Drug product: Symbicort Turbuhaler Drug substance(s): ST (Symbicort Turbuhaler ) Edition No.: 1.0 Study code: D5890C00010 Date: 15 March 2007 SYNOPSIS An 8-week, randomised, double blind, parallel-group, multi-centre, phase III study comparing the efficacy and safety of Symbicort Turbuhaler 160/4.5 µg twice daily and Pulmicort Turbuhaler 200 µg twice daily + Theolong tablet 200 mg twice daily in Japanese patients with asthma Co-ordinating investigator Not applicable Study centre(s) This study was conducted in Japan (57 centres). Publications None at the time of writing this report. Study dates Phase of development First patient enrolled 18 October 2005 Therapeutic confirmatory (III) Last patient completed 06 November 2006 Objectives The primary objective of this study was to confirm the efficacy (superiority) of Symbicort Turbuhaler 160/4.5μg (D.D.: delivered dose) twice daily for 8 weeks in comparison to Pulmicort Turbuhaler 200 µg (M.D.: metered dose) twice daily + Theolong tablet 200 mg twice daily by assessment of the following variables. Primary variable: Change in average morning peak expiratory flow (mpef) from the run-in to the treatment period.
Secondary variables: Change from the run-in period to the treatment period in average: Evening peak expiratory flow (epef) Asthma symptom score (daytime, night time and total) Use of short-acting β 2 -agonist (daytime, night time and total) Night time awakenings due to asthma symptoms Symptom free day Asthma control day Change from Visit 2 to the average of Visit 4 and 5: Forced expiratory volume in one second (FEV 1 ) The secondary objective of this study was to assess the safety of Symbicort Turbuhaler 160/4.5μg (D.D.) twice daily for 8 weeks compared with Pulmicort Turbuhaler 200 µg (M.D.) twice daily + Theolong tablet 200 mg twice daily in terms of the following variables. Adverse events (nature, incidence and severity) Haematology, clinical chemistry and urinalysis 12-lead electrocardiogram (ECGs), blood pressure, pulse rate Study design This was a randomised, double-blind, parallel group, multicentre study in Japanese patients with asthma aged 16 years or older. Target patient population and sample size Outpatients aged 16 years or older with asthma whose forced expiratory volume in one second (FEV 1 ) was 50% of predicted normal, and who were treated with inhaled corticosteroid and theophylline SR tablet as a basic asthma treatment. 2
Investigational product: dosage, mode of administration and batch numbers Test product Symbicort Turbuhaler 160/4.5μg (D.D.) (dry powder inhaler, budesonide 160 µg and formoterol fumarate dihydrate 4.5 µg/dose, 120 doses/inhaler) (Batch numbers: GE39) Placebo for test product Symbicort Turbuhaler 160/4.5μg (D.D.) placebo (matching Symbicort Turbuhaler 160/4.5μg), dry powder inhaler containing lactose, 120 doses/inhaler) (Batch numbers: GE21) The patient took one inhalation containing the active ingredient or one inhalation from the placebo inhaler twice daily in the treatment period. Comparator Pulmicort Turbuhaler 200 µg (M.D.) (dry powder inhaler, budesonide 200 µg/dose, 112 doses/inhaler) (Batch numbers: GF11) Theolong tablet 200 mg (Batch numbers: 54A10M) Placebo for comparator Pulmicort Turbuhaler 200 µg (M.D.) placebo (matching Pulmicort Turbuhaler, dry powder inhaler containing lactose, 112 doses/inhaler) (Batch numbers: GF11) Theolong tablet 200 mg placebo (matching Theolong tablet 200 mg) (Batch numbers: P56001AZA) The patient took one inhalation and one tablet containing the active ingredient, or one inhalation from the placebo inhaler and one placebo tablet twice daily in the treatment period. Duration of treatment Run-in period: 2 weeks Treatment period: 8 weeks Criteria for evaluation (main variables) Efficacy and pharmacokinetics Primary variable: Change in average morning peak expiratory flow (mpef) from the run-in to the treatment period. 3
Secondary variables: Change from the run-in period to the treatment period in average: Evening peak expiratory flow (epef) Asthma symptom score (daytime, night time and total) Use of short-acting β 2 -agonist (daytime, night time and total) Night time awakenings due to asthma symptoms Symptom free day Asthma control day Change from Visit 2 to the average of Visit 4 and 5: Forced expiratory volume in one second (FEV 1 ) Safety Adverse events (nature, incidence and severity) Haematology, clinical chemistry and urinalysis 12-lead electrocardiogram (ECGs), blood pressure, pulse rate Statistical methods The change in average mpef from the run-in period to the treatment period was the primary outcome variable. The period averages were calculated for the last 10 days of the run-in period and for the whole of the treatment period. Comparison between the treatments was performed using an analysis of covariance model (an additive model) including treatment as a fixed factor and the run-in period average as a covariate. The mean treatment difference was estimated from the model, and 95% confidence interval and p-value were calculated. The primary analysis set for efficacy was the Full Analysis Set. Patient population In total, 569 patients were enrolled and 348 patients were randomised to either of the two treatment groups (Symbicort group: n=178, Pulmicort +Theolong group: n=170) at 57 centres. The number of analysed patients was 346 (Symbicort group: n=176, Pulmicort + Theolong group: n=170) in the FAS and safety analysis set. There were few major protocol deviations (i.e. deviation from inclusion and exclusion criteria) and the compliance was generally good in the both treatment groups. The treatment groups were well-balanced with regards to demography and other baseline characteristics. 4
Table S 1 Patient population and disposition Symbicort PUL + Theolong Population Number of randomised (Number of planned) 178 (170) 170 (170) Demographic characteristics Race Oriental 178 (100.0%) 170 (100.0%) Sex Male 71 (39.9%) 60 (35.3%) Female 107 (60.1%) 110 (64.7%) Age (years) Mean (SD) 49.7 (16.2) 48.4 (16.6) Range (19 to 80) (17 to 85) Weight (kg) Mean (SD) c 61.2 (11.8) 61.4 (13.6) Range (30 to 94) (42 to 135) Height (cm) Mean (SD) c 160.2 (9.8) 159.7 (9.6) Range (143 to 187) (140 to 183) Baseline characteristics Duration of asthma (years) Mean (SD) c 12.79 (10.19) 11.93 (11.55) Range (0.3 to 57.4) d (0.3 to 52.2) d mpef (L/min) Mean (SD) c 329.3 (118.5) 322.5 (103.5) epef (L/min) Mean (SD) c 336.9 (118.6) 327.5 (103.4) FEV 1 (L) Mean (SD) c 2.029 (0.760) 2.009 (0.722) FEV 1 % of predicted normal Mean (SD) c 72.5 (13.0) 72.6 (15.5) FEV 1 reversibility % Mean (SD) c 21.8 (12.9) 22.1 (13.0) Asthma symptom score (total) Mean (SD) c 1.242 (0.824) 1.316 (0.867) Number of use of short-acting β 2 - Mean (SD) c 0.615 (1.039) 0.503 (0.933) agonist (total) Daily dose of inhaled steroid (μg) Mean (SD) c 402.3 (141.4) 417.6 (140.7) Daily dose of inhaled steroid Mean (SD) c 655.4 (192.7) 663.5 (189.0) (BDP equivalent a ) (μg) Disposition Number (%) of patients who Completed 167 (93.8%) 164 (96.5%) Discontinued 11 (6.2%) 6 (3.5%) Number of patients analysed for safety b 176 170 Number of patients analysed for efficacy (FAS) 176 170 Number of patients analysed for efficacy (PPS) 175 169 PUL: Pulmicort, SD: Standard deviation; FAS: Full Analysis Set; PPS: Per-protocol Set a: BDP equivalent was calculated with reference to JGL 2003. b: Number of patients who took at least 1 dose of randomised investigational product and had any safety data after randomisation c: Symbicort group n=177 d: Duration of asthma was calculated based upon consent signed date in this table. All patients had more than 6 months duration of asthma based upon Visit 1. 5
Efficacy results The increase in mpef as primary variable was statistically significantly greater in the Symbicort group than in the Pulmicort + Theolong group (p=0.0051: ANCOVA). Regarding secondary variables, the increase in epef was statistically significantly greater in the Symbicort group than in the Pulmicort + Theolong group (p=0.0355: ANCOVA), but there were no statistically significant differences in the change of other secondary variables (asthma symptom score, use of short-acting β 2 -agonist, night time awakenings due to asthma symptoms, symptom free day, asthma control day and FEV 1 ) between treatment groups. Table S 2 Analysis of change from run-in period to whole treatment period in morning PEF (L/min) (FAS) Treatment Estimate SEM 95% CI p-value Lower Upper Symbicort 15.24 2.18 10.95 19.52 - PUL + Theolong 6.47 2.22 2.11 10.84 - Symbicort - [PUL + Theolong] 8.76 3.11 2.64 14.88 0.0051 PUL: Pulmicort, SEM: Standard error of the mean, CI: Confidence interval ANCOVA model (an additive model) including treatment as fixed factor, and baseline as a covariate. Table S 3 Analysis of changes from run-in period to whole treatment period between Symbicort and Pulmicort+Theolong in secondary variables Secondary variable Difference of changes (Symbicort - [PUL+Theolong]) Estimate SEM 95% CI p-value Lower Upper Evening PEF (L/min) 6.23 2.95 0.43 12.04 0.0355 Asthma symptom score Daytime -0.04 0.04-0.12 0.03 0.2632 Night time -0.06 0.04-0.14 0.01 0.0910 Total -0.10 0.07-0.24 0.04 0.1437 Number of use of short-acting β 2 -agonist Daytime -0.02 0.05-0.11 0.07 0.6467 Night time -0.01 0.03-0.07 0.05 0.7483 Total -0.04 0.07-0.18 0.10 0.5812 % of short-acting β 2 -agonist free days -0.78 2.14-4.98 3.42 0.7148 % of night time awakening days 1.06 1.26-1.42 3.54 0.4013 % of symptom free days 4.77 2.96-1.06 10.59 0.1082 % of asthma control days 4.98 2.95-0.82 10.79 0.0919 FEV 1 0.05 0.03-0.00 0.11 0.0685 PUL: Pulmicort, SEM: Standard error of the mean, CI: Confidence interval ANCOVA model (an additive model) including treatment as fixed factor, and baseline as a covariate. 6
Safety results Overall, the both treatments were safe and well tolerated. The incidence and nature of AEs were similar between the both treatment groups. Nasopharyngitis and headache were the most common adverse events in both treatment groups. The number of drug-related AEs (all nonserious) was numerically higher in the Symbicort group (Symbicort group: 19 events in 14 patients, Pulmicort + Theolong group: 11 events in 7 patients), mainly caused by reports of class-related AEs for β 2 -agonists, such as headache and muscle spasms. No deaths were reported in the study. The incidence of SAEs was low in the both treatment groups (Symbicort group: 1 event in 1 patient, Pulmicort + Theolong group: 2 events in 1 patient) and there was no SAE that was assessed as causally related to the investigational product. The incidence of DAEs was similar between the two groups (Symbicort group: 6 events in 6 patients, Pulmicort+Theolong group: 5 events in 5 patients). No other significant AEs were identified in this study. There were no findings for clinical laboratory values, vital signs or ECG that gave any reason for concern regarding the safety of either treatment. Table S 4 Number (%) of patients who had at least 1 adverse event in any category, and total numbers of adverse events (safety analysis set) Symbicort PUL + Theolong (n=176) (n=170) n (%) n (%) Number of patients a Any AEs 81 (46.0) 69 (40.6) Serious AEs leading to death 0 0 Serious AEs not leading to death 1 (0.6) 1 (0.6) AEs that caused patients to discontinue the study 6 (3.4) 5 (2.9) Other significant AEs 0 0 Any drug-related AEs b 14 (8.0) 7 (4.1) Total number of recorded events: Any AEs 133 126 Serious AEs leading to death 0 0 Serious AEs not leading to death 1 2 AEs that caused patients to discontinue the study 6 5 Other significant AEs 0 0 Any drug-related AEs b 19 11 PUL: Pulmicort a: Patients with multiple events in the same category are counted only once in that category. Patients with events in more than 1 category are counted once in each of those categories. b: The causality was judged by the investigator. 7
Table S 5 Number (%) of patients with the most commonly reported a adverse events by preferred term (safety analysis set) Preferred term Symbicort PUL + Theolong (n=176) (n=170) n (%) n (%) NASOPHARYNGITIS 17 (9.7) 27 (15.9) HEADACHE 12 (6.8) 5 (2.9) ASTHMA 5 (2.8) 2 (1.2) PHARYNGITIS 4 (2.3) 3 (1.8) BACK PAIN 4 (2.3) 1 (0.6) MUSCLE SPASMS 4 (2.3) 0 UPPER RESPIRATORY TRACT INFECTION 3 (1.7) 2 (1.2) GASTRITIS 3 (1.7) 1 (0.6) DIARRHOEA 3 (1.7) 0 DYSMENORRHOEA 3 (1.7) 0 RASH 3 (1.7) 0 BRONCHITIS ACUTE 2 (1.1) 3 (1.8) CYSTITIS 2 (1.1) 2 (1.2) PHARYNGOLARYNGEAL PAIN 2 (1.1) 2 (1.2) ACUTE TONSILLITIS 2 (1.1) 1 (0.6) CONSTIPATION 2 (1.1) 1 (0.6) DYSPHONIA 2 (1.1) 1 (0.6) RHINITIS ALLERGIC 2 (1.1) 1 (0.6) DRY EYE 2 (1.1) 0 HYPOAESTHESIA 2 (1.1) 0 MYALGIA 2 (1.1) 0 REFLUX OESOPHAGITIS 2 (1.1) 0 NAUSEA 1 (0.6) 3 (1.8) ABDOMINAL PAIN UPPER 1 (0.6) 2 (1.2) STOMATITIS 1 (0.6) 2 (1.2) PYREXIA 0 3 (1.8) ARTHRALGIA 0 2 (1.2) GASTROENTERITIS 0 2 (1.2) INFLUENZA 0 2 (1.2) TOOTHACHE 0 2 (1.2) TREMOR 0 2 (1.2) PUL: Pulmicort a This table uses a cut-off of 1% of patients on PT level in any of the treatment groups 8
Conclusion(s) Symbicort Turbuhaler 160/4.5 μg 1 inhalation twice daily was more effective than Pulmicort Turbuhaler 200 μg 1 inhalation twice daily + Theolong 200 mg twice daily regarding effect on morning PEF and evening PEF. No difference in efficacy was demonstrated between these treatments based on other outcome variables. The both treatments were well tolerated in Japanese patient with asthma and no difference in safety was seen between the two treatments. Date of the report 15 March 2007 9