PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert.

Transcription

1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. PROPRIETARY DRUG NAME / GENERIC DRUG NAME: Caduet / Amlodipine besylate/atorvastatin calcium PROTOCOL NO.: A PROTOCOL TITLE: A Multi-Center, Open Label Study to Evaluate Long Term Safety of Caduet in Patient With Both of Hypertension and Hypercholesterolemia, or With Both of Angina Pectoris and Hypercholesterolemia Study Centers: A total of twenty (20) centers in Japan took part in the study and enrolled subjects. Study Initiation Date and Final Completion Date: 30 August 2010 to 18 February 2012 Phase of Development: Phase 4 Study Objectives: Primary Objective: The primary objective was to investigate the safety of amlodipine/atorvastatin 2.5 mg/5 mg, 2.5 mg/10 mg, 5 mg/5 mg or 5 mg/10 mg during 52 week treatment period. Secondary Objectives: The secondary objective was to investigate percent changes in low density lipoprotein cholesterol (LDL-C) and changes in trough systolic blood pressure (SBP) from baseline at each visit as the efficacy of amlodipine/atorvastatin combination tablets. In addition, percent changes in total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), and changes in apolipoprotein B, LDL-C/HDL-C and TC/HDL-C ratios and trough diastolic blood pressure (DBP) from baseline at each visit were investigated. METHODS Study Design: This was a multicenter, open-label study to evaluate the long-term safety profile of amlodipine/atorvastatin (2.5 mg/5 mg, 2.5 mg/10 mg, 5 mg/5 mg or 5 mg/10 mg doses). The trial consisted of 2 parts: a screening period and a treatment period. Subjects who met the eligibility criteria were enrolled in the treatment period, where subjects receiving a combination therapy of amlodipine and atorvastatin or amlodipine monotherapy were switched to one of the amlodipine/atorvastatin tablets (2.5 mg/5 mg, 2.5 mg/10 mg, 5 mg/5 mg and 5 mg/10 mg). For each subject, the dose of amlodipine contained in amlodipine/atorvastatin at Visit 1 was same as that used during the screening period. For Template version 1.1 Page 1

2 subjects who took atorvastatin during the screening period and whose LDL-C level at Visit 0 was <160 mg/dl, the dose of atorvastatin contained in amlodipine/atorvastatin at Visit 1 was same as that used during the screening period. For subjects who took atorvastatin 5 mg during the screening period and whose LDL-C level at Visit 0 was 160 mg/dl, the dose of atorvastatin contained in amlodipine/atorvastatin at Visit 1 was increased to 10 mg. For subjects who were untreated for hypercholesterolemia during the screening period (ie, subjects who had not received any statin therapy for at least 3 months during the previous year), the dose of atorvastatin contained in amlodipine/atorvastatin was determined by the Investigator. Figure 1 shows the study plan. Template version 1.1 Page 2

3 Figure 1 Study Design Caduet = amlodipine/atorvastatin. BP = Blood pressure; DBP = Diastolic blood pressure; LDL-C = Low density lipoprotein cholesterol; SBP = Systolic blood pressure; V = Visit; W = week. 1) Use of other antihypertensives than amlodipine was allowed on the condition that the same dose was used for at least 4 weeks before the start of the study treatment and the dosage regimen should not be modified during the study. 2) SBP and DBP levels at V1 (Week 0). 3) LDL-C level at V0 (Week 2). In the case of the subjects not achieving the target LDL-C level or BP levels after Week 12 (Visit 5), a change in the dose of amlodipine/atorvastatin may have been allowed at the Investigator's discretion at Week 12 (Visit 5). The schedule of study activities is summarized in Table 1. Template version 1.1 Page 3

4 Table 1. Schedule of Activities Screening Period Treatment Period Week (Allowance) ±7 d ±3d ±3d ±7d ±7d ±7d ±7d ±7d ±7d ±7d ±7d ±7d ±7d ±7d ±7 d Visit V0 V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 (Discontinued) a Informed consent X Confirmation of in/ex criteria X X Medical history X Vital signs (BP b and HR) X X X X X X X X X X X X X X X X Height, body weight X Pregnancy test (urine) c X X Physical examinations X Evaluation of adverse events (AE) X X X X X X X X X X X X X X Serious adverse events (SAE) X X X X X X X X X X X X X X X X Hematology d X X X X X Biochemical examination e X X X X X X Urinalysis (general test) f X X X X X 12-lead ECG X X Checking AP condition g X X X X X X X X X X X X X X X X Lipid parameters h X X X X X X PWV and/or CAVI i X X X Hs-CRP X X X Exploratory bio-markers j X X X Pharmacogenomic sampling (PGx) k X Prescription of the study drug X X X X X X X X X X X X X X Concomitant drugs and therapy X X X X X X X X X X X X X X X X Compliance checking X X X X X X X X X X X X X X X : Measurements were to be performed during the period. AP = angina pectoris; BP = blood pressure; CAVI = cardio ankle vascular index; d = days; ECG = electrocardiogram; HR = heart rate; Hs-CRP = high-sensitivity C-reactive protein; PGx = pharmacogenomic; PWV = pulse wave velocity; V = visit. Template version 1.1 Page 4

5 Table 1. Schedule of Activities a. If a subject permanently discontinued study prior to Week 52, the procedure scheduled to be performed at Week 52 visit was to be completed if possible. b. Trough blood pressure (BP) in the sitting position was measured after the subject remained sitting for 5 minutes, at Visit 1 (Week 0) to Visit 15 (Week 52). At Visit 0 (Week -2), the Investigator instructed the subject that administration of both amlodipine and atorvastatin on the day of the study visit as above, was pending until the instruction by the Investigator had been made, due to the trough BP being measured. c. This was mandatory for women of childbearing potential (WOCBP). d. White blood cell count, lymphocyte subsets (lymphocytes, monocytes, basophils, eosinophils, neutrophils), red blood cell count, hemoglobin, hematocrit, platelet count. e. Total protein (TP), total bilirubin (T-Bil), albumin (Alb), blood urea nitrogen (BUN), serum creatinine (scr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-gtp), sodium (Na+), potassium (K+), chloride (Cl-), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), urine analysis (UA). f. Protein, glucose, occult blood. g. Checking clinical condition of angina pectoris (eg, angina episodes happen more often, numbers of nitrate usage, or last longer than usual etc. were measured and recorded). h. Total cholestrol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and apolipoprotein B. i. Pulse Wave Velocity (PWV) was conducted as a prioritized measurement. If feasible both PWV and cardio ankle vascular index (CAVI) were performed. j. Malondialdehyde-modified low density lipoprotein (MDA-LDL) and 8-hydroxydeoxyguanosine (8-OHdG). k. Pharmacogenomics were conducted if possible (separate molecular profiling consent had to be obtained for pharmacogenomic sampling). Template version 1.1 Page 5

6 Number of Subjects (Planned and Analyzed): It was planned to enroll approximately 150 subjects in the study. A total of 159 subjects (143 subjects with both hypertension and hypercholesterolemia and 16 subjects with both angina pectoris and hypercholesterolemia) were enrolled and treated. Diagnosis and Main Criteria for Inclusion: Male and female subjects aged 20 years and older with both hypertension and hypercholesterolemia, or both angina pectoris and hypercholesterolemia, who took amlodipine 2.5 mg/day or 5 mg/day for at least 28 days before Week -2 with a well-controlled BP value (BP value <140/90 mmhg at Week 0), and clinically stable angina pectoris (subjects with hypercholesterolemia and angina pectoris only). In addition, subjects had to meet one of the following criteria: 1) took atorvastatin 5 mg/day or 10 mg/day for at least 28 days before Week -2; or 2) were statin-naïve, defined as receiving no statin therapy for at least 3 months during the previous 12 months, with LDL-C level 160 mg/dl and <250 mg/dl, and TG level <400 mg/dl at Week -2. Subjects who needed 3 or more multi-antihypertensive therapies to achieve the target BP level (defined as SBP <140 mmhg and DBP <90 mmhg) or with uncontrolled status of hypertension at Week 0 (Visit 1), and subjects who had uncontrolled or uncontrollable status of hypercholesterolemia at Week -2 (LDL-C 160 mg/dl) even though atorvastatin 10 mg was administered, were excluded from the study. Study Treatment: One amlodipine/atorvastatin tablet of the specified strength (2.5 mg/5 mg, 2.5 mg/10 mg, 5 mg/5 mg, or 5 mg/10 mg) was administered once daily after breakfast, in principle, for 52 weeks. Each subject was asked to visit the study site at the same time as far as possible, in the morning (in principle), at every visit. Subjects made each visit without taking breakfast to maintain the fasting state for at least 10 hours after the evening meal on the preceding day. Subjects took the investigational product on the preceding day of each visit scheduled for blood pressure monitoring, but did not take the morning dose on the day of a visit. Efficacy and Safety Endpoints: Primary Endpoints: The primary efficacy endpoint in this study was safety. Secondary Endpoints: Secondary efficacy endpoints are shown below: Changes in the following parameters from baseline (Visit 1, Week 0) were investigated at each assessment point [Visit 2 (Week 2), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12), Visit 6 (Week 16), Visit 7 (Week 20), Visit 8 (Week 24), Visit 9 (Week 28), Visit 10 (Week 32), Visit 11 (Week 36), Visit 12 (Week 40), Visit 13 (Week 44), Visit 14 (Week 48), and Visit 15 (Week 52)]: Changes in trough SBP Changes in trough DBP Template version 1.1 Page 6

7 Changes in the following parameters from baseline (Visit 1, Week 0) were investigated at each assessment point [Visit 3 (Week 4), Visit 5 (Week 12), Visit 8 (Week 24), and Visit 15 (Week 52)]: Percent changes and changes in LDL-C Percent changes and changes in TC, HDL-C, and TG Changes in LDL-C/HDL-C and TC/HDL-C ratios Percent changes and changes in apolipoprotein B Safety Evaluations: Adverse events (AEs) were monitored between the first day of study treatment and the last day of a visit, and were recorded in the case report form. Serious adverse events (SAEs) were reported between the day of informed consent and 28 days after the last dose of study treatment. The laboratory tests, excluding serum lipids for efficacy endpoints, were performed at Visit 0 (Week -2), Visit 1 (Week 0), Visit 5 (Week 12), Visit 8 (Week 24), and Visit 15 (Week 52 or at withdrawal). In addition, at Visit 3 (Week 4), only a blood chemistry test was performed. Conditions of angina pectoris at Visit 1 (Week 0) and at each observation were compared, and it was determined whether there was clinically significant worsening. Twelve-lead electrocardiograms were measured at Visit 0 (Week -2) or Visit 1 (Week 0), and Visit 15 (Week 52 or at withdrawal), and pulse rates were measured at all visits between Visit 0 (Week -2) and Visit 15 (Week 52 or at withdrawal). Statistical Methods: The efficacy analysis set included all subjects who received at least 1 dose of study drug and contributed data to baseline and at least 1 post-baseline efficacy assessment. The safety analysis set included all subjects who received at least 1 dose of study drug. Blood pressure was analyzed by subgroup (subjects with both hypertension and hypercholesterolemia, and subjects with both angina pectoris and hypercholesterolemia). Actual values and changes from baseline in SBP and DBP at each time point were summarized using descriptive statistics and 2-sided 95% confidence interval of the mean. With regard to lipids, actual values, percent changes and changes from baseline in LDL-C, TC, TG, HDL-C and apolipoprotein B at each time point were summarized using descriptive statistics and 2-sided 95% CI of the mean. Actual values and changes from baseline in the ratio of LDL-C to HDL-C and the ratio of TC to HDL-C at each time point were also summarized by summary statistics and 2-sided 95% CI of the mean. All the analyses on safety were performed in the safety analysis set. Safety endpoints were established in compliance with the Sponsor's Data Standards. AEs were coded into system organ classes and preferred terms using Medical Dictionary for Regulatory Activities version Template version 1.1 Page 7

8 Subject Disposition and Demography: In this study, 159 subjects were enrolled, and all the subjects received the study drug. Fourteen (14) subjects (8.8%) discontinued the study, namely due to withdrawal of consent (4 subjects, 2.5%), non treatment-related AEs (5 subjects, 3.1%), treatment-related AEs (3 subjects, 1.9%), and other reasons (2 subjects, 1.3%, 1 subject was arrested and the other subject had difficulty visiting the study site due to treatment of complications). Of 159 subjects, 143 subjects were subjects with both hypertension and hypercholesterolemia and 16 subjects were subjects with both angina pectoris and hypercholesterolemia (including those with all of angina pectoris, hypertension and hypercholesterolemia). In this study, these 16 subjects all had angina pectoris, hypertension and hypercholesterolemia. Of all the subjects, 145 subjects (91.2%) completed the study, consisting of 130 subjects (90.9%) with both hypertension and hypercholesterolemia and 15 subjects (93.8%) with angina pectoris, hypertension and hypercholesterolemia (Table 2). Table 2. Disposition of Subjects and Analysis Populations Number of Subjects (%) All Subjects Subjects With Both Hypertension and Hypercholesterolemia Subjects With all of Angina Pectoris, Hypertension and Hypercholesterolemia Assigned to study treatment Treated 159 (100) 143 (100) 16 (100) Completed 145 (91.2) 130 (90.9) 15 (93.8) Discontinued 14 (8.8) 13 (9.1) 1 (6.3) Withdrawal of consent 4 (2.5) 4 (2.8) 0 Non treatment-related AEs 5 (3.1) 4 (2.8) 1 (6.3) Treatment-related AEs 3 (1.9) 3 (2.1) 0 Others 2 (1.3) a 2 (1.4) a 0 Analyzed for efficacy 158 (99.4) 142 (99.3) 16 (100) Analyzed for safety AEs 159 (100) 143 (100) 16 (100) Laboratory test 159 (100) 143 (100) 16 (100) AE = adverse event. a. One subject was arrested and the other subject had difficulty visiting the study site due to treatment of complications. Demographic characteristics are provided in summarized in Table 3. Of 159 subjects, 108 subjects (67.9%) were female. The average age of the subjects was 65.0 years. Subjects aged 65 years or older accounted for 56.0% of all the subjects. The average body weight was 61.2 kg and the average body mass index was 24.9 kg/m 2. Template version 1.1 Page 8

9 Table 3. Demographic Characteristics Characteristics Male Female Total Number (%) of Subjects Age (years) < (7.8) 1 (0.9) 5 (3.1) (41.2) 44 (40.7) 65 (40.9) (51.0) 63 (58.3) 89 (56.0) Mean SD Range Race Asian 51 (100.0) 108 (100.0) 159 (100.0) Weight (kg) Mean SD Range N 51 (100.0) 108 (100.0) 159 (100.0) Body mass index (kg/m 2 ) Mean SD Range N 51 (100.0) 108 (100.0) 159 (100.0) Height (cm) Mean SD Range N 51 (100.0) 108 (100.0) 159 (100.0) Body Mass Index is defined as wt/(ht*.01)**2. N = total number of subjects; SD = standard deviation. Efficacy Results: There were no primary efficacy endpoints in this study. Secondary Efficacy Endpoints: The mean values of SBP and DBP generally changed to below baseline and were well-controlled throughout the study period, regardless of the presence/absence of angina pectoris. A summary of actual value and change from baseline in SBP endpoints at each visit is shown in Table 4. A summary of actual value and change from baseline in DBP endpoints at each visit is shown in Table 5. Template version 1.1 Page 9

10 Table 4. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Systolic Blood Pressure (mmhg) Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Actual Value Change From Statistics Baseline Baseline Baseline c - N Mean Std. Dev % CI (125.7, 128.7) - (125.4, 134.4) - Median Min Max Week 2 (Day 14) N Mean Std. Dev % CI (125.3, 128.8) (-1.6, 1.2) (120.6, 136.5) (-7.5, 5.3) Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (124.7, 128.5) (-2.1, 1.0) (121.2, 134.0) (-7.0, 2.3) Median Min Max Week 8 (Day 56) N Mean Std. Dev % CI (125.3, 129.2) (-1.8, 1.7) (122.9, 134.8) (-5.2, 3.1) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (124.9, 128.7) (-2.2, 1.3) (120.4, 135.1) (-7.0, 2.7) Median Min Max Template version 1.1 Page 10

11 Table 4. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Systolic Blood Pressure (mmhg) Week 16 (Day 112) Week 20 (Day 140) Week 24 (Day 168) Week 28 (Day 196) Week 32 (Day 224) Statistics Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Baseline Actual Value Change From Baseline N Mean Std. Dev % CI (123.8, 127.6) (-3.3, 0.4) (118.0, 137.3) (-9.4, 4.9) Median Min Max N Mean Std. Dev % CI (122.3, 126.1) (-4.5, -1.1) (121.2, 134.1) (-6.8, 2.2) Median Min Max N Mean Std. Dev % CI (123.5, 127.0) (-3.5, -0.2) (116.3, 130.1) (-11.5, -1.9) Median Min Max N Mean Std. Dev % CI (122.0, 125.7) (-4.9, -1.3) (116.3, 130.0) (-12.2, -1.3) Median Min Max N Mean Std. Dev % CI (120.1, 124.0) (-6.7, -3.0) (115.8, 128.3) (-13.6, -2.1) Median Min Max Template version 1.1 Page 11

12 Table 4. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Systolic Blood Pressure (mmhg) Week 36 (Day 252) Week 40 (Day 280) Week 44 (Day 308) Week 48 (Day 336) Week 52 (Day 364) Statistics Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Baseline Actual Value Change From Baseline N Mean Std. Dev % CI (120.4, 123.7) (-6.3, -3.3) (117.8, 131.7) (-11.1, -0.4) Median Min Max N Mean Std. Dev % CI (120.6, 124.3) (-5.9, -2.9) (121.1, 134.4) (-8.3, 2.8) Median Min Max N Mean Std. Dev % CI (121.0, 124.8) (-5.8, -2.1) (120.2, 133.4) (-10.0, 2.6) Median Min Max N Mean Std. Dev % CI (122.8, 126.4) (-4.1, -0.6) (124.2, 136.0) (-5.6, 4.8) Median Min Max N Mean Std. Dev % CI (123.5, 127.3) (-3.4, 0.4) (117.1, 135.0) (-11.7, 2.8) Median Min Max Template version 1.1 Page 12

13 Table 4. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Systolic Blood Pressure (mmhg) Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Actual Value Change From Statistics Baseline Baseline Week 52 (LOCF) N Mean Std. Dev % CI (123.9, 127.5) (-3.3, 0.3) (118.3, 135.3) (-10.4, 4.3) Median Min Max CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. a. Subject population that is defined as the subjects with both hypertension and hypercholesterolemia. b. Subject population that is defined as the subjects with both angina pectoris and hypercholesterolemia including the subjects with all of angina pectoris, hypertension and hypercholesterolemia. c. Baseline value for each subject is defined as the value of Week 0. Template version 1.1 Page 13

14 Table 5. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Diastolic Blood Pressure (mmhg) Statistics Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Baseline Actual Value Change From Baseline N Mean Std. Dev % CI (77.0, 79.3) - (74.6, 82.2) - Median Min Max Week 2 (Day 14) N Mean Std. Dev % CI (77.2, 79.8) (-0.8, 1.5) (74.2, 83.2) (-3.8, 5.3) Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (76.5, 79.1) (-1.5, 0.8) (73.5, 81.1) (-3.8, 1.5) Median Min Max Week 8 (Day 56) N Mean Std. Dev % CI (77.0, 79.7) (-1.0, 1.3) (73.7, 81.1) (-4.3, 2.3) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (76.8, 79.4) (-1.4, 1.0) (73.6, 81.0) (-4.7, 2.6) Median Min Max Template version 1.1 Page 14

15 Table 5. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Diastolic Blood Pressure (mmhg) Week 16 (Day 112) Week 20 (Day 140) Week 24 (Day 168) Week 28 (Day 196) Week 32 (Day 224) Statistics Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Baseline Actual Value Change From Baseline N Mean Std. Dev % CI (76.1, 78.9) (-1.9, 0.6) (72.3, 80.1) (-6.0, 1.6) Median Min Max N Mean Std. Dev % CI (75.1, 77.6) (-3.0, -0.5) (74.1, 80.9) (-4.5, 2.6) Median Min Max N Mean Std. Dev % CI (75.4, 77.9) (-2.8, -0.4) (70.8, 79.0) (-7.1, 0.1) Median Min Max N Mean Std. Dev % CI (74.2, 76.9) (-3.9, -1.4) (71.6, 79.2) (-6.5, 0.5) Median Min Max N Mean Std. Dev % CI (73.3, 76.1) (-4.8, -2.1) (69.4, 77.8) (-9.9, 0.3) Median Min Max Template version 1.1 Page 15

16 Table 5. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Diastolic Blood Pressure (mmhg) Week 36 (Day 252) Week 40 (Day 280) Week 44 (Day 308) Week 48 (Day 336) Week 52 (Day 364) Statistics Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Baseline Actual Value Change From Baseline N Mean Std. Dev % CI (72.7, 75.1) (-5.4, -3.2) (72.7, 80.0) (-5.9, 1.0) Median Min Max N Mean Std. Dev % CI (73.7, 76.3) (-4.4, -2.0) (72.4, 82.7) (-6.0, 3.5) Median Min Max N Mean Std. Dev % CI (74.3, 77.1) (-3.8, -1.2) (71.8, 80.6) (-7.6, 2.4) Median Min Max N Mean Std. Dev % CI (75.0, 77.4) (-3.3, -0.7) (74.3, 81.9) (-3.5, 2.2) Median Min Max N Mean Std. Dev % CI (76.3, 78.9) (-1.9, 0.8) (70.1, 78.6) (-8.2, -0.7) Median Min Max Template version 1.1 Page 16

17 Table 5. Summary of Actual Value and Change From Baseline in Blood Pressure Endpoints at Each Visit (by Primary Diagnoses) - Diastolic Blood Pressure (mmhg) Subject Population by Primary Diagnoses Hypertension/ Hypercholesterolemia a Angina Pectoris/ Hypercholesterolemia b Actual Value Change From Actual Value Change From Statistics Baseline Baseline Week 52 (LOCF) N Mean Std. Dev % CI (76.3, 78.8) (-1.8, 0.7) (70.9, 79.6) (-7.6, 1.3) Median Min Max CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. a. Subject population that is defined as the subject with both hypertension and hypercholesterolemia. b. Subject population that is defined as the subjects with both angina pectoris and hypercholesterolemia including the subject with all of angina pectoris, hypertension and hypercholesterolemia. c. Baseline value for each subject is defined as the value of Week 0. The mean percent change of LDL-C in the efficacy analysis set was decreased at Week 4 by about 10% from the baseline and then maintained that level until Week 52. In the evaluation of LDL-C by prior therapy for hypercholesterolemia, the mean percent change in LDL-C did not show significant changes throughout the 52 weeks in 116 subjects who received amlodipine/atorvastatin including the same dose of atorvastatin as that used during the screening period. There was only 1 subject who increased the dose of atorvastatin during the treatment period. Although appropriate evaluation is not possible because the number of subjects is small, the percent change from baseline at Week 4 was 23% in this subject. The effect continued until Week 24 and weakened at Week 52. The percent change from baseline was 9.5% at Week 52. The mean percent change in LDL-C in 40 subjects who did not receive prior therapy for hypercholesterolemia was decreased by 44.1% from baseline at Week 4 and the effect continued until Week 52 after that. By target disease, the mean percent change in LDL-C in subjects with hypertension and hypercholesterolemia showed similar changes as the efficacy analysis set. The mean percent change in LDL-C in subjects with all of angina pectoris, hypertension and hypercholesterolemia was 2.1% from baseline, which did not show significant changes by Week 24, but was decreased by 8.7% from baseline at Week 52. Out of 16 subjects with all of angina pectoris, hypertension and hypercholesterolemia, only 1 subject did not receive prior therapy for hypercholesterolemia. The other 15 subjects received the same dose of atorvastatin as that used during the screening period. For this reason, it was considered that no significant change was noted. A summary of actual value, change from baseline and percent change from baseline in LDL-C values at each visit (all subjects) is shown in Table 6. Template version 1.1 Page 17

18 Table 6. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Low Density Lipoprotein Cholesterol (LDL-C) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline N Mean Std. Dev % CI (106.5, 118.6) - - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (90.0, 95.9) (-25.3, -13.9) (-14.6, -7.1) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (93.6, 100.0) (-21.9, -10.1) (-11.4, -3.3) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (90.0, 95.6) (-25.2, -13.7) (-14.4, -6.6) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (88.2, 94.3) (-26.8, -15.0) (-16.2, -8.4) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (88.4, 94.2) (-26.7, -15.4) (-16.0, -8.5) Median Min Max Template version 1.1 Page 18

19 Table 6. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Low Density Lipoprotein Cholesterol (LDL-C) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. a. Baseline value for each subject is defined as the value of Week 0. Mean percent changes in TC and apolipoprotein B and mean changes of LDL-C/HDL-C and TC/HDL-C were decreased by Week 4, as observed for LDL-C, and the effect continued after that. The mean percent change in HDL-C showed a slightly increasing trend throughout the 52 weeks, except at Week 24 (1.5% to 4.0%). The mean percent change in TG also did not show significant changes throughout the 52 weeks ( 5.0 to 0.2 mg/dl). A summary of actual value, change from baseline and percent change from baseline in lipid endpoints at each visit (all subjects) is shown in Table 7 (TC), Table 8 (HDL-C), Table 9 (TG), Table 10 (LDL-C/HDL-C), Table 11 (TC/HDL-C) and Table 12 (apolipoprotein B). Template version 1.1 Page 19

20 Table 7. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Total Cholesterol (TC) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline N Mean Std. Dev % CI (192.9, 205.4) - - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (176.1, 183.6) (-25.3, -13.4) (-9.8, -4.8) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (179.9, 187.7) (-21.4, -9.0) (-7.7, -2.3) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (174.4, 181.5) (-27.5, -14.7) (-10.6, -5.2) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (174.8, 183.0) (-27.0, -14.2) (-10.6, -5.3) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (174.3, 182.2) (-26.9, -14.9) (-10.7, -5.6) Median Min Max CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. Template version 1.1 Page 20

21 Table 7. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Total Cholesterol (TC) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline a. Baseline value for each subject is defined as the value of Week 0. Template version 1.1 Page 21

22 Table 8. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - High Density Lipoprotein Cholesterol (HDL-C) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline N Mean Std. Dev % CI (60.1, 64.9) - - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (60.7, 65.2) (-0.7, 1.6) (-0.2, 3.2) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (62.0, 66.9) (0.6, 3.4) (1.8, 6.2) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (59.4, 64.1) (-2.2, 0.5) (-2.6, 1.6) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (61.5, 66.6) (-0.1, 2.3) (0.3, 4.0) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (61.2, 66.1) (0.0, 2.3) (0.6, 4.3) Median Min Max Template version 1.1 Page 22

23 Table 8. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - High Density Lipoprotein Cholesterol (HDL-C) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation a. Baseline value for each subject is defined as the value of Week 0. Template version 1.1 Page 23

24 Table 9. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Triglycerides (TG) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline N Mean Std. Dev % CI (110.6, 130.2) - - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (110.6, 128.9) (-9.4, 8.1) (0.0, 16.5) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (104.8, 125.8) (-15.4, 5.4) (-4.3, 11.5) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (107.8, 127.9) (-13.5, 7.3) (-0.9, 13.8) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (108.6, 133.9) (-11.6, 12.0) (-1.6, 18.7) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (107.3, 131.1) (-12.4, 10.1) (-2.4, 16.8) Median Min Max CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. Template version 1.1 Page 24

25 Table 9. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Triglycerides (TG) (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline a. Baseline value for each subject is defined as the value of Week 0. Template version 1.1 Page 25

26 Table 10. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Ratio of LDL-C/HDL-C Statistics Actual Value Change From Baseline N Mean Std. Dev % CI (1.8, 2.1) - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (1.5, 1.6) (-0.5, -0.3) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (1.5, 1.7) (-0.5, -0.2) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (1.5, 1.7) (-0.4, -0.2) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (1.4, 1.6) (-0.5, -0.3) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (1.4, 1.6) (-0.5, -0.3) Median Min Max Template version 1.1 Page 26

27 Table 10. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Ratio of LDL-C/HDL-C Statistics Actual Value Change From Baseline CI = confidence interval; HDL-C = high density lipoprotein-c; LOCF = last observation carried forward; LDL-C = low density lipoprotein-c; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. a. Baseline value for each subject is defined as the value of Week 0. Template version 1.1 Page 27

28 Table 11. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Ratio of TC/HDL-C Statistics Actual Value Change From Baseline N Mean Std. Dev % CI (3.2, 3.5) - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (2.9, 3.0) (-0.5, -0.3) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (2.9, 3.1) (-0.5, -0.2) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (2.9, 3.1) (-0.5, -0.2) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (2.8, 3.0) (-0.5, -0.3) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (2.8, 3.0) (-0.6, -0.3) Median Min Max Template version 1.1 Page 28

29 Table 11. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Ratio of TC/HDL-C Statistics Actual Value Change From Baseline CI = confidence interval; HDL-C = high density lipoprotein-c; LOCF; = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation; TC = total cholesterol. a. Baseline value for each subject is defined as the value of Week 0. Template version 1.1 Page 29

30 Table 12. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Apolipoprotein B (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline N Mean Std. Dev % CI (86.7, 94.5) - - Median Min Max Week 4 (Day 28) N Mean Std. Dev % CI (76.5, 80.7) (-15.4, -8.6) (-12.2, -6.3) Median Min Max Week 12 (Day 84) N Mean Std. Dev % CI (79.1, 83.8) (-12.6, -5.5) (-9.1, -2.4) Median Min Max Week 24 (Day 168) N Mean Std. Dev % CI (77.5, 81.8) (-14.5, -7.1) (-10.8, -4.1) Median Min Max Week 52 (Day 364) N Mean Std. Dev % CI (76.3, 81.1) (-15.5, -8.2) (-12.4, -5.8) Median Min Max Week 52 (LOCF) N Mean Std. Dev % CI (76.3, 80.9) (-15.5, -8.5) (-12.4, -6.1) Median Min Max CI = confidence interval; LOCF = last observation carried forward; Min = minimum; Max = maximum; N = number of subjects; Std. Dev. = standard deviation. Template version 1.1 Page 30

31 Table 12. Summary of Actual Value and Change From Baseline in Lipid Endpoints at Each Visit (All Subjects) - Apolipoprotein B (mg/dl) Statistics Actual Value Change From Baseline % Change From Baseline a. Baseline value for each subject is defined as the value of Week 0. Safety Results: Treatment emergent adverse events (TEAEs) (all causality) reported for 2% of subjects overall are summarized in Table 13. The AEs were all mild or moderate in severity with the exception of 1 severe event (colitis ischemic). The incidence and severity of AEs by target disease did not show major differences. Template version 1.1 Page 31

32 Table 13. Treatment-Emergent Non Serious Adverse Events by System Organ Class and Preferred Term (All Causalities) for Events Having a Frequency Rate 2% Number (%) of Subjects With Adverse Events by: System Organ Class and MedDRA Preferred Term n (%) Number (%) of subjects: Evaluable for adverse events 159 Number (%) of subjects: With adverse events 101 (63.5) Gastrointestinal disorders 16 (10.1) Abdominal discomfort 4 (2.5) Constipation 5 (3.1) Gastritis 4 (2.5) Gastrooesophageal reflux disease 5 (3.1) Infections and infestations 77 (48.4) Bronchitis 11 (6.9) Cystitis 6 (3.8) Nasopharyngitis 53 (33.3) Pharyngitis 17 (10.7) Injury, poisoning and procedural complications 9 (5.7) Fall 9 (5.7) Musculoskeletal and connective tissue disorders 19 (11.9) Arthralgia 6 (3.8) Back pain 6 (3.8) Musculoskeletal stiffness 4 (2.5) Periarthritis 4 (2.5) Nervous system disorders 6 (3.8) Headache 6 (3.8) Respiratory, thoracic and mediastinal disorders 14 (8.8) Asthma 6 (3.8) Upper respiratory tract inflammation 8 (5.0) Skin and subcutaneous tissue disorders 13 (8.2) Eczema 9 (5.7) Rash 4 (2.5) Subjects are only counted once per treatment for each row. Includes all data collected since the first dose of study drug. MedDRA (v14.1) coding dictionary applied. MedDRA = Medical Dictionary for Regulatory Activities; n = number of subjects; v =version. TEAEs (treatment-related) are summarized in Table 14. Treatment related AEs were all mild. Treatment related AEs reported in 2 or more subjects included only abdominal pain. Template version 1.1 Page 32

33 Table 14. Treatment-Emergent Adverse Events by MedDRA System Organ Class (Treatment Related) Number (%) of Subjects With Adverse Events by: System Organ Class n (%) Number (%) of subjects: Evaluable for adverse events 159 Number (%) of subjects: With adverse events 9 (5.7) Eye disorders 1 (0.6) Gastrointestinal disorders 3 (1.9) General disorders and administration site conditions 1 (0.6) Neoplasms benign, malignant and unspecified (including cyst and polyps) 1 (0.6) Nervous system disorders 1 (0.6) Psychiatric disorders 1 (0.6) Reproductive system and breast disorders 1 (0.6) Skin and subcutaneous tissue disorders 2 (1.3) Subjects are only counted once per treatment for each row. Includes all data collected since the first dose of study drug. MedDRA (v14.1) coding dictionary applied. MedDRA = Medical Dictionary for Regulatory Activities; n = number of subjects; v =version. SAEs are summarized in Table 15. SAEs were noted in 11 subjects (6.9%) among all subjects, but a causal relationship to the study drug was ruled out in all the subjects. Template version 1.1 Page 33

34 Table 15. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities) Number (%) of Subjects With Adverse Events by: System Organ Class and MedDRA Preferred Term n (%) Number (%) of subjects: Evaluable for adverse events 159 Number (%) of subjects: With adverse events 11 (6.9) Cardiac disorders 2 (1.3) Atrial fibrillation 1 (0.6) Atrioventricular block complete 1 (0.6) Gastrointestinal disorders 2 (1.3) Colitis ischaemic 1 (0.6) Colonic polyp 1 (0.6) Hepatobiliary disorders 1 (0.6) Cholecystitis acute 1 (0.6) Injury poisoning and procedural complications 2 (1.3) Humerus fracture 1 (0.6) Thoracic vertebral fracture 1 (0.6) Neoplasms benign, malignant and unspecified (including cyst and polyps) 4 (2.5) Benign soft tissue neoplasm 1 (0.6) Breast cancer 1 (0.6) Carcinoid tumour of the gastrointestinal tract 1 (0.6) Colon adenoma 1 (0.6) Rectal neoplasm 1 (0.6) Vascular disorders 1 (0.6) Aortic aneurysm 1 (0.6) Subjects are only counted once per treatment for each row. Includes all data collected since the first dose of study drug. MedDRA (v14.1) coding dictionary applied. MedDRA = Medical Dictionary for Regulatory Activities; n = number of subjects; v =version. Permanent Discontinuations due to AEs: Discontinuations due to AEs are summarized in Table 16. The study treatment was discontinued due to AEs in 8 subjects. Among these AEs, 3 events in 3 of the 8 subjects were assessed as related to the study drug. These 3 AEs were not serious and were all mild in severity. Template version 1.1 Page 34

35 Table 16. Discontinuations From Treatment Due to Adverse Events Serial No. System Organ Class 1 Gastrointestinal disorders Neoplasms benign, malignant and unspecified (including cyst and polyps) Neoplasm benign, malignant and unspecified (including cyst and polyps) 2 Cardiac disorders MedDRA Preferred Term Treatment Phase Treatment at Onset Study Start Day a /Study Stop Day a Colonic polyp b Active 164/ (>225) Carcinoid tumour of the gastrointestinal tract b Active 164/ (>225) Colon adenoma b Active 164/ (>225) Atrial fibrillation b Active 64/ (>64) Severity/ Outcome Moderate/Still present Moderate/Still present Moderate/Still present Mild/Still present Action/Causality Study drug action: (Permanently discontinued) Subject action: (D/C study)/other - unknown but not related to study drug Study drug action: (Permanently discontinued) Subject action: (D/C study)/other - unknown but not related to study drug Study drug action: (Permanently discontinued) Subject action: (D/C study)/other - unknown but not related to study drug Study drug action: (Permanently discontinued) Subject action: (D/C study)/other - because there is no change in before the start of the study and the use medicine SAE Yes Yes Yes Yes Template version 1.1 Page 35

36 Table 16. Discontinuations From Treatment Due to Adverse Events Serial No. System Organ Class 3 Nervous system disorders 4 Skin and subcutaneous tissue disorders 5 Cardiac disorders 6 Injury, poisoning and procedural complications MedDRA Preferred Term Treatment Phase Treatment at Onset Study Start Day a /Study Stop Day a Severity/ Outcome Action/Causality Headache b Active 19/21 Mild/Resolved Study drug action: (Permanently discontinued) Subject action: (D/C study)/study drug Eczema b Active 96/(>103) Mild/Still present Atrioventricular Active 110/(>120) Mild/Still block complete b present Thoracic vertebral Active 246/(>253) Moderate/Still fracture b present Study drug action: (Permanently discontinued) Subject action: (Treatment given, D/C study)/study drug Study drug action: (Permanently discontinued) Subject action: (D/C study)/other - because there was no change in the medicine used later ahead in the start of the study Study drug action: (Permanently discontinued) Subject action: (Treatment given, D/C study)/other - traffic accident SAE No No Yes Yes Template version 1.1 Page 36

37 Table 16. Discontinuations From Treatment Due to Adverse Events Serial No. System Organ Class MedDRA Preferred Term 7 Investigations Alanine aminotransferase increased b 8 Skin and subcutaneous tissue disorders Treatment Phase Treatment at Onset Study Start Day a /Study Stop Day a Severity/ Outcome Active 85/(>135) Mild/Still present Rash b Active 140/(>168) Mild/Still present () Values in brackets were imputed from incomplete dates and times. SAE = Serious Adverse Event (according to Investigators assessment). Treatment column gives study treatment at time of adverse event. MedDRA (v14.1) coding dictionary applied. a. Day relative to start of study treatment. First day of study treatment = Day 1. b. Treatment emergent. Action/Causality Study drug action: (Permanently discontinued) Subject action: (D/C study)/other illness - gall stone disease Study drug action: (Permanently discontinued) Subject action: (Treatment given, D/C study)/study drug SAE No No Template version 1.1 Page 37

38 Dose reduction or Temporary Discontinuation due to AEs: The study treatment was temporarily discontinued due to AEs in 2 subjects, but a causal relationship to the study drug was ruled out in both subjects. There were no dose reductions due to AEs. Deaths: Deaths due to AEs were not reported in this study. Common laboratory test abnormalities were urinary occult blood (positive) and gamma-glutamyl transpeptidase increased. Adverse events related to laboratory data were mild or moderate in severity, and a causal relationship to the study drug was ruled out for all the events. Vital signs also did not show apparent changes throughout the 52 weeks. On electrocardiograms, 2 AEs (atrial fibrillation and atrioventricular block complete) in 2 subjects were assessed as serious, and the study treatment was discontinued, although these events were mild in severity and a causal relationship to the study drug was ruled out for both. In 1 of these subjects the event improved, and in the other subject the event resolved. None of the subjects with concurrent angina pectoris were diagnosed with worsening symptoms of angina pectoris. CONCLUSIONS: In this study, amlodipine/atorvastatin combination tablets were administered for 52 weeks to subjects with both hypertension and hypercholesterolemia, or with both angina pectoris and hypercholesterolemia. The results obtained in the study are shown below. Deaths due to AEs were not reported in this study. For all SAEs, a causal relationship to study drug was ruled out. All causality AEs were all mild or moderate in severity, with the exception of 1 severe event (ischemic colitis). Treatment related AEs were all mild, and AEs reported in 2 or more subjects included only abdominal pain. The mean values of SBP and DBP generally changed to below baseline and were well-controlled throughout the study period regardless of the presence/absence of angina pectoris. In the mean percent change compared to the baseline at each time point, LDL-C decreased by about 10% until Week 4 and maintained that level by Week 52. When evaluated by the prior therapy for hypercholesterolemia, the mean percent change of LDL-C did not show significant changes throughout the 52 weeks in 116 subjects who received amlodipine/atorvastatin including the same dose of atorvastatin as that used during the screening period. Only 1 subject received an increase of the dose of atorvastatin during the treatment period and the decrease of the mean percent change of LDL-C was observed for the subject. The mean percent change in LDL-C decreased very effectively in 40 subjects who did not receive prior therapy for hypercholesterolemia. Regarding lipid endpoints other than LDL-C, mean percent changes in TC and apolipoprotein B and mean changes of LDL-C/HDL-C and TC/HDL-C were decreased by Week 4, consistent with those for LDL-C, and the effect continued after that. The mean percent change in HDL-C showed a slightly increasing trend throughout the Template version 1.1 Page 38