A subgroup analysis of the TONADO studies (ClinicalTrials.gov Identifiers: NCT01431274; NCT01431287) published in the International Journal of COPD demonstrated that combination therapy with tiotropium/olodaterol was comparable to either tiotropium or olodaterol monotherapy in terms of safety and tolerability regardless of the level of renal impairment, in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).
More than half of the patients in the TONADO studies had mild to severe renal impairment and/or a high level of pre-existing cardiovascular morbidity.
Although olodaterol is primarily metabolized by the liver and its metabolites are excreted in feces, tiotropium is mainly eliminated by the kidneys, and increases in plasma concentrations have been observed in patients with moderate to severe renal impairment.
Craig LaForce, MD, of NC Clinical Research in Raleigh, North Carolina, and colleagues, performed a subgroup analysis of two double-blind, randomized, parallel-group, 52-week, phase 3 studies that included 3041 patients to determine the safety and tolerability of a fixed-dose combination of olodaterol and tiotropium compared with either medication alone.
There was a high degree of comorbidity in this patient population: 43.8% had mild, 13.3% had moderate, and 0.2% had severe renal impairment; 23.4% had a history of cardiac disorder; 45.6% had hypertension; and 13.3% had glucose metabolism disorders, including diabetes. Renal impairment was evenly distributed across all treatment groups.
Adverse events (AEs) were pooled from both studies. When the researchers analyzed safety data according to renal impairment category, the percentage of patients experiencing an AE was comparable with the results of the TONADO studies, in which 74.4% of patients experienced one or more AE. In participants without renal impairment, AEs occurred in 75.1% of patients treated with olodaterol, 70.8% treated with tiotropoim, and 72.0% treated with combination tiotropium/olodaterol, and in 75.7%, 74.0%, and 73.3% of patients with mild impairment, respectively. In individuals with moderate renal impairment, AEs occurred in 84.3%, 79.5%, and 79.7%, respectively.
The researchers found no notable effect of renal impairment on the proportion of patients with an AE, or any differences between either monotherapy or combination therapy. Of note, no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects was observed with increasing severity of renal impairment.
The small number of patients (n=5) with severe renal impairment at baseline limited the researchers’ ability to determine the AE rate in the 3 different treatment groups. Creatinine clearance (CLcr) was estimated at baseline and not repeated during follow-up, which prevented the tracking of renal function changes during the course of the trial.
Nevertheless, the researchers observed no safety signals for tiotropium/olodaterol in patients with COPD and varying levels of renal impairment as measured by CLcr. They concluded that the combination therapy is as safe and tolerable as its individual components.
Disclosures: Several researchers report financial relationships with the following pharmaceutical companies: AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Roche, among others.
LaForce C, Derom E, Bothner U, Kloer IM, Trampisch M, Buhl R. Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies. Int J Chron Obstruct Pulmon Dis. 2018;13:1819-1831.