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SPIRIVA Tiotropium bromide Page: 1 of 4 Titel of Study: Investigator: A Multiple Dose Comparsion of 18 µg, 36 µg of Tiotropium Inhalation Capsules and Oxitropium Metered Dose Inhaler (2 puffs of 100 µg) in a 4-week, doubleblind, double-dummy, Safety and Efficacy Study in Patients with Chronic Obstructive Pulmonary Disease (COPD) Principal Investigator: Study centres: 42 centers Puplication (reference): N/A Clinical phase: III Objectives: Methodology: The objective of this study is to compare the efficacy and safety of Tiotropium inhalation capsules (18 µg or 36 µg once daily) and oxitropium (Tersigan ) metered dose inhaler (2 puffs of 100 µg t.i.d.) in patients with chronic obstructive pulmonary disease (COPD). 4-week, randomized, double-blind, double-dummy, verum controlled, parallel groups design No. of subjects: total: 201 each treatment: Tiotropium 18 µg: 67 Tiotropium 36 µg: 66 Oxitropium: 68 Diagnosis and main criteria for inclusion: Test product: dose: mode of admin: COPD (chronic bronchitis, and emphysema) patients aged 40 years, with FEV 1.0 70% predicted normal, FEV 1.0 /FVC 70%, and smoking history of more than 10 pack-years. Tiotropium inhalation capsule 18 µg or 36 µg once daily Powder inhalation via the HandiHaler
Tiotropium bromide Page: 2 of 4 batch no.: 002506, 0006001 (placebo capsule: 9806002) Duration of treatment: Reference therapy: dose: mode of admin.: 4 weeks Oxitropium (Tersigan ) Metered Dose Inhaler (MDI) 2 puffs of 100 µg oxitropium bromide three times daily Inhalation batch no.: 001742 (placebo MDI: 002721) Criteria for evaluation: Efficacy: (1) Primary endpoint Through FEV 1.0 response (2) Secondary variables FEV 1.0 response at one hour after drug administration Through FVC response FVC response at one hour after drug administration PEF (morning and evening) COPD symptom scores (cough, sputum, shortness of breath, nocturnal sleep) Frequency of rescue use of ß2 stimulant Patients impression Physician s global evaluation Safety: Adverse events Blood pressure/heart rate ECG Laboratory tests Statistical methods: The statistical model for the analysis of all continuous response was analysis of covariance with terms for treatment and baseline as a covariate. SUMMARY-CONCLUSION: Efficacy results: Through FEV 1.0 response at 2 weeks after administration was 0.10 L over baseline in both tiotropium 18 µg and 36 µg groups, and at 4 weeks after administration 0.12 L over baseline in tiotropium 18 µg group and 0.14 L over baseline in tiotropium 36 µg group, which were statistically significant (P<0.001) increases compared to those for oxitropium group (0.01 L and 0.02 L over baseline at 2 and 4 weeks after administration, respectively).
Tiotropium bromide Page: 3 of 4 FEV 1.0 response at one hour after administration on the first day of dosing was 0.15 L over baseline in tiotropium 18 µg group, 0.17 L over baseline in tiotropium 36 µg, and 0.15 L over baseline in oxitropium group, and there were no significant differences observed between the treatment groups. Also at 2 weeks and 4 weeks after administration, there were no significant differences observed in FEV 1.0 response at one hour after administration between the treatment groups. The results for FVC paralleled those for FEV 1.0. In respect of the weekly mean morning PEF, tiotropium 18 µg was significantly (P<0.05) superior to oxitropium at 2 weeks and 3 weeks, with the difference of 10 L/min. The differences at 4 weeks was 5.61 L/min (p=0.4284). Tiotropium 36 µg was significantly (P<0.05) superior to oxitropium at all weeks, with the difference of 11 to 17 L/min. In respect of the weekly mean evening PEF, there was no significant difference observed between tiotropium 18 µg and oxitropium at any weeks, while tiotropium 36 µg was significantly (P<0.05) superior to oxitropium at 2 to 4 weeks, with the difference of 12 to 14 L/min. In respect of COPD symptom scores, cough score decreased after administration compared to baseline score in each treatment group, and there were no significant differences among the treatment groups. For sputum score and nocturnal sleep score, there were no changes from the baseline scores seen in any treatment groups. For shortness of breath score, there was a decrease from the baseline scores seen in tiotropium 18 µg and 36 µg groups, and the amount of the decrease was larger in tiotropium 18 µg group than that in 36 µg group. Statistically significant difference (P<0.05) was seen between tiotropium 18 µg and oxitropium at 4 weeks. Safety results: Adverse events were reported in 28.4%, 42.2% and 23.5% of patients in tiotropium 18 µg group, 36 µg group, and oxitropium group, respectiverly. The incidence of dry mouth was 27.3% with tiotropium 36 µg group, 1.5% with tiotropium 18 µg and 4.4% with oxitropium group. Adverse events of which causal relationship with the study drug was not denied (adverse drug reactions) were reported in 7.5% of patients in tiotropium 18 µg group, 30.3% in 36 µg and 8.8% in oxitropium group. Adverse drug reactions which occurred in 3% or more of patients in any of the treatment groups were dry mouth, which was reported in 1.5% of patients in tiotropium 18 µg group, 27.3% in tiotropium 36 µg group and 2.9% in oxitropium group, constipation, which was reported in 4.5% only in tiotropium 36 µg group and dysuria, which was reported in 4.5% only in tiotropium 36 µg group.
Tiotropium bromide Page: 4 of 4 The only serious adverse event reported in patients treated with the study drug was syncope after urination, which was reported in one patient in tiotropium 36 µg group. Since this patient had developed syncopal attack two and four years before, the causal relationship with the study drug was denied. One patient (diarrhea) in tiotropium 18 µg group, and 2 patients (dry mouth & flush, and dry mouth & tachycardia) in tiotropium 36 µg group discontinued from the study due to adverse events. No patients in oxitropium group discontinued from the study. There were no clinically significant changes observed in laboratory tests and vital signs, without any significant difference among the three groups. In summary, although tiotropium 36 µg had a higher incidence of adverse events, especially dry mouth, tiotropium 18 µg showed no clinically relevant findings and there was no difference in the safety profile observed between tiotropium 18 µg and oxitropium. Conclusions: In 4-week treatment, tiotropium 18 µg and 36 µg administered once daily yielded a significant improvement in through FEV 1.0 compared to oxitropium administered three times daily, and there was no significant difference between 18 µg and 36 µg. For safety, tiotropium 18 µg was safe in 4-week treatment, whereas dry mouth was reported with a higher frequency in 36 µg. This study has demonstrated tiotropium 18 µg administered once daily is a safe and effective bronchodilator for maintenance treatment of bronchospasm in patients with COPD. The overall risk-benefit favors the 18 µg dose over the 36 µg dose.