A Phase 1 Randomized, Placebo-controlled, Observer-blinded Trial to Evaluate the Safety and Immunogenicity of Inactivated Streptococcus pneumoniae Whole-cell Vaccine in Adults.

BACKGROUND: Broadly protective pneumococcal vaccines that are affordable for low-resource countries are needed. Streptococcus pneumoniae whole cell vaccine (wSp) is an investigational vaccine that contains killed cells from a nonencapsulated strain of S. pneumoniae (SPn) with aluminum hydroxide adjuvant. Studies in mice demonstrated protection against nasopharyngeal carriage (T-cell-mediated) and invasive pneumococcal disease (antibody-mediated). The aim of this randomized, double-blind, placebo-controlled Phase 1 study was to assess safety, tolerability and immunogenicity of wSp in healthy adults. METHODS: Forty-two participants were randomized into 3 dose cohorts to receive 0.1, 0.3, or 0.6 mg of wSp or saline intramuscularly. Participants received a 3-dose vaccination schedule spaced by 4-week intervals. Postvaccination assessments included solicited reactogenicity events through day 7, blood chemistry and hematology assessments at day 7, and adverse events (AEs) through day 84. Participants were monitored for serum antibody and peripheral blood mononuclear cell cytokine responses to pneumococcal antigens. A 6-month telephone follow-up was completed to assess for any additional AEs. RESULTS: wSp was safe and well tolerated. Reactogenicity was acceptable and no untoward safety signals were observed. wSp elicited potentially clinically significant rises (defined arbitrarily as at least a 2-fold rise) in immunoglobulin G responses to multiple pneumococcal antigens, including pneumococcal surface protein A and pneumolysin. Functional antibody responses were observed with the highest dose of wSp (0.6 mg). Increases in T-cell cytokine responses, including interleukin 17A, were also seen among wSp vaccines. CONCLUSIONS: wSp was safe and well tolerated in healthy US adults, eliciting pneumococcal antigen-specific antibody and T-cell cytokine responses.

Carotid artery intima-media thickness after raloxifene treatment.

BACKGROUND: Raloxifene, a selective estrogen receptor modulator (SERM), decreases total and low-density lipoprotein cholesterol (LDL-C) in postmenopausal women and inhibits increases in intima-media thickness (IMT) in animal models. We tested whether up to 8 years exposure to raloxifene had an effect on subclinical atherosclerosis in the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial and the follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial. METHODS: A subsample of postmenopausal women with osteoporosis, who had completed the MORE and CORE trials and were on average 68 years of age and 19 years postmenopausal at randomization into MORE, participated in this substudy. Within 6 months of cessation of study drug in CORE, right common carotid artery IMT (CIMT) and carotid artery stiffness and arterial compliance were measured at one of two sites (San Diego and San Francisco) using high-resolution B-mode ultrasound. CIMT and arterial stiffness measures were compared between women who had received raloxifene vs. placebo; the primary analysis included only women who were >or=80% drug compliant and had used

Safety assessment of raloxifene over eight years in a clinical trial setting.

OBJECTIVE: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting. METHODS: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test. RESULTS: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively). CONCLUSION: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene.

OBJECTIVE: To determine the incidence of arterial and venous thromboembolic (VTE) events, to determine the effect of raloxifene on the incidence of combined vascular (arterial and VTE) events, and to identify patient characteristics associated with these vascular events, in women participating in the MORE trial. DESIGN: In a post hoc analysis using MORE data, arterial, VTE, and combined vascular event rates were compared between participants receiving placebo (n = 2,576) and those receiving 60 mg/d of raloxifene (n = 2,557). Baseline characteristics were compared between those who did and did not experience an arterial event. The same analysis was performed for VTE events. RESULTS: Overall, during a mean follow-up time of 41 months, 178 women experienced an arterial event and 40 experienced a VTE event. In the placebo group, the incidence of arterial events exceeded VTE events by at least sevenfold. Raloxifene had no significant effect on the incidence of combined vascular events in the overall cohort (hazard ratio 0.95, 95% CI, 0.73-1.24). In a subset of women retrospectively determined to be at increased cardiovascular risk, raloxifene was associated with a lower incidence of combined vascular events (hazard ratio 0.63, 95% CI, 0.40-0.97). Baseline characteristics differed between those who did and those who did not experience an arterial event, but this was generally not the case for VTE events. CONCLUSIONS: Arterial events were more common than VTE events. The characteristics of women experiencing an arterial event differed from those experiencing a VTE event. Raloxifene had a neutral effect on the risk of combined vascular events in the overall population, and was associated with a reduced combined vascular event rate in women at increased cardiovascular risk. Additional studies are needed to confirm the effect of raloxifene on overall vascular outcomes.

Effects of raloxifene and low-dose simvastatin coadministration on plasma lipids in postmenopausal women with primary hypercholesterolemia.

Abstract Raloxifene and low-dose simvastatin can each reduce low-density lipoprotein (LDL) cholesterol without affecting high-density lipoprotein (HDL) cholesterol and triglycerides. The objective of this double-blind, 12-week study is to determine whether raloxifene and simvastatin coadministration gives added benefit beyond either monotherapy in affecting fasting lipoproteins and apolipoproteins. Ninety-five postmenopausal women with moderately elevated LDL cholesterol (mean, 146 mg/dL) were randomized to placebo, raloxifene 60 mg/d, simvastatin 10 mg/d, or raloxifene 60 mg/d coadministered with simvastatin 10 mg/d. Raloxifene, simvastatin, and coadministration therapy reduced mean LDL cholesterol by 10.5%, 23.3%, and 31.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo), and mean apolipoprotein B by 10.4%, 24.2%, and 30.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo). Each active treatment decreased non-HDL cholesterol compared with placebo ( P < .01). Coadministration treatment was more effective than either monotherapy in reducing LDL cholesterol ( P < .05). Coadministration treatment reduced mean apolipoprotein B ( P < .001) and non-HDL cholesterol ( P < .001) when compared with raloxifene, but was not significantly different when compared with simvastatin. Coadministration therapy increased HDL cholesterol and apolipoprotein A1 levels compared with placebo ( P < .02). No significant effect on triglycerides, very low density lipoprotein cholesterol, and lipoprotein (a) occurred with any active treatment. Raloxifene, simvastatin, and the coadministration therapy were generally well tolerated with clinical adverse effects similar to placebo. No woman had clinically significant elevated liver function tests requiring drug discontinuation. Further data on safety and lipid-lowering effects are needed before raloxifene and statin coadministration may be considered as therapeutic interventions for treating postmenopausal women to achieve National Cholesterol Education Program-Adult Treatment Panel III treatment guidelines.

Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial.

OBJECTIVE: To assess the effect of raloxifene 60 mg/day (RLX) on year-by-year cardiovascular (CV) events in postmenopausal women participating in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a double-blind, placebo-controlled osteoporosis treatment trial. RESEARCH DESIGN AND METHODS: Post hoc analysis, using data from participants receiving placebo (N = 2576) or RLX 60 mg/day (N = 2557) in MORE, was performed to determine the relative risk (RR, 95% CI) of CV events in each individual trial year. Analyses were performed for the overall cohort and for women in high and low risk subsets. Women were retrospectively assessed as high CV risk using established criteria and the remaining women were considered low CV risk. RESULTS: The incidence of CV events did not differ between the RLX and placebo groups in the overall cohort (RR 0.86, 95% Cl 0.64-1.15), or the low CV risk subset (RR 1.01, 95% Cl 0.70-1.46). In the high-risk subset, the incidence of CV events was less in the RLX group (RR 0.60, 95% Cl 0.38-0.95). There was no significant increase in CV risk during any single year in the RLX group for either the overall cohort or the low or high CV risk subsets. CONCLUSION: In this post hoc analysis, the risk of CV events was not increased in any single year of MORE in women taking RLX, either in the overall cohort or in the low and high CV risk subsets.