Clinical Study
Lipids, Safety Parameters, and Drug Concentrations After an Additional 2 Years of Treatment With Anacetrapib in the DEFINE Study
Journal of Cardiovascular Pharmacology and Therapeutics 2014, Vol. 19(6) 543-549 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414529621 cpt.sagepub.com
Antonio M. Gotto Jr, MD, DPhil1, Uma Kher, MS2, Manash Shankar Chatterjee, PhD2, Yang Liu, PhD2, Xiujiang Susie Li, PhD2, Sanskruti Vaidya, MS, MPhil2, Christopher P. Cannon, MD3, Eliot A. Brinton, MD4, Jennifer E. Moon, PhD1, Sukrut Shah, PhD, RPh2, Hayes M. Dansky, MD2, Yale Mitchel, MD2, Philip Barter, MD, PhD5, and the DEFINE Investigators
Abstract Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n ¼ 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was *640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C. Keywords anacetrapib, long-term safety, plasma concentrations, lipids
Introduction Cholesteryl ester transfer protein (CETP) inhibitors are experimental agents that raise high-density lipoprotein cholesterol (HDL-C) levels by inhibiting the 2-way transfer of cholesteryl esters and triglycerides between HDL and apolipoprotein B-containing lipoproteins.1 Some CETP inhibitors also lower low-density lipoprotein cholesterol (LDL-C) through an unknown mechanism. Anacetrapib is a potent and selective CETP inhibitor in phase III development. The 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) study evaluated the effects of anacetrapib versus placebo on safety and lipid parameters in patients with coronary heart disease (CHD) or at high risk of CHD, who were treated with statins + other lipid-modifying agents.2 The trial revealed no differences in blood pressure, electrolytes, and other safety parameters between the anacetrapib and the placebo treatment groups.
Anacetrapib treatment was associated with a placeboadjusted 39.8% reduction in LDL-C (the primary efficacy end point), as calculated by the Friedewald equation, and a 138.1%
1
Office of the Vice President, Weill Cornell Medical College, New York, NY, USA 2 Merck Research Laboratories, Rahway, NJ, USA 3 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA 4 Utah Foundation for Biomedical Research and Utah Lipid Center, Salt Lake City, UT, USA 5 Centre for Vascular Research, University of New South Wales, Sydney, Australia, USA Manuscript submitted: January 21, 2014; accepted: March 03, 2014. Corresponding Author: Antonio M. Gotto Jr, Weill Cornell Medical College, 1305 York Ave. Y-805, New York, NY 10021, USA. Email: [email protected]
Downloaded from cpt.sagepub.com at Scott Memorial Library @ Thomas Jefferson University on March 11, 2015
544
Journal of Cardiovascular Pharmacology and Therapeutics 19(6)
increase in HDL-C. A subsequent analysis showed that compared to the reference b-quantification method, the Friedewald equation underestimates LDL-C levels after treatment with anacetrapib, so that the actual degree of LDL-C reduction may have been less than originally reported.3 A 2-year extension to the DEFINE study was conducted to further evaluate longterm safety, lipid effects, and anacetrapib drug concentrations. The current report describes the results of the DEFINE extension study.
Methods Study Design The design and results of the DEFINE base study (clinicaltrials.gov number, NCT00685776), a 76-week, worldwide, multicenter, randomized, double-blind, placebo-controlled trial, have been previously reported.2,4 During the active treatment phase, patients were randomized to anacetrapib 100 mg/d or placebo, and plasma samples for anacetrapib drug concentrations were collected at the 12, 24, and 76 week visits. Following this base study, there was an off-drug reversibility period of at least 12 and up to 24 weeks duration.5 A total of 1211 patients completed the base study including the reversibility period (n ¼ 548 on anacetrapib, n ¼ 663 on placebo).2 The proportion of patients completing the base study was lower in the anacetrapib group than in the placebo group because 18% of patients in the anacetrapib group (n ¼ 142) were discontinued due to protocol-specified criterion when the achieved LDL-C was ULN Chloride > ULN Bicarbonate > ULN Potassium < LLN Liver/muscle enzymes Consecutive elevations of ALT and/or AST 3 ULN Creatine kinase 10 ULN
Anacetrapib, n/N (%)
Placebo, n/N (%)
25/369 (6.8) 88/369 (23.8)
16/433 (3.7) 90/433 (20.8)
234/366 (63.9) 182/366 (49.7) 139/366 (38.0)
258/432 (59.7) 198/432 (45.8) 146/432 (33.8)
26/366 (7.1) 5/366 (1.4) 5/366 (1.4) 8/366 (2.2)
23/433 2/433 6/433 13/432
Absolute Difference, % (95% CI)
4.2 (2.6 to 10.9) 3.9 (3.1 to 10.8) 4.2 (2.5 to 10.9)
(5.3) (0.5) (1.4) (3.0)
1.8 (1.6 to 5.4) 0.9 (0.5 to 2.7) 0.0 (1.8 to 1.9) 0.8 (3.2 to 1.6)
1/366 (0.3)
4/433 (0.9)
0.7 (2.1 to 0.7)
0/366 (0.0)
0/433 (0.0)
0.0 (0.9 to 1.0) (continued)
Downloaded from cpt.sagepub.com at Scott Memorial Library @ Thomas Jefferson University on March 11, 2015
Gotto et al
547
Table 2. (continued) Continuous variables Adverse experiences and safety parameters Blood pressure Systolic BP Diastolic BP Electrolytes Sodium Chloride Bicarbonate Potassium Liver enzymes AST ALT
Anacetrapib Change From Placebo Change From Initial Baseline Initial Baseline
Least Squares Mean Difference (95% CI)
2.6 0.1
2.6 0.8
0.0 (2.1 to 2.1) 0.7 (0.5 to 1.9)
0.3 1.8 0.2 0.0
0.4 2.1 0.2 0.1
0.1 0.2 0.1 0.1
2.5 4.3
0.6 1.5
Root Mean Square Error 13.78 7.99
(0.2 to 0.4) (0.1 to 0.6) (0.3 to 0.4) (0.0 to 0.1)
2.0 (3.0 to 0.9) 2.8 (4.4 to 1.2)
1.91 2.43 2.19 0.35 6.82 10.58
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CI, confidence interval; LLN, lower limit of normal; ULN, upper limit of normal.
of treatment with anacetrapib, the placebo-adjusted mean percent reduction from the initial baseline was 39.9% for LDL-C, as estimated by the Friedewald equation, and the placeboadjusted mean percent increase from baseline was 153.5% for HDL-C (Table 4). Mean percentage reductions in non-HDL-C (30.9%) and apolipoprotein B (16.3%) and an increase in apolipoprotein A-I (44.5%) were also observed with anacetrapib compared to placebo.
Anacetrapib Concentrations Concentration time data for patients completing both the DEFINE 76-week base study and the 2-year extension study are shown in Figure 2. This plot represents trough plasma concentrations of anacetrapib at all time points except at the weeks 24 and 76 time points (base study) since time of dosing and plasma sampling were not available for those measures. The trough geometric mean (GM) concentration at week 12 of the base study was 541 nmol/L. The plasma concentration of anacetrapib appeared to increase modestly at weeks 24 (613 nmol/L) and 76 (666 nmol/L), although these were not trough values. Patients were off drug for at least 12 and up to 24 weeks after completion of the 76-week base study before entering the 2-year extension study. The residual mean plasma concentration of anacetrapib at the start of the 2-year extension study (week 0) was 219 nmol/L, about 40% of the on-treatment week 12 trough levels. During the 2-year extension study, anacetrapib levels increased in the plasma and seemed to reach a plateau at the extension week 40 time point (659 nmol/L). The time to achieve apparent steady state plasma concentrations was evaluated by assessing linear trend in log-transformed trough plasma concentrations. Based on the linear trend test, plasma concentrations of anacetrapib reached apparent steady state at around week 40 during the 2-year extension study. The slope of the concentration curve from extension weeks 40 to 104 was 0.0003 log nmol/L/week (90% CI, 0.0015-0.0009; P ¼ .69).
Table 3. Patients With Adjudicated Cardiovascular Adverse Events and Death During the 2-Year Extension Study.a Anacetrapib 100 mg (N ¼ 370) nb (%) Prespecified adjudicated CV SAE CV death 1 (0.3) Nonfatal stroke 2 (0.5) Nonfatal MI 9 (2.4) Unstable Angina 3 (0.8) Total 14 (3.8) Coronary revascularization 13 (3.5) Congestive heart failure 3 (0.8) Death CV death 1 (0.3) Non CV death 6 (1.6) Sudden death 1 (0.3) Unable to determine 1 (0.3) cause Total 9 (2.4)
Placebo (N ¼ 433) nb (%) 3 5 5 2 14 13 4
(0.7) (1.2) (1.2) (0.5) (3.2) (3.0) (0.9)
3 4 1 1
(0.7) (0.9) (0.2) (0.2)
9 (2.1)
Abbreviations: CV, cardiovascular; SAE, serious adverse event; MI, myocardial infarction. a See reference 4, appendix B for definitions of end points. b n ¼ number of patients with events.
Discussion During the DEFINE 2-year extension study, no clinically meaningful differences in liver enzymes, electrolytes, plasma glucose, blood pressure, or adverse experiences were detected, and the number of prespecified, adjudicated cardiovascular serious adverse events was similar between treatment groups. The effects of treatment with anacetrapib on LDL-C and HDL-C during this 104-week extension study were similar to those observed during the 76-week DEFINE base study. Compared to placebo, anacetrapib 100 mg/d increased HDL-C levels by 153.5% and decreased LDL-C levels by 39.9% as calculated by the Friedewald formula, both very similar to the
Downloaded from cpt.sagepub.com at Scott Memorial Library @ Thomas Jefferson University on March 11, 2015
548
Journal of Cardiovascular Pharmacology and Therapeutics 19(6)
Table 4. Changes in Lipid and C-Reactive Protein Levels During the 2-Year Extension Study. Variable FW LDL-C Placebo Anacetrapib HDL-C Placebo Anacetrapib Non-HDL-C Placebo Anacetrapib Total cholesterol Placebo Anacetrapib Apolipoprotein B Placebo Anacetrapib Apolipoprotein A-I Placebo Anacetrapib Triglycerides Placebo Anacetrapib C-reactive proteinb Placebo Anacetrapib
N
Initial Baseline Mean, mg/dL
Extension Week 104 Mean, mg/dL
Percent Change From Baseline, (95% CI)a
Least Squares Mean Difference (95% CI)
361 308
81.5 84.0
74.9 43.9
5.4 (8.1 to 2.6) 45.2 (48.2 to 42.3)
39.9 (43.8 to 36.0)
361 310
40.1 41.2
46.1 109.3
15.8 (11.7 to 19.8) 169.3 (165.0 to 173.7)
153.5 (147.9 to 159.2)
361 310
110.2 110.6
102.4 68.8
4.6 (7.0 to 2.3) 35.5 (38.1 to 33.0)
30.9 (34.2 to 27.5)
361 310
150.3 151.9
148.5 178.0
358 310
88.0 89.1
73.9 59.7
14.3 (16.2 to 12.4) 30.6 (32.6 to 28.6)
358 310
141.8 142.7
136.3 201.0
2.7 (4.8 to 0.5) 41.8 (39.5 to 44.1)
44.5 (41.6 to 47.4)
433 366
128.0 118.0
125.0 105.0
1.8 (5.9 to 2.3) 6.8 (10.8 to 2.9)
3.8 (8.6 to 0.9)
14.3 (22.92 to 5.65) 0.0 (11.00 to 11.00)
14.4 (4.8 to 25.0)c
369 316
0.14 0.14
0.12 0.14
0.1 (2.0 to 2.1) 18.8 (16.6 to 21.0)
18.7 (15.8 to 21.5)
16.3 (18.9 to 13.7)
Abbreviations: CI, confidence interval; cLDA, constrained longitudinal data analysis; FW LDL-C, Friedewald-calculated low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; non-HDL-C, nonhigh-density lipoprotein cholesterol. a Estimated from the cLDA model including terms for treatment, time, and its interaction with treatments as covariates. b C-reactive protein was analyzed using nonparametric analysis. c Hodges-Lehmann estimate of the difference between treatments with a corresponding distribution-free confidence interval based on Wilcoxon rank sum test.
138.1% increase in HDL-C and the 39.8% decrease in LDL-C observed in the base study. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 for patients in the 2-year extension of the DEFINE study, which suggests that apparent steady state was effectively achieved in plasma with an apparent steady state trough level of *640 nmol/L. The time scale of the approach to apparent steady state is difficult to predict from the data in the extension study since patients started with significant residual amounts of drug from the 76-week base study. However, plasma concentrations were already *85% of this apparent steady-state trough level by week 12 in the 76-week base study. There are important limitations to this extension study. First, the extension study enrolled a self-selected set of patients who completed the base study. The patient population does not include ineligible patients who finished the base study prior to the implementation of the extension, refused participation in the extension, or were discontinued in the base study due to the prespecified discontinuation criterion of LDL-C
Lipids, Safety Parameters, and Drug Concentrations After an Additional 2 Years of Treatment With Anacetrapib in the DEFINE Study
Journal of Cardiovascular Pharmacology and Therapeutics 2014, Vol. 19(6) 543-549 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414529621 cpt.sagepub.com
Antonio M. Gotto Jr, MD, DPhil1, Uma Kher, MS2, Manash Shankar Chatterjee, PhD2, Yang Liu, PhD2, Xiujiang Susie Li, PhD2, Sanskruti Vaidya, MS, MPhil2, Christopher P. Cannon, MD3, Eliot A. Brinton, MD4, Jennifer E. Moon, PhD1, Sukrut Shah, PhD, RPh2, Hayes M. Dansky, MD2, Yale Mitchel, MD2, Philip Barter, MD, PhD5, and the DEFINE Investigators
Abstract Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n ¼ 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was *640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C. Keywords anacetrapib, long-term safety, plasma concentrations, lipids
Introduction Cholesteryl ester transfer protein (CETP) inhibitors are experimental agents that raise high-density lipoprotein cholesterol (HDL-C) levels by inhibiting the 2-way transfer of cholesteryl esters and triglycerides between HDL and apolipoprotein B-containing lipoproteins.1 Some CETP inhibitors also lower low-density lipoprotein cholesterol (LDL-C) through an unknown mechanism. Anacetrapib is a potent and selective CETP inhibitor in phase III development. The 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) study evaluated the effects of anacetrapib versus placebo on safety and lipid parameters in patients with coronary heart disease (CHD) or at high risk of CHD, who were treated with statins + other lipid-modifying agents.2 The trial revealed no differences in blood pressure, electrolytes, and other safety parameters between the anacetrapib and the placebo treatment groups.
Anacetrapib treatment was associated with a placeboadjusted 39.8% reduction in LDL-C (the primary efficacy end point), as calculated by the Friedewald equation, and a 138.1%
1
Office of the Vice President, Weill Cornell Medical College, New York, NY, USA 2 Merck Research Laboratories, Rahway, NJ, USA 3 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA 4 Utah Foundation for Biomedical Research and Utah Lipid Center, Salt Lake City, UT, USA 5 Centre for Vascular Research, University of New South Wales, Sydney, Australia, USA Manuscript submitted: January 21, 2014; accepted: March 03, 2014. Corresponding Author: Antonio M. Gotto Jr, Weill Cornell Medical College, 1305 York Ave. Y-805, New York, NY 10021, USA. Email: [email protected]
Downloaded from cpt.sagepub.com at Scott Memorial Library @ Thomas Jefferson University on March 11, 2015
544
Journal of Cardiovascular Pharmacology and Therapeutics 19(6)
increase in HDL-C. A subsequent analysis showed that compared to the reference b-quantification method, the Friedewald equation underestimates LDL-C levels after treatment with anacetrapib, so that the actual degree of LDL-C reduction may have been less than originally reported.3 A 2-year extension to the DEFINE study was conducted to further evaluate longterm safety, lipid effects, and anacetrapib drug concentrations. The current report describes the results of the DEFINE extension study.
Methods Study Design The design and results of the DEFINE base study (clinicaltrials.gov number, NCT00685776), a 76-week, worldwide, multicenter, randomized, double-blind, placebo-controlled trial, have been previously reported.2,4 During the active treatment phase, patients were randomized to anacetrapib 100 mg/d or placebo, and plasma samples for anacetrapib drug concentrations were collected at the 12, 24, and 76 week visits. Following this base study, there was an off-drug reversibility period of at least 12 and up to 24 weeks duration.5 A total of 1211 patients completed the base study including the reversibility period (n ¼ 548 on anacetrapib, n ¼ 663 on placebo).2 The proportion of patients completing the base study was lower in the anacetrapib group than in the placebo group because 18% of patients in the anacetrapib group (n ¼ 142) were discontinued due to protocol-specified criterion when the achieved LDL-C was ULN Chloride > ULN Bicarbonate > ULN Potassium < LLN Liver/muscle enzymes Consecutive elevations of ALT and/or AST 3 ULN Creatine kinase 10 ULN
Anacetrapib, n/N (%)
Placebo, n/N (%)
25/369 (6.8) 88/369 (23.8)
16/433 (3.7) 90/433 (20.8)
234/366 (63.9) 182/366 (49.7) 139/366 (38.0)
258/432 (59.7) 198/432 (45.8) 146/432 (33.8)
26/366 (7.1) 5/366 (1.4) 5/366 (1.4) 8/366 (2.2)
23/433 2/433 6/433 13/432
Absolute Difference, % (95% CI)
4.2 (2.6 to 10.9) 3.9 (3.1 to 10.8) 4.2 (2.5 to 10.9)
(5.3) (0.5) (1.4) (3.0)
1.8 (1.6 to 5.4) 0.9 (0.5 to 2.7) 0.0 (1.8 to 1.9) 0.8 (3.2 to 1.6)
1/366 (0.3)
4/433 (0.9)
0.7 (2.1 to 0.7)
0/366 (0.0)
0/433 (0.0)
0.0 (0.9 to 1.0) (continued)
Downloaded from cpt.sagepub.com at Scott Memorial Library @ Thomas Jefferson University on March 11, 2015
Gotto et al
547
Table 2. (continued) Continuous variables Adverse experiences and safety parameters Blood pressure Systolic BP Diastolic BP Electrolytes Sodium Chloride Bicarbonate Potassium Liver enzymes AST ALT
Anacetrapib Change From Placebo Change From Initial Baseline Initial Baseline
Least Squares Mean Difference (95% CI)
2.6 0.1
2.6 0.8
0.0 (2.1 to 2.1) 0.7 (0.5 to 1.9)
0.3 1.8 0.2 0.0
0.4 2.1 0.2 0.1
0.1 0.2 0.1 0.1
2.5 4.3
0.6 1.5
Root Mean Square Error 13.78 7.99
(0.2 to 0.4) (0.1 to 0.6) (0.3 to 0.4) (0.0 to 0.1)
2.0 (3.0 to 0.9) 2.8 (4.4 to 1.2)
1.91 2.43 2.19 0.35 6.82 10.58
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CI, confidence interval; LLN, lower limit of normal; ULN, upper limit of normal.
of treatment with anacetrapib, the placebo-adjusted mean percent reduction from the initial baseline was 39.9% for LDL-C, as estimated by the Friedewald equation, and the placeboadjusted mean percent increase from baseline was 153.5% for HDL-C (Table 4). Mean percentage reductions in non-HDL-C (30.9%) and apolipoprotein B (16.3%) and an increase in apolipoprotein A-I (44.5%) were also observed with anacetrapib compared to placebo.
Anacetrapib Concentrations Concentration time data for patients completing both the DEFINE 76-week base study and the 2-year extension study are shown in Figure 2. This plot represents trough plasma concentrations of anacetrapib at all time points except at the weeks 24 and 76 time points (base study) since time of dosing and plasma sampling were not available for those measures. The trough geometric mean (GM) concentration at week 12 of the base study was 541 nmol/L. The plasma concentration of anacetrapib appeared to increase modestly at weeks 24 (613 nmol/L) and 76 (666 nmol/L), although these were not trough values. Patients were off drug for at least 12 and up to 24 weeks after completion of the 76-week base study before entering the 2-year extension study. The residual mean plasma concentration of anacetrapib at the start of the 2-year extension study (week 0) was 219 nmol/L, about 40% of the on-treatment week 12 trough levels. During the 2-year extension study, anacetrapib levels increased in the plasma and seemed to reach a plateau at the extension week 40 time point (659 nmol/L). The time to achieve apparent steady state plasma concentrations was evaluated by assessing linear trend in log-transformed trough plasma concentrations. Based on the linear trend test, plasma concentrations of anacetrapib reached apparent steady state at around week 40 during the 2-year extension study. The slope of the concentration curve from extension weeks 40 to 104 was 0.0003 log nmol/L/week (90% CI, 0.0015-0.0009; P ¼ .69).
Table 3. Patients With Adjudicated Cardiovascular Adverse Events and Death During the 2-Year Extension Study.a Anacetrapib 100 mg (N ¼ 370) nb (%) Prespecified adjudicated CV SAE CV death 1 (0.3) Nonfatal stroke 2 (0.5) Nonfatal MI 9 (2.4) Unstable Angina 3 (0.8) Total 14 (3.8) Coronary revascularization 13 (3.5) Congestive heart failure 3 (0.8) Death CV death 1 (0.3) Non CV death 6 (1.6) Sudden death 1 (0.3) Unable to determine 1 (0.3) cause Total 9 (2.4)
Placebo (N ¼ 433) nb (%) 3 5 5 2 14 13 4
(0.7) (1.2) (1.2) (0.5) (3.2) (3.0) (0.9)
3 4 1 1
(0.7) (0.9) (0.2) (0.2)
9 (2.1)
Abbreviations: CV, cardiovascular; SAE, serious adverse event; MI, myocardial infarction. a See reference 4, appendix B for definitions of end points. b n ¼ number of patients with events.
Discussion During the DEFINE 2-year extension study, no clinically meaningful differences in liver enzymes, electrolytes, plasma glucose, blood pressure, or adverse experiences were detected, and the number of prespecified, adjudicated cardiovascular serious adverse events was similar between treatment groups. The effects of treatment with anacetrapib on LDL-C and HDL-C during this 104-week extension study were similar to those observed during the 76-week DEFINE base study. Compared to placebo, anacetrapib 100 mg/d increased HDL-C levels by 153.5% and decreased LDL-C levels by 39.9% as calculated by the Friedewald formula, both very similar to the
Downloaded from cpt.sagepub.com at Scott Memorial Library @ Thomas Jefferson University on March 11, 2015
548
Journal of Cardiovascular Pharmacology and Therapeutics 19(6)
Table 4. Changes in Lipid and C-Reactive Protein Levels During the 2-Year Extension Study. Variable FW LDL-C Placebo Anacetrapib HDL-C Placebo Anacetrapib Non-HDL-C Placebo Anacetrapib Total cholesterol Placebo Anacetrapib Apolipoprotein B Placebo Anacetrapib Apolipoprotein A-I Placebo Anacetrapib Triglycerides Placebo Anacetrapib C-reactive proteinb Placebo Anacetrapib
N
Initial Baseline Mean, mg/dL
Extension Week 104 Mean, mg/dL
Percent Change From Baseline, (95% CI)a
Least Squares Mean Difference (95% CI)
361 308
81.5 84.0
74.9 43.9
5.4 (8.1 to 2.6) 45.2 (48.2 to 42.3)
39.9 (43.8 to 36.0)
361 310
40.1 41.2
46.1 109.3
15.8 (11.7 to 19.8) 169.3 (165.0 to 173.7)
153.5 (147.9 to 159.2)
361 310
110.2 110.6
102.4 68.8
4.6 (7.0 to 2.3) 35.5 (38.1 to 33.0)
30.9 (34.2 to 27.5)
361 310
150.3 151.9
148.5 178.0
358 310
88.0 89.1
73.9 59.7
14.3 (16.2 to 12.4) 30.6 (32.6 to 28.6)
358 310
141.8 142.7
136.3 201.0
2.7 (4.8 to 0.5) 41.8 (39.5 to 44.1)
44.5 (41.6 to 47.4)
433 366
128.0 118.0
125.0 105.0
1.8 (5.9 to 2.3) 6.8 (10.8 to 2.9)
3.8 (8.6 to 0.9)
14.3 (22.92 to 5.65) 0.0 (11.00 to 11.00)
14.4 (4.8 to 25.0)c
369 316
0.14 0.14
0.12 0.14
0.1 (2.0 to 2.1) 18.8 (16.6 to 21.0)
18.7 (15.8 to 21.5)
16.3 (18.9 to 13.7)
Abbreviations: CI, confidence interval; cLDA, constrained longitudinal data analysis; FW LDL-C, Friedewald-calculated low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; non-HDL-C, nonhigh-density lipoprotein cholesterol. a Estimated from the cLDA model including terms for treatment, time, and its interaction with treatments as covariates. b C-reactive protein was analyzed using nonparametric analysis. c Hodges-Lehmann estimate of the difference between treatments with a corresponding distribution-free confidence interval based on Wilcoxon rank sum test.
138.1% increase in HDL-C and the 39.8% decrease in LDL-C observed in the base study. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 for patients in the 2-year extension of the DEFINE study, which suggests that apparent steady state was effectively achieved in plasma with an apparent steady state trough level of *640 nmol/L. The time scale of the approach to apparent steady state is difficult to predict from the data in the extension study since patients started with significant residual amounts of drug from the 76-week base study. However, plasma concentrations were already *85% of this apparent steady-state trough level by week 12 in the 76-week base study. There are important limitations to this extension study. First, the extension study enrolled a self-selected set of patients who completed the base study. The patient population does not include ineligible patients who finished the base study prior to the implementation of the extension, refused participation in the extension, or were discontinued in the base study due to the prespecified discontinuation criterion of LDL-C
