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Pharma GmbH & Co. KG BI Trial No.: 1184.11 Page 3 --- Title of study: Investigator: Study centre: Publication (reference): Clinical phase: Objectives: Methodology: A randomised, open-label four-way crossover study to evaluate relative bioavailability of tiotropium and salmeterol after inhalation of a fixed combined single dose (7.5 µg tiotropium, 25 µg salmeterol, inhalation powder, hard capsule, HandiHaler 2), a free combined single dose of 18 µg tiotropium [Spiriva HandiHaler ] and 50 µg salmeterol [Serevent Diskus ], a single dose of 50µg salmeterol (Serevent Diskus ) and a single dose of 18 µg tiotropium (Spiriva HandiHaler ) in healthy male volunteers Human Pharmacology Centre, Dept. of Clinical Research, BI Pharma GmbH & Co. KG, Germany None at this time I Assessment of the relative bioavailability of a fixed dose combination of tiotropium and salmeterol compared to a free dose combination of the marketed products of tiotropium and salmeterol (Spiriva and Serevent Diskus ). Assessment of the relative bioavailability of a fixed dose combination of tiotropium and salmeterol compared to tiotropium and salmeterol administered as individual mono substances from the marketed products. Assessment of safety and tolerability of the fixed combination of tiotropium and salmeterol in a PE capsule administered via the HandiHaler 2. Open-label, randomised, four-way crossover design No. of subjects: planned: entered: 36 each treatment actual: enrolled: 36 Diagnosis and main criteria for inclusion: Healthy male volunteers, age 21 and 50 years, BMI range: 18.5 and <30 kg/m 2
Pharma GmbH & Co. KG BI Trial No.: 1184.11 Page 4 Test product: dose: Fixed-dose combination of tiotropium 7.5 µg and salmeterol 25 µg inhalation powder, hard PE capsule 25 µg salmeterol administered as the xinafoate salt, 7.5 µg tiotropium administered as the bromide salt (1 capsule), mode of admin.: Oral inhalation via the HandiHaler 2 batch no.: Duration of treatment: Reference therapy: Serevent Diskus dose: mode of admin.: Tiotropium/salmeterol 7,5 µg+25 µg B062000067 HandiHaler 2: B052000307 1 day (single dose) for each of the four treatments (test and reference) 50 µg salmeterol, administered as the xinafoate salt (1 actuation) Oral inhalation via the Diskus inhaler batch no.: Serevent Diskus : B062000052 Reference therapy: Spiriva dose: 18 µg tiotropium, administered as the bromide salt (1 actuation) mode of admin.: Oral inhalation via the HandiHaler batch no.: Tiotropium 18 µg: B052000294 Spiriva HandiHaler : B052000140 Reference therapy: Free combination of Spiriva and Serevent Diskus dose: 50 µg salmeterol, administered as the xinafoate salt (1 actuation) and 18 µg tiotropium, administered as the bromide salt (1 actuation) mode of admin.: Sequential oral inhalation via the HandiHaler and the Diskus inhaler batch no.: Salmeterol Diskus : B062000052 Tiotropium 18 µg: B052000294 Spiriva HandiHaler B052000140
Pharma GmbH & Co. KG BI Trial No.: 1184.11 Page 5 Criteria for evaluation: Efficacy: Safety: Statistical methods: SUMMARY CONCLUSIONS: Efficacy results: Pharmacokinetics: primary endpoints: C max and AUC 0- (salmeterol); Ae 0-8, (tiotropium) secondary endpoints: C max and AUC 0- (tiotropium), AUC 0-tz, AUC t1-t2,, t max, λ z, t ½, MRT ih, CL/F, V z /F, Ae t1-t2 (tiotropium), fe t1-t2 (tiotropium), CL R,t1-t2 (tiotropium) Physical examination, vital signs (BP, PR), ECG, laboratory tests, adverse events and tolerability Confidence intervals. Analysis of variance with terms for treatment, period, sequence, and subject within sequence (for controlled intra-individual comparisons); with terms for treatment and subject (for uncontrolled intraindividual comparisons); with term for treatment (for inter-individual comparisons). Descriptive statistics. Pharmacokinetics: Tiotropium systemic exposure Tiotropium systemic exposure was assessed using Ae 0-8 (urinary excretion over an 8 hour interval) and C max values. Ae 0-8 was used to assess the total systemic exposure to tiotropium. Based on Ae 0-8 values, administration of the fixed-dose combination of tiotropium and salmeterol was found to result in a similar total exposure to tiotropium from the free combination of Spiriva and Serevent Diskus as well as from Spiriva Based on C max values, administration of the fixed-dose combination was found to result in higher (25.8 %) maximum tiotropium concentration compared to the free combination of Spiriva and Serevent Diskus (90% CI: 111.46, 141.96) and similarly a higher (38.6%) maximum tiotropium concentration compared to Spiriva (90% CI: 122.66, 156.62). The plasma concentration of tiotropium was higher following the administration of the fixed-dose combination compared to the free combination of Spiriva and Serevent Diskus and to Spiriva until 15 minutes post dosing. Based on Ae 0-8 and C max data, administration of the free combination of Spiriva and Serevent Diskus resulted in similar total and maximum tiotropium exposure as Spiriva alone.
Pharma GmbH & Co. KG BI Trial No.: 1184.11 Page 6 Efficacy results: Salmeterol systemic exposure Salmeterol systemic exposure was assessed using AUC 0- and C max values. Based on AUC 0- values, administration of the fixed-dose combination was found to result in a similar total systemic exposure to salmeterol as the free combination (of Spiriva and Serevent Diskus ) and Salmeterol Diskus. Based on C max values, administration of the fixed-dose combination was found to result in higher (79%) maximum salmeterol concentration compared to the free combination of Spiriva and Serevent Diskus (90% CI: 161.68, 198.19) and similarly a higher (80.8%) maximum salmeterol concentration compared to Salmeterol Diskus (90% CI: 163.27, 200.15). The plasma concentration of salmeterol was higher following the administration of the fixed-dose combination compared to the free combination of Spiriva and Serevent Diskus and to Salmeterol Diskus until 30 minutes post dosing. Based on AUC 0- and C max data, administration of the free combination of Spiriva and Serevent Diskus resulted in similar total and maximum salmeterol exposure as Salmeterol Diskus alone. Safety results: Safety was a secondary objective of this pharmacokinetic study in healthy individuals. Deaths, serious adverse events or adverse events resulting in study discontinuation were not observed. 15/36 study subjects reported at least one AE, 6 AEs in three study subjects were considered drug related. These six adverse events consisted of four episodes of headache in two subjects (one episode of headache in each of the four treatments) and two episodes of pruritus of both hands in the same subject with onset 34 hours after Serevent Diskus mono and 8 hours after the combination PE capsule. All of these AEs considered drug related were mild in intensity and recovered without treatment. No adverse event in this study was judged to be severe. The analysis of laboratory values did not reveal any relevant findings. The analysis of vital signs and ECG variables (heart rate, QT, QTcF, QTcN and QTcB) did not reveal any relevant treatment differences.
Pharma GmbH & Co. KG BI Trial No.: 1184.11 Page 7 Conclusions: The test product, i.e., the fixed-dose combination was found to result in a similar total exposure but higher maximum concentration of tiotropium and salmeterol compared to the free combination of Serevent Diskus and Spiriva as well as to the individual products, i.e., Serevent Diskus and Spiriva administered alone. The plasma concentration of salmeterol was higher following the administration of fixed-dose combination compared to the administration of free combination of Spiriva and Serevent Diskus as well as to Serevent Diskus until 30 minutes post dosing. Similarly, the plasma concentration of tiotropium was higher following the administration of fixed-dose combination compared to the administration of free combination of Spiriva and Serevent Diskus as well as Spiriva until 15 minutes post dosing. Administration of a free combination of Serevent Diskus and Spiriva did not significantly alter the pharmacokinetics of either drug in comparison to when they were administered on their own. High doses of salmeterol and other ß2-agonists have been described to cause a dose-dependent increase in heart rate, QTc and systolic blood pressure as well as a decrease in diastolic blood pressure. In the trial described here only minimal changes concerning these parameters were observed. While in general the three treatment groups comprising salmeterol showed slightly higher increases than the Spiriva mono group for heart rate, QTc and systolic blood pressure, the differences between the three treatment groups comprising salmeterol were minimal and their ordering was not consistent among the parameters. In summary, the differences in the time course of exposure between the three treatment groups comprising salmeterol did not translate into a difference concerning the parameters which are known to show systemic effects of high doses of salmeterol and other ß 2 -agonists. In summary, all four different single dose treatments applied in this study were well tolerated in healthy subjects with no differences between treatments identifiable with the sample size and design of the present study.