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Summary Results The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country. 7$.(& 2FWREHU 6<1236,6 7LWOHRI6WXG\ A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 100 mg in Subjects With Type 2 Diabetes Currently Treated With Lipid-Lowering Therapy 1DPHRI6SRQVRU Takeda Global Research & Development Centre (Europe) Ltd. 1DPHRI$FWLYH,QJUHGLHQW Lapaquistat acetate 1DPHRI)LQLVKHG3URGXFW Not applicable ,QYHVWLJDWRUV6WXG\&HQWHUV 121 sites in Europe, South Africa, and the United States 3XEOLFDWLRQ None 6WXG\3HULRG 3KDVHRI'HYHORSPHQW 05 December 2005 to 09 May 2007 Phase 3 2%-(&7,9(6 3ULPDU\ The primary objective of this study was to evaluate the efficacy of lapaquistat acetate compared with placebo on low-density lipoprotein cholesterol (LDL-C) levels in subjects with type 2 diabetes currently treated with optimal doses of other lipid-lowering drugs. 6HFRQGDU\ The secondary objectives of this study were to evaluate the following: • Safety and tolerability (treatment-emergent adverse events [TEAEs], safety laboratory test results, physical examination findings, best corrected visual acuity [BCVA] results, electrocardiogram [ECG] assessments, vital signs, and weight). • Changes in secondary lipid variables (calculated LDL-C, non–high-density lipoprotein cholesterol [non-HDL-C], total cholesterol [TC], apolipoprotein B [Apo B], triglycerides [TG], HDL-C, apolipoprotein A1 [Apo A1], very–low-density lipoprotein cholesterol [VLDL-C], and other derived lipid variables [LDL-C/HDL-C, TC/HDL-C, and Apo B/Apo A1]). • Changes in high-sensitivity C-reactive protein (hs-CRP) and hemoglobin A1c (HbA1c). • The percentage of subjects who achieved LDL-C concentrations of less than 1.81, 2.59, and 3.37 mmol/L (70, 100, and 130 mg/dL, respectively) at the final visit. 0(7+2'2/2*< This was a phase 3, placebo-controlled, double-blind, randomized, multicenter study. Following a 4-week Dietary Run-in Period in which current lipid-lowering therapy was continued, subjects were randomly assigned to 1 of 2 treatment groups: placebo once daily (QD) or lapaquistat acetate 100 mg QD for 24 weeks of treatment; subjects in both treatment groups continued their current lipid-lowering therapy throughout the 24-week treatment period. 1XPEHURI6XEMHFWV Planned: 400 subjects (200 placebo and 200 lapaquistat acetate). Analyzed: 397 subjects (200 placebo and 197 lapaquistat acetate). 7$.(& 2FWREHU 7LWOHRI6WXG\ A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 100 mg in Subjects With Type 2 Diabetes Currently Treated With Lipid-Lowering Therapy 'LDJQRVLVDQG0DLQ&ULWHULDIRU,QFOXVLRQ Men or women at least 18 years of age who met the following criteria were eligible for participation in the study: • Documented type 2 diabetes: plasma glucose of ≥11.1 mmol/L (200 mg/dL) from 2-hour oral glucose tolerance test or fasting plasma glucose of ≥7 mmol/L (126 mg/dL), with an HbA1c of ≤9.5% and stable glucose control. • Stable dose of lipid-lowering medication: atorvastatin (10 mg, 20 mg, or 40 mg), simvastatin (20 mg or 40 mg), rosuvastatin (10 mg or 20 mg) or fenofibrate (≤200 mg). • Mean LDL-C values ≥2.59 mmol/L (100 mg/dL) from 2 consecutive samples taken no less than 1 week apart with the difference between the 2 values not exceeding 15% of the higher value, and mean TG value ≤4.52 mmol/L (400 mg/dL). 7HVW3URGXFW 'RVHDQG0RGHRI$GPLQLVWUDWLRQ /RW1XPEHUV Lapaquistat acetate 100 mg tablet, oral, QD Z5537081, Z5537111 Placebo tablet, oral, QD Z5535071, Z5535091 5HIHUHQFH7KHUDS\ 'RVHDQG0RGHRI$GPLQLVWUDWLRQ /RW1XPEHUV Atorvastatin (Lipitor£) 10 mg, 20 mg, 40 mg, oral, QD Not supplied by Sponsor Rosuvastatin (Crestor£) 10 mg, 20 mg, oral, QD Simvastatin (Zocor£) 20 mg, 40 mg, oral, QD Fenofibrate (Tricor£) not to exceed 200 mg, oral QD 'XUDWLRQRI7UHDWPHQW A 4-week dietary Run-in, followed by a 24-week treatment period. &ULWHULDIRU(YDOXDWLRQ (IILFDF\ The primary efficacy variable was fasting plasma LDL-C concentration based on direct measurement. The secondary efficacy variables were the fasting plasma concentrations of calculated LDL-C, non–HDL-C (derived as TC minus HDL-C), TC, Apo B, TG, HDL-C, Apo A1, VLDL-C, derived ratios (TC/HDL-C, LDL-C/HDL-C, and Apo B/Apo A1), and the percentage of subjects who achieved direct fasting plasma LDL-C concentrations of less than 1.81, 2.59, and 3.37 mmol/L (70, 100, and 130 mg/dL, respectively) at the final visit. In addition, hs-CRP and HbA1c were evaluated. 6DIHW\ Safety variables included TEAEs (events that occurred on or after the first dose of double-blind study medication and within 30 days of last dose), clinical laboratory data (chemistry, hematology, and urinalysis), physical examination findings, BCVA results, ECG assessments, vital signs, and weight. 6WDWLVWLFDO0HWKRGV All statistical analyses were based on the statistical analysis plan, which was finalized before unblinding. The statistical analysis of efficacy was based on the full analysis set, which was defined as all subjects in the safety set who had both a baseline value and at least 1 postbaseline efficacy value. The primary efficacy variable for this study was fasting plasma direct LDL-C. The primary analysis was based on the percentage change from Baseline in LDL-C at Week 24 or last on-treatment visit. The treatment groups were compared using an analysis of covariance (ANCOVA) model with terms for treatment effect and baseline value (as covariate). Secondary variables were analyzed using the same analysis model as the primary analysis. For time-effect displays, primary and secondary variables were summarized and analyzed by study visit. ANCOVA models similar to the model used in the primary analysis were used in these analyses. For TG, the assumption of normality was assessed using the Shapiro-Wilk statistic. If the assumptions were found not to hold, a nonparametric analysis based on the Wilcoxon Rank-Sum test was used to corroborate or supersede the parametric analysis. 7$.(& 2FWREHU 7LWOHRI6WXG\ A Placebo-Controlled, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 100 mg in Subjects With Type 2 Diabetes Currently Treated With Lipid-Lowering Therapy The estimate of treatment differences in median and 95% confidence intervals (CIs) was based on the Hodges-Lehmann method and the distribution-free CI, respectively. The proportions of subjects who achieved LDL-C concentrations of less than 1.813, 2.590, and 3.367 mmol/L (<70, 100, and 130 mg/dL) at Week 24 (or time of early withdrawal) were summarized in a shift table; no formal statistical analysis was performed. In the safety analyses, adverse events were coded using the Medical Dictionary for Regulatory Activities (Version 8.1) and summarized using descriptive statistics. Clinical laboratory test results were summarized descriptively by treatment. Markedly abnormal laboratory values were summarized by treatment group, including the number and percentage of subjects in each laboratory parameter group. Shift tables were produced that included the number of subjects per group with low, normal, or high values with respect to the reference ranges, and the number and percentage of subjects in each shift combination. Descriptive statistics of vital signs, ECG intervals, and BCVA evaluations were produced for each treatment group. 6800$5<2)5(68/76 For simplification, subjects will be referred to as placebo- or lapaquistat acetate–treated subjects throughout this report, since both groups were administered a stable dose of lipid-lowering medication during the study (atorvastatin, simvastatin, rosuvastatin, or fenofibrate). 6XEMHFW'LVSRVLWLRQ Of the 400 subjects randomized to treatment, 344 subjects completed the study and 56 subjects (14.4% placebo, 13.6% lapaquistat acetate) prematurely discontinued the study. Three subjects (1 placebo, 2 lapaquistat acetate) discontinued the study before taking study drug. The most common reasons for discontinuation were voluntary withdrawal and AEs. The majority of subjects were White (95.0%), 58.9% were women, and the mean age was 60.8 years. There were no other important differences between treatment groups in any of the baseline demographic characteristics or baseline efficacy parameters. (IILFDF\5HVXOWV 6XPPDU\RI/LSLG9DULDEOHV/HDVW6TXDUHV0HDQ 6( 3HUFHQW&KDQJH)URP%DVHOLQHDW:HHN /2&) &KDQJH)URP%DVHOLQH 'LIIHUHQFH 3ODFHER /$3PJ )URP3ODFHER 9DULDEOH Q Q &, 3YDOXH Direct LDL-C 4.60 (1.662) -20.15 (1.658) -24.75 (-29.368, -20.129) <0.001 Calculated LDL-C 7.24 (1.755) -21.12 (1.755) -28.36 (-33.242, -23.478) <0.001 Non–HDL-C 6.83 (1.580) -17.61 (1.580) -24.44 (-28.831, -20.044) <0.001 TC 5.13 (1.185) -13.48 (1.185) -18.61 (-21.906, -15.310) <0.001 Apo B 5.57 (1.377) -15.15 (1.373) -20.72 (-24.54, -16.90) <0.001 TG (a) 2.59 (a) -8.20 (a) -10.99 (-17.024, -4.990) (a) <0.001 HDL-C 1.17 (0.994) 0.58 (0.994) -0.59 (-3.359, 2.183) 0.677 Apo A1 1.86 (0.886) -1.59 (0.884) -3.44 (-5.91, -0.98) 0.006 VLDL-C 9.81 (2.522) -5.08 (2.522) -14.89 (-21.903, -7.874) <0.001 LAP=lapaquistat acetate. All subjects were coadministered atorvastatin (10 mg, 20 mg, or 40 mg), rosuvastatin (10 mg or 20 mg), simvastatin (20 mg or 40 mg), or fenofibrate (not to exceed 200 mg daily). (a) Median TG presented due to variability; difference in medians and 95% CIs based on Hodges-Lehmann method and distribution-free CIs, respectively.
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