Synopsis Name of the sponsor Takeda Pharmaceutical Company Limited Name of the finished product UNISIA Combination Tablets LD, UNISIA Combination Tablets Name of active ingredient Title of the study Study centers Related publications Study period (Date of obtaining first subject s informed consent - Date of completing the study treatment in the last subject) Phase of development Objective of the study Method of the study Number of subjects (planned and analyzed) Main entrance criteria HD Candesartan cilexetil/ amlodipine besylate Double-blind study of TCV-116 and amlodipine besylate in patients with mild/moderate essential hypertension 20 study centers Manuscript in preparation Date of first consent among subjects included in the treatment period: December 16, 2006 Date of last observation of last subject: December 25, 2007 Phase III To evaluate the efficacy and safety of the concomitant use of TCV-116 and amlodipine besylate in patients with mild/moderate essential hypertension by double-blind comparison. Multicenter, double-blind, randomized, parallel-group comparative study (Planned) Number of randomized subjects: 425 patients Number of subjects included in primary endpoint evaluation: 375 patients (Analyzed) Number of randomized subjects: 444 patients Full Analysis Set (FAS): 444 patients Safety Analysis Set: 444 patients Inclusion criteria: (1) Patients with mild/moderate essential hypertension. (2) Blood pressure: A sitting diastolic blood pressure of 90 mmhg and < 110 mghg and a sitting systolic blood (3) Age: 20 years. (4) Gender: male or female. (5) Patient status: outpatient. pressure of 140 mmhg and < 180 mmhg at two points during the control observation period.
(6) Able to understand this study and to comply with the procedure of it. (7) Able to give written consent to participate in this study prior to participation. Exclusion criteria: Subjects who met any of the following criteria were excluded from the study. (1) Patients with secondary hypertension, severe hypertension or malignant hypertension. (2) Patients received concomitant therapy with more than 3 different types of antihypertensives within 4 weeks prior to the control observation period. (3) Patients received concomitant therapy with candesartan cilexetil and amlodipine besylate within 4 weeks prior to the control observation period. (4) Pregnant women, lactating women, woman of child-bearing potential, or women planning to become pregnant. (5) Patients with a history of hypersensitivity to an ARB or Ca antagonist. (6) Patients with a clinically defined hepatic disorder. (7) Patients with a clinically defined renal disorder. (8) The following serious diseases or symptoms among the cardiovascular complications listed as factors influencing prognosis in the WHO-ISH Guidelines for the Management of Hypertension, 1999. 1. Heart diseases: Myocardial infarction, coronary arterial revascularization, angina pectoris, congestive heart failure, arrhythmia requiring treatment, valve stenosis and atrial fibrillation 2. Cerebrovascular disorders: Cerebral infarction/cerebral hemorrhage and transient cerebral ischemia attack 3. Renal diseases: Renal failure and severe renal disorders 4. Vascular diseases: Dissecting aortic aneurysm and arteriosclerosis obliterans 5. Advanced hypertensive retinopathy: Hemorrhages, exudates
or papilledema (9) Patients with hyperkalemia. (10) Patients with a malignant tumor. (11) Patients with drug abuse or dependence or with a history of drug abuse or dependence. (12) Patients received another investigational product within 12 weeks prior to the control observation period. (13) Other patients judged inappropriate for entry in this study by the investigator or subinvestigator. Test product, dose and mode of administration, and batch number Investigational products - TCV-116 tablets (each tablet contains 4 or 8 mg of candesartan cilexetil) - TCV-116 placebo tablets (indistinguishable from TCV-116 tablets in appearance) - Amlodipine besylate capsules (each capsule contains any of the following combinations of amlodipine besylate 2.5 mg and placebo [2 tablets in total], and were indistinguishable in appearance from each other). - 0-mg capsules: Each capsule contains two placebo tablets of amlodipine besylate. - 2.5-mg capsules: Each capsule contains one amlodipine besylate 2.5 mg tablet and one placebo tablet of amlodipine besylate [2 tablets in total]. - 5-mg capsules: Each capsule contains two amlodipine besylate 2.5 mg tablets. Dose and mode of administration: During the control observation period, one TCV-116 placebo tablet and one amlodipine besylate capsule were simultaneously administered once daily. During the treatment period, a combination of one TCV-116 0-, 4- or 8-mg tablet and one amlodipine besylate 0-, 2.5- or 5-mg capsule were administered simultaneously once daily (0 mg/0 mg, 8 mg/0 mg, 4 mg/2.5 mg, 8 mg/2.5 mg, 0 mg/5 mg, 4 mg/5 mg, 8 mg/5 mg). Batch numbers: Investigational products for the control observation period (TCV-116 placebo tablets and amlodipine besylate capsules): Z5425195
Duration of Treatment Endpoint Investigational products for the treatment period (TCV-116 tablets, TCV-116 placebo tablets and amlodipine besylate capsules): DB5429276 Four weeks of control observation and 12 weeks of treatment Efficacy Primary endpoint Trough sitting diastolic blood pressure Secondary endpoint Trough sitting systolic blood pressure Statistical Methods Safety Adverse events, vital signs, body weight, resting 12-lead ECG and laboratory tests Analyses of efficacy endpoints (1) Primary analysis of the primary endpoint The following analyses were performed using the Full Analysis Set (FAS). i) Summary statistics for the trough sitting diastolic blood pressure (change from the end of the control observation period at the end of the treatment period) and 95% confidence interval for the mean were calculated for each group. The mean and standard deviations were displayed as a graph. ii) The data were analysed using the following response surface method. Change in trough sitting diastolic blood pressure (the end of the treatment period the end of the control observation period) = β 0 + β 1 D TCV-116 + β 2 D amlodipine besylate + ε where, DTCV-116 and D amlodipine besylate are the daily dose of TCV-116 and amlodipine besylate, respectively. β 1 and β 2 are the parameters indicating the first-order dose-response relationship of TCV-116 and amlodipine besylate, respectively. ε is an error variable. Using the above model, the estimate, standard error and p-value of each parameter were calculated. For reference, designating the above model as the initial model, the final model was selected by the hierarchical step-up method using a significance level of 10% (two-sided) for the second-order term or
interaction term of TCV-116 and amlodipine besylate. The following analyses were performed using the final model. 1. The estimate, standard error and p-value of each parameter were calculated. 2. Using this model, the mean change in trough sitting diastolic blood pressure at each dose (0 mg/0 mg, 8 mg/0 mg, 4 mg/2.5 mg, 8 mg/2.5 mg, 0 mg/5 mg, 4 mg/5 mg, 8 mg/5 mg) and its two-sided 95% confidence interval were estimated. 3. A response surface was estimated within the dose ranges of TCV-116 (0 to 8 mg) and amlodipine besylate (0 to 5 mg) and displayed as a graph. (2) Secondary analyses of the primary endpoint i) The point estimate of the mean in each group in the FAS and its two-sided 95% confidence interval were calculated using a one-way analysis of variance, with treatment group (0 mg/0 mg, 8 mg/0 mg, 4 mg/2.5 mg, 8 mg/2.5 mg, 0 mg/5 mg, 4 mg/5 mg, 8 mg/5 mg) as the independent variable. In addition, the point estimate of the inter-group difference (concomitant therapy [8 mg/5 mg] group each monotherapy [8 mg/0 mg and 0 mg/5 mg] group) in the mean trough sitting diastolic blood pressure and its two-sided 95% confidence interval were calculated. A contrast test (comparison between 8 mg/0 mg and 8 mg/5 mg) using a contrast coefficient (0, -1, 0, 0, 0, 0, 1) and a contrast test (comparison between 0 mg/5 mg and 8 mg/5 mg) using a contrast coefficient (0, 0, 0, 0, -1, 0, 1) were performed for the groups (0 mg/0 mg, 8 mg/0 mg, 4 mg/2.5 mg, 8 mg/2.5 mg, 0 mg/5 mg, 4 mg/5 mg, 8 mg/5 mg). (3) Secondary endpoint The data regarding the secondary endpoint were subjected to the same analyses as the primary analysis and the secondary analyses of the primary endpoint. Analyses of the safety endpoints Adverse events in the Safety Analysis Set were summarized. The
incidence of adverse events was summarized by causality with the investigational product for the treatment period for each group. For the safety evaluation, the incidence of adverse events was analyzed by the χ-square test for a contingency table between groups. The incidence of adverse events was determined in two situations, i.e., when events not related to the investigational product for the treatment period were included or excluded. For each symptom/sign handled as an adverse event, the incidence was summarized by causality with the investigational product for the treatment period, by severity and causality with the investigational product for the treatment period, and by onset time and causality with the investigational product for the treatment period for each group. Summary results and conclusion Efficacy 1. Primary endpoint The change (mean ± standard deviation) from the end of the control observation period in trough sitting diastolic blood pressure at the end of the treatment period was -10.20 ± 8.450 mmhg in the 4 mg/2.5 mg group, -17.14 ± 6.912 mmhg in the 4 mg/5 mg group, -11.88 ± 5.554 mmhg in the 8 mg/2.5 mg group, -16.18 ± 8.476 mmhg in the 8 mg/5 mg group, -7.79 ± 8.185 mmhg in the 8 mg/0 mg group, -11.23 ± 7.057 mmhg in the 0 mg/5 mg group and -3.00 ± 8.349 mmhg in the 0 mg/0 mg group. The results of the analysis using the initial response surface model are shown below. The estimates of the first-order effects of the daily doses of TCV-116 and amlodipine besylate were -0.600 (S.E. = 0.108, p<0.0001) and -1.767 (S.E. = 0.172, p<0.0001), respectively. In the final model, the first-order effects of the daily doses of TCV-116 and amlodipine besylate, and the second-order effect of the daily dose of TCV-116 were included. The interaction term of the daily doses of TCV-116 and amlodipine besylate was not included in this model. The estimates of the first-order effects of the daily doses of TCV-116 and amlodipine besylate were -1.635 (S.E. = 0.529, p=0.0021) and -1.728 (S.E. = 0.172, p<0.0001), respectively. The estimate of the second-order effect of the daily dose of TCV-116 was 0.127 (S.E. = 0.064, p<0.0464). The estimates of the mean change in trough sitting diastolic blood pressure at each dose and its 95% confidence interval
determined using the final model were -11.528 (95% CI, -13.389 to -9.668) mmhg in the 4 mg/2.5 mg group, -15.847 (95% CI, -17.705 to -13.989) mmhg in the 4 mg/5 mg group, -11.967 (95% CI, -12.958 to -10.976) mmhg in the 8 mg/2.5 mg group, -16.286 (95% CI, -17.587 to -14.985) mmhg in the 8 mg/5 mg group, -7.648 (95% CI, -8.954 to -6.342) mmhg in the 8 mg/0 mg group, -11.340 (95% CI, -12.729 to -9.952) mmhg in the 0 mg/5 mg group and -2.703 (95% CI, -4.510 to -0.895) mmhg in the 0 mg/0 mg group. The change from the end of the control observation period in trough sitting diastolic blood pressure at the end of the treatment period was analyzed by the one-way ANOVA model. The point estimates of the inter-group difference (concomitant therapy [8 mg/5 mg] group each monotherapy [8 mg/0 mg and 0 mg/5 mg] group) in the mean trough sitting diastolic blood pressure and its two-sided 95% confidence interval were -8.388 (95% CI, -10.542 to -6.234) for the difference between the 8 mg/5 mg and 8 mg/0 mg groups, and -4.946 (95% CI, -7.105 to -2.786) for the difference between the 8 mg/5 mg and 0 mg/5 mg groups. The contrast test revealed a significant difference between the 8 mg/5 mg and 8 mg/0 mg groups (p<0.0001), and between the 8 mg/5 mg and 0 mg/5 mg groups (p<0.0001). 2. Secondary endpoint The change from the end of the control observation period in trough sitting systolic blood pressure at the end of the treatment period was -16.31 ± 12.347 mmhg in the 4 mg/2.5 mg group, -27.08 ± 11.626 mmhg in the 4 mg/5 mg group, -20.15 ± 9.562 mmhg in the 8 mg/2.5 mg group, -26.77 ± 10.520 mmhg in the 8 mg/5 mg group, -13.91 ± 11.168 mmhg in the 8 mg/0 mg group, -19.91 ± 10.710 mmhg in the 0 mg/5 mg group and -6.22 ± 11.996 mmhg in the 0 mg/0 mg group. In contrast, the results of the analysis using the initial response surface model are shown below. The estimates of the first-order effects of the daily doses of TCV-116 and amlodipine besylate were -0.888 (S.E. = 0.152, p<0.0001) and -2.753 (S.E. = 0.243, p<0.0001), respectively. The final model was the same as the initial model in that the interaction term of the daily doses of TCV-116 and amlodipine besylate was not
included. In addition, the model selected for analyses was the same as the initial model. The estimates of the mean change in trough sitting systolic blood pressure at each dose and its 95% confidence interval determined using the final model were -16.953 (95% CI, -18.067 to -15.840) mmhg in the 4 mg/2.5 mg group, -23.836 (95%CI, -25.200 to -22.472) mmhg in the 4 mg/5 mg group, -20.506 (95%CI, -21.867 to -19.145) mmhg in the 8 mg/2.5 mg group, -27.389 (95%CI, -29.168 to -25.609) mmhg in the 8 mg/5 mg group, -13.623 (95%CI, -15.462 to -11.784) mmhg in the 8 mg/0 mg group, -20.284 (95%CI, -22.130 to -18.438) mmhg in the 0 mg/5 mg group and -6.518 (95%CI, -9.048 to -3.989) mmhg in the 0 mg/0 mg group. The change from the end of the control observation period in trough sitting systolic blood pressure at the end of the treatment period was analyzed by the one-way ANOVA model. The estimate of the inter-group difference (concomitant therapy [8 mg/5 mg] group each monotherapy [8 mg/0 mg and 0 mg/5 mg] group) in the mean trough sitting systolic blood pressure and its two-sided 95% confidence interval was -12.862 (95% CI, -15.914 to -9.811) for the difference between the 8 mg/5 mg and 8 mg/0 mg groups, and -6.853 (95%CI, -9.912 to -3.794) for the difference between the 8 mg/5 mg and 0 mg/5 mg groups. The contrast test revealed a significant difference between the 8 mg/5 mg and 8 mg/0 mg groups (p<0.0001), and between the 8 mg/5 mg and 0 mg/5 mg groups (p<0.0001). Safety One subject in the 8 mg/0 mg group died during the treatment period. One other serious adverse event occurred in the 8 mg/0 mg group during the treatment period. These events were not related to the investigational product in the investigator s opinion. Two events in two subjects in the 8 mg/0 mg group, including the above death, led to the withdrawal of treatment during the treatment period. Neither event was deemed to be related to the investigational product. The incidence of adverse events including those not related to the investigational product was 44.6% (45/101) in the 8 mg/5 mg group, 47.2% (17/36) in the 8 mg/2.5 mg group, 42.0% (42/100) in the 8 mg/0 mg group, 49.0% (49/100) in the 0 mg/5 mg group, 44.4% (16/36) in
the 0 mg/0 mg group, 41.7% (15/36) in the 4 mg/5 mg group and 45.7% (16/35) in the 4 mg/2.5 mg group. The differences in the incidence of adverse events among the groups were not significant (p = 0.9737). The incidence of adverse events excluding those not related to the investigational product was 7.9% (8/101) in the 8 mg/5 mg group, 5.6% (2/36) in the 8 mg/2.5 mg group, 10.0% (10/100) in the 8 mg/0 mg group, 7.0% (7/100) in the 0 mg/5 mg group, 8.3% (3/36) in the 0 mg/0 mg group, 2.8% (1/36) in the 4 mg/5 mg group and 5.7% (2/35) in the 4 mg/2.5 mg group. The differences in the incidence of adverse events among the groups were not significant (p = 0.8650). The types and severity of the adverse events commonly observed in this study were similar to those already reported in the package inserts of TCV-116 and amlodipine besylate. With the exception of the death in the 8 mg/0 mg group during the treatment period, all adverse events were mild or moderate. No severe adverse events occurred. Conclusion Concomitant therapy with TCV-116 and amlodipine besylate (8 mg/5 mg) given orally once daily for 12 weeks is expected to have a sufficient therapeutic effect and a good safety profile in patients with mild/moderate essential hypertension. Date of Report June 3, 2011