A Bioequivalence Comparison Between the Once-Daily Extended-Release Tablet and the Twice-Daily Tablet Formulations of Deutetrabenazine at Steady State.

Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once-daily (test) and twice-daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24 mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7 days. Plasma concentrations were collected on Days 4-6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α-dihydrotetrabenazine (α-HTBZ) and ß-dihydrotetrabenazine (ß-HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration-time curve over 24 hours at steady state (AUC0-24 h,ss ) and for maximum plasma concentrations at steady state (Cmax,ss ). The GMRs for AUC0-24 h,ss were 115% for deutetrabenazine and 95% for deuterated total (α+ß)-HTBZ; and the GMR for Cmax,ss for deutetrabenazine was 95%. Relative bioavailability was assessed for Cmax,ss of the active metabolites; the GMR was 78% for total (α+ß)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and Cmax, and the active metabolites were bioequivalent with regard to AUC0-24 h,ss .

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma.

BACKGROUND: Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. METHODS: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. RESULTS: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. CONCLUSIONS: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01343043 , Registered 27 April 2011.

Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma.

This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1c259TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 1010 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval [CI], 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286.

Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study.

BACKGROUND: The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia. METHODS: PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1-17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 10(9) per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12-17, 6-11, and 1-5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6-17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1-5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1-5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12-17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6-11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1-5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 10(9) per L or more at least once from weeks 1-6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037. FINDINGS: Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12-17 years, 19 aged 6-11 years, and ten aged 1-5 years) and 22 to receive placebo (eight children aged 12-17 years, nine aged 6-11 years, and five aged 1-5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 10(9) per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39-13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase. INTERPRETATION: Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults. FUNDING: GlaxoSmithKline.

Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial.

BACKGROUND: The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. METHODS: PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. FINDINGS: Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. INTERPRETATION: Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. FUNDING: GlaxoSmithKline.

Non-cirrhotic thrombocytopenic patients with hepatitis C virus: Characteristics and outcome of antiviral therapy.

BACKGROUND AND AIM: Thrombocytopenia is frequently observed in patients with chronic hepatitis C virus (HCV) infection and cirrhosis, although it can also be observed in patients without cirrhosis by a virus-mediated phenomenon. This study assessed the prevalence, characteristics, and outcomes of antiviral therapy in patients with chronic HCV infection and thrombocytopenia not associated with cirrhosis. METHODS: The study included 1268 patients with HCV infection and thrombocytopenia enrolled in the phase 3 ENABLE studies that assessed the impact of eltrombopag on achieving a sustained virologic response to pegylated interferon and ribavirin. The study population was subdivided according to baseline FibroSURE test results into patients with non-cirrhosis (FibroSURE < 0.4) and cirrhosis-related (FibroSURE ≥ 0.75) thrombocytopenia. RESULTS: Compared with patients with cirrhosis-related thrombocytopenia (n = 995; 78.5%), non-cirrhotic patients with thrombocytopenia (n = 59; 4.6%) were younger (mean age [95% confidence interval (CI)]: 43.9 [40.7-47.2] vs 52.7 [52.2-53.3] years; P < 0.0001), predominantly female (64% [51-76] vs 30% [27-33]; P < 0.0001), and less frequently had a Model for End-Stage Liver Disease score ≥ 10 (24% [14-37] vs 45% [42-49]; P = 0.0012), low albumin levels (≤ 35 g/L; 2% [0-9] vs 32% [29-35]; P < 0.0001), and prevalence of diabetes mellitus (3% [0-12] vs 21% [19-24]; P = 0.0005). The sustained virologic response rate was higher in non-cirrhotic patients with thrombocytopenia (46% [95% CI, 33-59] vs 16% [14-18]; P < 0.0001). CONCLUSIONS: Patients with thrombocytopenia associated with HCV who have lower FibroSURE test results may have better preserved liver function and higher sustained virologic response rates than patients with cirrhosis.

Efficacy and safety of carvedilol in treatment of heart failure with chronic kidney disease: a meta-analysis of randomized trials.

BACKGROUND: The safety and efficacy of different types of ß-blocker therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of systolic HF with carvedilol is efficacious and safe in adults with CKD. METHODS AND RESULTS: We performed a post hoc analysis of pooled individual patient data (n=4217) from 2 multinational, double-blinded, placebo-controlled, randomized trials, CAPRICORN (Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction Study) and COPERNICUS (Carvedilol Prospective Randomized, Cumulative Survival study). Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, HF mortality, first HF hospitalization, the composite of cardiovascular mortality or first HF hospitalization, and sudden cardiac death. Non-dialysis-dependent CKD was defined by estimated glomerular filtration rate ≤60 mL/min/1.73 m(2), using the abbreviated Modification of Diet in Renal Disease equation. CKD was present in 2566 of 4217 (60.8%) of the cohort, 50.4% of whom were randomly assigned to carvedilol therapy. Within the CKD group, treatment with carvedilol decreased the risks of all-cause mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63 to 0.93; P=0.007), cardiovascular mortality (HR, 0.76; 95% CI, 0.62 to 0.94; P=0.011), HF mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P=0.003), first hospitalization for HF (HR, 0.74; 95% CI, 0.61 to 0.88; P=0.0009), and the composite of cardiovascular mortality or HF hospitalization (HR, 0.75; 95% CI, 0.65 to 0.87; P<0.001) but was without significant effect on sudden cardiac death (HR, 0.76; 95% CI, 0.56 to 1.05; P=0.098). There was no significant interaction between treatment arm and study type. Carvedilol was generally well tolerated by both groups of patients, with an increased relative incidence in transient increase in serum creatinine without need for dialysis and other electrolyte changes in the CKD patients. However, in a sensitivity analysis among HF subjects with estimated glomerular filtration rate <45 mL/min/1.73 m(2) (CKD stage 3b), the efficacy of carvedilol was not significantly different from placebo. CONCLUSIONS: This analysis suggests that the benefits of carvedilol therapy in patients with systolic left ventricular dysfunction with or without symptoms of HF are consistent even in the presence of mild to moderate CKD. Whether carvedilol therapy is similarly efficacious in HF patients with more advanced kidney disease requires further study.

Effect of combining extended-release carvedilol and lisinopril in hypertension: results of the COSMOS study.

Hypertension treatment commonly requires multiple agents to achieve target blood pressure (BP). ß-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed in clinical practice although few data are available that test their additivity on BP lowering. The efficacy and safety of once-daily extended-release carvedilol (carvedilol CR) combined with the ACEI lisinopril in a double-blind, randomized, factorial design study were studied. Patients (N=656) with stage 1 or 2 hypertension were randomized evenly to 1 of 15 groups for 6 weeks: carvedilol CR monotherapy 20 mg, 40 mg, or 80 mg/d; lisinopril monotherapy 10 mg, 20 mg, or 40 mg/d; or 1 of 9 combinations of carvedilol CR plus lisinopril initiated simultaneously. Primary efficacy measures (assessed by ambulatory BP monitoring [ABPM]) were change from baseline in 24-hour mean diastolic BP (DBP) and in trough (20-24 hours) DBP. Continuous efficacy variables were assessed using analysis of covariance. Whether any combination dose was superior to its monotherapy components was assessed using the Hung AVE procedure. Despite the presence of additional BP lowering observed with most of the combinations compared with their monotherapy components, the Hung AVE test was not significant for either primary efficacy measures. Post hoc analyses of the high-dose combination groups (carvedilol CR/lisinopril regimens of 80/10 mg, 80/20 mg, 80/40 mg, 20/40 mg, and 40/40 mg) showed a significant treatment difference compared with both carvedilol CR 80 mg and lisinopril 40 mg for 24-hour mean DBP but not for trough DBP. With the exception of dizziness, individual adverse events did not increase with ascending doses or combinations. The superiority of initiating combination treatment with carvedilol CR and lisinopril compared with the monotherapy components was not demonstrated with the ABPM measurements. Nonetheless, the post hoc assessment combining all high-dose groups did produce significant 24-hour mean BP reduction when compared with the high-dose monotherapy groups. The tolerability profile of initiating combination therapy was generally comparable to the initiation of treatment with monotherapy.

Importance of blood pressure control in left ventricular mass regression.

Blood pressure (BP) reduction to 140/90 mm Hg or lower using renin-angiotensin-system blockers reportedly provides the greatest left ventricular (LV) mass regression; ß-blockers have less effect. This study examined whether combination antihypertensive therapy would provide greater benefit. With a double-blind, parallel-group design, the effects of 3 different combinations, carvedilol controlled-release (CR)/lisinopril, atenolol/lisinopril, and lisinopril, on left ventricular mass index (LVMI) were assessed by MRI after 12 months. Patients were treated to achieve guideline-recommended BP (<140 mm Hg/<90 mm Hg; diabetes: <130 mm Hg/<80 mm Hg). Sample size was calculated to achieve 90% power to detect a 5 g/m(2) difference in mean change from baseline in LVMI between the carvedilol CR/lisinopril group and each of the other treatment groups. Of 287 patients randomized, more than 50% were titrated to maximum dosage; 73% reached targeted BP. At month 12 (last observation carried forward ≥ month 9) for 195 evaluable subjects, mean BP was similar in all groups (carvedilol CR/lisinopril: 128.8/77.9; atenolol/lisinopril: 128.7/76.5; lisinopril: 126.3/80.3 mm Hg). Compared with baseline, mean LVMI decreased to a similar extent in all groups (carvedilol CR/lisinopril: -6.3; atenolol/lisinopril: -6.7; lisinopril: -7.9 g/m(2)). Achievement of targeted BP control is more important than treatment regimen in achieving LV mass reduction.

Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis.

PURPOSE: Nonhormonal treatment options have been investigated as treatments for hot flashes, a major clinical problem in many women. Starting in 2000, a series of 10 individual double-blind placebo-controlled studies has evaluated newer antidepressants and gabapentin for treating hot flashes. This current project was developed to conduct an individual patient pooled analysis of the data from these published clinical trials. PATIENTS AND METHODS: Individual patient data were collected from the various study investigators who published their study results between 2000 and 2007. Between-study heterogeneity for study characteristics and patient populations was tested via chi2 tests before a pooled analysis. The primary end point, the change in hot flash activity from baseline to week 4, for each agent was calculated via both weighted and unweighted approaches, using the size of the study as the weight. Basic summary statistics were produced for hot flash score and frequency using the following three statistics: raw change, percent reduction, and whether or not a 50% reduction was achieved. RESULTS: This study included seven trials of newer antidepressants and three trials of gabapentin. The optimal doses (defined by individual study results) of the newer antidepressants paroxetine, venlafaxine, fluoxetine, and sertraline decreased hot flash scores by 41%, 33%, 13%, and 3% to 18% compared with the corresponding placebo arms, respectively. The three gabapentin trials decreased hot flashes by 35% to 38% compared with the corresponding placebo arms. CONCLUSION: Some newer antidepressants and gabapentin, within 4 weeks of therapy initiation, decrease hot flashes more than placebo.

Low doses of controlled-release paroxetine in the treatment of late-life depression: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and tolerability of low daily doses of controlled-release (CR) paroxetine in patients with late-life depression. METHOD: This was a 10-week, multicenter, placebo-controlled, double-blind, fixed-dose trial randomly assigning patients >or= 60 years old to daily doses of paroxetine CR 12.5 mg (N = 168), paroxetine CR 25 mg (N = 177), or placebo (N = 180). Patients had major depressive disorder (DSM-IV criteria) and 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of >or= 18. The primary efficacy variable was the change from baseline to study endpoint in total HAM-D scores. The study was conducted from June 2003 to October 2004. RESULTS: The drug/placebo difference in HAM-D change from baseline at study endpoint was -1.8 (95% CI = -3.41 to -0.19, p = .029) for paroxetine CR 12.5 mg, and -3.3 (95% CI = -4.84 to -1.68, p < .001) for paroxetine CR 25 mg. A significantly larger percentage of patients achieved remission (HAM-D total score or= 60 years of age, although effect sizes are relatively smaller with the 12.5 mg/day dose.

Demographic analyses of the effects of carvedilol vs metoprolol on glycemic control and insulin sensitivity in patients with type 2 diabetes and hypertension in the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) study.

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, carvedilol added to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had neutral or beneficial effects on glycemic measures compared with metoprolol tartrate. For the 1235 diabetic hypertensive GEMINI patients, the authors assessed treatment differences by race (white/black/other), age (continuous variable), and sex on hemoglobin A(1c), insulin resistance (homeostasis model assessment-insulin resistance [HOMA-IR]), and blood pressure. Both treatments significantly reduced blood pressure in all subgroups, but the metabolic effects of carvedilol were more beneficial in subgroups of race and sex. Carvedilol did not affect hemoglobin A(1c) but improved HOMA-IR results in all subgroups, significantly in males and "other race" subgroups. Metoprolol significantly increased hemoglobin A(1c) in all subgroups except "other race," with no effect on HOMA-IR findings. Differences vs metoprolol significantly favored carvedilol for hemoglobin A(1c) in white and female subgroups and favored carvedilol for HOMA-IR in black, "other race," and male subgroups. Carvedilol effects were favorable to adjustment of age as a covariate. In hypertensive patients with diabetes, carvedilol may be a more appropriate choice when beta-blockade is indicated.

Lowering blood pressure with beta-blockers in combination with other renin-angiotensin system blockers in patients with hypertension and type 2 diabetes: results from the GEMINI Trial.

The effects of beta-blockade in addition to more specific renin-angiotensin system (RAS) blockers on blood pressure (BP) in patients with diabetes are described. After washout of medications other than angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, patients were titrated to a BP level <130/80 mm Hg using therapy with carvedilol 6.25 to 25 mg bid (n=498) or metoprolol tartrate 50 to 200 mg bid (n=737). At the end of the beta-blocker titration period, a BP level <130/80 mm Hg was achieved in 37% of carvedilol-treated and 36% of metoprolol-treated participants who continued to receive a renin-angiotensin system blocker. In the approximately 60% of participants in whom a BP level <130/80 mm Hg was not attained with renin-angiotensin system blockade plus beta-blockade, hydrochlorothiazide was added in 43% and 44% of carvedilol and metoprolol groups, respectively; 25% (both arms) also required a calcium channel blocker. Among those in whom goal BP was not achieved, 42% of carvedilol- and 40% of metoprolol-treated participants were not titrated to the highest dose of beta-blocker. The use of carvedilol compared with metoprolol did not effect glycemic control.

Efficacy of a once-daily formulation of carvedilol for the treatment of hypertension.

Beta-blockers with pharmacologic effects that differ from conventional agents might add to antihypertensive treatment options. This study evaluated a new once-daily formulation of the beta-/alpha1-blocker, carvedilol controlled-release (CR), in hypertensive patients off treatment or while still taking up to 2 (non-beta-blocker) agents. After a 4-week run-in phase, patients were randomized either to placebo (n=76) or carvedilol CR 20 mg (n=82), 40 mg (n=76), or 80 mg (n=86) once daily. After 6 weeks of treatment, ambulatory blood pressure monitoring was repeated to measure the primary end point of changes in mean 24-hour diastolic blood pressure. During treatment, 24-hour diastolic blood pressure fell in the placebo and carvedilol CR 20-mg, 40-mg, and 80-mg groups by (mean +/- SE) 0.4+/-0.9, 4.4+/-0.9, 7.9+/-0.9, and 9.6+/-0.9 mm Hg, respectively (P< or =.001, trend test for all carvedilol CR doses with placebo). Corresponding 24-hour systolic blood pressure changes were 0.6+/-1.4, 6.8+/-1.3, 10.1+/-1.4, and 12.5+/-1.3 mm Hg, respectively (P< or =.001, trend test). Diastolic blood pressure trough-to-peak ratios (placebo-corrected) based on ambulatory blood pressure monitoring (trough = mean of 20- to 24-hour post-dose readings; peak = mean of 3- to 7-hour post-dose readings) for 20-mg, 40-mg, and 80-mg doses were 0.73, 0.64, and 0.65, respectively. Adverse events, including clinical chemistry values, were similar in the drug-treated and placebo groups. Carvedilol CR has a clinically meaningful defined dose-dependent antihypertensive effect that persists throughout a 24-hour period.

Controlled-release carvedilol in the treatment of essential hypertension.

Carvedilol is a beta1-, beta2-, and alpha1-adrenergic blocker that is approved for the treatment of hypertension. A new once-daily, controlled-release (CR) formulation of carvedilol has been shown to be effective in a double-blind, randomized, multicenter, placebo-controlled, parallel-group study. In this article, we summarize the primary results of, and present additional analyses from, that trial. A total of 338 patients with essential hypertension (sitting diastolic blood pressure [DBP] >/=90 and 0.6 for each carvedilol CR dose. Heart rate and pulse pressure were each significantly reduced compared with placebo for each carvedilol CR dose. We conclude that carvedilol CR is a very effective antihypertensive agent with clear dose-related peak blood pressure reduction and continuous 24-hour control.

Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database.

OBJECTIVE: Paroxetine is a potent selective serotonin reuptake inhibitor with antidepressant and anxiolytic activity that is effective in the treatment of generalized anxiety disorder (GAD), improving the core symptoms of anxiety, worry, and tension. The majority of patients with GAD have chronic symptomatology and significant comorbid mood and anxiety disorders that often require ongoing pharmacotherapy. This article reviews the efficacy and tolerability of paroxetine in the short- and long-term treatment of GAD including remission data. DATA SOURCES: Data from more than 1800 outpatients with DSM-IV-defined GAD were analyzed from 3 short-term (8-week) studies and a longer (6-month) relapse prevention study. These studies were all randomized, double-blind, placebo-controlled trials of paroxetine. DATA SYNTHESIS: The results emphasize the benefit of paroxetine treatment in GAD, enabling a substantial proportion of patients to achieve clinical remission and preventing relapse. Long-term treatment with paroxetine also shows good tolerability with no evidence of weight gain. CONCLUSION: Given the high comorbidity of psychiatric depression and anxiety, the long-term efficacy and tolerability of paroxetine are important considerations when selecting a first-line therapy for patients with GAD.

The rationale and design of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial.

Beta-blockers utilized in the Type 2 diabetic patient result in an even greater decrease in cardiac events than in the nondiabetic patient. Unfortunately, first-and second-generation beta-blockers are associated with the worsening of insulin resistance, deterioration of glycemic control, peripheral vasoconstriction, potentially worsening peripheral vascular disease, and more frequent and severe hypoglycemia. The third-generation beta-blockers have unique properties, including alpha1-blockade, and have been shown to lower insulin resistance, improve glycemic control, and vasodilate resistance arterioles. The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial has been designed to compare a third-generation (carvedilol) with a second-generation beta-blocker (metoprolol) in a cohort of participants with hypertension and Type 2 diabetes. The primary outcome measure of the study is change in the HbA1c. The study is powered to detect a difference in HbA1c of 0.3 units (%) between the groups. Secondary endpoints include changes in insulin resistance, fasting glucose, and the lipid profile. Differences in the side-effect profile (cold extremities, fatigue, impotence, and hypoglycemia) will also be assessed. The GEMINI trial, therefore, is the first large randomized trial to assess whether utilizing a third-generation beta-blocker yields a favorable metabolic profile in the patient with Type 2 diabetes and hypertension.

Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder.

OBJECTIVE: To assess the efficacy and tolerability of controlled-release paroxetine (paroxetine CR) in the treatment of adults with panic disorder. METHOD: Paroxetine CR (25-75 mg/day; N = 444) was compared with placebo (N = 445) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical, double-blind, placebo-controlled, 10-week clinical trials that were pooled for analysis. RESULTS: Paroxetine CR was statistically superior to placebo in the primary outcome measure, percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint. Of the total population that completed or prematurely terminated treatment, 63% and 53% of paroxetine CR-and placebo-treated patients, respectively, were panic-free during the final 2 weeks (p < .005; odds ratio [OR] = 1.63; 95% CI = 1.21 to 2.19). For week 10 completers (72% of total), 73% and 60% of paroxetine CR- and placebo-treated patients, respectively, were panic-free at week 10 (p < .005; OR = 2.11; 95% CI = 1.45 to 3.07). Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale. Adverse events leading to study withdrawal were minimal and occurred in 11% of the paroxetine CR group and 6% of the placebo group. Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study. There were no unexpected adverse events, and serious adverse events were uncommon (10 [2.3%] of the 444 patients treated with paroxetine CR vs. 8 [1.8%] of the 445 patients treated with placebo). CONCLUSION: Paroxetine CR is an effective and well-tolerated treatment for panic disorder. Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events.

Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial.

CONTEXT: Standard therapy for hot flashes has been hormone replacement with estradiol or progestational agents, but recent data suggest that antidepressants inhibiting serotonin reuptake may also be effective. OBJECTIVE: To evaluate a selective serotonin reuptake inhibitor (paroxetine controlled release [CR]) in treating the vasomotor symptoms displayed by a general cross-section of menopausal women. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, parallel group study conducted across 17 US sites, including urban, suburban, and rural clinics. PATIENTS: A total of 165 menopausal women aged 18 years or older experiencing at least 2 to 3 daily hot flashes and must have discontinued any hormone replacement therapy for at least 6 weeks. Women were excluded if they had any signs of active cancer or were undergoing chemotherapy or radiation therapy. INTERVENTION: After a 1-week placebo run-in phase, study participants were randomized to receive placebo or receive 12.5 mg/d or 25.0 mg/d of paroxetine CR (in a 1:1:1 ratio) for 6 weeks. MAIN OUTCOME MEASURES: Mean change from baseline to week 6 in the daily hot flash composite score (frequency x severity). RESULTS: Fifty-six participants were randomly assigned to receive placebo and 51 to receive 12.5 mg/d and 58 to receive 25.0 mg/d of paroxetine CR. The mean reductions in the hot flash frequency composite score from baseline to week 6 were statistically significantly greater for those receiving paroxetine CR than for those receiving placebo. By week 6, the mean daily hot flash frequency went from 7.1 to 3.8 (mean reduction, 3.3) for those in the 12.5-mg/d and from 6.4 to 3.2 (mean reduction, 3.2) for those in the 25-mg/d paroxetine CR groups and from 6.6 to 4.8 (mean reduction, 1.8) for those in the placebo group. Mean placebo-adjusted reduction in hot flash composite scores were -4.7 (95% confidence interval, - 8.1 to -1.3; P =.007) comparing 12.5-mg/d paroxetine CR with placebo; and -3.6 (95% confidence interval, -6.8 to -0.4; P =.03) comparing 25.0-mg/d paroxetine CR with placebo. This corresponded to median reductions of 62.2% for those in the 12.5-mg/d and 64.6% for those in the 25.0-mg/d paroxetine CR groups compared with 37.8% for those in the placebo group. CONCLUSION: Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other therapies in treating menopausal hot flash symptoms.

Paroxetine treatment of generalized anxiety disorder: a double-blind, placebo-controlled study.

OBJECTIVE: This study assessed the efficacy of two fixed doses of paroxetine in the treatment of generalized anxiety disorder. METHOD: Outpatients (N=566) with generalized anxiety disorder and no other axis I disorder were eligible if they scored >/=20 on the Hamilton Rating Scale for Anxiety (with a score of 2 or higher on the anxious mood and tension items). Following a 1-week placebo run-in phase, patients were randomly assigned to 8 weeks of treatment with paroxetine, 20 or 40 mg/day, or placebo. The primary outcome measure was the change from baseline in total score on the Hamilton anxiety scale. Response was defined as a rating of "very much improved" or "much improved" on the Clinical Global Impression global improvement measure; remission was defined as a Hamilton anxiety scale score