Dataset Information

Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD.

ABSTRACT:

Introduction

During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 μg, and compare it with the dose response of olodaterol monotherapy.

Methods

In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 μg or a fixed-dose combination of tiotropium 5 μg with olodaterol 2 μg, 5 μg, or 10 μg, delivered once daily via the Respimat^® for 4 weeks (NCT00696020). Patients had a diagnosis of chronic obstructive pulmonary disease and post-bronchodilator forced expiratory volume in 1 s (FEV₁) ≥ 30 and < 80% of predicted normal. The primary endpoint was trough FEV₁ response (change from baseline) after 4 weeks. Secondary endpoints included FEV₁ and forced vital capacity (FVC) over 6 h after dosing.

Results

Compared with tiotropium 5 μg, mean (standard error) trough FEV₁ increased with the addition of olodaterol 2 μg by 0.024 L (0.027), olodaterol 5 μg by 0.033 L (0.027), and olodaterol 10 μg by 0.057 L (0.027). Statistically significant improvements in FEV₁ versus tiotropium were seen across all timepoints up to 6 h with all doses of tiotropium/olodaterol. Similar results were observed for FVC.

Conclusion

There was a benefit of tiotropium/olodaterol compared with tiotropium monotherapy in FEV₁ and FVC. There was a dose-response relationship for olodaterol on top of tiotropium for FEV₁ and FVC similar to the dose response previously seen for olodaterol monotherapy. These results, together with the results of a study investigating the dose response of tiotropium on top of olodaterol, helped to inform the dose selection for the phase III studies.

Funding

Boehringer Ingelheim International GmbH.

SUBMITTER: Maltais F

PROVIDER: S-EPMC6824359 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD.

Maltais François F Hamilton Alan A Voß Florian F Maleki-Yazdi M Reza MR

Advances in therapy 20190306 4

<h4>Introduction</h4>During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 μg, and compare it with the dose response of olodaterol monotherapy.<h4>Methods</h4>In this double ...[more]

PMID: 30843141

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Project description:ObjectivesChronic obstructive pulmonary disease (COPD) guidelines advocate treatment with combinations of long-acting bronchodilators for patients with COPD who have persistent symptoms or continue to have exacerbations while using a single bronchodilator. This study assessed the cost-utility of the fixed dose combination of the bronchodilators tiotropium and olodaterol versus two comparators, tiotropium monotherapy and long-acting β2 agonist/inhaled corticosteroid (LABA/ICS) combinations, in three European countries: Finland, Sweden and the Netherlands.MethodsA previously published COPD patient-level discrete event simulation model was updated with most recent evidence to estimate lifetime quality-adjusted life years (QALYs) and costs for COPD patients receiving either tiotropium/olodaterol, tiotropium monotherapy or LABA/ICS. Treatment efficacy covered impact on trough forced expiratory volume in 1 s (FEV1), total and severe exacerbations and pneumonias. The unit costs of medication, maintenance treatment, exacerbations and pneumonias were obtained for each country. The country-specific analyses adhered to the Finnish, Swedish and Dutch pharmacoeconomic guidelines, respectively.ResultsTreatment with tiotropium/olodaterol gained QALYs ranging from 0.09 (Finland and Sweden) to 0.11 (the Netherlands) versus tiotropium and 0.23 (Finland and Sweden) to 0.28 (the Netherlands) versus LABA/ICS. The Finnish payer's incremental cost-effectiveness ratio (ICER) of tiotropium/olodaterol was €11 000/QALY versus tiotropium and dominant versus LABA/ICS. The Swedish ICERs were €6200/QALY and dominant, respectively (societal perspective). The Dutch ICERs were €14 400 and €9200, respectively (societal perspective). The probability that tiotropium/olodaterol was cost-effective compared with tiotropium at the country-specific (unofficial) threshold values for the maximum willingness to pay for a QALY was 84% for Finland, 98% for Sweden and 99% for the Netherlands. Compared with LABA/ICS, this probability was 100% for all three countries.ConclusionsBased on the simulations, tiotropium/olodaterol is a cost-effective treatment option versus tiotropium or LABA/ICS in all three countries. In both Finland and Sweden, tiotropium/olodaterol is more effective and cost saving (ie, dominant) in comparison with LABA/ICS.

Project description:BackgroundEscalation to triple therapy (long-acting muscarinic antagonist/β2-agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma.MethodsIn this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy.ResultsFor the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy.ConclusionsICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Project description:BackgroundAs lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history.MethodsFour subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George's Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks.ResultsIn all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment.ConclusionsThese data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease.Trial registrationClinicalTrials.gov: NCT01964352 and NCT02006732 .

Project description:IntroductionIn patients with chronic obstructive pulmonary disease (COPD), treatment with long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination therapy significantly improves lung function versus LABA/inhaled corticosteroid (ICS). To investigate whether LAMA/LABA could provide better clinical outcomes than LABA/ICS, this non-interventional database study assessed the risk of COPD exacerbations, pneumonia, and escalation to triple therapy in patients with COPD initiating maintenance therapy with tiotropium/olodaterol versus any LABA/ICS combination.MethodsAdministrative healthcare claims and laboratory results data from the US HealthCore Integrated Research Databasesm were evaluated for patients with COPD initiating tiotropium/olodaterol versus LABA/ICS treatment (January 2013-March 2019). Patients were aged at least 40 years with a diagnosis of COPD (but not asthma) at cohort entry. A Cox proportional hazard regression model was used (as-treated analysis) to assess risk of COPD exacerbation, community-acquired pneumonia, and escalation to triple therapy, both individually and as a combined risk of any one of these events. Potential imbalance of confounding factors between cohorts was handled using fine stratification, reweighting, and trimming by exposure propensity score (high-dimensional); subgroup analyses were conducted on the basis of blood eosinophil levels and exacerbation history.ResultsThe total population consisted of 61,985 patients (tiotropium/olodaterol n = 2684; LABA/ICS n = 59,301); after reweighting, the total was 42,953 patients (tiotropium/olodaterol n = 2600; LABA/ICS n = 40,353; mean age 65 years; female 54.5%). Patients treated with tiotropium/olodaterol versus LABA/ICS experienced a reduction in the risk of COPD exacerbations (adjusted hazard ratio 0.76 [95% confidence interval 0.68, 0.85]), pneumonia (0.74 [0.57, 0.97]), escalation to triple therapy (0.22 [0.19, 0.26]), and any one of these events (0.45 [0.41, 0.49]); the combined risk was similar irrespective of baseline eosinophils and exacerbation history.ConclusionsIn patients with COPD, tiotropium/olodaterol was associated with a lower risk of COPD exacerbations, pneumonia, and escalation to triple therapy versus LABA/ICS, both individually and in combination; the combined risk was reduced irrespective of baseline eosinophils or exacerbation history.Trial registrationClinicalTrials.gov identifier, NCT04138758 (registered 23 October 2019).

Dataset Information

Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD.

Introduction

Methods

Results

Conclusion

Funding

Publications

Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD.

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