STUDY DESIGN

The study was of a double-blind, randomized, placebo-controlled, double-dummyparalell-group design.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION/EXCLUSION

Diagnosis asthmaInclusion criteria: Male or female out-patients with asthma acc. to ATS, aged 18 - 60 years,not treated with inhaled GCS for the last 6 months prior to visit 1. Patients should havePC20(methacholine) less than 16 mg/mL and were atopic asthmatis showing a late responsefollowing the screening og high dose allergen challenge. Patients were non smoking one

month prior to visit 1 and non-smoker at present with a history of less than 10 pack-yearsever. Signed inform consent was given by the patient.

Exclusion criteria: Respiratory infection and other diseases that may interfere with studyassessments, as judged by the investigator. No asthma exacerbation within 30 days prior tovisit 1. Patients having a FEV1less than 70% of predicted normal. Pregnant or lactatingwomen. Previous treatment with leukotriene modifiers. Known intolerance to any of thestudy drugs or inhaled lactose.

TEST PRODUCT, DOSAGE AND MODE OF ADMINISTRATION

Budesonide (Pulmicort^® )Turbuhaler®(powder for inhalation) delivering 200 µg/dose, 200doses. Daily dose 400 µg once daily.

COMPARATOR PRODUCT, BATCH NUMBER, DOSAGE AND MODE OF ADMINISTRATION

Tablet Montelukast sodium (Singulair^® ) 10 mg, Daily dose 10 mg, one tablet once daily. Placebo (lactose) Pulmicort Turbuhaler, 200 doses. Lactose. Once daily. Tablet Placebo montelukast Singulair 64 tablets, Lactose. Daily dose once daily.DURATION OF TREATMENT- Eight weeks

MAIN VARIABLE(S):

- EFFICACY

The change in sputum eosinophils following low-dose allergen challenge was the primary variable.

Secondary variables were the exhaled nitric oxide (ENO), bronchial hyperresponsiveness

(BHR) measured as PC20 methacholine, and differential white blood cell count (WBC) inperipheral blood and sputum. Eosiniphils and eosinophilic cationic protein (ECP) inbronchial biopsies. Furthermore, in sputum samples, biopsies and the perpheral blood wereinvestigated exploratively for levels of soluble and cellular markers. Other secondary variables were lung function (FEV1) and peak expiratory flow (PEF) as well as symptoms scores and use of rescue medication

- SAFETY

The safety is this study was the reporting of Serious Adverse Events (SAE) and Discontinuation due to adverse event.

STATISTICAL METHODS

An intention To Treat type analysis was used with all available data. Missing data were replaced using the Last Value Extended (LVE) principle, within the run-in period and within the treatment period separately. No values were extended between periods. Any variable measured both before and after Low Dose Allergen Challenge (LDAC) was considered as two separate variables and LVE was not used to replace a missing value after LDAC with one taken before LDAC, and conversely, missing values before LDAC were not replaced by values after LDAC. The same type of analysis was used for the majority of variables. An ANOVA model with treatment and centre as factors, and with the baseline value as covariate was used for all variables. A multiplicative ANOVA model, i.e. the endpoint and the covariate were log-transformed before analysis, was used for all variables with the exception of lung function variables (FEV₁, FVC, and VC) and diary card variables (PEF, rescue use and symptoms) where an additive model was used. All hypothesis testing was done using two-sided alternative hypothesis. P-value less than or equal to 5% were considered statistically significant.

SUMMARY - CONCLUSION(S)

The study failed to show any statistical significant effect of budesonide and montelukast incomparison with placebo on sputum eosinophils after low dose allergen challenge (LDAC).

The original protocol stipulated the study population should have increased levels of sputumeosinophils, and this was ensured by an inclusion criteria reguiring sputum eosinophil levelsof more than 3% at both visit 1 and 2. In reality these patients could not be found and thiscriteria was replaced with one that reguired a response to high dose allergen challenge.However, the inclusion criteria did not stipulate sensitivity to LDAC nor elevated eosinophillevels in response to LDAC. Furthermore the criteria of PC 20 was changed from less than8mg/mL to less than 16mg/mL. With these changes, the study population became less strictwith respect to evaluation of the primary variable - change in sputum eosinophil levels inresponse to LDAC.

The response to LDAC decreased over time in all treatment groups, making the basis forconclusions regarding differences in treatment effects hazardous. Furthermore, since thestudy included many variables of explorative nature, the presence of a statisticallysignificant effect in one variable could not be excluded as a finding of change if it was notsubstantiated by similar findings in associated variables.In conclusion, the study failed to show any statistical significant effect of budesonide andmontelukast in comparison with placebo on sputum eosinophils after low dose allergenchallenge.

- SAFETY RESULTS

Based on the limited amount of safety data colleted (registration of SAEs/DAEs), no newsafety signals were identified.

Reference:

None at this time

 
As with any comprehensive clinical trial programme, individual studies may include both approved and non-approved treatment regimens, including doses higher than those approved for clinical use. Before prescribing Pulmicort™ (budesonide), Healthcare Professionals should view their specific country information.