On-treatment Values Research Articles

Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values.

On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory's reference population (×ULN) and multiples of the subjects' baseline (×BLN) values. The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects' baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject's baseline and population threshold values.

Comparison of on-Statin Lipid and Lipoprotein Levels for the Prediction of First Cardiovascular Event in Type 2 Diabetes Mellitus.

A substantial cardiovascular disease risk remains even after optimal statin therapy. Comparative predictiveness of major lipid and lipoprotein parameters for cardiovascular events in patients with type 2 diabetes mellitus (T2DM) who are treated with statins is not well documented. From the Korean Nationwide Cohort, 11,900 patients with T2DM (≥40 years of age) without a history of cardiovascular disease and receiving moderate- or high-intensity statins were included. The primary outcome was the first occurrence of major adverse cardiovascular events (MACE) including ischemic heart disease, ischemic stroke, and cardiovascular death. The risk of MACE was estimated according to on-statin levels of low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), highdensity lipoprotein cholesterol (HDL-C), and non-HDL-C. MACE occurred in 712 patients during a median follow-up period of 37.9 months (interquartile range, 21.7 to 54.9). Among patients achieving LDL-C levels less than 100 mg/dL, the hazard ratios for MACE per 1-standard deviation change in ontreatment values were 1.25 (95% confidence interval [CI], 1.07 to 1.47) for LDL-C, 1.31 (95% CI, 1.09 to 1.57) for non-HDL-C, 1.05 (95% CI, 0.91 to 1.21) for TG, and 1.16 (95% CI, 0.98 to 1.37) for HDL-C, after adjusting for potential confounders and lipid parameters mutually. The predictive ability of on-statin LDL-C and non-HDL-C for MACE was prominent in patients at high cardiovascular risk or those with LDL-C ≥70 mg/dL. On-statin LDL-C and non-HDL-C levels are better predictors of the first cardiovascular event than TG or HDL-C in patients with T2DM.

Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)-mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open-label, single-arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2-year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last-available on-treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on-treatment versus 8.6 g/dL at baseline), bilirubin (16.5 μmol/L on-treatment versus 52.1 μmol/L at baseline), and FACIT-Fatigue scores (40.5 on-treatment versus 32.4 at baseline). In the 9-week follow-up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2-year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017.

Hepatocellular carcinoma prediction model performance decreases with long-term antiviral therapy in chronic hepatitis B patients.

Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65-0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61-0.68; untreated models: 0.51-0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

Circulating neutrophils and tumor-associated myeloid cells function as a powerful biomarker for response to chemoradiation in locally advanced cervical cancer.

The immune system's role in mediating the cytotoxic effects of chemoradiotherapy remains not completely understood. The integration of immunotherapies into treatment will require insight into features and timing of the immune microenvironment associated with treatment response. Here, we investigated the role of circulating neutrophils and tumor-associated myeloid cells (TSAMs) as potential agents and biomarkers for disease-related outcomes in locally advanced cervical cancer (LACC). Hematologic parameters for two LACC patient cohorts, a retrospective clinical and a prospective translational cohort, were obtained at baseline, weekly during chemoradiotherapy for the retrospective cohort, biweekly during chemoradiotherapy for the prospective cohort, and at the first follow-up visit for both cohorts (mean 14.7weeks, range 8.1-25.1weeks for the prospective cohort and 5.3weeks with a range of 2.7-9.0weeks for the retrospective cohort). In both cohorts, baseline as well as mean and lowest on-treatment values for platelets, hemoglobin, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) were analyzed for correlations with disease-related outcomes. In the prospective cohort, circulating myeloid cells were isolated from peripheral blood mononuclear cells (PBMCs), and TSAMs were isolated from tumor tissue via a novel serial cytobrush sampling assay. The samples were analyzed by flow cytometry. In both cohorts, the only hematologic parameter significantly associated with survival was elevated on-treatment mean ANC (mANC), which was associated with lower local failure-free and overall survival rates in the retrospective and prospective cohorts, respectively. mANC was not associated with a difference in distant metastases. CD11b+CD11c- TSAMs, which act as a surrogate marker for intratumoral neutrophils, steadily decreased during the course of chemoRT and nadier'd at week 5 of treatment. Conversely, circulating myeloid cells identified from PBMCs steadily increased through week 5 of treatment. Regression analysis confirmed an inverse relationship between circulating myeloid cells and TSAMs at this time point. These findings identify on-treatment mean neutrophil count as a predictor of disease-related outcomes, suggest that neutrophils contribute to chemoradiation treatment resistance, and demonstrate the importance of techniques to measure intratumoral immune activity.

Intravoxel Incoherent Motion MRI and PET in Locally Advanced Cervical Carcinoma Undergoing Concurrent Chemoradiation Therapy

<h3>Purpose/Objective(s)</h3> Dynamic contrast enhanced (DCE) CT or MRI and FDG PET have been used to evaluate the impact of tumor perfusion and metabolism on the course and effectiveness of concurrent chemoradiation therapy (CCRT) for cervical cancer. Combining perfusion and metabolic measures allows better identification of radioresistant sub-volumes: however, use of contrast and additional dose are barriers to frequent dual perfusion-metabolic imaging. Here, we investigated a contrast-free, non-ionizing alternative to DCE: intravoxel incoherent motion (IVIM) MRI which provides both perfusion and diffusion measurements. Our objective was to evaluate changes of PET and IVIM parameters in cervical cancer patients before and during CCRT and to correlate these parameters and their changes with tumor volume response during CCRT. <h3>Materials/Methods</h3> Pre- and on-treatment IVIM scans were performed on 15 cervical cancer patients undergoing definitive chemoradiation (median [range] age: 66 [29 to 85]; FIGO: 1 IB1, 1 IIA, 3 IIB, 1 IIIB, 1 IIIC, 5 IIIC1, 2 IIIC2, 1 IVA; hist: 11 squamous cell carcinoma, 3 endocervical adenocarcinoma, 1 large cell neuroendocrine carcinoma), of whom 14 also underwent pre-treatment PET scans. The on-treatment MRI occurred generally during the last week or shortly after completing EBRT. Diffusion weighted images (DWIs) were acquired at 3T scanners using a free-breathing single shot spin echo planar imaging (EPI) sequence. IVIM MRI maps were generated by Bayesian fitting of a two-compartment IVIM model to the DWIs. Three-dimensional co-registered maps of PET standardized uptake value (SUV) and IVIM diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) were generated. Summary statistics (mean +/- standard deviation) for these and other imaging parameters were calculated pre- and on-treatment. Univariate analysis was performed to determine relationships between relative change in gross tumor volume (ΔGTV) and pre-treatment imaging measurements. <h3>Results</h3> In tumors, pre- versus on-treatment values significantly changed for the following parameters: ΔGTV (66.8 +/- 43.2 vs. 32.0+/-23.0 ml, p<.001) and D (0.00109 +/- 0.00023 vs. 0.00120 +/- 0.00026 mm²/s, p=.02). The perfusion fraction f increased and D* decreased, but not significantly (f: 0.127 +/- 0.022 vs. 0.154 +/- 0.057 %, p=.07, D*: 0.0137 +/- 0.0035 vs. 0.0133 +/- 0.0039 mm²/s, p=.6). Pre-treatment SUV_max (r=.76, p=.002) and SUV_mean (r=.70, p=.007) were positively related with ΔGTV, while pre-treatment f, D*, and D were negatively but not significantly related with ΔGTV (r=-.44, p=.1; D*: r=-.14, p=.6; D: r=-.12, p=.7). <h3>Conclusion</h3> Both perfusion fraction and diffusion coefficient IVIM increased in locally advanced cervical carcinoma patients undergoing CCRT – reflecting changes in the tumor microenvironment during treatment. These weak relationships observed here suggest a potential complementary role and motivating the combined use of these modalities for tumor characterization.

Circulating and Tumor-Associated Neutrophils Function as a Powerful Biomarker for Response to Chemoradiation in Locally Advanced Cervical Cancer

The role of the immune system in mediating the cytotoxic effects of chemoradiotherapy, remains incompletely understood. The integration of immunotherapies into treatment will require insight into features and timing of immune microenvironment associated with treatment response. Here, we investigate the role of circulating and tumor-associated neutrophils (TANs) as potential agents and biomarkers for disease-related outcomes in LACC.Hematologic parameters for two patient cohorts, a retrospective clinical and a prospective translational cohort, were obtained at baseline, weekly during chemoradiation, and at first follow up visit. Baseline, mean and lowest on-treatment values for platelets, hemoglobin, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) were correlated with disease-related outcomes using univariate (UVA) and multivariable analyses (MVA). Circulating neutrophils were isolated from peripheral blood mononuclear cells (PBMCs) and TANs were isolated from tumor tissue via a novel serial cytobrush sampling assay. The samples were analyzed by flow cytometry and correlated via linear regression analysis.A total of 151 patients were included in the retrospective cohort with a median follow up of 33 months. Of the tested hematologic parameters elevated on-treatment mean ANC (mANC) was associated with lower rate of local control on UVA (HR 1.314; 95% CI, 1.102-1.567, P = 0.002) and MVA (HR 1.369; 95% CI, 1.104-1.697, P = 0.004). mANC was the only hematologic factor associated with lower survival on MVA (HR 1.255; 95% CI, 1.048-1.502, P = 0.013). mANC was not associated with a difference in distant metastases (HR 1.002; 95% CI, 0.810-1.241, P = 0.984). In an independent, prospectively-accrued cohort, mANC was similarly associated with lower OS (HR 1.636, 95% CI, 1.172-2.285, P = 0.004) on UVA. Analysis of the tumor-associated neutrophils (TAN) demonstrated that neutrophils constituted 22.4% (standard error [SE] 3.96%) of all live leukocytes in the tumor at baseline, which steadily increased and peaked at 41.3% (SE 7.8%) at week 5 of treatment (P = 0.027). Neutrophils constituted of 78.2% (SE 4.6%) of live leukocytes in PBMCs at baseline, and steadily decreased with a nadir of 65.7% (SE 8.5%) at week 5 of treatment (P = 0.137). Regression analysis showed an inverse relationship between circulating neutrophils and TANs, with the strongest correlation observed at week 5 of chemoradiation (R2 = 0.29).These findings implicate neutrophils in chemoradiation treatment resistance, identify on-treatment mean neutrophil count as a robust and optimal predictor of disease-related outcomes, and establish an inverse relationship between circulating and tumor-associated neutrophils.O. Gjyshi: None. A. Grippin: Student; University of Florida. D. Boyce-Fappiano: None. A. Jhingran: American Board of Radiology. L.L. Lin: Employee; VA Hospital. Research Grant; AstraZeneca. Travel Expenses; AstraZeneca. P.J. Eifel: Travel Expenses; National Cancer Center Network. Stock; Apple Computer. M.M. Joyner: Consultation with executive management and participation in board meetings; Frontline Bioenergy. J. Sastry: None. K. Court: None. T. Solley: None. V. Hegde: None. L. Colbert: None. A.H. Klopp: Research Grant; MD Anderson Cancer Center SPORE Grant.

Twelve-month post-treatment parameters are superior in predicting hepatocellular carcinoma in patients with chronic hepatitis B.

There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population. We included two treatment-naïve CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n=1480, Korea prospective SAINT cohort) and the validation cohort (n=426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine and random forest algorithms to develop the HCC prediction model and selected the most optimal method. We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-foetoprotein and platelet at 12months showed the best performance (AUROC=0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC=0.844) and better than other existing prediction models including the APA, PAGE-B and GAG models (AUROC=0.769 to 0.818). We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844) (Clinical trial number: KCT0003487).

How to implement the new 2018 ESH/ESC guidelines for the management of arterial hypertension in patients with metabolic syndrome and diabetes?

Blood pressure (BP) control in hypertensive patients remains poor worldwide, particularly in high-risk patients with hypertension and diabetes. New ESH/ESC guidelines recommend more stringent BP targets (on-treatment values of ≤ 130/80 mm Hg in the general population and ≤ 140/90 mm Hg in older hypertensive people), which will make the achievement of BP control even more challenging. The most effective evidence-based treatment strategy to improve BP control is one that: encourages the use of combination treatment, enables the use of single-pill combination (SPC) therapy for most patients to improve adherence to treatment, with the use of SPC therapy as initial therapy. The combination of perindopril with thiazide-like diuretic indapamide is one of the widely tested SPC in multicentre clinical trials for diabetic patients. Studies suggested that two-drug combination therapy will control BP in approximately two-thirds of patients. For patients whose BP is not controlled by two-drug combination therapy, the logical option is to increase treatment to three-drug combination therapy: usually a RAS blocker, a CCB and a diuretic. The combination of perindopril with indapamide and amlodipine is particularly recommended in population of hypertensive patients with metabolic complications because of favourable, neutral effect on blood glucose and cholesterol level. This combination has proven hypotensive effect in group of patients with difficult-to-control hypertension.

\u03b2-Blockers Improve Presinusoidal Portal Hypertension

BackgroundPresinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas β-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown.AimsTo evaluate the hemodynamic effect of β-blockers in non-cirrhotic patients with presinusoidal portal hypertension.MethodsWe measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off β-blocker treatment (random sequence).ResultsThe β-blockers reduced the gradient from a mean off-treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%).Conclusionsβ-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic β-blockage in patients with presinusoidal portal hypertension.

Daratumumab in Combination with Lenalidomide Plus Dexamethasone Induces Clonality Increase and T-Cell Expansion: Results from a Phase 3 Randomized Study (POLLUX)

Daratumumab in Combination with Lenalidomide Plus Dexamethasone Induces Clonality Increase and T-Cell Expansion: Results from a Phase 3 Randomized Study (POLLUX)

Comparison of Nocturia Response to Desmopressin Treatment between Patients with Normal and High Nocturnal Bladder Capacity Index

Objective. To compare efficacy of desmopressin for treatment of nocturia between patients with normal and high nocturnal bladder capacity index (NBCi). Methods. Retrospective analysis of adult patients treated with desmopressin for nocturia. Patients were analyzed according to high or normal NBCi value before treatment. Results. 55 patients were identified, aged 49–84, 47 males, 8 females, who started desmopressin 0.2 mg nocte between 2009 and 2011. Two groups (N: normal and H: high NBCi) were similar regarding number, gender, age, 24 h urine volume, and nocturnal urine volume. On treatment, nocturnal volume decreased by mean of 364 mL. Number of nightly voids decreased in N group from 3.11 to 1.50, in H from 3.96 to 1.44. Nocturnal polyuria and nocturia indices also decreased significantly. NBCi remained the same in N group (0.56 on therapy) and in H group decreased to mean 0.63. All on-treatment values were statistically similar in N and H groups. Pretreatment differences were abolished with treatment. NBCi was significantly correlated to nocturia reduction—larger reduction was observed in patients with higher NBCi. In 8/55 patients, hyponatremia was detected, but without clinical consequences. Conclusions. The results indicate that the effectiveness of desmopressin on nocturia is not dependent upon the patient's pretreatment NBCi.

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

Evaluating Patients for Second-Line Antiretroviral Therapy in India: The Role of Targeted Viral Load Testing

The identification and management of first-line antiretroviral therapy (ART) failure is a key challenge for HIV programs in resource-limited settings. In 2008, the National AIDS Control Organisation, India piloted a national strategy to provide second-line ART. We assessed the National AIDS Control Organisation second-line ART evaluation algorithm. Adult patients who had received 6 months or more of standard first-line ART were referred for second-line ART evaluation if they demonstrated CD4 decline to pre-ART values, CD4 drop to less than 50% of peak on-treatment value, failure to achieve CD4 greater than 100 c/mm(3), or development of a new World Health Organization Stage 3 or 4 AIDS-defining illness. Patients received HIV RNA testing, and those with HIV RNA 10,000 c/mL or greater qualified to switch to second-line ART. World Health Organization-defined clinical and CD4 criteria for ART failure were compared against virologic failure criteria. Between January and June 2008, 154 patients met criteria for evaluation. Of 122 (79%) patients who had HIV RNA testing, 87 (71%) had viral load 10,000 c/mL or greater and were recommended to start second-line ART, 29 (24%) had viral load less than 400 c/mL, and six (5%) had viral load between 400 and 10,000 c/mL. The positive predictive value of World Health Organization clinical/immunologic criteria to detect virologic failure was 71% (95% confidence interval, 63% to 79%). Second-line ART was initiated in the public sector in India using an approach combining clinical and immunologic evaluation with confirmation of virologic failure. Almost 25% of patients who met clinical/immunologic failure criteria demonstrated virologic suppression. Inclusion of targeted HIV RNA testing in the evaluation of treatment failure can prevent unnecessary switches to second-line ART.

Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol

Budesonide/formoterol maintenance and reliever therapy maintains asthma control and reduces exacerbation frequency compared with higher fixed-dose combination regimens. Its effects on eosinophilic airway inflammation and structure are unknown. We sought to compare the effects of budesonide/formoterol 200/6 microg twice daily plus as-needed with budesonide/formoterol 800/12 microg twice daily on airway eosinophils and remodeling. This 52-week, parallel-group, randomized, double-blind study of 127 asthma patients who were symptomatic despite therapy compared (1) the change between induced sputum percent eosinophils at baseline and the geometric mean of 4 on-treatment values and (2) the change in endobronchial biopsy eosinophil counts pre- and post-treatment. Mean daily doses of budesonide/formoterol were 604/18 microg in the maintenance and reliever therapy group and 1,600/24 microg in the high fixed-dose group. In the former, the geometric mean percent sputum eosinophils remained unchanged (1.6% to 1.9%), whereas biopsy specimen subepithelial eosinophils increased (6.2 to 12.3 cells/mm(2)). Sputum and biopsy eosinophil counts decreased with high fixed-dose treatment (2.2% to 1.2% and 7.7 to 4.8 cells/mm(2), respectively), resulting in significant treatment differences of 0.7% (ratio, 1.8; 95% CI, 1.2-2.8; P = .0038) and 7.5 cells/mm(2) (ratio, 2.9; 95% CI, 1.6-5.3; P < .001), respectively. There were no between-treatment differences in reticular basement membrane thickness, exhaled nitric oxide, exacerbation frequency, or FEV(1). Compared with fixed-dose combination treatment containing a 4-fold higher maintenance dose of budesonide, budesonide/formoterol maintenance and reliever therapy is associated with higher eosinophil counts, but these remain within the range associated with stable clinical control.

A phase 2, randomized, double-blind, placebo-controlled trial of clinical activity and safety of subcutaneous Å6 in women with asymptomatic CA125 progression after first-line chemotherapy of epithelial ovarian cancer

Objectives Å6 is a novel peptide that interferes with single-chain urokinase plasminogen activator activity and has shown anti-angiogenic, anti-migratory, and anti-invasive properties. We evaluated clinical efficacy and safety of subcutaneously administered Å6 in women with epithelial ovarian cancer. Methods Women with epithelial ovarian, fallopian tube, or primary peritoneal cancer in clinical remission after first-line chemotherapy with 2 consecutive increases of CA125 values above normal but with no disease on physical examination or imaging studies were randomly assigned to receive daily subcutaneous injections of placebo, low-dose Å6 (150 mg), or high-dose Å6 (300 mg) until disease progression or end of study participation. Primary endpoints were time to clinical progression of disease and safety of Å6. Secondary endpoints were changes in serum CA125 and biomarkers of the urokinase system. Results Data are available for 24 women (placebo, n = 12; low-dose, n = 8; high-dose n = 4). Å6 therapy was associated with a statistically significant delay in time to clinical progression (log-rank p-value 0.01) with a median of 100 days (95% CI: 64,168) for women who received Å6 compared with 49 days (95% CI: 29,67) for women who received placebo. The treatments appeared to be well tolerated. Treatment was not associated with CA125 response ( p = 0.44). On-treatment values for plasma urokinase plasminogen activator receptor were statistically significantly lower in the Å6 groups compared with placebo ( p = 0.02). Conclusions Å6 therapy increases time to clinical disease progression and appears to be well tolerated in this patient population.

Increased High-Density Lipoprotein Cholesterol Predicts the Pioglitazone-Mediated Reduction of Carotid Intima-Media Thickness Progression in Patients With Type 2 Diabetes Mellitus

Measurement of carotid intima-media thickness (CIMT) has been validated as a measure of atherosclerosis and as a predictor of future cardiovascular events. Compared with glimepiride, pioglitazone has been shown to slow the progression of atherosclerosis measured by CIMT in patients with type 2 diabetes mellitus. We evaluated individual cardiovascular risk factors as predictors of the change in CIMT produced by pioglitazone treatment by determining whether their addition to a baseline model resulted in loss of significance for the treatment effect on CIMT. Pioglitazone treatment led to improvement in levels of multiple cardiovascular risk markers, including high-sensitivity C-reactive protein, apolipoprotein B, apolipoprotein A1, high-density lipoprotein (HDL) cholesterol, triglyceride, insulin, and free fatty acid. At 24 weeks, there were significant differences in HDL cholesterol, triglyceride, total cholesterol, low-density lipoprotein cholesterol, insulin, body mass index, hip circumference, and high-sensitivity C-reactive protein between the pioglitazone and glimepiride treatment groups. After adjustment for 24-week on-treatment values of cardiovascular risk factors, only inclusion of the changes in HDL cholesterol and insulin significantly impacted the magnitude and significance of the treatment effect on CIMT. Furthermore, irrespective of treatment assignment, increased HDL cholesterol at 24 weeks was a significant predictor of reduced CIMT progression at 72 weeks. The beneficial effect of pioglitazone on HDL cholesterol at 24 weeks predicted its beneficial effect for reducing CIMT progression at 72 weeks. Changes in HDL cholesterol at 24 weeks, irrespective of treatment, predicted less progression of CIMT at 72 weeks. These results suggest that suppression of atherosclerosis with pioglitazone therapy is linked to its ability to raise HDL cholesterol.

Abstract 682: Lapaqistat Acetate Monotherapy: Effects of a Novel Squalene Synthase Inhibitor on LDL-C Levels and Other Lipid Parameters in Patients with Primary Hypercholesterolemia

Background: Lapaquistat acetate (LAPA) inhibits squalene synthase, an important enzyme in the cholesterol biosynthetic pathway. Early studies showed that LAPA reduced LDL-C and improved lipid profiles in animals and humans. Methods: This multicenter, phase III, randomized, double-blind, parallel-group, placebo-controlled study assessed LAPA monotherapy in nondiabetic patients ≥ 18 yrs old with primary hypercholesterolemia (mean LDL-C &gt; 130 mg/dL and &lt; 220 mg/dL; mean triglyceride [TG] ≤400 mg/dL). Treatment-naïve patients or patients discontinuing previous lipid-lowering therapy underwent a 6-wk dietary stabilization period, then were randomized to 100 mg LAPA (n = 241) or Placebo (n = 120) once daily for 12 wks. The primary endpoint was percent (%) change from baseline compared with Placebo in direct LDL-C at Wk 12 or last on-treatment value. Secondary endpoints included: % change in calculated LDL-C, non-HDL-C, total cholesterol (TC), Apo B, HDL-C, VLDL-C, Apo A1, TG, and hs-CRP. Safety was monitored using clinical and laboratory examinations. Results: LAPA significantly reduced LDL-C levels (see Table ) within 2– 4 wks of treatment initiation that were maintained throughout the study. LDL-C remained relatively unchanged in the Placebo group. Compared with Placebo, LAPA lowered LDL-C levels 20.09% by end of study (p &lt; 0.001). Non-HDL-C, TC, Apo B, VLDL-C, Apo A1, TG, and hs-CRP were also significantly reduced vs Placebo. Both the overall adverse event (AE) profile and the rate of AEs considered potentially related to study drug (~24%), were similar between treatment groups. Two serious AEs occurred in each group; the 2 SAEs in lapaquistat-treated patients were considered not related to study drug. Conclusion: LAPA (100 mg/day) monotherapy provided significant improvements in LDL-C, non-HDL-C, TC, Apo B, VLDL-C, TG, and hs-CRP levels, was generally safe and well tolerated, and potentially represents a novel treatment for hypercholesterolemic patients.

Interim Results Presented at EASL From PROVE 1 Clinical Trial of Investigational Drug Telaprevir in Patients with Genotype 1 Hepatitis C

In a late-breaking presentation at the 42nd Annual Meeting of the European Association for the Study of the Liver (EASL) on April 14, researchers presented data from a planned interim analysis of the PROVE 1 clinical trial (Table 1). This is the first trial to evaluate short-duration therapy with the investigational hepatitis C protease inhibitor telaprevir (TVR; Vertex Pharmaceuticals, Cambridge, MA; VX-950) in combination with pegylated interferon alfa 2a (peg-IFN) and ribavirin (RBV) in treatment-naïve, genotype 1-infected hepatitis C patients.Table 1Interim HCV RNA Results for Patients Enrolled in the PROVE 1 TrialTreatment assignmentPatients with HCV RNA <30 IU/mL at end of 4 weeks of dosingPatients with HCV RNA <10 IU/mL at end of 4 weeks of dosingPatients with HCV RNA <10 IU/mL at end of 12 weeks of dosing, DC = FaIntent-to-treat, discontinuation = failure analysis. Patients who had HCV RNA <10IU/mL at the time of discontinuation are counted as failures; however, these patients will be followed postdiscontinuation to determine if the achieve a sustained virologic response (SVR).Patients with HCV RNA <10 IU/mL at end of 12 weeks of dosing (last on-treatment value carried forward)TVR = peg-IFN + RBV (arms B, C, and D)153/175 (88%)138/175 (79%)123/175 (70%)149/175 (85%)Placebo + peg-IFN = RBV (arm A)12/75 (16%)8/75 (11%)29/75 (39%)32/75 (43%)HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin; TVR, telaprevir.a Intent-to-treat, discontinuation = failure analysis. Patients who had HCV RNA <10IU/mL at the time of discontinuation are counted as failures; however, these patients will be followed postdiscontinuation to determine if the achieve a sustained virologic response (SVR). Open table in a new tab HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin; TVR, telaprevir. The data from PROVE 1 demonstrated a high rate of rapid viral response (RVR) in the TVR groups and a low rate of on-treatment viral breakthrough, and suggested that 12 weeks of TVR-based therapy enabled some patients to clear the virus. “The high rates of RVR observed in the TVR groups in and the fact that some patients have remained persistently viral negative 20 weeks after stopping the 12 weeks of TVR-based therapy, suggest that we may be able to shorten the treatment duration in genotype 1 [hepatitis C virus] HCV patients,” said Dr John McHutchison, Principal Investigator for the PROVE 1 study and Director of Gastroenterology and Hepatology Research at Duke Clinical Research Institute. At 4 weeks, 88% and 79% of patients receiving TVR achieved a RVR as measured by plasma HCV RNA <30 IU/mL and <10 IU/mL, respectively. Six of 9 patients in 1 treatment arm who completed 12 weeks of treatment and who had achieved an RVR as defined by the study protocol (<10 IU/mL) continued to have undetectable HCV RNA 20 weeks after stopping all treatment. The treatment discontinuation rate due to adverse events through 12 weeks was 11% in TVR arms and 3% in the control arm. Rash, gastrointestinal events, and anemia were the most common events leading to discontinuation in the TVR arms. A total of 250 patients were enrolled in PROVE 1 and received ≥1 dose of TVR or placebo in addition to peg-IFN + ribavirin (RBV) in the study. A total of 175 patients received ≥1 dose of TVR in 1 of 3 arms (treatment arms; B, C, and D) and 75 patients received ≥1 dose of placebo (arm A). Treatment with TVR resulted in a high proportion of patients achieving a RVR at 4 weeks. At the time of the interim analysis, all patients had either completed 12 weeks or discontinued from the study before week 12. “These interim results are encouraging and suggest that high sustained viral response (SVR) rates may be achieved with regimens that are 24 weeks in total duration. We look forward to 24 week follow-up data from the initial group of patients who stopped treatment at 12 weeks, and follow-up data from patients in the study who received 24 weeks of treatment,” McHutchison said.

Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects

The metabolic syndrome (MS) is often accompanied by atherogenic dyslipidemia, which is characterized by elevated triglycerides (TG), reduced high-density lipoprotein cholesterol (HDL-C), and elevated numbers of small, dense low-density lipoprotein (LDL) particles. It was hypothesized that a threshold exists for the circulating TG level needed to produce changes in LDL subclass distribution. Hypertriglyceridemic (TG > or =300 and <1000 mg/dl) subjects with the MS were randomly assigned to placebo (n=50) or 130 mg/day of micronized fenofibrate-coated microgranules (n=96) for 8 weeks. In the overall analysis, fenofibrate treatment resulted in significant (p < 0.05) changes versus placebo in TG (-36.6%), non-HDL-C (-7.5%), very low-density lipoprotein-C (-32.7%), LDL-C (15.0%), HDL-C (14.0%), remnant lipoprotein-C (-35.1%), apolipoprotein B (-6.0%), apolipoprotein A-I (5.3%), and apolipoprotein C-III--29.7%). Changes in LDL particle diameter in the fenofibrate group were significantly inversely associated with the TG level achieved on treatment (p = 0.019). When individually matched for percent change in TG, subjects with on-treatment TG < 200 mg/dl, in contrast to those with on-treatment values > or =200 mg/dl, had significantly different median responses (p < 0.05) in LDL size (0.79 vs. -0.06 nm) and cholesterol carried by small (-35 vs. 21 mg/dl) and large (31 vs. 11 mg/dl) particles. These data support the view that a threshold exists below which the TG level must be lowered to produce shifts in LDL particle size.