Long-Term Safety of Tiotropium/Olodaterol Respimat in Elderly Patients with Moderate to Very Severe COPD in the TONADO Studies

Rationale:

The safety, lung-function efficacy, and symptomatic benefits of combined tiotropium (T), and olodaterol (O), in COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287). Elderly COPD patients may be at increased risk of adverse events (AEs) because of decreased protective organ functions and increased co-morbidity. We investigated the long-term safety of T/O in elderly patients in the TONADO studies®.

Methods:

Two replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials assessed T/O 2.5/5 and 5/5 µg compared to the monocomponents T 2.5 and 5 µg, and O 5 µg (all via Respimat® inhaler) in patients with moderate to very severe COPD. In a pre-specified safety analysis, investigator-reported treatment-emergent AEs were pooled from the studies. Patients were grouped into four cohorts: < 65 years, 65-< 75 years, 75-< 85 years, and ≥85 years. Results for the marketed doses (T/O 5/5 µg, T 5 µg, and O 5 µg) are presented. Patients aged ≥85 years are excluded due to low numbers.

Fig. 1: *Significant decrease with 95% CI not including 1.0;
^a≥85 years not displayed due to low patient numbers (n = 8);
^bTreatment exposure time adjusted.
CI, confidence interval; MACE, major adverse cardiac events; n/a, not applicable; Olo, olodaterol; Tio, tiotropium.

Results:

Of 3100 patients included, 1585 (51.1%) were < 65 years (T/O, n = 525; T, n = 540; O, n = 520), 1198 (38.7%) were 65-< 75 years (T/O, n = 407; T, n = 383; O, n = 408), 309 (10.0%) were 75-< 85 years (T/O, n = 96; T, n = 106; O, n = 107), and eight (0.3%) were ≥85 years (T/O, n = 1; T, n = 4; O, n = 3). Almost half (46.5%) had pre-existing cardiac disease, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. Overall, the proportion of patients with AEs appeared to increase with increasing age: 72% (T/O), 70% (T), and 75% (O) at < 65 years; 75% (T/O), 76% (T), and 78% (O) at 65-< 75 years; and 79% (T/O), 83% (T), and 79% (O) at 75-< 85 years. There was no differential increase or decrease in AE incidence with age comparing T/O versus T or O. The majority of AEs were respiratory. Overall, there was no difference between the treatment groups in the incidence of major adverse cardiac events, nor other age-related or typical anticholinergic AEs (Figure).

Conclusions:

The TONADO® studies included a considerable proportion of elderly patients with co-morbidities. There was a low incidence of potential age-related effects. There was no increase in AE incidence with T/O versus T or O alone, and T/O was safe and well tolerated at all ages.

Sponsered by Boehringer Ingelheim

Previously presented at ATS 2017