Validation, respiratory symptomsUsing the Patient Global Impression of Severity-Respiratory (PGI-S R) as an anchor during validation of the QOL-B respiratory domain, researchers observed that the QOL-B respiratory domain demonstrated both known-groups validity and concurrent validity.
When researchers compared the QOL-B respiratory domain least-squares means estimate with the number of patients that fell into the five PGI-S R severity groups, the ordering went in "the same direction," showcasing known-groups validity, Daley said.
Researchers observed concurrent validity by placing the QOL-B respiratory domain against four other respiratory and fatigue patient-reported outcome scales and comparing direction and level of correlation.
"We looked to see, did they move in the right direction in the right amounts?" Daley said. "It turns out, they do."
Moving forward, researchers utilized empirical cumulative distribution function curves and determined that an additional 14.8 points was the estimated clinically meaningful within-patient change threshold for the QOL-B respiratory domain score.
According to this threshold for meaningful change, a greater proportion of patients receiving ALIS vs. Placebo achieved improvement (43.8% vs. 33.3%).
In an adjusted analysis, the ALIS group also had a larger change in QOL-B respiratory domain from baseline to month 7 vs. The placebo group (least-squares mean, 12.24 vs. 7.76).
"The findings demonstrate that the QOL-B respiratory domain has reliability, validity and responsiveness for assessing symptoms in adults with newly diagnosed or recurrent MAC lung disease," Daley said.
"This looks like an instrument that can be used in clinical trials," he added.
Microbiologic outcomes, safetyWhen evaluating culture conversion rates at month 6 and month 7, researchers observed higher rates in the ALIS group vs. The placebo group during both assessments (month 6, 80.6% vs. 63.9%; month 7, 78.8% vs. 47.1%).
Daley further highlighted that patients receiving ALIS had a faster median time to first culture conversion compared with patients receiving placebo (1 month vs. 2 months).
"[In the ALIS arm,] the conversion is occurring at a higher frequency and sooner," he said.
Among those who met the study's criteria for culture conversion, fewer patients in the ALIS group vs. The placebo group had recurrence of MAC (12.8% vs. 50%).
Daley added, "Fortunately, no patients in either arm developed macrolide or amikacin resistance during the course of the trial."
With regard to safety, patients receiving ALIS did not report any new or unexpected safety signals, according to Daley.
The majority of patients in each group experienced a treatment-emergent adverse event (ALIS, 91.7%; placebo, 80.4%). For those receiving ALIS, dysphonia occurred the most often (41.7%), followed by cough (27.1%), diarrhea (27.1%) and COVID-19 (12.5%).
Seven serious treatment-emergent adverse events (n =7) occurred in the ALIS group, which was comparable to the eight serious treatment-emergent adverse events (n = 3) observed in the placebo group.
For adverse events that fell under the category of ototoxicity, such as dizziness, tinnitus and vertigo, Daley said both treatment groups had low rates and did not differ from each other much.
"The next thing we're waiting for is a 15-month confirmatory study that is ongoing now," Daley said. "This is evaluating the efficacy and safety of ALIS in the same patient population. The difference is this is a 12-month treatment and then evaluation 3 months off-treatment, so double the length of ARISE."
Sources/DisclosuresCollapse Source: Daley CL. Scientific symposium. B13. Breaking news: Clinical trial results in pulmonary medicine. Presented at: American Thoracic Society International Conference; May 17-22, 2024; San Diego.Disclosures: Daley reports receiving grant support, advisory board fees and consulting fees from Insmed Incorporated; receiving grant support from AN2 Therapeutics, Bugworks, Paratek Pharmaceuticals and Juvabis; having advisory board work with AN Therapeutics, AstraZeneca, Cepheid, Hyfe, ManKind, Matinas Biopharma, NobHill, Spero Therapeutics and Zambon; consulting with Genentech and Pfizer; and having data monitoring committee work with Otsuka Pharmaceutical, Eli Lilly and Company, and Bill & Melinda Gates Foundation.
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Late-Breaking Data From Clinical Trials Show Promise For The Future Of ...
Study authors shared late-breaking data in a session on clinical trial results in pulmonary medicine at the American Thoracic Society 2024 International Conference.
Investigators shared late-breaking data from 3 studies in a session titled "Breaking News: Clinical Trial Results in Pulmonary Medicine" at the American Thoracic Society (ATS) 2024 International Conference.
Newly presented trial data reveal evidence on the efficacy of various treatments for COPD.Image Credit: © kimly - stock.Adobe.Com
ARISE Study Highlights Efficacy and Safety of ALIS in Treating Mycobacterium Avium Complex Lung Disease
According to presenter Charles L. Daley, MD, from National Jewish Health and the University of Colorado School of Medicine, the ARISE study has provided promising new data on the treatment of Mycobacterium avium complex lung disease (MACLD), a major cause of nontuberculous mycobacterial lung infections. The condition, often exacerbating chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and bronchiectasis, is associated with significant symptom burdens and remains challenging to treat effectively.1
Despite guideline-based treatments, many patients fail to achieve successful outcomes, highlighting the need for improved therapeutic strategies and robust patient-reported outcome (PRO) instruments. The ARISE study aimed to validate the Quality of Life-Bronchiectasis Respiratory Domain (QOL-B RD) and Patient-Reported Outcomes Measurement Information System-Fatigue (PROMIS-F) tools, assessing their reliability, validity, and responsiveness in capturing symptom improvements in patients with MACLD. Additionally, the study evaluated the microbiologic outcomes and safety of treatment regimens.
ARISE enrolled adults with noncavitary MACLD who had not yet received antibiotic therapy for their current infection. Participants were randomized 1:1 to receive either 590 mg of amikacin liposome inhalation suspension (ALIS) or a control (empty liposome) along with 250 mg of azithromycin and 15 mg/kg of ethambutol daily for 6 months, followed by 1 month off treatment.
The primary end points focused on the psychometric properties of the QOL-B RD and PROMIS-F instruments, including cross-sectional properties, test-retest reliability, and meaningful within-patient change using anchor-based methods and empirical cumulative distribution function (eCDF) plots. Secondary end points included culture conversion rates, time to culture conversion, time to first negative culture, and safety assessments.
The study enrolled 99 patients (48 in the ALIS arm and 51 in the comparator arm) with a median age of 69 years. The majority were female (77.8%) and White (80.8%). For 72.7% of patients, this was their first MAC lung infection. The infections were predominantly caused by M avium (32.3%) and M intracellulare (43.4%).
The QOL-B RD and PROMIS-F instruments demonstrated strong reliability and validity in this patient population. The eCDF plots showed clear separation in symptom scores between patients reporting improvements, defined as 1 or more category changes in Patient Global Impression of Severity, and those reporting no change, confirming the responsiveness of these PROs.
By month 6, the culture conversion rate was significantly higher in the ALIS arm (80.6%) compared with the comparator arm (63.9%). This trend continued at month 7, a month post treatment, with conversion rates of 78.8% for ALIS vs 47.1% for the comparator (P = .0010). Additionally, patients in the ALIS arm achieved their first negative culture-defining conversion faster, with 74.3% achieving this by month 1, compared with 46.7% in the comparator arm. The median time to first negative culture was 1.0 month for ALIS and 2.0 months for the comparator.
"Among those who have been converted by month 6, the first negative culture that defined that was observed in 1 month and 74% of those on ALIS vs only about 47% in the comparator arm in patients in the ALESTORM version about a month earlier, and there was no resistance that developed, no new safety signal," Daley said in the presentation.
Common treatment-emergent adverse events in the ALIS arm included dysphonia and cough, but no serious adverse events were related to ALIS, and no deaths were reported.
"So the next thing we're waiting for is this 15-month confirmatory study that is ongoing now," he explained. "This is evaluating the efficacy and safety of ALIS in the same patient population. The difference is this is 12 months of treatment, and then evaluating 3 months off treatment."
Tezepelumab Shows Promise in Reducing COPD Exacerbations in Phase 2a COURSE Study
Late-breaking data on the potential benefits of tezepelumab in treating COPD were shared by Dave Singh, MD, of Manchester University NHS Foundation Trust, University of Manchester. The researchers investigated tezepelumab efficacy and safety in patients with moderate to very severe COPD, a population that continues to suffer from significant exacerbations despite standard therapy.2
TSLP is an epithelial cytokine involved in initiating and perpetuating chronic airway inflammation, making it a promising target for COPD treatment. The COURSE study aimed to evaluate whether tezepelumab could reduce COPD exacerbations in patients receiving triple inhaled maintenance therapy—comprising inhaled corticosteroids (ICS), long-acting β-agonists (LABA), and long-acting muscarinic antagonists (LAMA)—and who had a history of frequent exacerbations.
This double-blind study enrolled 333 patients aged 40 to 80 years, randomized 1:1 to receive either tezepelumab 420 mg or placebo subcutaneously every 4 weeks for up to 52 weeks. Key eligibility criteria included at least 2 moderate or severe COPD exacerbations in the previous year and ongoing triple inhaled maintenance therapy. Exclusion criteria included a history of asthma or other significant pulmonary diseases, with no exclusions based on baseline blood eosinophil count (BEC).
The primary end point was the annualized rate of moderate or severe COPD exacerbations over 52 weeks. Secondary end points included the rate of severe exacerbations, changes in prebronchodilator forced expiratory volume in one second (FEV1), St. George's Respiratory Questionnaire (SGRQ) total score, and COPD Assessment Test (CAT) score from baseline to week 52. Safety was also assessed.
Primary end point:
Secondary end points:
Adverse events and serious adverse events were balanced between the tezepelumab and placebo groups. No new safety signals were identified, supporting tezepelumab's favorable safety profile.
"In this phase 2 study, where we were looking for an effect on moderate to severe exacerbations, there was a numerical reduction of 17% which did not reach statistical significance," Singh said in his presentation. "We similarly saw numerical reductions in severe exacerbations, improvements in lung function and quality of life. As a preplanned secondary analysis, we saw that the benefit of tezepelumab increased with iron, blood eosinophil counts, and the safety and tolerability in this phase 2 study were consistent with what we know about the drug."
Dupilumab Significantly Reduces Exacerbations in COPD Patients with Type 2 Inflammation: Findings From the NOTUS Trial
Surya Bhatt, MD, an associate professor in the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, shared late-breaking data from the phase 3 NOTUS trial, which provided compelling evidence that dupilumab, a fully human monoclonal antibody, significantly reduces exacerbation rates and improves lung function in patients with COPD with type 2 inflammation.3
Type 2 inflammation in COPD is driven by cytokines such as IL-4 and IL-13. Dupilumab, which blocks the shared receptor component of IL-4 and IL-13, has shown efficacy in reducing exacerbations in COPD with type 2 inflammation, as evidenced by the phase 3 BOREAS trial. The NOTUS trial aimed to replicate and further evaluate the efficacy and safety of dupilumab in this patient population.
The NOTUS trial was a 52-week, phase 3, randomized, double-blind, placebo-controlled study. Participants were assigned to receive either subcutaneous dupilumab 300 mg every 2 weeks or placebo, as an add-on to their existing therapy. Eligible patients had moderate to severe COPD with type 2 inflammation, indicated by BEC of at least 300 cells/μL at screening. They were also on triple inhaled maintenance therapy ICS, LABA, and LAMA, or LABA/LAMA if ICS was contraindicated. Key inclusion criteria included:
Exclusion criteria included a current diagnosis or history of asthma or other significant pulmonary diseases.
A total of 935 participants were randomized, with 465 receiving placebo and 470 receiving dupilumab. The primary end point analysis, conducted with an interim data cut (92% information fraction), revealed the following key results.
Primary end point:
Secondary end points:
Safety:
"Dupilumab significantly reduced exacerbations, just like they saw in the BOREAS trial, improved lung function and quality of life as well as symptoms in patients with COPD and type 2 inflammation," Bhatt said in his presentation. "And the safety was consistent with its known safety profile and it's already approved for 6 to 7 indications and is being used in clinical practice. And we saw exactly the same kind of safety profile infrastructures."
References
1. Daley CL, Chalmers JD, Flume PA, et al. Microbiologic outcomes from a randomized, double-blind trial of amikacin liposome inhalation suspension in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease: the ARISE study. Am J Respir Crit Care Med. 2024;209:A1033.
2. Singh D, Bafadhel M, Brightling CE, Rabe KF, Han MK, Bhutani M; COURSE study investigators. Tezepelumab in adults with moderate to very severe chronic obstructive pulmonary disease (COPD): efficacy and safety from the phase 2a COURSE study. Am J Respir Crit Care Med. 2024;209:A2782.
3. Bhatt SP, Rabe KF, Hanania NA, et al. Efficacy and safety of dupilumab in patients with moderate-to-severe COPD and type 2 inflammation: phase 3 NOTUS trial. Am J Respir Crit Care Med. 2024;209:A2996.
BACES Score Linked To Clinical Treatment Outcomes In M. Avium Complex ...
October 09, 2024
2 min read
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BOSTON — BACES score in Mycobacterium avium complex lung disease is linked to clinical treatment outcomes and may be able to predict clinical improvement, according to data presented at the CHEST Annual Meeting.
Factors involved in the BACES score, which is used to predict all-cause mortality in non-tuberculosis mycobacteria lung disease, include a BMI less than 18.5 kg/m2, age 65 years or older, cavity presence, elevated erythrocyte sedimentation rate and male sex, according to researchers.
BACES score in Mycobacterium avium complex lung disease is linked to clinical treatment outcomes and may be able to predict clinical improvement, according to presented data. Image: Adobe Stock"Our study findings are important, but they would need larger and ideally prospective cohort studies to validate," Patricio Escalante, MD, MSc, professor of medicine at Mayo Clinic Rochester, told Healio. "If these study results hold true with additional studies, then the BACES score can help clinicians to make important treatment decisions with their patients to start antibiotics or more intensive treatments earlier rather that carefully wait with active clinical and radiological surveillance to determine individual disease progression for these patients."
In this retrospective cohort study, Escalante and colleagues assessed 86 U.S. Patients (median age, 69.1 years; BMI, 22 kg/m2) with non-cavitary M. Avium complex lung disease (MAC-LD) to find out the impact of BACES scores on three types of treatment outcomes: clinical, radiological and microbiological.
"The BACES score was validated to predict mortality in an Asian cohort of patients with non-tuberculous mycobacterial lung disease but not to determine risk of disease progression and treatment response, which are different and are also an important disease characteristic that can be challenging to predict for clinicians and patients," Escalante told Healio.
Within the study population, more patients had received treatment with antimicrobials vs. With a non-antimicrobial approach over 2 years (53 patients vs. 33 patients). None of the patients had significant cavitary disease, according to researchers.
Patients with a BACES score of 1 had the highest rate of clinical improvement/stability at 100%, followed by patients with a BACES score of 0 (90%), a BACES score of 2 (82.6%) and a BACES score of 3 (40%). The link between BACES score and this rate was significant (P < .001), according to the presentation.
In terms of overall clinical-radiological improvement-stability response rates, researchers again observed the highest rate in the group with a score of 1 (100%). Those with a score of 0 had the second highest response rate at 90%, followed by a score of 2 (81.8%) and a score of 3 (40%). Significance was also found between BACES score and this rate (P < .001).
"We found that this BACES score [in addition to predicting mortality] can also be associated with clinical treatment response but in a cohort of patients with mostly non-cavitary lung disease in our region in the United States," Escalante told Healio.
Unlike above, the link between BACES score and worsening radiological response rates was not significant.
Additionally, significance was not reported between BACES score and the sputum culture persistence rate. Patients with BACES scores of 0, 1 or 2 had similar rates (21.1% vs. 26.7% vs. 29.4%), according to researchers.
"We envision that a future study will be prospective to reduce selection bias and include not only the BACES score but also other promising prognostic parameters and/or novel biomarkers to accurately determine individual disease trajectories and help to make appropriate shared treatment decisions for these difficult-to-treat chronic lung infections," Escalante told Healio.
"We are hopeful that ongoing studies in the U.S. And abroad, including the one we are conducting at our institution sites in collaboration with our research partners from Purdue University and other institutions, will help us to better understand the main factors that drive disease progression in these patients," Escalante added.
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