SUMMARY

ASTRAZENECA PHARMACEUTICALS

FINISHED PRODUCT: Oxis®

ACTIVE INGREDIENT: formoterol

Trial title (number): Protective effect of salbutamol against methacholine bromide in asthmatic patients pre-treated with formoterol Turbuhaler or salmeterol Diskhaler.

Development phase:IV
First subject recruited: 08 April 1998
Last subject completed: 23 March 2000
Approval date: 25 February 2002

OBJECTIVES
To evaluate whether pre-treatment with formoterol (full b₂-agonist) or salmeterol (partial b₂-agonist) in influences the protective effect of salbutamol against methacholine in asthmatic patients.

METHODS
Study Design:
Double-blind, double-dummy, crossover and randomised design. After enrolment, the patients were treated with formoterol Turbuhaler 9mg (delivered dose, 12mg metered dose) b.i.d. At visit 2, after two (max three) weeks of treatment with formoterol, FEV₁  as well as PC₂₀were measured 1 hour after the morning dose of formoterol. The patients who fulfilled all inclusion and exclusion criteria were randomised into the study and treated with formoterol Turbuhaler 9mg b.i.d. or salmeterol Diskhaler 50mg b.i.d, for two (max three) weeks prior to visit 3. For each pre-treatment, there were four methacholine challenge days. At visits 3-10, the patients inhaled the morning dose of formoterol or salmeterol (reference time). Spirometry for baseline FEV₁  was performed 60 (±5) minutes after the morning dose. A single dose of salbutamol Turbuhaler 200, 400 or 800mg or placebo was inhaled 70 (±5) minutes after the reference time. Methacholine challenge testing started 15 (max 20) minutes after the salbutamol/placebo inhalation. At least 48 hours (due to the risk of developing methacholine refractivity if shorter intervals) but not more than 14 days separated each methacholine challenge. Treatment with formoterol or salmeterol continued during the methacholine challenge periods.

Diagnosis and Main Criteria for Inclusion/Exclusion

Male and female asthmatic patients treated with a constant dose of inhaled steroids ³ 200 mg/day were to be included in the study. The patients had to have a baseline FEV₁  ³ 40% of predicted normal values. After two weeks of treatment with formoterol Turbuhaler 9 mg b.i.d., the patients had to have a FEV₁  ³ 70% of predicted normal values (one hour after the morning dose) and a PC₂₀  £ 9.8 mg/mL. The patients had to have no change in prescribed asthma medication within one month prior to visit 1 or hospitalised due to exacerbation of asthma within two months prior to visit 1.

Test Product, Dosage and Mode of Administration

Formoterol fumarate dihydrate (Oxis), 9mg/dose (delivered dose, metered dose 12mg/dose) b.i.d. inhaled via Turbuhaler.

Comparator Product, Dosage and Mode of Administration

Salmeterol (Serevent), 50mg/dose (metered dose) b.i.d. inhaled via Diskhaler.Salbutamol sulphate (Inspiryl), 100mg/dose (metered dose) inhaled via Turbuhaler. Placebo for Inspiryl Turbuhaler.

Duration of Treatment

The study duration ranged from 58 to 117 days. A run-in period with formoterol Turbuhaler b.i.d. during two (max three) weeks. Two periods with treatment of formoterol Turbuhaler or salmeterol Diskhaler b.i.d. After two (max three) weeks of treatment, four single treatments with salbutamol Turbuhaler 200, 400 or 800mg or placebo were added to the maintenance treatment of formoterol or salmeterol with at least 48 hours and not more than 14 days in between.

Main Measurement(s) and Variable(s)

- Pharamodynamics

The primary variable was the concentration of methacholine bromide causing a 20% fall in FEV₁(PC₂₀) determined after single doses of salbutamol or placebo and pre-treatment with formoterol or salmeterol.

- SAFETY

Adverse events were collected by means of standard questions. At enrolment (visit 1) and at follow-up (visit 10), health checks were performed including physical examination, measurements of pulse and blood pressure, ECG and laboratory tests.

 Methods for Data Evaluation

- FEV₁  MEASURED AFTER THE MORNING DOSE OF FORMOTEROL OR SALMETEROL

FEV₁  values, measured one hour after the morning dose of formoterol or salmeterol, were compared between the two pre-treatments using a multiplicative (i.e. log-transformation of the response was used) analysis of variance model with patient, period and pre-treatment as fixed factors. The mean treatment ratio was estimated and 95% confidence limits were calculated.

- FEV₁  MEASURED AFTER SALBUTAMOL OR PLACEBO

Geometric mean FEV₁  values (as ratio versus FEV₁  at visit 2) were estimated using a multiplicative analysis of variance model with patient, period and treatment as fixed factors. The levels within treatment were the eight combinations of pre-treatment and placebo/salbutamol dose. The eight treatments were compared in pairs and treatment differences were described with geometric mean ratios and 95% confidence intervals.

- PC₂₀

The concentration of methacholine bromide causing a 20% fall in FEV₁ from the post-saline value (PC₂₀) was calculated from the lowest FEV₁  value measured after each methacholine concentration. Log-linear interpolation of the dose versus % fall in FEV₁  curve was used to calculate PC20. Geometric mean PC₂₀values (as mg/mL or as ratio versus PC₂₀at visit 2) were estimated using a multiplicative analysis of variance model with patient, period and treatment as fixed factors. The levels within treatment were the eight combinations of pre-treatment and placebo/salbutamol dose. The eight treatments were compared in pairs and treatment differences were described with geometric mean ratios and 95% confidence intervals. Various nonlinear models were fitted to the estimated means using weighted least squares regression.