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

Adv Ther. 2019 Apr;36(4):962-968. doi: 10.1007/s12325-019-00911-y. Epub 2019 Mar 6.

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.

Keywords: COPD; Dose-finding; Fixed-dose combination; Long-acting muscarinic antagonist; Long-acting β2-agonist; Respiratory/pulmonary.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzoxazines* / administration & dosage
  • Benzoxazines* / adverse effects
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / adverse effects
  • Dose-Response Relationship, Drug*
  • Double-Blind Method
  • Drug Combinations
  • Drug Monitoring
  • Female
  • Forced Expiratory Volume / drug effects
  • Humans
  • Male
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Respiratory Function Tests / methods
  • Tiotropium Bromide* / administration & dosage
  • Tiotropium Bromide* / adverse effects
  • Treatment Outcome

Substances

  • Benzoxazines
  • Bronchodilator Agents
  • Drug Combinations
  • tiotropium-olodaterol
  • Tiotropium Bromide

Associated data

  • ClinicalTrials.gov/NCT00696020
  • figshare/10.6084/m9.figshare.7713635