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Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study.

ABSTRACT: BACKGROUND:Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD). METHODS:This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 ?g administered once daily (QD), and UMEC 15.6 ?g and 31.25 ?g administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0-24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined. RESULTS:One hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose-response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 ?g (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 ?g QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 ?g and below. UMEC 125 ?g QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0-12 hours were similar to those observed over 12-24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 ?g QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5-12%). CONCLUSIONS:UMEC is a potent QD bronchodilator with geometric mean ED50 of 37 ?g. A dose ordering over the range of UMEC 15.6-125 ?g QD doses was observed, with UMEC 125 ?g showing the greatest improvement in trough FEV1.

SUBMITTER: Church A

PROVIDER: S-EPMC4029330 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study.

Church Alison A Beerahee Misba M Brooks Jean J Mehta Rashmi R Shah Palvi P

BMC pulmonary medicine 20140106

<h4>Background</h4>Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD).<h4>Methods</h4>This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 μg administered once daily (QD), and UMEC 15.6 μg and 31.25 μg administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-l ...[more]

PMID: 24393134

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Project description:OBJECTIVE:To compare perinatal outcome and glycaemic control in two groups of pregnant diabetic patients receiving two insulin regimens. DESIGN:Randomised controlled open label study. SETTING:University affiliated hospital, Israel. PARTICIPANTS:138 patients with gestational diabetes mellitus and 58 patients with pregestational diabetes mellitus received insulin four times daily, and 136 patients with gestational diabetes and 60 patients with pregestational diabetes received insulin twice daily. INTERVENTION:Three doses of regular insulin before meals and an intermediate insulin dose before bedtime (four times daily regimen), and a combination of regular and intermediate insulin in the morning and evening (twice daily regimen). MAIN OUTCOME MEASURES:Maternal glycaemic control and perinatal outcome. RESULTS:Mean daily insulin concentration before birth was higher in the women receiving insulin four times daily compared with twice daily: by 22 units (95% confidence interval 12 to 32) in patients with gestational diabetes and by 28 units (15 to 41) in patients with pregestational diabetes. Glycaemic control was better with the four times daily regimen than with the twice daily regimen: in patients with gestational diabetes mean blood glucose concentrations decreased by 0.19 mmol/l (0.13 to 0.25), HbA(1c) by 0.3% (0.2% to 0.4%), and fructosamine by 41 micromol/l (37 to 45), and adequate glycaemic control (mean blood glucose concentration <5.8 mmol/l) was achieved in 17% (8% to 26%) more women; in patients with pregestational diabetes mean blood glucose concentration decreased by 0.44 mmol/l (0.28 to 0.60), HbA(1c) by 0.5% (0.2% to 0.8%), and fructosamine by 51 micromol/l (45 to 57), and adequate glycaemic control was achieved in 31% (15% to 47%) more women. Maternal severe hypoglycaemic events, caesarean section, preterm birth, macrosomia, and low Apgar scores were similar in both dose groups. In women with gestational diabetes the four times daily regimen resulted in a lower rate of overall neonatal morbidity than the twice daily regimen (relative risk 0.59, 0.38 to 0.92), and the relative risk for hyperbilirubinaemia and hypoglycaemia was lower (0.51, 0.29 to 0.91 and 0.12, 0.02 to 0.97 respectively). The relative risk of hypoglycaemia in newborn infants to mothers with pregestational diabetes was 0.17 (0.04 to 0.74). CONCLUSIONS:Giving insulin four times rather than twice daily in pregnancy improved glycaemic control and perinatal outcome without further risking the mother.

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Dataset Information

Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study.

Publications

Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study.

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