Merck Tests First Dual PDE3/4 Exacerbation Claim With No Clean Precedent

Unresolved optimal dose, route and duration: Existing literature suggests low-dose oral corticosteroids are as efficacious as high-dose, intravenous regimens, and shorter durations are as efficacious as traditional durations, with low-dose defined as initial dose 30-80 mg prednisone equivalent/day and high-dose as initial dose ≥80 mg prednisone equivalent/day, yet guidelines continue to rely on studies that excluded patients requiring ventilatory support.

Limited benefit in ICU and ventilated patients: Subgroup analysis showed a non-significant difference of effect in ICU patients (OR = 1.34, 95% CI = 0.61 to 2.95; p = 0.46) whereas in non-ICU patients the effect was significant (OR = 1.87, 95% CI = 1.18 to 2.99; p = 0.01), with no difference whether patients were ventilated with tracheal intubation or non-invasive ventilation, and in ventilated patients ICU mortality was not significantly decreased (OR = 1.09; 95% CI 0.62-1.91; p = 0.78) with no significant difference for duration of ventilation, length of ICU stay, or NIV failure (OR = 1.17; 95% CI 0.83-1.67; p = 0.37).

Significant safety burden without mortality reduction: Overall there was no difference in mortality rate between steroid-treated group and controls (OR = 1.07, 95% CI = 0.67 to 1.71; p = 0.77), while rate of adverse events increased significantly (OR = 2.36, 95% CI = 1.67 to 3.33; p < 0.0001), including increased hyperglycemia risk and hyperglycemic episodes requiring initiation or alteration of insulin therapy (OR = 2.96, 95% CI = 1.69 to 5; p < 0.0001), with new/worsening hyperglycemia in 96 (50.5%) and hypertension in 13 (6.8%) in severe AECOPD.

Poor guideline concordance in practice: Institutions continue to use higher doses and longer durations, with 130 of 137 patients (94.9%) receiving doses exceeding GOLD recommendations at an average daily dose of 147.5 mg of prednisone equivalents, and only 4 patients (2.1%) having both appropriate dose of prednisone 40 mg (or equivalent) for 5 days and duration.

Persistent treatment failure, relapse and readmission: Blood eosinophilia ≥2% was a risk factor for relapse (HR = 2.351; 95% CI 1.335-4.139), 30-day readmission occurred in 46 (24.2%) and 90-day readmission in 78 (41.1%), with odds ratio for readmission of 2.11 (95% CI, 1.07-4.15, P = .03) for congestive heart failure, 3.30 (95% CI, 1.05-9.75, P = .04) for arrhythmia, and 1.99 (95% CI, 1.04-3.81, P = .04) for LTOT users.

Heterogeneity and antibiotic stewardship gaps: Limitations are represented by heterogeneity in study populations, lack of standardized eosinophil thresholds, and sparse data in critically ill or comorbid patients, while antibiotic use induces risk of Clostridium difficile infection, diarrhea, and antibiotic resistance, with identification of risk factors for antibiotic treatment failure urgently needed.

ALIENTO and ARNASA were randomized, double-blind, placebo-controlled trials with similar designs in participants with COPD, a history of frequent exacerbations, and who were current/former smokers, irrespective of blood eosinophil count and chronic bronchitis. Participants were randomized 1:1:1 to astegolimab 476 mg every 2 weeks, every 4 weeks or placebo for 52 weeks, plus optimized maintenance therapy, with 2682 participants included in the pooled intent-to-treat population. The primary endpoint was annualized rate of moderate/severe exacerbations, with secondary endpoints including annualized rate of severe exacerbations.

Two replicate, randomized, double-blind, placebo-controlled, parallel-group studies of oral roflumilast 500 μg or placebo once daily for 52 weeks were combined in a post-hoc, pooled analysis including 2686 randomized patients. The REACT study was a 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial enrolling 1945 eligible participants randomized to roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination, with 973 to the roflumilast group and 972 to the placebo group. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year, and the primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year.

The RE(2)SPOND study was a Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial in which participants were randomized 1:1 stratified by long-acting muscarinic antagonist use to receive roflumilast or placebo, plus ICS/LABA fixed-dose combination, for 52 weeks, with 2,354 participants randomized. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate-severe exacerbations within 12 months, and were receiving ICS/LABA fixed-dose combination for ≥3 months. The primary efficacy measure is the rate of moderate or severe COPD exacerbations per participant per year, with secondary efficacy outcomes including mean change in prebronchodilator forced expiratory volume in 1 second over 52 weeks, rate of severe exacerbations, and rate of moderate, severe, or antibiotic-treated exacerbations.

A post-hoc analysis of a randomized, double-blinded, placebo-controlled parallel-group clinical trial evaluated 6-month treatment with ELOM-080 (3×300 mg) in patients with chronic bronchitis and concomitant COPD, of which 64 patients fulfilled the inclusion criteria for COPD with 35 on ELOM-080 and 29 on placebo. The primary outcome was the proportion of subjects with at least one exacerbation over the 6-month study period, with secondary outcomes including the total number of exacerbations and the proportion of acute exacerbations necessitating an antibiotic treatment, monthly evaluations of sputum and cough symptoms, and the general state of health.

A multicenter, multinational, randomized, double-blind study of two parallel treatment arms compared oral moxifloxacin 400 mg qd for 5 days with standard therapy with amoxicillin 500 mg tid for 7 days, clarithromycin 500 mg bid for 7 days, or cefuroxime-axetil 250 mg bid for 7 days in outpatients ≥45 years old with stable chronic bronchitis, smoking history of ≥20 pack-years, two or more acute exacerbations of chronic bronchitis in the previous year, and FEV1 <85% of predicted value, with 354 patients receiving moxifloxacin and 376 receiving standard therapy. The primary efficacy variable was clinical success 7 to 10 days after therapy, with secondary predefined end points of clinical cure, further antimicrobial use, time to next acute exacerbation of chronic bronchitis, and bacteriologic success.