Professional Slides: Clinical studies

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In a double-blind (within-device), single-dose crossover study, 62 patients with stable asthma were randomised at five study centres to receive five out of eight possible treatments: ipratropium bromide/fenoterol (IB/FEN) dosages of 5/12.5, 10/25, 20/50, 40/100 or 80/200 µg delivered via Respimat® SMI; IB/FEN dosages of 20/50 or 40/100 µg delivered using a conventional CFC-MDI; and placebo via Respimat® SMI.

Pulmonary function results were based on the per-protocol data set, comprising 47 patients. All IB/FEN treatments produced significantly greater increases in forced expiratory volume in 1 second (FEV1) than placebo (p=0.0001).

This slide shows the adjusted mean change in FEV1 over the 6-hour period after dosing produced by each of the drug treatments. IB/FEN delivered via Respimat® SMI is as effective as higher doses given via a CFC-MDI.

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A log-linear dose-response relationship was observed for the average increase in FEV ₁ from baseline over the 6-hour period after dosing, expressed as the area under the curve (AUC _0-6h).

A similar relationship was not observed for the two doses of IB/FEN administered via CFC-MDI.

The mean AUC _0-6h for four out of five Respimat® SMI dosages was superior to that obtained with the 40/100 µg dosage from the CFC-MDI.

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In the dose-ranging study, the systemic pharmacokinetics of IB and FEN were evaluated as a secondary endpoint. These were determined by measuring plasma levels and urinary excretion of both drugs following delivery in 34 of the 47 patients.

Pharmacokinetic data indicated a 2-fold greater systemic availability of both drugs following inhalation of the same microgram doses by Respimat® SMI compared with CFC-MDI.

The systemic exposure to IB and FEN was proportional to the dose of drug inhaled.

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In patients with stable asthma, delivery of IB/FEN via Respimat® SMI is as effective as delivery via CFC-MDI, even when considerably lower doses are used.

All treatments of IB/FEN were well tolerated whether administered via Respimat® SMI or CFC-MDI.

Further studies are required to confirm the efficacy and safety of IB/FEN delivered via Respimat® SMI in the long-term treatment of patients with asthma and COPD.

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The aim of this study was to establish the cumulative dose of IB/FEN via Respimat® SMI that would produce bronchodilator activity equivalent to that of a cumulative dose of IB/FEN 320/800 µg delivered by a CFC-MDI.

In a randomised, crossover design, 43 patients inhaled cumulatively 16 actuations of IB/FEN 20/50 µg, 20/25 µg or 10/25 µg per actuation via Respimat® SMI or IB/FEN 20/50 µg per actuation via CFC-MDI, on each of 4 test days.

The primary endpoint of the study was the mean increase in FEV ₁ from baseline between 45 and 245 minutes after the first inhalation.

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Cumulative doses of IB/FEN 160/400 µg and 320/400 µg via Respimat® SMI produced bronchodilation equivalent to that achieved with a cumulative dose of IB/FEN 320/800 µg via CFC-MDI (p=0.0036 and p=0.0002, respectively).

When identical cumulative doses from each device (i.e. IB/FEN 320/800 µg) were compared, Respimat® SMI produced a greater bronchodilator response to IB/FEN than the CFC-MDI.

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The FEV1 increase noted after each of the first two doses was considerably larger following administration of IB/FEN 20/50 µg via Respimat® SMI than IB/FEN 20/25 µg or 10/25 µg via Respimat® SMI, and was lowest after IB/FEN 20/50 µg via CFC-MDI.

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IB/FEN delivered via Respimat® SMI is as effective as via CFC-MDI, but at half the cumulative dose.

The tolerability of IB/FEN delivered via Respimat® SMI is also comparable to that of twice the dose delivered via CFC-MDI.

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This multicentre, randomised, double-blind, placebo- and active-controlled, parallel-group, phase III study compared the efficacy and safety of IB/FEN via Respimat® SMI versus CFC-MDI in asthma patients.

631 patients were randomised to one of five treatments: Respimat® SMI containing IB/FEN 10/25 µg, IB/FEN 20/50 µg or placebo, one actuation four times daily (qid), or CFC-MDI IB/FEN 20/50 µg, two actuations qid (40/100 µg), or placebo, two actuations qid, for 12 weeks.

The primary endpoint was the change in FEV ₁ during the first 6 hours after dosing (AUC _0-6h) on day 85.

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All active treatment groups displayed similar time-response curves for FEV ₁ with a rapid onset of action, reaching a peak effect after ~1 hour.

Change in FEV ₁ (days 1, 29, 57 and 85) showed that both IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI were not therapeutically inferior to IB/FEN 40/100 µg via CFC-MDI. Most secondary efficacy parameters supported non-inferiority of IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI.

The results show that, despite a 2- to 4-fold reduction in the nominal dose, IB/FEN delivered from Respimat® SMI is as effective and well tolerated as when delivered from a CFC-MDI.

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All active treatment groups displayed similar time-response curves for FEV ₁ with a rapid onset of action, reaching a peak effect after ~1 hour.

Change in FEV ₁ (days 1, 29, 57 and 85) showed that both IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI were not therapeutically inferior to IB/FEN 40/100 µg via CFC-MDI. Most secondary efficacy parameters supported non-inferiority of IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI.

The results show that, despite a 2- to 4-fold reduction in the nominal dose, IB/FEN delivered from Respimat® SMI is as effective and well tolerated as when delivered from a CFC-MDI.

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Overall, the safety profile of Respimat® SMI was comparable to that of the CFC-MDI.
As expected in an asthma population, the most common adverse events were related to the respiratory system.
The frequency of adverse events considered to be treatment-related was generally low across all groups. Most adverse events were of mild or moderate intensity.
There were no reports of paradoxical bronchoconstriction (PB) in patients using Respimat® SMI.

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In conclusion, these results demonstrate that IB/FEN administered via Respimat® SMI produces a bronchodilator response comparable to that achieved via a CFC-MDI.

Furthermore, they show that Respimat® SMI enables a 2- to 4-fold reduction of the daily dose of IB/FEN without loss of therapeutic efficacy.

Thus, Respimat® SMI may be a useful alternative to pMDIs for the administration of inhaled drug therapy in asthma. Overall, the safety profile of Respimat® SMI was comparable to that of the CFC-MDI.

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This study compared the efficacy and safety of IB/FEN delivered from Respimat® SMI with that from a CFC-MDI plus spacer in children with asthma. The study followed a multicentre, randomised, double-blind, parallel-group design.

Patients were randomised to: Respimat® SMI containing IB/FEN 10/25 µg or IB/FEN 20/50 µg, one actuation three times daily (tid) or CFC-MDI containing IB/FEN 20/50 µg per actuation, two actuations tid (pMDI 40/100 µg), for 4 weeks.

The primary endpoint was the mean change in FEV ₁ during the first 60 minutes after dosing (AUC _0-1h) on day 29.

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After 4 weeks’ treatment, both IB/FEN 10/25 µg and 20/50 µg tid via Respimat® SMI showed comparable efficacy to IB/FEN 40/100 µg tid via CFC-MDI plus spacer.

Time-response curves for FEV ₁ on day 29 showed similar bronchodilation profiles for all three active treatment groups, with a rapid onset of action followed by further increases in FEV ₁ up to the last time-point of 1 hour.

The results show that neither IB/FEN 10/25 µg nor 20/50 µg via Respimat® SMI are inferior to IB/FEN 40/100 µg via CFC-MDI plus spacer.

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After 4 weeks’ treatment, both IB/FEN 10/25 µg and 20/50 µg tid via Respimat® SMI showed comparable efficacy to IB/FEN 40/100 µg tid via CFC-MDI plus spacer.

Time-response curves for FEV ₁ on day 29 showed similar bronchodilation profiles for all three active treatment groups, with a rapid onset of action followed by further increases in FEV ₁ up to the last time-point of 1 hour.

The results show that neither IB/FEN 10/25 µg nor 20/50 µg via Respimat® SMI are inferior to IB/FEN 40/100 µg via CFC-MDI plus spacer.

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The safety profiles of IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI were comparable to that of IB/FEN 40/100 µg via CFC-MDI.

The overall incidence rate of adverse events was higher in the IB/FEN 40/100 µg via CFC-MDI group (34%) than in the IB/FEN 10/25 µg (25%) and IB/FEN 20/50 µg (24%) via Respimat® SMI groups. However, no clinically relevant between-treatment differences were observed. Asthma exacerbation and coughing were the most frequent adverse events in all treatment groups and were slightly more common in those receiving IB/FEN via CFC-MDI (9.0% and 7.9%, respectively) than in the two Respimat® SMI groups (5.6-6.7%). Most adverse events were of mild or moderate intensity.

There were no spontaneous reports of PB.

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IB/FEN 10/25 µg and 20/50 µg delivered via Respimat® SMI produce bronchodilator responses that are non-inferior to IB/FEN 40/100 µg administered via CFC-MDI plus spacer in children with asthma.

Thus, Respimat® SMI enables a reduction in the nominal dose of IB/FEN while offering similar therapeutic efficacy to a CFC-MDI plus spacer. Respimat® SMI also offers greater convenience, as each individual dose from Respimat® SMI can be delivered in one actuation as opposed to two from the CFC-MDI. Respimat® SMI obviates the need for a spacer.

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This was a multicentre, randomised, double-blind (within-device), placebo- and active-controlled, parallel-group study to compare the efficacy and safety of IB/FEN delivered via Respimat® SMI and from a CFC-MDI in patients with moderate-to-severe COPD.

A total of 892 patients were randomised to one of the following five treatments, for 12 weeks: IB/FEN 10/25 µg, IB/FEN 20/50 µg or placebo, one actuation qid, via Respimat® SMI; IB/FEN 20/50 µg, two actuations qid (40/100 µg), or placebo, two actuations qid, via CFC-MDI.

The primary endpoint was the change in FEV ₁ during the first hour after dosing (AUC _0-1h) on day 85.

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The bronchodilator response to IB/FEN on day 85 in the per-protocol population showed that IB/FEN 20/50 µg qid via Respimat® SMI was not inferior to IB/FEN 40/100 µg qid via CFC-MDI.

The study failed by a narrow margin to demonstrate that IB/FEN 10/25 µg qid via Respimat® SMI was also non-inferior to IB/FEN 40/100 µg qid via CFC-MDI. As in the adult and paediatric asthma studies, time-response curves for FEV ₁ on the final test day showed similar profiles for all active treatment groups. Thus, Respimat® SMI enables a reduction of the nominal daily dose of IB/FEN while offering similar therapeutic efficacy to the corresponding CFC-MDI.

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The bronchodilator response to IB/FEN on day 85 in the per-protocol population showed that IB/FEN 20/50 µg qid via Respimat® SMI was not inferior to IB/FEN 40/100 µg qid via CFC-MDI.

The study failed by a narrow margin to demonstrate that IB/FEN 10/25 µg qid via Respimat® SMI was also non-inferior to IB/FEN 40/100 µg qid via CFC-MDI. As in the adult and paediatric asthma studies, time-response curves for FEV ₁ on the final test day showed similar profiles for all active treatment groups. Thus, Respimat® SMI enables a reduction of the nominal daily dose of IB/FEN while offering similar therapeutic efficacy to the corresponding CFC-MDI.

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Overall, the safety profiles of both IB/FEN 10/25 µg and 20/50 µg via Respimat® SMI were comparable to that of IB/FEN 40/100 µg via CFC-MDI.

The incidences of adverse events and withdrawals were similar between treatment groups. There were no spontaneous reports of paradoxical or administration-related bronchoconstriction during the study.

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Respimat® SMI enables a 50% reduction of the nominal daily dose of IB/FEN while offering similar therapeutic efficacy and safety to the corresponding CFC-MDI. Respimat® SMI thus has the potential to be a useful alternative to pMDIs for the delivery of inhaled drugs to COPD patients.