2 CLINICAL STUDY SYNOPSIS FINAL REPORT N0. CCD-0402-RS-0002 Title of the study: Evaluation of the 24-hour trough FEV 1 following 7 days of dosing with 2 µg once daily. A multicentre, double-blind, double-dummy, randomised, parallel group, placebo and active (formoterol 12 µg b.i.d.) controlled study followed by a 3-week open label extension (to either 2 µg q.d. or formoterol 12 µg b.i.d. in a 2:1 ratio) for the evaluation of safety and tolerability Coordinating Investigator: Pr Study centres: In total 19 active centres in 4 countries: Bulgaria (7), Romania (6), Malaysia (5), and the United Kingdom (1). Publication (reference): Pending Studied period (years): Phase of development: IIb (date of first enrolment): 27/AUG/2005 (date of last completed): 05/NOV/2005 Objectives: Core phase (8-days treatment period): Primary: To characterise the mean trough 23-24 h FEV 1 following 7 days of dosing of 2µg given once a day and to compare it with placebo. Secondary: In the morning of day 8: to compare the mean through 23-24 h FEV 1 observed with 2 µg once a day with the one following first administration of 2 µg o.d. In the morning of day 8, to compare the mean through of FEV 1 - observed with with the one observed with formoterol 12 µg b.i.d. - observed with formoterol 12 µg b.i.d. with the one observed with placebo - to compare the FEV 1 at 1 h, 2 h and 3 h post morning dose administration, the peak FEV 1 value and the normalised AUC0-3h observed with with the one observed with placebo and formoterol. In the morning of day 2, to compare the mean trough 23-24 h FEV 1 - observed with with the one observed with placebo - observed with formoterol with the one observed with placebo - observed with to the one observed with formoterol. - to compare the FEV 1 at 1 h, 2 h and 3 h post morning dose administration, the peak FEV 1 value and the normalised AUC 0-3h observed with with the one observed with placebo and formoterol. V
To monitor for safety and tolerability: adverse events, physical examination, vital signs, 12- lead ECG, serum potassium and blood glucose. Open label extension phase (3-week treatment period in a subgroup of patients): Secondary: In the morning of Day 29 to compare: - the mean 23-24 h FEV 1 trough observed with with the one observed with formoterol - the FEV 1 at 1 h, 2 h and 3 h post morning dose administration, the peak FEV 1 and the normalised AUC 0-3h observed with with the one observed with formoterol. To monitor for safety and tolerability: adverse events, physical examination, vital signs, 12- lead ECG, serum potassium and blood glucose. Methodology: Core phase Double-blind, randomised, placebo and active treatment controlled, parallel groups clinical trial. The core phase entailed two periods. Period 1, a run-in period of 7 days duration (Visits 1 to 2), was followed by a randomised double-blind, double-dummy treatment period (1:1:1 randomisation) of 8 days (Core Period 2; Visits 2, 3 and 4). Open extension phase (period 3) At the end of Visit 4, a subgroup of patients was re-randomised in a 2:1 ratio to either 2 µg once a day, or formoterol 12 µg b.i.d., for an additional 3-week treatment period in an open label fashion (open label extension; Visits 4 to 5). Number of patients (planned and analysed): 126 patients were planned to be randomised to core phase (1:1:1 randomisation). 80 patients were planned to be re-randomised to either 2 µg o.d. or formoterol 12 µg b.i.d. (2:1 ratio) in the extension phase. Analysed Core phase : Populations (Core phase) Non Randomised Randomised PLACEBO FORMOTEROL Total Total Screened population 29 42 39 43 124 153 Randomised population - 42 (100.0%)39 (100.0%)43 (100.0%)124 (100.0%)124 (100.0%) Safety population - 42 (100.0%)39 (100.0%)43 (100.0%)124 (100.0%)124 (100.0%) ITT population - 42 (100.0%)39 (100.0%)43 (100.0%)124 (100.0%)124 (100.0%) PP population - 36 (85.7%)30 (76.9%)32 (74.4%)98 (79.0%)98 (79.0%) Open label extension phase VI
Populations (Extension phase) FORMOTEROL Total Randomised population 29 (100.0%) 55 (100.0%) 84 (100.0%) Safety population 29 (100.0%) 55 (100.0%) 84 (100.0%) ITT population 29 (100.0%) 55 (100.0%) 84 (100.0%) Compliant to Extension Phase Protocol (CEPP) population 22 (75.9%) 41 (74.5%) 63 (75.0%) Diagnosis and criteria for inclusion: Clinical diagnosis of persistent asthma not adequately controlled on existing therapy, age 18 years, FEV 1 90% of the predicted for the patient normal value, positive response to the reversibility test (i.e. 15% and 200 ml), ability to be trained to use the pmdi or Aerolizer inhaler correctly, non smokers or ex-smokers with cumulative tobacco consumption <5 packyears and having stopped smoking >1 year, written informed consent. Test product, dose and mode of administration, batch number: pmdi 2 µg, once daily, (Chiesi batch number:, expiry date: ). placebo: batch number:, expiry date:. Reference therapy, dose and mode of administration, batch number: Formoterol 12 µg (Foradil Aerolizer ), twice daily, batch number:. Formoterol placebo: batch number:, expiry date:. Duration of treatment: Core phase: 8 days randomised treatments period Extension phase: 21 days per re-randomised patient, expiry date: Criteria for evaluation: Primary efficacy variable: - Trough FEV 1 (L) (mean of 23 and 24 hours) at Day 8 (Visit 4) after 7 days of dosing. Secondary efficacy variables: - Trough FEV 1 (L)(mean of 23 and 24 hours) following first test drug administration as recorded on Day 2 (Visit 3), and Day 29 (Visit 5) - Normalised FEV 1 AUC 0-24 on Day 2 (Visit 3) - FEV 1 (L) at 1 h, 2 h, 3 h post-morning test drug on Day 1, Day 2, Day 8 and Day 29 (Visits 2, 3, 4 and 5) including normalised AUC 0-3h - Peak FEV 1 changes on Day 1, Day 2, Day 8 and Day 29 (Visits 2, 3, 4 and 5): maximum FEV 1 response over baseline (L and %) on clinic visits. VII
- Change from baseline to Day 2 (V3), Day 8 (V4) and Day 29 (V5) in 23 hours, 24 hours and in mean trough 23-24 hours FEV 1 value (L and %), - At each visit (Day 1/ V2, Day 2/V3, Day 8/V4 and Day 29/V5), change from pre-dose FEV 1 value to FEV 1 at T1H, T2H, T3H and to peak FEV 1 value (L and %), - 23 hours, 24 hours, mean trough 23-24 hours and peak FEV 1 expressed as % of predicted normal value on Day 1/V2, Day 2/V3 and Day 8/V4, - Mean daily consumption of rescue medication (puffs/day) calculated on the whole Core treatment period Day1/V2-Day8/V4. Safety variables: Adverse events and adverse drug reactions (i.e. those with certain, probable or possible correlation with study drug), laboratory parameters (K+ and Glucose), ECG results with QTc interval, vital signs (heart rate and blood pressure) and potential indicator of paradoxical bronchospasm. Statistical methods: Core phase Primary efficacy analysis: The primary efficacy variable was the mean trough 23-24 hours FEV 1 (L) following 7 days of dosing. The primary efficacy analysis was the comparison of the primary efficacy variable observed with with the one observed with placebo, using an ANCOVA model with the V2 pre-dose FEV 1 value as covariate, and the treatment and country as the analysis factors. Secondary efficacy analyses: Inferential analyses were performed for the mean trough 23-24 hours FEV 1, 23 and 24 hours FEV 1, normalised AUC0-3h, normalised AUC0-24h, peak FEV 1. All these variables were also summarised using descriptive statistics. In addition, all the other efficacy variables were summarised by treatment arm by using descriptive statistics including when relevant the 95%CI of the changes from baseline in order to assess the within treatment evolution. Safety analyses: Safety analyses were performed on the Safety population. VIII
Determination of the safety profile was assessed through the monitoring of the following parameters: - adverse events (AEs) recorded throughout the study, - physical examination, - vital signs at pre-dose and 30 min post-dose, - 12-lead ECG assessed at pre-dose and 30 min post-dose on Day 1 and Day 8 (QTc, HR), - serum potassium and blood glucose at pre-dose and 30 min post-dose, on Day 1 and Day 8. - potential indicator of paradoxical bronchospasm during the 3 hours post-dose on Day 1, Day 2 and Day 8. Extension phase Efficacy analyses: Efficacy analyses were performed on the ITT and CEPP populations. Comparison between treatment arms ( vs. Formoterol) on trough FEV 1, Peak FEV 1 and normalised FEV 1 AUC 0-3h at Day 29 (Visit 5) were assessed using an ANCOVA model with baseline value (pre-dose Day 8/Visit 4) as covariate and extension treatment, core treatment, and country as factors. Estimated least square means (LSMEANS) in each extension treatment group were given, as well as the adjusted means difference between groups ( minus formoterol). The two-sided 95% CI of these differences and relative p-value were calculated. As planned, the Extension treatment by Core treatment interaction was investigated although not included in the main model. Efficacy data will be summarised by treatment group (Formoterol, ) and stratified by study drug received during the core period (Placebo, Formoterol, ). Within treatment evolutions were assessed using descriptive statistics including changes from baseline and relative 95% CI. Safety analyses: Safety analyses were performed on the Safety population. Safety data were summarised by treatment group (formoterol, ) and overall. In addition, the following safety criteria were stratified by study drug received during the core period (placebo, formoterol, ): - Vital signs (SBP, DBP, HR) - ECG parameters (HR, QTcB, ECG interpretation according to the investigator) - Laboratory data (serum potassium and blood glucose levels) IX
Physical examination, extension phase adverse events (AEs), and potential indicator of paradoxical bronchospasm at Day 29 were included in the safety analysis. CORE PHASE Summary - Conclusions Efficacy Results The three treatment groups were well matched for demography, medical history, smoking history, and baseline values of all efficacy and safety parameters; the FEV 1 reversibility was 33.0% in the placebo group, 30.7% in formoterol, and 30.1% in. However, values in the formoterol group as absolute FEV 1 value and percentage of predicted value appeared to be slightly higher than in the other groups; the mean FEV 1 % of predicted value at baseline being 60.6% in the placebo group, 69.6% in formoterol, and 65.0% in. There were 3 withdrawals after randomisation: 2 in formoterol group (adverse events: nausea and vertigo, and acute asthma exacerbation) and 1 in (protocol violation). Based on both statistical and medical consideration, one patient ( ) with an outstanding response to the reversibility test [247% (from 1.36L to 4.72L) increase of FEV 1 ] and outstanding response to placebo during the study period [after the first dose, change in FEV 1 at 1h was 1.54L and change in trough FEV 1 was 1.58 L], was considered an outlier. As suggested by ICHE9 guideline, one additional analysis excluding this patient (ITT population excluding the outlier) was performed and difference between results discussed. Besides, this patient was also receiving Seretide during the treatment period. Hence he was considered as a major protocol violator and was also excluded from the PP population. After 7 days of treatment, the mean 23-24hours FEV 1 trough resulted in a significant improvement over baseline in the group once a day and was similar to the one observed in the formoterol twice a day. The differences over placebo in trough FEV 1 of 2µg given once a day ranged from 0.11L to 0.16L (0.11L, 0.16L, 0.15L in the ITT, PP and ITT population excluding the outlier, respectively) and were similar to those of formoterol 12µg given twice daily (0.10L in the ITT, 0.15L in the PP and 0.15L in the ITT population excluding the outlier). In the ITT analysis only a trend was found with the 95% CI (-0.03 to 0.25L) clearly shifted in favour of but the difference failed to achieve statistical significance. Once the outlier was excluded from the ITT population, the difference of over placebo (0.15L [95% CI: 0.02 to 0.28L]) was statistically significant (p=0.013). This analysis suggests that results in the placebo group were leaded by this single patient with outstanding response. X
Results in the PP analysis were consistent with the ITT excluding the outlier analysis with a difference of over placebo of 0.16L (p=0.015). Results with formoterol were very similar in the same populations and no difference was observed between the two active drugs. On Day 2 (i.e 24h after first drug administration), the FEV 1 mean 23-24h trough difference over placebo of ranged from 0.08L to 0.15L ( 0.08L, 0.14L, 0.13L in the ITT, PP and ITT population excluding the outlier population respectively). These differences were slightly higher in the formoterol group (0.14L, 0.17L and 0.19L in the ITT, PP and ITT population excluding the outlier patient). There was no enhancement of the effect on FEV 1 at trough after repeated dose. However, there was clinically meaningful sustained bronchodilation at the end of the 24 hours dosing interval following repeated doses both with q.d. and formoterol b.i.d. showed superiority over placebo in the 3h average FEV 1 at all visits (Day 1, Day 2 and Day 8) and whatever population considered. Results in the formoterol group were similar to. Peak FEV 1 effect over baseline same days was around 25% and 26% for formoterol and respectively after drug administration and then decreased similarly in both treatment groups to around 12% and 14%, respectively, after 7 days of treatment. This is obviously due to the increased baseline following active drugs administration. The proportion of patients using rescue medication was similar in the group and the formoterol group (37.2% and 36.8% respectively) and was lower in both groups compared to placebo (53.7%). The median number of puffs intake per day was low in all treatment groups (<1/day). Safety and Tolerability Results: Eighteen (14.5%) patients presented with at least one TEAE (Treatment Emergent Adverse Event). Six patients (14.3%) in the placebo group, 7 patients (17.9%) in the formoterol group, and 5 patients (11.6%) in the group. There was no statistically significant difference among treatment groups (Chi-Square, p=0.72). In total, 15 TEAEs in 8 patients (6.5%) were considered by the investigator as related to treatment (relationship to study drug assessed as certain/definite, probably / likely or possible): 11 in 5 patients (12.8%) in the formoterol group, and 4 in 3 patients (7.0%) in the group. The most frequent TEAEs related to study medication referred to the nervous system XI
disorders in both active groups. One serious TEAE ( acute asthma exacerbation ) was reported by one patient in the formoterol group, and was considered as not related to the study medication by the investigator. There were no severe adverse events. A total of 2 patients (all in the formoterol group) discontinued the study due to TEAEs (one due to vertigo and nausea, the other due to acute asthma exacerbation ). Overall, the most commonly reported TEAEs referred to the nervous system disorders which accounted for 8 events in 8 patients (6.5%): 1 event in 1 patient (2.4%) in the placebo group, 3 events in 3 patients (7.7%) in the formoterol group and 4 events in 4 patients (9.3%) in the group. Headache was the most frequently reported TEAE in the group (3 episodes in 3 patients, 7.0%), and palpitations was the most frequently reported TEAE in the formoterol group (3 episodes in 3 patients, 7.7%). The mean values of serum glucose and potassium were normal in all treatment groups on Day 8 without any clinically significant change from baseline (serum glucose changes of 0.02mmol/L in the placebo group, 0.06mmol/L in the formoterol group, and -0.08mmol/L in the group; serum potassium changes of 0.08mmol/L in the placebo group, 0.14mmol/L in the formoterol group, and 0.05mmol/L in the group). No decrease in serum potassium was observed. The vital signs did not change significantly. The mean SBP / DBP changes from Day 1 to Day 8 were 0.50 / 0.38 mmhg in the placebo group, -3.21 / -1.36 mmhg in the formoterol group, and - 3.02 / 0.62 mmhg in the group. There was no cardiovascular safety concern. The mean heart rate and QTcB changes were negligible (changes in heart rate of 1.02, -1.53, and -0.69bpm in the placebo, formoterol and groups, respectively and changes in QTcB were 3.86, -11.81, and -5.88msec, same groups respectively). FEV 1 decrease >15% over baseline after drug administration considered as a potential marker for paradoxical bronchospasm was mainly observed in the placebo group during the first 3 hours after dosing across visits. It was observed once in the group 2h after dosing at Day 8; none was observed in the formoterol group. XII
Conclusion: 2 µg administered once daily was clinically and significantly superior to placebo after 7 days of treatment and was as effective as formoterol 12µg administered twice daily in 23-24- hours trough FEV 1. The results were well supported by all the secondary efficacy variables. Safety and tolerability profile was assessed as favourable and was similar to formoterol s. Date of the report: 07 July 2006 XIII