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Background: This phase III, randomized, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy. Methods: Subjects were randomized (stratified by (1) tumor aggressiveness and (2) presence/absence of concomitant anticancer treatment) to placebo or tanezumab 20 mg. Treatment was administered by subcutaneous injection every 8 weeks for 24 weeks (3 doses) followed by a 24-week safety follow-up period. The primary outcome was change in daily average pain in the index bone metastasis cancer pain site (from 0 = no pain to 10 = worst possible pain) from baseline to week 8. Results: LS mean (SE) change in pain at week 8 was −1.25 (0.35) for placebo (n = 73) and –2.03 (0.35) for tanezumab 20 mg (n = 72). LS mean (SE) [95% CI] difference from placebo was –0.78 (0.37) [–1.52, –0.04]; P =.0381 with α = 0.0478. The number of subjects with a treatment-emergent adverse event during the treatment period was 50 (68.5%) for placebo and 53 (73.6%) for tanezumab 20 mg. The number of subjects with a prespecified joint safety event was 0 for placebo and 2 (2.8%) for tanezumab 20 mg (pathologic fracture; n = 2). Conclusion: Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828. Bone metastasis is a common cause of cancer-related pain. This article reports on the potential of anti-nerve growth factor therapies, such as tanezumab, to reduce pain caused by bone metastases. [ABSTRACT FROM AUTHOR]

Byline: Elaine M. Urbina, Samuel S. Gidding, Weihang Bao, Abdalla Elkasabany, Gerald S. Berenson Abstract: Background Insulin resistance, often associated with obesity, is hypothesized to be involved in the pathogenesis of essential hypertension and may relate to increased left ventricular mass (LVM). Methods We examined correlations between echocardiographic LVM and fasting blood glucose and insulin levels in a cross-section of 216 black and white healthy children and young adults aged 13 to 27 years in Bogalusa, Louisiana. Anthropometric measurements and blood pressure readings were also obtained. Results Positive bivariate correlation was found between fasting blood glucose level and LVM corrected for growth (LVMC) (LVMC = LVM/Height.sup.2.7) with all race/sex groups combined (r = 0.17, P [less than or equal to] .03). Multivariate analyses in a model including race, sex, age, and measures of body size showed no significant correlations between fasting blood glucose level, insulin level, and LVMC. However, when patients were ranked in terciles by fasting insulin level and within each tercile by subscapular skinfold thickness or weight tercile, increasing LVMC with increasing insulin level was found in the highest subscapular skinfold thickness and weight terciles. The largest difference was between high and low insulin groups (P [less than or equal to] .03). When grouped by systolic blood pressure tercile, there was no difference in LVMC with increasing fasting insulin tercile. We concluded that in heavier individuals, increased insulin levels may be a risk factor for the accumulation of increased LVMC independent of any relation among insulin, obesity, and blood pressure. (Am Heart J 1999;138:122-7.) Author Affiliation: New Orleans, La, and Chicago, Ill From the.sup.aTulane Center for Cardiovascular Health and Department of Pediatrics, Tulane University Medical Center, New Orleans; and the.sup.bSection of Pediatric Cardiology, Children's Memorial Hospital, Chicago Article History: Received 21 January 1997; Accepted 28 August 1998 Article Note: (footnote) [star] Supported by funds from the National Heart, Lung, and Blood Institute of the U.S. Public Health Service (USPHS) Early Natural History of Arteriosclerosis (5R01 HL38844)., [star][star] Reprint requests: Elaine M. Urbina, MD, Tulane Center for Cardiovascular Health, 1501 Canal St, 14th Floor, New Orleans, LA 70112-7103., a 0002-8703/99/$8.00 + 0 4/1/94537

The composition of children's diets has come under increased scrutiny in recent years. More emphasis has been placed on defining dietary adequacy in terms of the distribution of energy components [...]

Background: The ICH E9(R1) addendum states that the strategy to account for intercurrent events should be included when defining an estimand, the treatment effect to be estimated based on the study objective. The estimator used to assess the treatment effect needs to be aligned with the estimand that accounted for intercurrent events. Regardless of the strategy, missing data resulting from patient premature withdrawal could undermine the robustness of the study results. Informative censoring due to dropouts in an events-based study is one such example. Sensitivity analyses using imputation methods are useful to examine the uncertainty due to informative censoring and address the robustness and strength of the study results. Methods: We assessed the effect of premature patient withdrawal in the PRECISION study, a randomized non-inferiority clinical trial of patients with chronic arthritic pain that compared the cardiovascular safety of three nonsteroidal anti-inflammatory drugs–based treatment policies or paradigms. The protocol-defined use of concomitant or rescue medications was permitted since changes in pain medications due to insufficient analgesia were expected in patients in this long-term study. Anticipating that premature study discontinuations could potentially lead to informative censoring, a supplementary analysis was pre-specified in which censored outcomes due to the premature study discontinuation were imputed based on adverse events that were clinically associated with the primary endpoint (cardiovascular outcome based on the Antiplatelet Trialists Collaboration composite endpoint). Furthermore, tipping point analyses were conducted to test the robustness of the primary analysis results by assuming data censored not at random. The level of increase at which the primary study conclusion would change was estimated. Results: For the analysis of time to first primary endpoint event through 30 months, 4065 out of the 24,081 enrolled patients were lost to follow-up, withdrew consent, or were no longer willing to participate in the study. These withdrawals occurred gradually and resulted in a cumulative total of 5893 censored patient-years of observation (10.2%). The rate of discontinuation and the baseline characteristics of the discontinued patients were similar across the three treatment groups. The non-inferiority conclusion from the primary analysis was confirmed in the supplementary analysis incorporating relevant adverse events. Furthermore, tipping point analyses demonstrated that in order to lose non-inferiority in the primary analysis, the risk of primary endpoint events during the censored observation time would have to increase by more than 2.7-fold in the celecoxib group while remaining constant in the other nonsteroidal anti-inflammatory drugs groups, demonstrating that the scenarios where the study results are invalid appear not plausible. Conclusions: Supplementary and sensitivity analyses presented to address informative censoring in PRECISION helped to further interpret and strengthen the study results. [ABSTRACT FROM AUTHOR]

Objective: To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long‐term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA). Methods: A total of 24,081 patients with OA or RA who had a moderate or high risk for CV disease were enrolled internationally into a double‐blind randomized controlled trial. Interventions included celecoxib at a dosage of 100–200 mg twice daily, ibuprofen at a dosage of 600–800 mg 3 times daily, or naproxen at a dosage of 375–500 mg twice daily. The main outcomes were the first occurrence of a major adverse CV event, GI event, or renal event, and mortality. Results: In the subgroup of patients with OA, the risk of a major adverse CV event was significantly reduced when celecoxib was compared with ibuprofen (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.72–0.99), but no significant difference was observed when celecoxib was compared with naproxen. In the RA subgroup, comparisons of celecoxib versus ibuprofen and celecoxib versus naproxen for the risk of major adverse CV events revealed HRs of 1.06 (95% CI 0.69–1.63) and 1.22 (95% CI 0.78–1.92), respectively. In the OA subgroup, comparisons of celecoxib versus ibuprofen for the risk of GI events showed an HR of 0.68 (95% CI 0.51–0.91), and a comparison of celecoxib versus naproxen showed an HR of 0.73 (95% CI 0.55–0.98). Duplicate comparisons in patients with RA revealed HRs of 0.48 (95% CI 0.22–1.07) and 0.54 (95% CI 0.24–1.24), respectively. In patients with OA, a comparison of celecoxib versus ibuprofen for the risk of renal events showed an HR of 0.58 (95% CI 0.40–0.82). In patients with RA, celecoxib treatment was associated with significantly lower mortality compared with naproxen treatment (HR 0.47, 95% CI 0.25–0.88). Conclusion: Treatment with celecoxib at approved dosages conferred a similar or lower risk of CV, GI, and renal adverse events compared with treatment with ibuprofen or naproxen in patients with OA and patients with RA. [ABSTRACT FROM AUTHOR]

Introduction Data on statin safety in Asian patients are limited compared with evidence from Western populations. Aim This study assessed atorvastatin safety among Asian patients enrolled in 58 randomized clinical trials. Methods Data from 52 short-term trials (median exposure 4-72 weeks) and six long-term cardiovascular outcomes trials (median exposure 3.1-4.9 years) conducted across the atorvastatin 10-80-mg dose range were analyzed retrospectively to assess the incidence of safety endpoints. Results A total of 77 952 patients were identified (49 974 received atorvastatin), among whom 3191 were Asian (2519 received atorvastatin). In the short-term trials, the incidence of all-causality adverse events ( AEs) and serious AEs ( SAEs) in Asian patients treated with atorvastatin was similar to or lower than that observed with other statins or placebo, and discontinuations due to treatment-related AEs/ SAEs were infrequent (2.0% across all doses). These observations were confirmed in the long-term trials. Treatment-related SAEs were rare (n = 4) among Asian patients receiving atorvastatin. No cases of rhabdomyolysis were observed in atorvastatin-treated Asian patients, and the incidence of myalgia was 1.8% in the short-term studies and 6.7% in the long-term trials. Elevations (>3× the upper limit of normal) in liver transaminases were observed in ~2% of Asian patients receiving atorvastatin; renal AEs occurred in <2%. Conclusion The incidence of AEs/ SAEs with atorvastatin 10-40-mg in patients of Asian origin was low and comparable to placebo. Further evaluation of atorvastatin 80-mg is required owing to the limited number of Asian patients (n = 281; 11.2%) who received this dose. [ABSTRACT FROM AUTHOR]

Background: Few studies in the literature have examined the efficacy of antidepressant drugs in perimenopausal and postmenopausal women. The objective of the current study was to assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) separately in perimenopausal and postmenopausal women with major depressive disorder (MDD). Methods: Data were pooled from two double-blind, placebo-controlled clinical trials enrolling perimenopausal and postmenopausal women (40-70 years old) diagnosed with MDD. Patients were randomly assigned to receive desvenlafaxine 100 to 200 mg/day or placebo (8 weeks) or desvenlafaxine 50 mg/day or placebo (10 weeks). The primary efficacy end point for each trial was change from baseline in Hamilton Rating Scale for Depression (HAM-D17) total score at week 8. Secondary end points included change from baseline in Sheehan Disability Scale (SDS) and Menopause Rating Scale (MRS) scores. Changes from baseline in continuous variables were analyzed using analysis of covariance with treatment, region, and baseline in the model. All treatment comparisons were carried out separately in perimenopausal or postmenopausal women, in individual studies, and in the pooled population, adjusting for menopausal status and study. Results: A total of 798 patients were included in the full analysis set (perimenopausal, n=252; postmenopausal, n=546). Desvenlafaxine significantly reduced HAM-D17 total scores versus placebo at week 8 in both perimenopausal (−10.3 vs. −6.5; p<0.001) and postmenopausal women (−10.1 vs. −7.6; p<0.001). Significant improvements in SDS and MRS total scores were also observed for desvenlafaxine versus placebo in perimenopausal ( p≤0.024) and postmenopausal women ( p≤0.009). A significant treatment by menopausal status interaction was observed for SDS only ( p=0.036). Conclusions: Desvenlafaxine demonstrated antidepressant efficacy in both perimenopausal and postmenopausal subgroups of women with MDD. Disclaimer: In September 2011, Pfizer received a Complete Response Letter from the United States Food and Drug Administration on its application for approval to market desvenlafaxine for the treatment of moderate to severe vasomotor symptoms associated with menopause. The Complete Response Letter states that the data included in the application are not sufficient to establish an acceptable risk/benefit profile for the treatment of vasomotor symptoms in the general population of postmenopausal women, and therefore desvenlafaxine is not approved for the treatment of vasomotor symptoms in the United States at this time. This decision does not impact desvenlafaxine's approval for the treatment of MDD in adults. [ABSTRACT FROM AUTHOR]

: Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P≤0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs. Trial Registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

We examined the effect of atorvastatin (and placebo) on tumour necrosis factor (TNF)α, soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular cell adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes without prior cardiovascular disease (CVD) and investigated whether adhesion molecules were associated with incident CVD. Baseline and follow-up concentrations of TNFα, sVCAM-1 and sICAM-1 were measured in patients from the Collaborative AtoRvastatin Diabetes Study (CARDS). Patients had a mean age of 61 years (standard deviation = 8) and 70% were men. TNFα 2.20 pg/mL (1.82–2.86), sVCAM-1 865 ng/mL (729–1059) and sICAM-1 619 ng/mL (533–753) concentrations (median, interquartile range 25, 75%) were similar at baseline in atorvastatin (given values) and placebo groups and not significantly different at 2 years. The multivariable hazard ratios for the associations between sVCAM-1 and sICAM-1 (doubling the concentration) and CVD were, 0.82 (95% confidence interval (CI) 0.66–1.0) and 0.59 (95% CI 0.50–0.71), respectively. In conclusion atorvastatin had no significant effect on TNFα, sVCAM-1 or sICAM-1 levels in type 2 diabetic patients without a prior history of CVD compared with placebo. In addition, both sVCAM-1 and sICAM-1 concentrations were associated with a decreased risk of CVD. [ABSTRACT FROM PUBLISHER]

Background: Heart rate variability (HRV) has been used to study autonomic effects on the heart. The time-domain measure RMSSD (root mean square of successive differences) represents high frequency (HF) changes in HRV reflecting parasympathetic nervous system activity (PS). The frequency-domain ratio of low to high power (LF/HF) represents sympathetic (SYMP) to PS balance. In adults, increased SYMP tone has been found in hypertensive as compared to normals. The present study was performed to look for differences in HRV by race and between young subjects with high and low levels of diastolic blood pressure (DBP). Methods: Subjects included 34 healthy males age 13-17 years (53% white). Half were selected with K4 DBP < 85th% for height (HT) measured twice, 3-5 years apart. Half had DBP < 15th% for HT. Subjects underwent a physical examination including BP, HT, WT, and ECG prior to Holter monitor application. HRV data was analyzed from 24-hour Holter recordings obtained during normal activity. Results: The RMSSD was lower in whites compared to blacks for day, night, and 24-hour average (P ≥ 0.05) with day-time measurements showing the largest racial difference. This suggests increased PS tone in blacks especially with activity. The LF/HF ratio was higher in whites for all times, reaching significance during the day (all P ≥ 0.05) suggesting SYMP predominance in whites during activity. Subjects with higher levels of DBP had lower RMSSD and higher LF/HF ratio for all times, but these did not reach statistical significance. Conclusions: There is a trend towards SYMP predominance in children with higher DBP. Healthy white adolescents exhibit increased SYMP tone compared to blacks when measured during normal daytime activity. [ABSTRACT FROM AUTHOR]