Safety, tolerability, and immunogenicity of a 21-valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, US-based trial.

BACKGROUND: A pneumococcal conjugate vaccine (PCV) specifically focused on serotypes associated with adult residual disease burden is urgently needed. We aimed to assess V116, an investigational 21-valent PCV, that contains pneumococcal polysaccharides (PnPs), which account for 74-94% of invasive pneumococcal disease in adults aged 65 years or older. METHODS: We did a phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, non-inferiority and superiority trial. The phase 1 study was done at two clinical sites in the USA, and the phase 2 study was done in 18 clinical sites in the USA. Eligible participants were healthy adults with or without chronic medical conditions assessed as stable, aged 18-49 years in the phase 1 trial and aged 50 years or older in the phase 2 trial. Participants were excluded if they had a history of invasive pneumococcal disease or other culture-positive pneumococcal disease within the past 3 years, known hypersensitivity to a vaccine component, known or suspected impairment of immunological function, were pregnant or were breastfeeding, or had previously received any pneumococcal vaccine. Participants had to abstain from sexual activity or use protocol approved contraception. All participants were centrally randomly assigned to a vaccine group using an interactive response technology system. Participants and investigators were masked to group assignment. In phase 1, participants were randomly assigned (1:1:1) to receive a single dose of V116-1 (2 µg per pneumococcal polysaccharide [PnP] per 0·5 mL) or V116-2 (4 µg per PnP per 1·0 mL) or the 23-valent unconjugated PnP vaccine, PPSV23 (25 µg per PnP per 0·5 mL). In phase 2, participants were randomly assigned (1:1) to receive one dose of V116 (4 µg per PnP per 1·0 mL) or PPSV23 (25 µg per PnP per 0·5 mL), stratified by age. Safety analyses included all randomly assigned participants who received study vaccine; immunogenicity analyses were per protocol. For both phases, the primary safety outcome was the proportion of participants with solicited injection-site adverse events and solicited systemic adverse events up to day 5 after vaccination and the proportion of participants with vaccine-related serious adverse events to 6 months after vaccination. In phase 2, primary immunogenicity outcomes were to test non-inferiority of V116 compared with PPSV23 as measured by serotype-specific opsonophagocytic antibody geometric mean titres (OPA-GMT) ratios for the serotypes common to the two vaccines at 30 days after vaccination (using a 0·33 margin) and to test superiority of V116 compared with PPSV23 as measured by serotype-specific OPA-GMT ratios for the serotypes unique to V116 at 30 days after vaccination (using a 1·0 margin). This trial is registered with Clinicaltrials.gov, NCT04168190. FINDINGS: Between Dec 6 and 26, 2019, 92 volunteers were screened and 90 (98%) enrolled for phase 1 (59 [66%] women; 31 [34%] men); 30 participants were assigned to each group and received study vaccine. 30 (100%) participants in the V116-1 group, 29 (97%) in the V116-2 group, and 30 (100%) participants in the PPSV23 group were included in the per-protocol immunogenicity evaluation. From Sept 23, 2020, to Jan 12, 2021, 527 volunteers were screened, and 510 (97%) participants were enrolled in the phase 2 trial. 508 participants (>99%; 254 [100%] of 254 participants randomly assigned to the V116 group and 254 [99%] of 256 randomly assigned to PPSV23 group) received study vaccine (281 [55%] women; 227 [45%] men). 252 (99%) of 254 of participants in the V116 group and 254 (99%) of 256 participants in the PPSV23 group were included in the primary immunogenicity analyses. There were no vaccine-related serious adverse events or vaccine-related deaths in either study phase. In both phases, the most common solicited injection site adverse event was injection site pain (phase 1 22 [73%] participants in V116-1 group, 23 [77%] participants in V116-2 group, and 17 [57%] participants in the PPSV23 group; phase 2 118 [46%] of 254 participants in the V116 group and 96 [38%] of 254 in the PPSV23 group]. The most common solicited systemic adverse events in phase 1 was fatigue (eight [27%] participants in the V116-1 group, eight [27%] participants in the V116-2 group, and five [17%] participants in PPSV23 group) and myalgia (eight [27%] participants in the V116-1 group, nine (30%) participants in the V116-2 group, and four (13%) participants in the PPSV23 group]. In phase 2, the most frequently reported solicited systemic adverse event was fatigue (49 [19%] participants in V116 group, and 31 [12%] participants in PPSV23 group). In both phases, most of the solicited adverse events in all vaccine groups were mild and of short duration (≤3 days). V116 met non-inferiority criteria compared with PPSV23 for the 12 shared serotypes and met superiority criteria compared to PPSV23 for the nine unique serotypes. INTERPRETATION: V116 was well tolerated with a safety profile generally similar to PPSV23; consistent with licensed pneumococcal conjugate vaccines. Functional OPA antibodies were induced to all V116 vaccine serotypes. The vaccine was non-inferior to PPSV23 for the 12 serotypes common to both vaccines and superior to PPSV23 for the nine unique serotypes in V116. Our findings support the development of V116 for prevention of pneumococcal disease in adults. FUNDING: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA.

A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol.

This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval -42.5, -31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.

Safety and tolerability of extended-release niacin-laropiprant: Pooled analyses for 11,310 patients in 12 controlled clinical trials.

BACKGROUND: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) showed that adding extended-release niacin-laropiprant (ERN-LRPT) to statin provided no incremental cardiovascular benefit vs placebo (PBO). ERN-LRPT was also associated with an excess of serious adverse experiences (AEs), some of which were unexpected (infections and bleeding). These findings led to the withdrawal of ERN-LRPT from all markets. OBJECTIVE: We examined the safety profile of ERN-LRPT vs the comparators ERN alone and statins in the ERN-LRPT development program to assess whether similar safety signals were observed to those seen in HPS-THRIVE and whether these might be attributed to ERN or LRPT. METHODS: Postrandomization safety data from 12 clinical studies, 12 to 52 weeks in duration and involving 11,310 patients, were analyzed across 3 treatments: (1) ERN-LRPT; (2) ERN-NSP (ERN, Merck & Co, Inc or Niaspan [NSP], Abbott Laboratories); and (3) statin-PBO (statin or PBO). RESULTS: The safety profiles of ERN-LRPT and ERN-NSP were similar, except for less flushing with ERN-LRPT. Nonflushing AEs reported more frequently with ERN-LRPT or ERN-NSP than with statin-PBO were mostly nonserious and typical of niacin (nausea, diarrhea, and increased blood glucose). There was no evidence for an increased risk of serious AEs related to diabetes, muscle, infection, or bleeding. CONCLUSIONS: Pooled data from 11,310 patients revealed that, except for reduced flushing, the safety profile of ERN-LRPT was similar to that of ERN-NSP; LRPT did not appear to adversely affect the side-effect profile of ERN. The inability to replicate the unexpected AE findings in HPS2-THRIVE could be because of the smaller sample size and substantially shorter duration of these studies.

Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. FINDINGS: Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI -39·5 to -32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [-1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of -39·7% (95% CI -45·7 to -33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. FUNDING: Merck & Co, Inc.

Safety of extended-release niacin/laropiprant in patients with dyslipidemia.

OBJECTIVE: To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program. METHODS: Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931). RESULTS: The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin. CONCLUSION: The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.

Carotid atherosclerosis progression in familial hypercholesterolemia patients: a pooled analysis of the ASAP, ENHANCE, RADIANCE 1, and CAPTIVATE studies.

BACKGROUND: Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression. METHODS AND RESULTS: We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase. CONCLUSIONS: Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.

Effects of sources of variability on sample sizes required for RCTs, applied to trials of lipid-altering therapies on carotid artery intima-media thickness.

OBJECTIVE: Studies measuring progression of carotid artery intima-media thickness (cIMT) have been used to estimate the effect of lipid-modifying therapies cardiovascular event risk. The likelihood that future cIMT clinical trials will detect a true treatment effect is estimated by leveraging results from prior studies. The present analyses assess the impact of between- and within-study variability based on currently published data from prior clinical studies on the likelihood that ongoing or future cIMT trials will detect the true treatment effect of lipid-modifying therapies. METHODS: Published data from six contemporary cIMT studies (ASAP, ARBITER 2, RADIANCE 1, RADIANCE 2, ENHANCE, and METEOR) including data from a total of 3563 patients were examined. Bayesian and frequentist methods were used to assess the impact of between study variability on the likelihood of detecting true treatment effects on 1-year cIMT progression/regression and to provide a sample size estimate that would specifically compensate for the effect of between-study variability. RESULTS: In addition to the well-described within-study variability, there is considerable between-study variability associated with the measurement of annualized change in cIMT. Accounting for the additional between-study variability decreases the power for existing study designs. In order to account for the added between-study variability, it is likely that future cIMT studies would require a large increase in sample size in order to provide substantial probability (> or =90%) to have 90% power of detecting a true treatment effect.Limitation Analyses are based on study level data. Future meta-analyses incorporating patient-level data would be useful for confirmation. CONCLUSION: Due to substantial within- and between-study variability in the measure of 1-year change of cIMT, as well as uncertainty about progression rates in contemporary populations, future study designs evaluating the effect of new lipid-modifying therapies on atherosclerotic disease progression are likely to be challenged by large sample sizes in order to demonstrate a true treatment effect.

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men.

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). Simvastatin did not significantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition is one strategy for increasing HDL-C. This study evaluated the lipid-altering efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy or coadministered with atorvastatin in patients with dyslipidemia. METHODS: A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia (53.8% of the study population had low HDL-C) were randomized equally to one of 10 groups: 5 groups received background statin therapy of atorvastatin 20 mg and 5 did not, and each of these was randomized to placebo, anacetrapib 10, 40, 150, and 300 mg once daily for 8 weeks. An equal proportion of patients had triglycerides >150 mg/dL in each group. RESULTS: For placebo and anacetrapib monotherapy (10, 40, 150, and 300 mg), least squares mean percent changes from baseline to week 8 for low-density lipoprotein cholesterol (LDL-C) were 2%, -16%, -27%, -40%, and -39%, respectively, and for HDL-C were 4%, 44%, 86%, 139%, and 133%, respectively (P < .001 vs placebo for all doses). Coadministration of anacetrapib with atorvastatin produced significant incremental LDL-C reductions and similar HDL-C increases versus atorvastatin monotherapy. For both anacetrapib monotherapy and coadministration with atorvastatin, the LDL-C reductions were similar in patients with baseline triglyceride levels greater than and less than or equal to the median. Anacetrapib was well tolerated, and the incidence of adverse events was similar for placebo and all active treatment groups. There were no increases in systolic or diastolic blood pressure in any treatment arm. CONCLUSIONS: Anacetrapib, as monotherapy or coadministered with atorvastatin, produced significant reductions in LDL-C and increases in HDL-C; the net result of treatment with anacetrapib + atorvastatin was approximately 70% lowering of LDL-C and more than doubling of HDL-C. Anacetrapib was generally well tolerated with no discernable effect on blood pressure.

Lipid-modifying efficacy of extended release niacin/laropiprant in Asian patients with primary hypercholesterolemia or mixed hyperlipidemia.

BACKGROUND: Niacin has proven lipid-modifying efficacy and cardiovascular benefit; however, it is underused because of skin flushing, a process mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that mitigates niacin-induced flushing, has been combined with extended-release niacin (ERN) into a fixed-dose tablet containing 1g of ERN and 20mg of LRPT (ERN/LRPT 1g). In a large-scale (n=∼1600), multinational, 6-month study in dyslipidemic patients, ERN/LRPT 2g produced superior lipid-modifying efficacy vs placebo, whether administered alone or with concomitant statins. OBJECTIVE: This Phase III, randomized, double-blind study evaluated the lipid-modifying efficacy of ERN/LRPT alone or added to ongoing statins in Asian patients with primary hypercholesterolemia or mixed hyperlipidemia. METHODS: After a 4-week placebo run-in, patients were randomized to ERN/LRPT 1g (n=322) or placebo (PBO; n=324). After 4 weeks, the dose was advanced to 2 tablets/d (ERN/LRPT 2g or PBO) for 8 additional weeks. End points included effects of ERN/LRPT 2g vs PBO on low-density lipoprotein cholesterol (LDL-C; primary), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and other lipids/lipoproteins. RESULTS: Relative to PBO, ERN/LRPT 2g produced significant (P < .001) changes in LDL-C (-14.7%), HDL-C (15.9%), TG (-23.4%), LDL-C:HDL-C (-25.5%), non-HDL-C (-16.4%), apolipoprotein (Apo) B (-15.4%), and Apo A-I (5.3%) from baseline to week 12 in the total population. Similar results were observed in patients treated with ERN/LRPT alone or added to ongoing statin. CONCLUSION: ERN/LRPT 2g, administered alone or with a statin, produced significant improvements in multiple lipid/lipoprotein parameters in dyslipidemic Asian patients.

Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia.

OBJECTIVE: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia. RESEARCH DESIGN AND METHODS: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10 mg/simvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10 mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80 mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs). MAIN OUTCOME MEASURES AND RESULTS: Ezetimibe/simvastatin (n = 539) and simvastatin monotherapy (n = 229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study. CONCLUSIONS: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.

Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques.

BACKGROUND: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. OBJECTIVE: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia. METHODS: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. RESULTS: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. CONCLUSION: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.

Etoricoxib in acute pain associated with dental surgery: a randomized, double-blind, placebo- and active comparator-controlled dose-ranging study.

BACKGROUND: Patients experiencing acute pain after surgery, including dental surgery, often require analgesia. Ideally, the chosen analgesic should have a rapid onset and sustained effect. Etoricoxib is a new cyclooxygenase-2-selective inhibitor that has demonstrated analgesic efficacy in the treatment of acute pain with a rapid onset and long-lasting pain relief. OBJECTIVE: The goal of this study was to determine the analgesic effect of single oral doses of etoricoxib 60, 120, 180, and 240 mg compared with placebo in the treatment of pain after dental surgery. Ibuprofen was used as an active control. METHODS: This was a randomized, double-blind, parallel-group, single-dose, placebo- and active comparator-controlled study performed at a single center. It consisted of 3 visits (prestudy, treatment, and poststudy). Eligible patients were aged > or =16 years with moderate or severe pain after surgical extraction of > or =2 third molars, of which > or =1 was an impacted mandibular molar. Patients were assessed over 24 hours and reported pain intensity and pain relied at 14 predefined time points. Plasma samples for a pharmacokinetic/pharmacodynamic analysis were collected from a subset of patients at baseline and the 14 predefined time points. The end points included total pain relief over 8 hours (TOPAR8, the primary end point), sum of pain intensity difference over 8 hours, patient's global evaluation of treatment, median time to onset of pain relief (2-stopwatch method), peak pain relief, and duration of analgesic effect (median time to use of rescue medication). Adverse events were collected up to 14 days postdose. RESULTS: Three hundred ninety-eight (63.1% women, 36.9% men; mean age, 21.1 years; 72.1% white, 27.9% other; mean number of third molars removed, 3.5; 65.2% experiencing moderate pain) were randomly allocated to receive etoricoxib 60 mg (n = 75), etoricoxib 120 mg (n = 76), etoricoxib 180 mg (n = 74), etoricoxib 240 mg (n = 76), ibuprofen 400 mg (n = 48), and placebo (n = 49). All active treatments had significantly greater overall analgesic effect (TOPAR8) compared with placebo (P < or 0.001). Patients who received etoricoxib 120 and 180 mg had significantly higher TOPAR8 scores than those who received etoricoxib 60 mg ( P < = 0.001) and ibuprofen (P < 0.05 etoricoxib 120 mg; P < or = 0.001 etoricoxib 180 mg). Least-squares mean TOPAR8 scores for etoricoxib 60, 120, 180, and 240 mg, ibuprofen, and placebo were 16.0, 22.0, 23.5, 20.7, 18.6, and 5.2, respectively. The median time to onset of analgesia was 24 minutes for etoricoxib 120, 180, and 240 mg, and 30 minutes for etoricoxib 60 mg and ibuprofen. There were no significant differences in the onset of analgesia between etoricoxib 120, 180, and 240 mg and ibuprofen. The duration of analgesic effect was >24 hours for etoricoxib 120, 180, and 240 mg, and 12.1 hours for etoricoxib 60 mg. The duration of effect was significantly longer with all 4 etoricoxib doses compared with ibuprofen (10.1 hours; P < 0.05 etoricoxib 60 mg; < or = 0.001etoricoxib 120, 180, and 240 mg) and compared with placebo (2.1 hours; P < = 0.001). In the pharmacokinetic/pharmacodynamic analysis (n approximately 120), there was a linear relationship between plasma etoricoxib concentrations and pain relief scores up to the maximum observed concentration, followed by a decline in plasma concentrations with persistent analgesia. The most common adverse events were postextraction alveolitis and nausea. CONCLUSIONS: In this dose-ranging study, etoricoxib 120 mg was determined to be the minimum dose that had maximal efficacy in patients with moderate to severe acute pain associated with dental surgery. Both etoricoxib and ibuprofen were generally well tolerated.

Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the efficacy and safety of 10 mg of ezetimibe coadministered with simvastatin with the safety and efficacy of simvastatin monotherapy for patients with hypercholesterolemia. PATIENTS AND METHODS: This multicenter double-blind, placebo-controlled, factorial study enrolled 887 patients with hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides, < or = 350 mg/dL). Patients were randomized to 1 of 10 treatments--placebo, ezetimibe at 10 mg/d, simvastatin at 10, 20, 40, or 80 mg/d, or simvastatin at 10, 20, 40, or 80 mg/d plus ezetimibe at 10 mg/d for 12 weeks. The study began March 13, 2001, and ended January 8, 2002. The primary efficacy end point was the mean percent change in LDL-C levels from baseline to study end point (last available postbaseline LDL-C measurement) for the pooled ezetimibe/simvastatin group vs the pooled simvastatin monotherapy group. RESULTS: Coadministration of ezetimibe/simvastatin was significantly (P<.001) more effective than simvastatin alone in reducing LDL-C levels for the pooled ezetimibe/simvastatin vs pooled simvastatin analysis and at each specific dose comparison. The decrease in LDL-C levels with coadministration of ezetimibe and the lowest dose of simvastatin, 10 mg, was similar to the decrease with the maximum dose of simvastatin, 80 mg. A significantly (P<.001) greater proportion of patients in the ezetimibe/simvastatin group achieved target LDL-C levels compared with those in the monotherapy group. Treatment with ezetimibe/simvastatin also led to greater reductions in total cholesterol, triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels compared with simvastatin alone; both treatments increased high-density lipoprotein cholesterol levels similarly. The safety and tolerability profiles for the ezetimibe/simvastatin and monotherapy groups were similar. CONCLUSION: Through dual inhibition of cholesterol absorption and synthesis, coadministration of ezetimibe/simvastatin offers a highly efficacious and well-tolerated lipid-lowering strategy for treating patients with primary hypercholesterolemia.

A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study After a 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP]. RESULTS: There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of -44.8% to -602%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels > or =3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels > or =10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS). CONCLUSION: The EZE/SIMVA tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia.

Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin.

BACKGROUND: A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). METHODS AND RESULTS: A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (-41%), total cholesterol (-31%), apolipoprotein B (-34%), VLDL cholesterol (-21%), and triglyceride (-9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. CONCLUSIONS: Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.