The first-in-class oral selective phosphodiesterase 4 inhibitor (PDE4i), roflumilast, decreased the rate of exacerbations in 2 large simulated phase 3 trials of modeled data from patients with chronic obstructive pulmonary disease (COPD), according to a paper published in The Journal of Clinical Pharmacology. The reduction in the trial simulations, however, failed to reach statistical significance.
Alex Facius, PhD, from Takeda Pharmaceuticals International in Zurich, Switzerland, and colleagues constructed 2 dose-linked clinical trials (ClinicalTrials.gov identifier: NCT00297102 and NCT00297115) for the primary and secondary end points to identify the most appropriate patients to receive roflumilast. The primary end point was annualized COPD exacerbation rates and the secondary end point was change from baseline in forced expiratory volume in 1 second (FEV1).
The models were used to design the pivotal clinical phase 3 trials, which led to the approval of roflumilast. The models demonstrated that the severity of bronchitis, defined by cough-and-sputum scores, were solid predictors of exacerbation rates.
The simulation studies had similar end point values as the resulting pivotal studies. The FEV1 end point study model prediction (n=4592) was 48.88 mL (95% CI, 32.41-65.20 mL) and 16.73% (95% CI, 3.13%-28.45%) for the exacerbation count model (n=2414). In the pivotal trials, the FEV1 and exacerbation count end points were 48 mL (95% CI, 35-62 mL) and 17% (95% CI, 8%-25%), respectively.
Several key factors played a role in the trial outcomes. Patients who had chronic bronchitis benefited more than patients with emphysema. In both model studies, more than 65% of patients did not experience COPD exacerbations, diminishing the trial’s power. Exacerbation rates were higher in patients who used inhaled corticosteroids (ICS) before the trial and patients with high cough-and-sputum scores (1.7% per unit).
Some study limitations include patient criteria; approximately two-thirds of patients did not experience any exacerbations during the trial period, so the reduction in annual exacerbations was observed only in one-third of the population.
“Our models showed that disease severity and bronchitis, particularly the severity of bronchitis expressed in cough-and-sputum scores, were good predictors of exacerbation rate and elucidated a disease space where roflumilast had an effect,” reported the researchers. “In addition, the previous use of ICS was a good predictor of exacerbation rate.”
The researchers report financial relationships with AstraZeneca and Takeda Pharmaceuticals.
Facius A, Krause A, Claret L, Bruno R, Lahu G. Modeling and simulation of pivotal clinical trials using linked models for multiple endpoints in chronic obstructive pulmonary disease with roflumilast. [published online April 17, 2017]. J Clin Pharmacol. doi:10.1002/jcph.885