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BI Trial No.: 1207.26 Page 3-15 FEB 07 04 OCT 05 to 30 NOV 05 Title of study: Investigator: Study center(s): Publication (reference): Clinical phase: Objectives: Methodology: A randomised, open label, four-way crossover phase I trial to investigate the in vivo specificity of a single oral dose of 320 mg KUC 7483 CL co-administered with bisoprolol (10 mg daily), propranolol (160 mg daily), and acipimox (500 mg daily) over 5 days and a single inhalative dose of 100 µg salmeterol in healthy male subjects Dept. of Clinical Research, Human Pharmacology Centre Binger Str. 173, 55216 Ingelheim/Rhein, Germany n.a. Phase I To compare the metabolic and electrolyte effects of a single oral dose of 320 mg ritobegron administered alone or with a pre- and comedication with bisoprolol, propranolol and acipimox. In addition, to compare the metabolic and electrolyte effects of a single dose of 320 mg ritobegron with those of a single inhalatory dose of 100 µg salmeterol The study was to be performed according to a randomised, open label, four-way crossover design for the interaction treatments (treatment A: ritobegron alone; treatment B: bisoprolol + ritobegron; treatment C: propranolol + ritobegron; acipimox + ritobegron) followed by a sequential, open label positive control of salmeterol (treatment E). Treatments A, B, C, and D were randomly assigned according to period-balanced sequences. There was an interval of at least 6 days between consectuive periods. Investigators and volunteer subjects were not blinded with regard to the medication assigned and administered in each period. No. of subjects: planned: entered: 12 actual: enrolled: 12 Treatment A, B, C, D & E (crossover): entered: 12 treated: 12 analysed (for primary endpoint): 12 One subject (Subject 6) was discarded from the per-protocol data-set (PPS) for the second period (treatment D) due to a relevant protocol deviation
BI Trial No.: 1207.26 Page 4 15 FEB 07 04 OCT 05 to 30 NOV 05 Diagnosis and main criteria for inclusion: Healthy male Caucasian volunteers, age 30 and 60 years of age, BMI range: 18.5 and 29.9 kg.m -2, judged to be healthy on the basis of extensive prestudy investigation at the screening visit), willing and able to provide informed consent Test product: KUC 7483 CL Ritobegron 80 mg tablets for oral administration dose: Four 80 mg (320 mg) tablets on the morning of day 1 of periods 1, 2, 3, and 4 (Treatments A, B, C, and D) mode of admin.: Oral administration with 240 ml water after and overnight fast and rest while the subjects remained fasted until 4 hours after dosing batch no.: B05020 Test product for interaction (Tr. B): dose: Bisoprolol (Concor ) 5 mg tablet (Merck Pharma GmbH, Darmstadt, Germany) Treatment B: 1 tablet on the morning of day -5 and 2 (24 hours after dosing of ritobegron); two tablets once on the morning of days -4 to 1; ½ tablet on the morning of day 3 (48 hours after dosing of ritobegron) mode of admin.: Oral administration with 100 ml water batch no.: 3262306 Test product for interaction (Tr. C) dose: Propranolol (Dociton ) 80 mg tablet (mibe GmbH Arzneimittel, Brehna, Germany) Treatment C: 1 tablet on the morning of day -5 and 1 (one hour before dosing of ritobegron); one tablet in the morning and in the evening of days -4 to -1; ½ tablet on the morning of day 2 (24 hours after dosing of ritobegron) mode of admin.: Oral administration with 100 ml water batch no.: 050101 Test product for interaction (Tr. C) dose: mode of admin.: batch no.: Acipimox (Olbemox ) 250 mg capsule (Pfizer Pharma GmbH, Karlsruhe, Germany) Treatment D: capsule on the morning of day -4 and 1 (one hour before dosing of ritobegron); one capsule in the evening of days -4 to -1 Oral administration with 100 ml water A240E
BI Trial No.: 1207.26 Page 5 15 FEB 07 04 OCT 05 to 30 NOV 05 Duration of treatment: Ritobegron: single doses of 320 mg on the morning of day 1 of the first four periods; bisoprolol (treatment B): day -5 until the morning of day 3; propranolol (treatment C): day -5 until the morning of day 2; acipimox (treatment D): from the morning of day -4 until the morning of day 1); salmeterol (treatment E see below): single inhalatory dose of 100 µg on the morning of day 1 of the fifth period. The periods were separated by a 6-day washout period. The first period was preceded by a screening visit (SCR) within 21 days before the first medication; the end-of-study evaluation followed within 4-10 days after the last administration of the investigational medication Reference therapy: Salmeterol for inhalation (Serevent ) (Glaxo Smith Kline GmbH & Co. KG, München, Germany) dose: Treatment E (fifth period in all subjects): 2 puffs on the morning of day 1 mode of admin.: batch no.: By inhalation 4M774 Criteria for evaluation: Efficacy: Not applicable Pharmacokinetics: C max, t max and AUC 0-4 of KUC 7322 ZW (Treatments A, B, C and D) Safety: Primary (all treatments): Blood glucose, FFA, Insulin, C-Peptide, Potassium, Magnesium, and camp before dosing and at 0:30, 1:00, 2:00, 3:00, 4:00, and 24:00 hh:mm after dosing of ritobegron/salmeterol on day 1 summarised by the absolute and percentage response and weighted average value after dosing Secondary - general safety (all treatments): adverse events and wellbeing (throughout), physical examination (screening and end-of-study evaluation); vital functions (recumbent resting SBP/DBP and PR - before dosing and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00 and 24:00 hh:mm after dosing on day 1), digital ECG (HR, PR, QRS, QT, QTcB, QTcF, QTcN before dosing and at 0:30, 1:00, 2:00, 3:00, 4:00, 6:00 and 24:00 hh:mm after dosing on day ), clinical laboratory safety tests (haematology, clinical chemistry and urinalysis - at screening, at the end-of-study evaluation, and before and 24:00 hh:mm after dosing on day 1 in each study period); global assessment of safety and tolerability by the investigator at the end of each period
BI Trial No.: 1207.26 Page 6 15 FEB 07 04 OCT 05 to 30 NOV 05 Statistical methods: SUMMARY CONCLUSIONS: Efficacy results: Safety results: The study serves an exploratory descriptive purpose. Individual data were listed and extensive descriptive statistics were tabulated. No formal hypotheses were tested. Treatment contrasts were reported as the parametrically estimated differences of the true means for treatments B, C, and D vs. treatment A and for treatment E vs. treatment A; the estimates were reported with their 95% conficence interval estimate; p-values were reported for descriptive purposes; there was no adjustment for multiplicity; contrasts were considered nonsimultaneously Maximum plasma concentrations of KUC 7322 ZW occurred 0.5 to 1 hour post dose. Geometric mean C max were 2420, 2750, 2290, and 2820 ng/ml after administration of 320 mg ritobegron alone, following pre-treatment with bisoprolol, following pre-treatment with propranolol and following pre-treatment with acipimox, respectively, with an AUC 0-24 of 7320, 7410, 7330, and 7340 ng h/ml. Primary Treatment with ritobegron alone (treatment A) led to an average 8.9% increase in glucose, 254% increase in FFA, with an average 141% increase in insulin and 48.6% increase in C-peptide, an average 83% increase in camp with an average maximum change in potassium of -0.2 mmol/l, but no distinct change of the magnesium levels. In comparison with salmeterol (treatment E), the increases in glucose, FFA, insulin, C-peptide, and camp after ritobegron were distinctly larger, whereas the reduction in potassium was about the same. Pre- and comedication with bisoprolol (treatment B) had little effect on the rise in glucose (estimated difference µ B -µ A of the absolute response: -2.3 mg/dl, 95% CI: -6.2 to 1.6), the rise in FFA (estimated difference µ B -µ A of the absolute response: 0.07 nmol/l, 95% CI: -0.06 to 0.20), in insulin (estimated difference µ B -µ A of the absolute response: -0.77 µu/l, 95% CI: -3.03 to 1.5), and C-peptide (estimated difference µ B -µ A of the absolute response: -0.07 ng/ml, 95% CI: -0.31 to 0.16), whereas there was a discrete trend towards a slightly smaller rise in camp (estimated difference µ B -µ A of the absolute response: -3.28 nmol/l, 95% CI: -6.57 to 0.01). In contrast, pre- and comedication with propranolol (treatment C) reduced the rise in glucose (estimated difference µ C -µ A of the absolute response: -10.5 mg/dl, 95% CI: -14.4 to -6.6), the rise in insulin (estimated difference µc-µa of the absolute response: -7.0 µu/l, 95% CI: -9.3 to -4.8), the rise in C-peptide
BI Trial No.: 1207.26 Page 7 15 FEB 07 04 OCT 05 to 30 NOV 05 Safety results: (estimated difference µ C -µ A of the absolute response: -0.56 ng/ml, 95% CI: -0.80 to -0.33), and the rise in camp (estimated difference µ C -µ A of the absolute response: -14.3 nmol/l, 95% CI: -17.6 to -11.0); in contrast, there was no effect on the rise in FFA (estimated difference µ C -µ A of the absolute response: 0.06 nmol/l, 95% CI: -0.07 to 0.19). Propranolol also tended to reduce the rise in potassium (estimated difference µ C -µ A of the absolute response: -0.12 mmol/l, 95% CI: -0.03 to 0.27). Pre- and comedication with acipimox (treatment D) reduced the rise in FFA (estimated difference µ D -µ A of the absolute response: -0.35 nmol/l, 95% CI: -0.51 to -0.18), the rise in insulin (estimated difference µ D -µ A of the absolute response: -6.4 µu/l, 95% CI: -8.8 to -4.0), and the rise in C-peptide (estimated difference µ D -µ A of the absolute response: -0.45 ng/ml, 95% CI: -0.69 to -0.21); in contrast, acipimox had no effect on the rise in glucose (estimated difference µ D -µ A of the absolute response: -0.4 mg/dl, 95% CI: -4.3 to 3.5) and the rise in camp (estimated difference µ D -µ A of the absolute response: 0.88 nmol/l, 95% CI: -2.41 to 4.18). Secondary Eleven AE were reported in 6 subjects; no AE were reported for treatment with salmeterol and most AE for the further treatments related to the pre-medication days, those with acipimox, in particular. The most frequent event was flushing (7 AE in 5/12 subjects): it was mostly reported with acipimox (flushing in 4/12 subjects), but also once for ritobegron alone (treatment A) and for ritobegron combined with bisoprolol. Headache was reported on three occasions in two subjects, but the causal relationship vs. the investigational medication(s) is not conclusive in this regard. The AE were mostly mild, but considered to be related to the trial medication (including the medications used concomitantly). All AE recovered spontaneously and without sequels. None of the AE was severe. There were no serious AE. There were no AE that led to the discontinuation of trial subjects. There was no indication of noteworthy i.e. safety relevant individual or average values or changes for the conventional clinical laboratory tests over the course of the study or of possible treatment effects thereof. There was no indication of relevant changes upon physical examination over the course of the study. There was no indication of consistent treatment related changes in the vital parameters (changes from baseline) except for a reduction in resting recumbent SBP, DBP and PR during the premedications with bisoprolol and propranolol. With ritobegron alone, there was little if any - change in SBP and PR, but a slight reduction in average DBP.
BI Trial No.: 1207.26 Page 8 15 FEB 07 04 OCT 05 to 30 NOV 05 Conclusions: For treatment A (ritobegron alone) there were 3 subjects with at least one noteworthy change in QTcF ( 30 to < 60 msec); similar observations were made in one subject on treatment B and one subject on treatment D. For QTcB, there were 6, 1, 0, 2, 3 subjects with at least one noteworthy change for treatments A, B, C, D, and E, respectively. On average, over the first 2 hours after dosing, ritobegron was associated with a small increase in HR (+1.5 bpm), a distinct average increase in QT (+13.5 msec) and an even larger increase in QTc (QTcF: +17.3 msec), QTcB (+19.2 msec), and QTcN (+17.1 msec). The observed changes in HR over the first 2 hours after ritobegron were not affected by pre- and comedication bisoprolol and acipimox, but were reduced by propranolol; the observed increase in QT was unaffected by bisoprolol and propranolol, but was clearly reduced by acipimox; the observed increase in QTcF was blunted by all pre- and comedications (bisoprolol, propranolol, and acipimox), but mostly by propranolol. Pre- and co-medication with propranolol, bisoprolol and acipimox did not result in a change in peak and total exposure to KUC 7322 ZW. Single oral doses of 320 mg ritobegron induced metabolite and electrolyte effects that are larger than those of a single inhalatory dose of 100 µg salmeterol. These metabolic and electrolyte effects reflect both ß 3 - and ß 2 -adrenoceptor agonistic properties. Single oral doses of 320 mg ritobegron were generally well tolerated. There were no relevant effects on blood pressure and pulse rate, physical examination and overall clinical laboratory safety tests. Single oral doses of 320 mg ritobegron were associated with relevant prolongation of the electrocardiographic QT- and QTc-interval.