Efficacy of tiotropium/olodaterol compared with tiotropium in patients naive to LAMA, LABA and ICS: Pooled analysis of four clinical trials

Rationale: The efficacy of tiotropium/olodaterol (T/O) compared with tiotropium (Tio) has been demonstrated in a large Phase III clinical program. We investigated the treatment effect in patients who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting β₂-agonists (LABAs) or inhaled corticosteroids (ICS) at study entry.

Methods: TONADO 1 and 2 (NCT01431274, NCT01431287) and OTEMTO 1 and 2 (NCT01964352, NCT02006732) were randomized, double-blind, parallel-group, Phase III trials in patients with COPD. TONADO 1 and 2 were 52-week studies including patients with post-bronchodilator FEV₁ < 80% predicted; OTEMTO 1 and 2 were 12-week studies including patients with post-bronchodilator FEV₁ ≥ 30% and < 80% predicted. In this post hoc analysis, we examined the treatment differences between T/O 5/5 µg and Tio 5 µg in trough FEV₁ response, St. Georgeʼs Respiratory Questionnaire (SGRQ) total score change from baseline and Transition Dyspnea Index (TDI) score at 12 weeks in patients who were not receiving LAMA, LABA or ICS, as monotherapy or combination therapy, at baseline in all four studies.

Results: The four trials included 1,078 patients in the T/O and Tio arms who were not receiving LAMA, LABA or ICS at trial enrollment. The pooled analysis shows a significantly greater increase in trough FEV₁ from baseline with T/O compared with Tio at Week 12 (0.056 L; 95% confidence interval [CI] 0.033 – 0.079; P < 0.0001) ([Table 1]). There were significant improvements with T/O versus Tio in SGRQ total score (− 1.780; 95% CI − 3.126 to − 0.434; P = 0.0096) and TDI score (0.409; 95% CI 0.077 – 0.741; P = 0.0158) at Week 12. There was a greater chance of being an SGRQ responder (≥ 4 unit improvement) with T/O treatment (59.6% of patients) than Tio (48.8% of patients; odds ratio 1.5443; 95% CI 1.2014 – 1.9851; P = 0.0007), and a TDI responder (≥ 1-unit improvement) with T/O (63.3% of patients) than with Tio (55.0% of patients; odds ratio 1.4327; 95% CI 1.1101 – 1.8489; P = 0.0057).

Table 1 Treatment differences in trough FEV₁, SGRQ total score and TDI score after 12 weeks in TONADO and OTEMTO.

	n T/O / Tio	T/O vs. Tio, mean difference (95% CI)	P value
Mixed effect model repeated measures including fixed effects of treatment, study (combined analysis only), planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction; patient as a random effect (trough FEV1 analysis only); spatial power covariance structure for within-patient errors and Kenward – Roger approximation for denominator degrees of freedom. CI, confidence interval; FEV1, forced expiratory volume in 1 second; SGRQ, St. Georgeʼs Respiratory Questionnaire; T/O, tiotropium/olodaterol; TDI, Transition Dyspnea Index; Tio, tiotropium.
Trough FEV1, L
TONADO	347/375	0.071 (0.042 – 0.099)	< 0.0001
OTEMTO	163/173	0.023 (− 0.018 to 0.064)	0.2672
Combined	510/548	0.056 (0.033 – 0.079)	< 0.0001
SGRQ total score
TONADO	328/353	− 1.588 (− 3.343 to 0.167)	0.0762
OTEMTO	160/168	− 2.203 (− 4.336 to − 0.070)	0.0429
Combined	488/521	− 1.780 (− 3.126 to − 0.434)	0.0096
TDI score
TONADO	334/357	0.323 (− 0.090 to 0.736)	0.1251
OTEMTO	160/168	0.604 (0.053 – 1.156)	0.0317
Combined	494/525	0.409 (0.077 – 0.741)	0.0158

Conclusions: There were greater improvements in lung function, health status and breathlessness with T/O compared with Tio in patients who were not receiving LAMA, LABA or ICS at baseline, suggesting that T/O may be an effective first-line option for treatment-naïve patients with COPD who have poor lung function and/or a high symptom burden.