Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

AIMS: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). METHODS: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. RESULTS: No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes. CONCLUSIONS: LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes.

Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study).

AIMS: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus(®)) insulin glargine (IGlar) in combination with oral antihyperglycaemic medications in patients with type 2 diabetes (T2D). METHODS: This phase III, randomized, double-blind, 24-week study enrolled patients with T2D who were insulin-naïve [glycated haemoglobin (HbA1c) ≥7 and ≤11.0%] or previously on IGlar (HbA1c ≤11%) and treated with ≥2 oral antihyperglycaemic medications. Patients were randomized to receive once-daily LY IGlar (n = 376) or IGlar (n = 380) for 24 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar, as measured by change in HbA1c from baseline to 24 weeks. RESULTS: Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met non-inferiority criteria compared with IGlar for change in HbA1c from baseline [-1.29 vs -1.34%; respectively, least-squares mean difference 0.052% (95% confidence interval -0.070 to 0.175); p > 0.05]. There were no treatment differences (p > 0.05) in fasting plasma glucose, proportion of patients reaching HbA1c <7% or insulin dose at 24 weeks. Adverse events, allergic reactions, weight change, hypoglycaemia and insulin antibodies were similar between treatment groups. Similar findings were observed in patients who were insulin-naïve or previously treated with IGlar at baseline. CONCLUSIONS: Both LY IGlar and IGlar, when used in combination with oral antihyperglycaemic medications, provided effective and similar glucose control with similar safety profiles in patients with T2D.

Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus®) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study.

AIMS: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus®) insulin glargine (IGlar) in patients with type 1 diabetes (T1D). METHODS: This phase III, randomized, open-label, 52-week study enrolled patients with T1D [glycated haemoglobin (HbA1c) ≤11%] being treated with basal (once-daily) and bolus insulin. Patients were randomized to receive once-daily LY IGlar (n = 268) or IGlar (n = 267) in combination with mealtime insulin lispro for 52 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks. RESULTS: Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met the non-inferiority criteria compared with IGlar for change in HbA1c from baseline to 24 weeks [-0.35 vs -0.46%, least-squares mean difference 0.108% (95% confidence interval -0.002 to 0.219), p > 0.05]. There were no significant (p > 0.05) treatment differences in other efficacy measures, including proportion of patients reaching HbA1c <7%, daily mean blood glucose, and insulin dose at 24 and 52 weeks. At 52 weeks, similar findings were observed between LY IGlar and IGlar for safety outcomes, including adverse events, allergic reactions, hypoglycaemia, weight change and insulin antibodies. CONCLUSIONS: Both LY IGlar and IGlar, when used in combination with mealtime insulin lispro, provided effective and similar glucose control and similar safety profiles.

Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. II. Pharmacokinetics and immune response.

Twenty-five patients with metastatic gastrointestinal adenocarcinoma received one to four infusions of large doses (400 mg) of murine monoclonal antibody CO17-1A (17-1A). The pharmacokinetics of 17-1A at the time of first, second, third, or fourth infusion were not statistically different; plasma half-lives were 15.0 +/- 1.7 hours (n = 5), 15.1 +/- 1.8 (n = 10), 25.3 +/- 6.2 (n = 3), and 14.4 +/- 1.8 (n = 5), respectively. Most patients had an antibody response to 17-1A, with peak levels occurring 15-22 days after infusion. The presence of serum antibody to 17-1A at the time of the second or third infusion did not significantly alter the pharmacokinetics of this large dose of antibody. Four of 25 patients failed to develop an antibody response, but this did not correlate with the amount of 17-1A administered. The administration of four doses of 400 mg over 1 week provided continuously circulating 17-1A for 10 days.

Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile.

Kinetics of 5-fluorouracil (FUra) and FUra metabolites in plasma and urine were investigated in 10 cancer patients following i.v. bolus administration of 500 mg/m2 FUra with 600 microCi of [6-3H]FUra. Biliary excretion was examined in two patients with external biliary catheters. Quantitation of unchanged drug and metabolites was assessed by a highly specific high-performance liquid chromatographic method. FUra plasma levels declined rapidly with an apparent elimination half-life of 12.9 +/- 7.3 min. Dihydrofluorouracil was detected within 5 min in most patients, demonstrating rapid catabolism and reached maximum peak levels of 23.7 +/- 9.9 microM at approximately 60 min. The apparent elimination half-life of dihydrofluorouracil (61.9 +/- 39.0 min) was consistently greater than that of the unchanged drug. The apparent elimination half-lives of the subsequent metabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine were prolonged with values of 238.9 +/- 175.4 min and 1976 +/- 358 min, respectively. Approximately 60-90% of the administered dose was excreted in urine within 24 h, primarily as alpha-fluoro-beta-alanine. Biliary excretion accounted for 2-3% of total administered radioactivity. The major fraction of this radioactivity eluted on high-performance liquid chromatography as a previously unrecognized FUra metabolite. Analysis of its structure is currently ongoing in our laboratory. In conclusion, this study provides the first comprehensive analysis of the formation and excretion of FUra metabolites in plasma, urine, and bile following i.v. bolus administration of FUra in humans.

Reproducibility of two-dimensional exercise echocardiography.

To determine the reproducibility of two-dimensional exercise echocardiography, duplicate studies were performed on the same patients a median of 14 days apart. Because measurements are operator-dependent, interobserver variability was calculated for two experienced readers who interpreted the findings independently in a blinded manner. A high degree of interobserver agreement was found in evaluation of both ejection fraction measurements and wall motion abnormalities. Readings for ejection fraction immediately after exercise taken on different days could be estimated within 4% of the values measured in the first test; similarly measured wall motion score index was within 6% of that in the first test. Ejection fractions and wall motion scores were highly correlated between tests 1 and 2. The correlation coefficients between tests 1 and 2 were 0.92 for both the pre- and postexercise ejection fractions and 0.98 for both the pre- and postexercise wall motion scores. Quantitative two-dimensional echocardiography immediately after exercise is highly reproducible, providing a valuable tool for assessing serial changes in left ventricular function.

Effect of adenine nucleotides on granulopoiesis and lithium-induced granulocytosis in long-term bone marrow cultures.

Studies were undertaken to evaluate the role of adenine nucleotides in regulating hematopoiesis using a long-term liquid culture system. In contrast to early investigations using clonogenic stem cell assays, where inhibitory effects were observed, adenosine and adenosine-5'-monophosphate (AMP) were found to stimulate myelopoiesis whereas the dibutyryl derivative of cyclic adenosine-3',5'-monophosphate (dcAMP) had either a modest inhibitory effect or no effect on long-term hematopoiesis. Dose effects for AMP enhancement of hematopoiesis were relatively narrow. When cultures were exposed to a broad range of concentrations (10 mM-10 nM), stimulation was only seen at a molar concentration of 1 X 10(-4) M. Stem cell assays revealed stimulation of multipotent stem cells (CFU-S), as well as committed progenitor cells (CFU-C). Lithium chloride has been shown to cause granulocytosis both in vivo and in vitro. Reductions in intracellular cAMP levels resulting from adenylate cyclase inhibition is a proposed mechanism for this stimulatory effect. However, lithium-induced granulocytosis in long-term cultures could not be blocked by the addition of dcAMP. Measurement of nucleotide levels on spent medium revealed rapid utilization and/or degradation of these reagents. This suggests that failure to abrogate the lithium effect with dcAMP may have been related to the inability to maintain constant intracellular concentrations. The varied observations regarding adenine nucleotide effects on hematopoiesis, as well as the reproducible stimulation by lithium, may be explained by our current appreciation of the complex adenylate cyclase system, which contains both inhibitory and stimulatory subunits for nucleotides and monovalent cations.

A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women.

This randomized, double-blind, placebo-controlled, multicenter, 8-week study evaluated short-term effects of raloxifene on bone turnover, serum lipids, and endometrium in healthy, postmenopausal women. A total of 251 women received either placebo, raloxifene HCl 200 or 600 mg/day, or conjugated estrogens (Premarin, 0.625 mg/day). Bone turnover (serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline cross-links, urinary calcium excretion, urinary hydroxyproline) and serum lipids (total serum cholesterol, high- and low-density lipoprotein cholesterol [HDL-C and LDL-C]) were evaluated at weeks 0, 2, 4, and 8. Endometrial biopsies were performed at weeks 0 and 8. Treatment groups were compared for each parameter for baseline-to-endpoint changes. The estrogen and raloxifene groups experienced similar decreases in serum alkaline phosphatase (range 10-11%), serum osteocalcin (range 21-26%), urinary pyridinoline cross-links (range 20-26%), and urinary calcium excretion (range 45-72%). These decreases differed significantly compared with placebo-treated subjects for all markers except serum osteocalcin, the raloxifene HCl 200 mg group. LDL-C decreased significantly in the estrogen and both raloxifene groups (range 5-9%) compared with placebo-treated subjects. HDL-C increased significantly in the estrogen group (16%) but was unchanged in the raloxifene groups. HDL-C:LDL-C ratios increased significantly in the estrogen and raloxifene groups (range 9-29%). Serum cholesterol decreased significantly in both raloxifene groups (range 4-8%) but was unchanged in the estrogen group. Uterine biopsies of raloxifene-treated subjects showed no change in the endometrium during this short-term treatment. Biopsies of the estrogen group showed significant endometrial stimulation. The only adverse event possibly related to raloxifene was vasodilatation (hot flashes) which was most common in the raloxifene HCl 600 mg group. Study results indicate that raloxifene may provide beneficial effects to bone and serum lipids in humans without uterine stimulatory effects.

Assessment of total immunoreactive lactoferrin in hematopoietic cells using flow cytometry.

Cell-associated lactoferrin (Lf) was analyzed using a new method involving cell permeabilization, indirect immunofluorescence staining, and flow cytometry. Statistical techniques to evaluate the results for percentage of positive cells, relative fluorescence and homogeneity of Lf distribution were also devised. Most normal adult neutrophils (97.1 +/- 0.3% (SEM), range 92.7-99.6%, n = 41) had brilliant fluorescence homogeneously distributed among the cells. There was significantly greater homogeneity of neutrophil Lf distribution in post-menopausal than pre-menopausal females. In chronic myelogenous leukemia (n = 13) and cord blood (n = 7), fractions of Lf-positive neutrophils were decreased (77.3 +/- 7.5%, range 13.3-96.3%; 71.4 +/- 9.3, range 32.0-95.6%, respectively). Normal monocyte-rich isolates had moderate fluorescence (28.7 +/- 3.6%, range 9.3-76.8%, n = 22). Among blood lymphocyte-rich preparations, 13.1 +/- 1.3% of cells had weak positivity (range 4.9-26.6%, n = 19); monoclonal B and T lymphocytes had similar parameters. No other cells had detectable Lf. Our results were significantly correlated with those obtained manually (r = 0.98, P less than 0.001), and are consistent with Lf quantity and distribution determined using other methods.

Iron-binding reactivity in mature neutrophils: relative cell content quantification by cytochemical scoring.

We have developed a technique that permits evaluation and semi-quantification of iron-binding function in mature neutrophils. Neutrophil iron-binding reactivity (NFeBR) visualized using the iron nitrilotriacetate-acid ferrocyanide technique was rated 0 to 5+ in 100 segmented cells; the ratings were totaled to yield a score (NFeBRS). Males and post-menopausal females had significantly higher NFeBRS than pre-menopausal females. Neonates had low values, and a homogeneous distribution of NFeBR among neutrophils. In pregnancy and acute infection, NFeBRS were significantly increased. In a patient with congenital lactoferrin (Lf) deficiency, the NFeBRS was very low. In Ph1-positive chronic myelogenous leukemia, 13 of 17 patients had low NFeBRS due to decreased NFeBR, which was heterogeneously distributed among mature neutrophils. By ultrastructural analysis of mature neutrophils in two such patients, the stain deposits in FeBR-positive granules were of normal intensity, but the numbers of positive granules were decreased in many cells. NFeBRS were also low in 12 of 23 patients with other myeloproliferative disorders, and in seven of 15 patients with acute non-lymphoblastic leukemia, but in only seven of 63 patients with other neoplasms. NFeBRS were significantly correlated (p less than 0.008) with values of neutrophil Lf content quantified by immunologic assays in a wide variety of conditions and over a broad range of values. These results augment observations of neutrophil Lf made using immunological methods.

Seasonal changes in lead absorption in laboratory rats.

A retrospective study of the relationship of season to the absorption of radiolead in laboratory rats was performed using data representing 305 animals from 36 experiments over 6 calendar years. Male Wistar rats weighing 200 to 250 g were given 1 microgram of radiolabeled lead in an aqueous solution, pH 4.0, in isolated small intestine, and absorption of the radiolead was quantified after a 4-hour interval using whole-body counting. Similar values of absorption occurred in the summer (June-August) and fall (September-November), 20.51 +/- 1.11% (1 SEM) and 23.0 +/- 1.23% of the test dose, respectively, but significantly lower values occurred in the winter (December-February) and spring (March-May): 16.51 +/- 0.77%, p less than 0.01, and 11.87 +/- 0.99%, p less than 0.01, respectively. Harmonic analysis yielded an excellent approximation of the mean quarterly absorption data. The resulting cosine function had a period of 4.08 +/- 0.05 quarter-years with an amplitude of 7.32 +/- 1.06%; predicted peak absorption values fell precisely between summer and fall. The relationships of these observations to possible mechanisms of lead absorption and to summertime epidemics of lead poisoning in children are discussed.

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.

Adverse events reported by postmenopausal women in controlled trials with raloxifene.

OBJECTIVE: To assess the incidence of adverse events in postmenopausal women treated with raloxifene compared with placebo, hormone replacement therapy (HRT), or unopposed estrogen. METHODS: Common treatment groups were pooled across eight randomized, parallel clinical trials (6-30 months' duration) of raloxifene to create the following three databases: placebo-controlled, HRT-controlled, and estrogen-controlled databases. Incidence and severity of all treatment-emergent adverse events, defined as events that first occurred or worsened during treatment, were compared among groups in each of the databases. RESULTS: Discontinuation rates overall, and those related to adverse events, were not significantly different between treatment groups in any database. There was no significant difference in incidence of vaginal bleeding or breast discomfort between women treated with raloxifene (60 mg/d) or placebo. Both of these events were reported more frequently in women receiving HRT or estrogen. Vaginal bleeding was responsible for significantly more discontinuations from the HRT groups compared with the raloxifene group. Hot flashes was the only event common to all three databases that was significantly increased in the raloxifene group, but this event did not increase the discontinuation rates. The incidence of leg cramps was greater in raloxifene-treated women compared with placebo-treated women in the placebo-controlled database, but did not cause any discontinuations of therapy. Raloxifene had no effect on the incidence of vaginal symptoms or central nervous system events. CONCLUSION: Raloxifene had an adverse event profile distinct from HRT and unopposed estrogen and was well tolerated by postmenopausal women.

Effect of premixed nph and regular insulin on glucose control and health-related quality of life in patients with type 2 diabetes mellitus.

OBJECTIVE: To compare the effect of the addition of regular insulin as a premixed 70/30 insulin to the treatment regimen of patients with type 2 diabetes who had used NPH insulin alone relative to overall glycemic control (postprandial blood glucose), patient satisfaction, and health-related quality of life. METHODS: We studied 90 patients with type 2 diabetes in a 10-week, randomized, double-blind, crossover trial involving 9 clinical investigators. Patients previously treated with NPH insulin alone were transferred to 30% regular insulin added to 70% NPH as a premixed insulin (70/30) administered twice daily. Patients in one sequence group received NPH insulin twice daily for 4 weeks followed by 70/30 insulin for 4 weeks; in the second sequence group, the order was reversed. RESULTS: The magnitude of the 1.5- and 2-hour postprandial glucose excursion was reduced with 70/30 insulin in comparison with NPH insulin, and patients treated with 70/30 insulin experienced fewer hypoglycemic events than with NPH insulin. With regard to health-related quality of life, patients treated with 70/30 insulin rated their physical functioning as better; rated their ability to be spontaneous, follow the meal plan, and interact socially to be less difficult; and had less fear of hypoglycemia and perceived their diabetes to be better controlled than when treated with NPH insulin alone. CONCLUSION: In patients with type 2 diabetes mellitus, premixed 70/30 insulin improved postprandial glycemic control and health-related quality of life without increasing the frequency of hypoglycemic events and without any additional cost.

Demonstration of the reproducibility of treatment efficacy from a single multicenter trial.

According to the Food and Drug Administration's Guidelines for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, approval of a new drug "should be supported by more than one well-controlled trial and carried out by independent investigators. This interpretation is consistent with the general scientific demand for replicability." Nevius has described a four-point proposal for assessing statistical evidence in a single multicenter trial. Briefly, these four points are: (1) combined analysis shows significant results, (2) consistency over centers in terms of direction, (3) consistency over centers in terms of producing nominally significant results in centers with sufficient power, and (4) evidence of efficacy after adjustment for multiple comparisons. What is not clear from Nevius' proposal is how to quantify whether the amount of evidence in a single multicenter trial is equivalent to that from two separate trials. It is proposed that the post hoc subdivision of a multicenter trial may address this issue if the inherent multiple testing problem is accommodated. A minimax statistic is developed to test the hypothesis that the effect of the drug has been reproduced in a single multicenter trial. Monte Carlo simulation is used to generate the distribution of the minimax statistic under the null and several alternative hypotheses. Data from a multicenter trial are used to demonstrate the technique. Bootstrapping is used to determine the null distribution of the minimax statistic.

A framework establishing clear decision criteria for the assessment of drug efficacy.

Much has been published on various aspects of data analysis and reporting from clinical trials within the biopharmaceutical environment. This ranges from regulatory guidelines on the format and content of registration dossiers to recommendations on data presentation and the statistical methodologies that are appropriate for the diverse types of data one observes in clinical trials. Little has been written about designing a clinical trial analysis and reporting package that focuses on the decisions that must be made throughout the drug development process. Pharmaceutical companies today are under enormous pressure to develop drugs quickly and (cost-) efficiently. Because of this, drugs often move into the later phases of drug development before evidence from prior phases is completely understood. This provides a challenge to clinical trialists to design and execute a clinical trial programme which can expedite drug development. The statistician, as a clinical trialist, must strive to determine the optimum analytical methodology that facilitates decision making for this clinical trial programme. This paper proposes a new framework for the assessment of efficacy in drug development called the 'one programme, one p-value' framework. This framework will accelerate drug development by providing clear criteria for the decisions which must be made along the way. The 'one programme, one p-value' framework is based on the notion that the clinical trial programme comprises exploratory and confirmatory phases. The use of the likelihood function in the exploratory phase facilitates the decision whether (or when) to move into the confirmatory phase. The confirmatory phase consists of one confirmatory trial with a single hypothesis test of the drug's efficacy; hence 'one p-value'. Sponsor interaction with regulatory agencies is necessary at each decision point. Finally, the paper considers how analysis and reporting of efficacy data can be accomplished from a clinical trial programme as described.

Modelling paired survival data with covariates.

The objective of this paper is to consider the parametric analysis of paired censored survival data when additional covariate information is available, as in the Diabetic Retinopathy Study, which assessed the effectiveness of laser photocoagulation in delaying loss of visual acuity. Our first approach is to extend the fully parametric model of Clayton (1978, Biometrika 65, 141-151) to incorporate covariate information. Our second approach is to obtain parameter estimates from an independence working model together with robust variance estimates. The approaches are compared in terms of efficiency and computational considerations. A fundamental consideration in choosing a strategy for the analysis of paired survival data is whether the correlation within a pair is a nuisance parameter or a parameter of intrinsic scientific interest. The approaches are illustrated with the Diabetic Retinopathy Study.

Antiestrogenic properties of raloxifene.

This 21-day, open-label study evaluated the effects of raloxifene and tamoxifen on estrogen-induced changes in serum levels of anterior pituitary hormones (prolactin, luteinizing hormone, and follicle-stimulating hormone), sex steroids (testosterone, estradiol), and binding globulins [thyroid binding globulin (T3 resin uptake), transcortin, sex steroid binding globulin]. Seventeen healthy male volunteers completed the study after being randomized to one of three treatments: raloxifene, tamoxifen, or placebo. Six subjects received raloxifene (200 mg daily) for 10 days, 6 subjects received tamoxifen [20 mg twice a day (b.i.d.)] for 10 days, and 5 subjects received placebo for 10 days. All subjects received ethinyl estradiol (20 micrograms b.i.d.) for 7 days starting 3 days after initiation of study drug or placebo treatment. Results of the primary analysis of this study indicate that for six of the seven analyzable parameters of estrogen action (excluding luteinizing hormone) raloxifene blunted the estrogen response; this effect was significant only for T3 resin uptake. Tamoxifen administration significantly blunted or reversed the estrogen effect in all six of these parameters. Raloxifene, an effective antiestrogen in animal models, is also antiestrogenic in humans.

Effects of raloxifene hydrochloride on the endometrium of postmenopausal women.

OBJECTIVE: We evaluated subtle endometrial morphologic changes in postmenopausal women assigned to placebo, raloxifene hydrochloride 200 or 600 mg/day, or conjugated estrogens (Premarin 0.625 mg/day) according to a new estrogenicity scoring system. Raloxifene, a new selective estrogen receptor modulator, was not expected to stimulate the endometrium. STUDY DESIGN: Baseline and end point endometrial biopsies were performed during this double-blind, placebo-controlled 8-week study. A scoring system that was based on standard glandular and stromal morphologic criteria was used to quantitate estrogen-induced effects. Baseline, end point, and baseline-to-end point changes were analyzed for treatment differences. RESULTS: Treatment groups were similar at baseline with most women showing no estrogenic effects. At end point, statistically significant moderate and marked estrogenic effects were noted in 77% of estrogen-treated women versus 15% of placebo-treated women versus 0% of raloxifene-treated women. CONCLUSIONS: As expected, estrogen treatment stimulated postmenopausal endometrium. In contrast, raloxifene did not induce histopathologic evidence of endometrial stimulation in healthy postmenopausal women.