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BI Trial No.: 1236.5 Page 3 Title of trial: Bioequivalence of 80 mg telmisartan/10 mg ramipril fixed-dose combination compared with the monocomponents, telmisartan and ramipril (two different formulations) given concomitantly to healthy male and female volunteers (an open-label, randomised, single-dose, three-way crossover study) Principal Investigator: Trial site: Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: planned: entered: 84 Data of this study have not been published I Germany To demonstrate the bioequivalence of 80 mg telmisartan/10 mg ramipril fixeddose combination versus its monocomponents given concurrently Open-label, randomised, single-dose, 6-sequence, 3-way crossover design actual: enrolled: 129 entered: 84 Test treatment: telmisartan and ramipril, fixed-dose combination entered: 84 treated: 83 analysed (for primary endpoint): 83 Diagnosis and main criteria for inclusion: Reference treatment 1: telmisartan (Micardis ) tablet + ramipril (Altace ) capsule entered: 84 treated: 84 analysed (for primary endpoint): 83 Reference treatment 2: telmisartan (Micardis ) tablet + ramipril (Delix ) tablet entered: 84 treated: 82 analysed (for primary endpoint): 82 Healthy male and female volunteers, age 18 and 55 years, body mass index (BMI) range: 18.5 and 29.9 kg/m 2
BI Trial No.: 1236.5 Page 4 Test product: Telmisartan and ramipril, fixed-dose combination tablet dose: 80 mg telmisartan/10 mg ramipril mode of admin.: Oral administration after an overnight fast of at least 10 hours, with 240 ml water batch no.: Reference therapy 1: dose: mode of admin.: batch no.: Reference therapy 2: dose: mode of admin.: batch no.: Duration of treatment: G67682 (B071000165 CTSS) Telmisartan (Micardis ) tablet and ramipril (Altace ) capsule 80 mg telmisartan and 10 mg ramipril Oral administration after an overnight fast of at least 10 hours, with 240 ml water Telmisartan (Micardis ): 508965 (B061000323), Ramipril (Altace ): 26074 (B061000675) Telmisartan (Micardis ) tablet and ramipril (Delix ) tablet 80 mg telmisartan and 10 mg ramipril Oral administration after an overnight fast of at least 10 hours, with 240 ml water Telmisartan (Micardis ): 508965 (B061000323), Ramipril (Delix ): N534 (B061002812 CTSS) Single dose during each of 3 consecutive treatment periods with sampling for 96 hours, followed by a 2-week washout period between treatments
BI Trial No.: 1236.5 Page 5 Criteria for evaluation: Efficacy / clinical pharmacology: Safety: Statistical methods: Bioequivalence of the telmisartan/ ramipril fixed-dose combination (FDC) and the monocomponents Micardis and Altace (Mic+Alt) and Micardis and Delix (Mic+Del) Primary endpoints: AUC 0- of telmisartan and ramiprilat (FDC, Mic+Alt, Mic+Del) and ramipril (FDC, Mic+Del); C max of telmisartan and ramiprilat (FDC, Mic+Alt, Mic+Del) and ramipril (FDC, Mic+Del); AUC 0-24 of telmisartan and ramiprilat (FDC, Mic+Alt, Mic+Del); AUC 0-tz of ramipril (FDC, Mic+Del) Secondary endpoints: AUC 0- of ramipril (Mic+Alt); C max of ramipril (Mic+Alt); AUC 0-tz of ramipril (Mic+Alt); t max, λ z, t 1/2, MRT po, CL/F, and V z /F of all analytes Comparison of treatments regarding bioequivalence was done in hierarchical order i.e.: 1. FDC versus Micardis plus Altace regarding telmisartan and ramiprilat AUCs and C max, if successful then 2. FDC versus Micardis plus Delix regarding telmisartan, ramiprilat and ramipril AUCs and C max, if successful then 3. Micardis plus Altace versus Micardis plus Delix regarding ramiprilat AUC and C max. If one of these comparisons failed than the successive tests were only descriptively interpreted. Physical examination, vital signs (blood pressure [BP], pulse rate [PR]), 12-lead electrocardiogram (ECG), clinical laboratory tests, adverse events (AEs), and tolerability Pharmacokinetic parameters of telmisartan, ramipril and ramiprilat were evaluated separately. The statistical model was an analysis of variance (ANOVA) on log transformed parameters including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'. Confidence intervals (CIs) were based on the residual error from ANOVA. Two-sided 90% CIs for the intra-subject ratio of telmisartan's and ramiprilat's AUC 0-, AUC 0-24, and C max, and ramipril's AUC 0-, AUC 0-tz, and C max were calculated to determine whether the CIs were contained in the acceptance range for bioequivalence (BE).
BI Trial No.: 1236.5 Page 6 BE regarding AUCs of telmisartan and AUCs and C max of ramiprilat and ramipril was assessed using the conventional acceptance range of 80-125%. As telmisartan is a highly variable drug, BE regarding C max of telmisartan was assessed using the extended acceptance range of 75-133%. For all other parameters, descriptive statistics were calculated. For all categorical parameters, frequencies were tabulated. SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: For this trial, 129 healthy subjects were enrolled. Of these, 84 subjects were randomised. All randomised subjects received at least 1 dose of trial drug, forming the safety population. There were 2 discontinuations; all other 82 subjects (97.6% of the safety population) completed the study as planned. All but 1 of 84 subjects were white (98.8%); 56.0% of subjects were female. The mean (SD) age was 39.1 (10.2) years. There were no relevant medical history or concomitant medical conditions reported at baseline. Geometric mean plasma concentration-time profiles were superimposable for telmisartan and ramiprilat for all treatments; ramipril showed a delayed absorption for Mic+Alt treatment, compared with FDC and Mic+Del treatment. Comparable pre-dose ramiprilat concentrations were detected in period 2 and 3 for all treatments (FDC, Mic+Alt, Mic+Del). For the comparison of the FDC versus the monocomponent treatments for telmisartan, the adjusted gmean ratios (Test/Reference) and their 90% CIs were all contained in the acceptance range for bioequivalence of 80% to 125% (FDC vs. Mic+Alt: C max : 91.67% [84.00%, 100.04%], AUC 0- : 94.31% [89.90%, 98.94%], AUC 0-24 : 93.02% [89.21%, 96.99%]; FDC vs. Mic+Del: C max : 94.20% [86.29%, 102.85%], AUC 0- : 98.58% [93.95%, 103.44%], AUC 0-24 : 97.54% [93.53%, 101.73%]). For the comparison of the FDC with the monocomponents administered in a replicated design for telmisartan, the adjusted gmean ratios and their 90% CIs were all contained in the acceptance range for bioequivalence of 80% to 125% (FDC vs. free combinations: C max : 92.92% [86.22%, 100.14%], AUC 0- : 96.40% [92.18%, 100.82%], AUC 0-24 : 95.24% [91.61%, 99.01%]). For the comparison of the FDC with the monocomponent treatments for
BI Trial No.: 1236.5 Page 7 ramiprilat, the adjusted gmean ratios and their 90% CIs were all within the acceptance range for bioequivalence of 80% to 125% (FDC vs. Mic+Alt: C max : 99.35% [94.00%, 105.00%], AUC 0- : 98.55% [95.76%, 101.42%], AUC 0-24 : 97.96% [94.83%, 101.21%]; FDC vs. Mic+Del: C max : 95.57% [90.40%, 101.03%], AUC 0- : 99.92% [97.08%, 102.84%], AUC 0-24 : 96.41% [93.31%, 99.62%]). For the comparison of the FDC versus the monocomponents for ramipril, all adjusted gmean ratios and their 90% CIs were contained in the acceptance range for bioequivalence of 80% to 125% (FDC vs. Mic+Alt: C max : 93.07% [84.43%, 102.59%], AUC 0- : 93.67% [88.59%, 99.05%], AUC 0-tz : 93.28% [88.16%, 98.71%]; FDC vs. Mic+Del: C max : 93.13% [84.46%, 102.70%], AUC 0- : 93.42% [88.33%, 98.80%], AUC 0-tz : 93.15% [88.00%, 98.59%]). For the comparison between the 2 monocomponent treatments for ramiprilat and ramipril, all adjusted gmean ratios and their 90% CIs were contained in the acceptance range for bioequivalence of 80% to 125% (ramiprilat: C max : 96.20% [91.00%, 101.69%], AUC 0- : 101.39% [98.51%, 104.35%], AUC 0-24 : 98.42% [95.25%, 101.69%]; ramipril: C max : 100.07% [90.75%, 110.36%], AUC 0- : 99.73% [94.30%, 105.48%], AUC 0-tz : 99.85% [94.34%, 105.69%]). Female subjects had a higher telmisartan exposure and lower inter-individual variability than male subjects in all treatment periods. For the 3 treatments, the intra-individual variability was comparable for both female and male subjects; the adjusted gmean ratios and their 90% CIs were not different by gender. Safety results: Out of 84 randomised subjects, 82 subjects received all 3 planned doses of study medication (80 mg telmisartan/10 mg ramipril, administered as FDC, Mic+Alt, and Mic+Del). One subject discontinued after treatment period 2, receiving only 2 doses of 80 mg telmisartan/ 10 mg ramipril; another subject discontinued in the course of period 1, receiving only 1 dose of 80 mg telmisartan/10 mg ramipril. In this trial, 55 subjects (65.5%) reported at least 1 AE, including 2 subjects (2.4%) with AEs at screening, no subject with AEs in the post-study period, and 55 subjects (65.5%) with AEs during the treatment periods. The incidence of AEs was lower under FDC treatment (31.3%) than under the other treatments (Mic+Alt: 44.0%, Mic+Del: 37.8%). The most frequently reported AEs by preferred term were headache (32.1%),
BI Trial No.: 1236.5 Page 8 fatigue (28.6%), dizziness (21.4%), nausea (9.5%), and diarrhoea (8.3%). For headache, fatigue, and diarrhoea, the incidences were similar over treatments. Incidences of dizziness and nausea were lower under FDC treatment (dizziness: 3.6%, nausea: 0.0%) than under Mic+Alt treatment (dizziness: 11.9%, nausea: 4.8%), or Mic+Del treatment (dizziness: 11.0%, nausea: 7.3%). Most reported AEs were of mild intensity (39.3% overall; FDC: 24.1%, Mic+Alt: 32.1%, Mic+Del: 23.2%) or of moderate intensity (23.8% overall, FDC: 7.2%, Mic+Alt: 10.7%, Mic+Del: 13.4%). There were 2 subjects (2.4%) with severe AEs (Mic+Alt: 1 subject, Mic+Del: 1 subject). Forty-seven subjects (56.0%) reported AEs that were considered drug-related. The incidence of drug-related AEs was slightly lower under FDC treatment (24.1%) than under Mic+Alt treatment (32.1%) or Mic+Del treatment (30.5%). Under all treatments, headache, fatigue, and dizziness were the most frequent drug-related AEs. No death and no SAEs were reported. There occurred 1 other significant AE; the subject discontinued study participation (Mic+Alt, drug hypersensitivity). For several laboratory parameters, mean changes from baseline differed by >10% from baseline. In 1 subject in the FDC period, changes of laboratory values (number of neutrophils) were reported as AE (neutropenia). The mean blood pressure reduction from baseline was highest 8 hours after drug intake (systolic BP [SBP]/ diastolic BP [DBP], FDC: 17.0/ 14.3 mmhg, Mic+Alt: 14.9/ 13.2 mmhg, Mic+Del: 16.8/ 14.7 mmhg). The mean BP remained below baseline 24 hours after drug intake (FDC: 8.5/ 6.7 mmhg, Mic+Alt: 6.9/ 6.8 mmhg, Mic+Del: 8.6/ 7.7 mmhg), and returned to baseline at 96 hours after drug intake. In a number of subjects under all treatments, a SBP of <100 mmhg and/or DBP <60 mmhg was observed, which remained at a reduced level for up to 24 hours. A number of these subjects experienced AEs (preferred term: dizziness, headache, fatigue), which may have been related to the observed reduction in BP. Most of these AEs were of mild intensity; all of the subjects recovered from their AEs. The PR declined after intake of the study medication in all treatment periods, with the greatest decrease 4 hours after drug intake (mean change from baseline, FDC: 6.1 bpm, Mic+Alt: 7.6 bpm, Mic+Del: 5.8 bpm). The mean PR returned to baseline 24 hours after drug intake in all treatment periods. At 96
BI Trial No.: 1236.5 Page 9 hours after drug intake, PR values were increased (mean change from baseline, FDC: 6.4 bpm, Mic+Alt: 5.0 bpm, Mic+Del: 5.2 bpm). None of these changes were considered clinically relevant. The overall tolerability of subjects was mostly considered 'good' by the investigator (FDC: good =100.0% of subjects; Mic+Alt: good =97.6%, satisfactory =1.2%, not satisfactory =1.2%; Mic+Del: good =97.6%, satisfactory =2.4%). Overall, no clinically relevant safety issues were reported. Conclusions: This trial established the bioequivalence of a 80 mg telmisartan/10 mg ramipril fixed-dose combination (FDC) compared with the monocomponents, telmisartan and ramipril, given either as Micardis 80 mg plus Altace 10 mg or as Micardis 80 mg plus Delix 10 mg concurrently in healthy volunteers. Also, Altace 10 mg was shown to be bioequivalent to Delix 10 mg under coadministration of Micardis. The FDC was shown to be safe and well tolerated with a safety profile comparable to the monocomponents.