10-mg Group Research Articles

Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis

Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). 114 centers in 19 countries. 792 patients with active RA despite nonbiologic DMARD therapy. Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. Pfizer.

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

BackgroundAlzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease.MethodsWe conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.ResultsThe trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, −9.0 points in the placebo group, −10.5 points in the 100-mg group, and −12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.ConclusionsAs compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a long-acting release (LAR) formulation of pasireotide (SOM230) in patients with gastroenteropancreatic neuroendocrine tumors: results from a randomized, multicenter, open-label, phase I study

PurposePasireotide (SOM230), a novel multireceptor ligand somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst1–3, 5). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics profiles of pasireotide long-acting release (LAR) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor (GEP NET) refractory to other SSAs.MethodsIn this randomized, multicenter, open-label, phase II study, patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were randomly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20, 40, or 60 mg once every 28 days for 3 months.ResultsForty-two patients received pasireotide LAR. Adverse events were reported by 34 (81 %) patients, with the most frequently reported including diarrhea, fatigue, abdominal pain, and nausea. Mean fasting glucose levels were increased compared with baseline at all points throughout the study. After the third injection of pasireotide LAR, the median trough plasma concentrations on day 84 were 4.82, 12.0, and 19.7 ng/mL in the 20-, 40-, and 60-mg treatment groups, respectively. Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections (accumulation ratios were approximately 1 from all dose levels).ConclusionsThis study demonstrated that a new, once-monthly, intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET. Steady state levels of plasma pasireotide were achieved after three injections.

THU0096 Mavrilimumab in rheumatoid arthritis: Results of a phase 2 double-blind, placebo controlled study

BackgroundPreclinical and animal models have identified GM-CSF as a key cytokine in rheumatoid arthritis (RA). Mavrilimumab (CAM-3001), a human mAb targeting GM-CSFRα, is being evaluated for the treatment of RA.ObjectivesTo...

Evaluation of Pharmacokinetic and Pharmacodynamic Profiles and Tolerability After Single (2.5, 5, or 10 mg) and Repeated (2.5, 5, or 10 mg BID for 4.5 days) Oral Administration of Ivabradine in Healthy Male Korean Volunteers

BackgroundIvabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti-ischemic efficacy as well as improvement in heart failure outcomes. ObjectiveThe purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects. MethodsThis was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study. ResultsForty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean Cmax levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC0–last values were 30, 52, and 121 ng h/mL. At steady state, mean Cmax,ss levels were 11, 19, and 42 ng/mL, reached at a median Tmax of 0.67 hour for all 3 doses. The mean AUC0–τ levels were 43, 58, and 139 ng h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After the repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae. ConclusionsSingle and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration–response relationship of ivabradine is similar between Korean and white subjects.

The Mark Coventry Award: Higher Tissue Concentrations of Vancomycin With Low-dose Intraosseous Regional Versus Systemic Prophylaxis in TKA

In response to increasing antibiotic resistance, vancomycin has been proposed as an alternative prophylactic agent in TKA. However, vancomycin requires a prolonged administration time, risks promoting further antibiotic resistance, and can cause systemic toxicity. Intraosseous regional administration (IORA) is known to achieve markedly higher antibiotic concentrations than systemic administration and may allow the use of a lower vancomycin dose. We assessed whether low-dose IORA vancomycin can achieve tissue concentrations equal or superior to those of systemic administration in TKA and compared complications between patients treated with IORA and intravenous vancomycin. We randomized 30 patients undergoing primary TKA to receive 250 or 500 mg vancomycin via IORA or 1 g via systemic administration. IORA was performed as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet immediately before skin incision. Subcutaneous fat and bone samples were taken during the procedure and antibiotic concentrations measured. The overall mean tissue concentration of vancomycin in subcutaneous fat was 14 μg/g in the 250-mg IORA group, 44 μg/g in the 500-mg IORA group, and 3.2 μg/g in the systemic group. Mean concentrations in bone were 16 μg/g in the 250-mg IORA group, 38 μg/g in the 500-mg IORA group, and 4.0 μg/g in the systemic group. One patient in the systemic group developed red man syndrome during infusion. Low-dose IORA vancomycin results in tissue concentrations equal or superior to those of systemic administration. IORA optimizes timing of vancomycin administration, and the lower dose may reduce the risk of systemic side effects while providing equal or enhanced prophylaxis in TKA.

Retraction notice to “Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) Trial” [J Am Coll Cardiol 2012;59:1778–1784

Roeland Huijgen, MD,* S. Matthijs Boekholdt, MD, PhD,*† Benoit J. Arsenault, PhD,* Weihang Bao, PhD,‡ Jean-Michel Davaine, MD,§ Fatiha Tabet, PhD,‖ Francine Petrides, BSC,‖ Kerry-Anne Rye, PhD, ‖¶ David A. DeMicco, PharmD,‡ Philip J. Barter, MD, PhD,‖¶ John J. P. Kastelein, MD, PhD,* Gilles Lambert, PhD§‖From the *Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; †Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands; ‡Pfizer Inc., New York, New York; §Laboratoire Inserm U957, Faculté de Médecine, Université de Nantes, Nantes, France; ‖The Heart Research Institute, Sydney, New South Wales, Australia; and the ¶Faculty of Medicine, University of Sydney, New South Wales, AustraliaThis article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the author.The main findings of the TNT Trial were published in 2005 (1). Since that time, members of the Steering Committee and other investigators have published 32 papers based upon additional analyses of TNT. The data for these papers were derived from analyses of the TNT clinical database, managed by Pfizer. The clinical database has been crosschecked many times and the data in it is valid. During the trial, blood samples were drawn from the patients at regular intervals for subsequent analysis. We performed a nested case-control study that included 507 patients who experienced a CV event and 1,020 control patients in the main biomarker analysis, and 496 patients who experienced a CV event and 1,117 control patients in the PCSK9 analysis. The biomarker database was sesimple-parate from the clinical database. An anonymization code was run in 2007 to link patients from one database to the other.In late 2012, the TNT frozen blood samples were integrated into a large automated biobank that includes samples from other Pfizer trials. At that time discrepancies were noted among the samples, indicating that an error had occurred when the samples were anonymized in 2007. Further investigation revealed that the code created to manually anonymize the data was accidentally run twice. During the first run, anonymized subject identifiers were successfully assigned to both biosamples and clinical data. However, after this first run had passed quality control checks, the anonymization code was re-run inadvertently, replacing the first correct set of identifiers with a random and incorrect set. We do not understand how or why the code was re-run. The study team, who were blinded as to patient identity, thus reported on mismatched clinical and biomarker data. The investigators of the biomarkers study were puzzled that none of the 18 biomarkers were predictive of cardiovascular events. However we were reassured because on-treatment LDL-cholesterol, HDL-cholesterol and triglyceride levels were all strongly predictive of events, and we reported this in the paper. These lipid levels were part of the clinical database, and thus were not subject to the error that occurred with the biomarkers. In the PCSK9 analysis, PCSK9 levels were predictive of events in the atorvastatin 10-mg group (p 0.039) but not in the 80-mg group. This finding, which we now realize is totally spurious, was not unexpected and raised no red flags. Similarly, the failure of vitamin D levels to predict events, as reported in the AHJ paper, was not surprising.Since the error was discovered, we have created a new anonymized clinical and biomarker database by restoring the original set of anonymized identifiers. We are currently reanalyzing the data according to our original study plans. However, the nested case-control feature of the original study design has been lost because the patient selection for biomarker sampling was random. Only approximately one tenth of patients now had an event, compared to one third in the original study design. Thus, the power to detect a difference in the level of a biomarker between patients with and without events has been attenuated.All authors of these manuscripts are anguished to have made this mistake and publishing incorrect information.

Tabalumab in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate and Naive to Biologic Therapy: A Phase II, Randomized, Placebo‐Controlled Trial

Tabalumab, a fully human IgG4 monoclonal antibody, neutralizes soluble and membrane-bound BAFF. The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate. In this randomized, double-blind, placebo-controlled, parallel, multiple-dose study, patients who were naive to biologic therapy received infusions of tabalumab (30, 60, or 160 mg) or placebo at weeks 0, 3, and 6 in combination with methotrexate and were evaluated for 24 weeks. The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. At week 16, the percentages of patients achieving an ACR20 response in the 30-mg (57.6%), 60-mg (67.6%), and 160-mg (51.5%) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group (29.4%; P<0.05). There were initial transient increases from baseline in the frequency of CD20+ and IgD+/CD27- B cells, followed by reductions, although B cells were not completely depleted. Also, the frequency of IgD-/CD27+ B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study. The incidence of adverse events was similar across all treatment groups; no deaths occurred. Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group. There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group. Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment.

Langzeitwirkung von Dapagliflozin bei Typ-2-Diabetikern unter hoch dosierter Insulintherapie

Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin. To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs. A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231). 126 centers in Europe and North America from 30 April 2008 to 19 November 2009. 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs. Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks. The primary outcome was change in hemoglobin A1c from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods. 800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79 % to 0.96 % with dapagliflozin compared with 0.39 % with placebo (mean difference, -0.40 % [95 % CI, -0.54 % to -0.25 %] in the 2.5-mg group, -0.49 % [CI, -0.65 % to -0.34 %] in the 5-mg group, and -0.57 % [CI, -0.72 % to -0.42 %] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6 % vs. 51.8 %), events suggesting genital infection (9.0 % vs. 2.5 %), and events suggesting urinary tract infection (9.7 % vs. 5.1 %). Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety. Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.

An open-label, long-term evaluation of the safety, efficacy and tolerability of avanafil in male patients with mild to severe erectile dysfunction

Determine the long-term efficacy, safety and tolerability of avanafil, a highly specific, rapidly absorbed phosphodiesterase type 5 inhibitor in male patients with mild to severe erectile dysfunction (ED), with or without diabetes. This was a 52-week, open-label extension of two 12-week, randomised, placebo-controlled, phase 3 trials. Patients were assigned to avanafil 100 mg, but could request 200 mg (for increased efficacy; '100/200-mg' group) or 50 mg (for improved tolerability). Primary end points included percentage of sexual attempts ending in successful vaginal penetration [Sexual Encounter Profile 2 (SEP2)] and intercourse (SEP3) and erectile function domain score per the International Index of Erectile Function (IIEF-EF). Some 712 patients enrolled; 686 were included in the intent to treat population and contributed to the data. All primary end points showed sustained improvement. SEP2 and SEP3 success rates improved from 44% to 83% and from 13% to 68% (100-mg group) and from 43% to 79% and from 11% to 66% (100/200-mg group), respectively. Mean IIEF-EF domain scores improved from 13.6 to 22.2 (100-mg group) and from 11.9 to 22.7 (100/200-mg group). Avanafil was effective in some patients ≤ 15 min and > 6 h postdose. Sixty-five per cent (112/172) of 'nonresponders' to avanafil 100 mg responded to the 200-mg dose. The most common (≥ 2%) treatment-emergent adverse events were headache, flushing, nasopharyngitis and nasal congestion; < 3% of patients discontinued therapy because of adverse events. The long-term tolerability and improvement in sexual function, coupled with rapid onset, suggest that avanafil is well suited for the on-demand treatment of ED.

Tofacitinib: Janus Bifrons in Ulcerative Colitis Treatment

Tofacitinib: Janus Bifrons in Ulcerative Colitis Treatment

Randomized Dose-Ranging Study of the 14-Day Early Bactericidal Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive Pulmonary Tuberculosis

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

Effects of Food Intake on the Pharmacokinetic Properties of Mirabegron Oral Controlled-Absorption System: A Single-Dose, Randomized, Crossover Study in Healthy Adults

BackgroundMirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. ObjectiveThis study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. MethodsIn this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0–∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. ResultsThirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0–∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%–125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%–68.6%]) and AUC0–∞, by 17% (GMR, 83.2% [90% CI, 74.2%–93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0–∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%–78.7%]) and 18% (82.4% [72.6%–93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%–31.3%]) and AUC0–∞ by 51% (48.7% [43.3%–54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%–46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%–60.5%]) for AUC0–∞. The fed/fasted ratios for mirabegron Cmax and AUC0–∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5–2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. ConclusionsMirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.

An Open-Label Dose Escalation Study to Evaluate the Safety of Administration of Nonviral Stromal Cell-Derived Factor-1 Plasmid to Treat Symptomatic Ischemic Heart Failure

Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.

Dexamethasone to Prevent Postoperative Nausea and Vomiting

Dexamethasone has an established role in decreasing postoperative nausea and vomiting (PONV); however, the optimal dexamethasone dose for reducing PONV when it is used as a single or combination prophylactic strategy has not been clearly defined. In this study, we evaluated the use of 4 mg to 5 mg and 8 mg to 10 mg IV doses of dexamethasone to prevent PONV when used as a single drug or as part of a combination preventive therapy. A wide search was performed to identify randomized clinical trials that evaluated systemic dexamethasone as a prophylactic drug to reduce postoperative nausea and/or vomiting. The effects of dexamethasone dose were evaluated by pooling studies into 2 groups: 4 mg to 5 mg and 8 mg to 10 mg. The first group represents the suggested dexamethasone dose to prevent PONV by the Society for Ambulatory Anesthesia (SAMBA) guidelines, and the second group represents twice the dose range recommended by the guidelines. The SAMBA guidelines were developed in response to studies, which have been performed to examine different dosages of dexamethasone. Sixty randomized clinical trials with 6696 subjects were included. The 4-mg to 5-mg dose dexamethasone group experienced reduced 24-hour PONV compared with control, odds ratio (OR, 0.31; 95% confidence interval [CI], 0.23-0.41), and number needed to treat (NNT, 3.7; 95% CI, 3.0-4.7). When used together with a second antiemetic, the 4-mg to 5-mg dexamethasone group also experienced reduced 24-hour PONV compared with control (OR, 0.50; 95% CI, 0.35-0.72; NNT, 6.6; 95% CI, 4.3-12.8). The 8-mg to 10-mg dose dexamethasone group experienced decreased 24-hour PONV compared with control (OR, 0.26; 95% CI, 0.20-0.32; NNT, 3.8; 95% CI, 3.0-4.3). Asymmetric funnel plots were observed in the 8-mg to 10-mg dose analysis, suggesting the possibility of publication bias. When used together with a second antiemetic, the 8-mg to 10-mg dose group also experienced reduced incidence of 24-hour PONV (OR, 0.35; 95% CI, 0.22-0.53; NNT, 6.2; 95% CI, 4.5-10). In studies that provided a direct comparison between groups, there was no clinical advantage of the 8-mg to 10-mg dexamethasone dose compared with the 4-mg to 5-mg dose on the incidence of postoperative nausea and/or vomiting. Our results showed that a 4-mg to 5-mg dose of dexamethasone seems to have similar clinical effects in the reduction of PONV as the 8-mg to 10-mg dose when dexamethasone was used as a single drug or as a combination therapy. These findings support the current recommendation of the SAMBA guidelines for PONV, which favors the 4-mg to 5-mg dose regimen of systemic dexamethasone.

Long‐term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes

In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10 mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26 weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52 weeks. Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10 mg, while the linagliptin groups maintained dosage. In all, 540 patients received at least one dose of linagliptin 5 or 10 mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10 mg. These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10 mg for up to 52 weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain.

Effects of Interleukin-1β Inhibition With Canakinumab on Hemoglobin A1c, Lipids, C-Reactive Protein, Interleukin-6, and Fibrinogen

Background— To test formally the inflammatory hypothesis of atherothrombosis, an agent is needed that reduces inflammatory biomarkers such as C-reactive protein, interleukin-6, and fibrinogen but that does not have major effects on lipid pathways associated with disease progression. Methods and Results— We conducted a double-blind, multinational phase IIb trial of 556 men and women with well-controlled diabetes mellitus and high cardiovascular risk who were randomly allocated to subcutaneous placebo or to subcutaneous canakinumab at doses of 5, 15, 50, or 150 mg monthly and followed over 4 months. Compared with placebo, canakinumab had modest but nonsignificant effects on the change in hemoglobin A1c, glucose, and insulin levels. No effects were seen for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non–high-density lipoprotein cholesterol, although triglyceride levels increased ≈10% in the 50-mg ( P =0.02) and 150-mg ( P =0.03) groups. By contrast, the median reductions in C-reactive protein at 4 months were 36.4%, 53.0%, 64.6%, and 58.7% for the 5-, 15-, 50-, and 150-mg canakinumab doses, respectively, compared with 4.7% for placebo (all P values ≤0.02). Similarly, the median reductions in interleukin-6 at 4 months across the canakinumab dose range tested were 23.9%, 32.5%, 47.9%, and 44.5%, respectively, compared with 2.9% for placebo (all P ≤0.008), and the median reductions in fibrinogen at 4 months were 4.9%, 11.7%, 18.5%, and 14.8%, respectively, compared with 0.4% for placebo (all P values ≤0.0001). Effects were observed in women and men. Clinical adverse events were similar in the canakinumab and placebo groups. Conclusions— Canakinumab, a human monoclonal antibody that neutralizes interleukin-1β, significantly reduces inflammation without major effect on low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. These phase II trial data support the use of canakinumab as a potential therapeutic method to test directly the inflammatory hypothesis of atherosclerosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00900146.

Ofatumumab (OFA) in Combination with CHOP for Previously Untreated Follicular Lymphoma: Follow-up Results

AbstractAbstract 1632 Background:OFA is a fully human monoclonal antibody that binds to both the large and small extracellular loops of CD20. OFA is currently approved for patients (pts) with refractory chronic lymphocytic leukemia and has demonstrated activity in non-Hodgkin's lymphomas, including follicular lymphoma (FL). We previously reported results of a phase II study of OFA in combination with CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg daily for 5 days) chemotherapy (O-CHOP) in pts with previously untreated FL (Czuczman et al. Br J Haematol. 2012;157:438). We now report updated efficacy, safety and pharmacokinetic (PK) follow-up data for this study. This trial is registered at www.clinicaltrials.gov (NCT00494780). Methods:Fifty-nine pts with previously untreated FL were randomized to OFA 500 mg (n = 29) or 1000 mg (n = 30) on day 1, with CHOP on day 3, every 3 weeks for 6 cycles. The primary end point was overall response rate (ORR), as assessed by an independent end points review committee. Secondary end points included complete response (CR), progression-free survival (PFS), overall survival, adverse events (AEs) and PK. Follow-up assessments after therapy were done every 3 months (mo) until mo 12 and then every 6 mo until alternative FL therapy or mo 60. Positron emission tomography (PET) was done at baseline and 3 mo after last therapy. Blood samples for PK analyses were collected to determine OFA serum concentrations, and noncompartmental methods were used to estimate PK parameter values. Results:Fifty-eight pts received therapy; 1 pt in the 1000-mg group withdrew before initiation of therapy. The ORR was 90% for the 500-mg group (n=29) and 100% for the 1000-mg group (n=29); 55% of pts achieved CR or unconfirmed CR (CRu), including 67% of pts with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3–5. At baseline, 57 pts were PET positive, and 49 pts underwent repeat PET scans after therapy. Forty of 49 pts (82%) became PET negative, including 27 of 29 (93%) pts who achieved CR/CRu and 13 of 20 pts (65%) who achieved partial response (PR). With a median follow-up of 33.8 mo, the median PFS for the 500-mg group was 27.6 mo and the median PFS for the 1000-mg group was not reached (P=0.46). Median PFS for pts with FLIPI scores of 0–1 (n=17), 2 (n=20) and 3–5 (n=21) was not reached, 27.6 mo and 27.6 mo, respectively (P=0.68). Median PFS for pts (n=32) who achieved CR/CRu was also not reached and was 28.3 mo for pts (n=23) achieving PR. Median PFS for PR pts who were PET positive and PET negative after therapy was not reached and 28.3 mo, respectively. No deaths have been reported. No hematologic serious AEs (SAEs) were experienced during the follow-up period. During the follow-up period, non-hematologic SAEs were reported in 1 pt in the 500-mg group (pneumonia) and 5 pts in the 1000-mg group (abdominal hernia, erysipelas, intervertebral disc protrusion, meniscus lesion and vulval cancer); none were ofatumumab-related. After repeated dosing, OFA clearance values were 6.3 and 5.9 mL/h, and half-life values were 27.2 and 26.8 days in the 500-mg and 1000-mg groups, respectively. Conclusions:O-CHOP achieved durable remissions in previously untreated pts with FL. There were no observed PK or PFS differences between the 500-mg and 1000-mg arms, but the study was not powered to detect such differences. O-CHOP was effective in pts with high-risk FLIPI scores, and CR/CRu and PFS rates were not affected by FLIPI score. PET status after therapy did not predict PFS in responding pts, although the study was too small to make such a determination. These results indicate that O-CHOP should be studied as a therapy for FL pts with high-risk FLIPI scores. [Display omitted] Disclosures:Czuczman:GlaxoSmithKline: Advisory board Other, Honoraria. Off Label Use: Ofatumumab in follicular lymphoma. Belada:GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Gupta:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Employment, Equity Ownership. Winter:GlaxoSmithKline: Employment, Equity Ownership. Goldstein:GlaxoSmithKline: Employment, Equity Ownership. Jewell:GlaxoSmithKline: Employment, Equity Ownership. Lisby:Genmab: Employment, Equity Ownership.

Adjunctive Oral Ziprasidone in Patients With Acute Mania Treated With Lithium or Divalproex, Part 1

To assess the efficacy and safety of adjunctive ziprasidone in subjects with acute mania treated with lithium or divalproex, with an inadequate response to the mood stabilizer. The study enrolled subjects aged 18-65 years who had a primary DSM-IV diagnosis of bipolar I disorder, with the most recent episode manic or mixed, with or without rapid cycling, and a Young Mania Rating Scale (YMRS) score ≥ 18. Subjects were randomized under double-blind conditions to receive ziprasidone, 20 to 40 mg (n = 226) or 60 to 80 mg (n = 232), or placebo (n = 222) twice a day for 3 weeks in addition to their mood stabilizer. The primary efficacy variable was change in YMRS scores from baseline to 3 weeks. Secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness and -Improvement scales, and Global Assessment of Functioning. Computer-administered YMRS was included for quality control and to evaluate study performance. The study was conducted between April 2006 and December 2008. Least-squares mean ± standard error changes in YMRS scores from baseline to week 3 were -10.2 ± 0.80 in the mood stabilizer + ziprasidone 60- to 80-mg group, -11.0 ± 0.80 in the mood stabilizer + ziprasidone 20- to 40-mg group, and -9.5 ± 0.80 in the mood stabilizer + placebo group. Mean treatment differences between adjunctive ziprasidone groups and placebo were not statistically significant on primary or secondary efficacy measures. Ziprasidone was well tolerated. Adjunctive ziprasidone treatment failed to separate from mood stabilizer (lithium or divalproex) treatment on primary and secondary end points. ClinicalTrials.gov identifier: NCT00312494.

Efficacy and Tolerability of Mirabegron, a β3-Adrenoceptor Agonist, in Patients with Overactive Bladder: Results from a Randomised European–Australian Phase 3 Trial

BackgroundMirabegron, a β3-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB). ObjectiveTo assess the efficacy and tolerability of mirabegron versus placebo. Design, setting, and participantsMulticenter randomised double-blind, parallel-group placebo- and tolterodine-controlled phase 3 trial conducted in 27 countries in Europe and Australia in patients ≥18 yr of age with symptoms of OAB for ≥3 mo. InterventionAfter a 2-wk single-blind placebo run-in period, patients were randomised to receive placebo, mirabegron 50mg, mirabegron 100mg, or tolterodine extended release 4mg orally once daily for 12 wk. Outcome measurements and statistical analysisPatients completed a micturition diary and quality-of-life (QoL) assessments. Co–primary efficacy end points were change from baseline to final visit in the mean number of incontinence episodes and micturitions per 24h. The primary comparison was between mirabegron and placebo with a secondary comparison between tolterodine and placebo. Safety parameters included adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, and postvoid residual volume. Results and limitationsA total of 1978 patients were randomised and received the study drug. Mirabegron 50-mg and 100-mg groups demonstrated statistically significant improvements (adjusted mean change from baseline [95% confidence intervals]) at the final visit in the number of incontinence episodes per 24h (−1.57 [−1.79 to −1.35] and −1.46 [–1.68 to −1.23], respectively, vs placebo −1.17 [−1.39 to –0.95]) and number of micturitions per 24h (−1.93 [−2.15 to −1.72] and −1.77 [−1.99 to −1.56], respectively, vs placebo −1.34 [−1.55 to −1.12]; p<0.05 for all comparisons). Statistically significant improvements were also observed in other key efficacy end points and QoL outcomes. The incidence of treatment-emergent AEs was similar across treatment groups. The main limitation of this study was the short (12-wk) duration of treatment. ConclusionsMirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability. Trial identificationThis study is registered at ClinicalTrials.gov, identifier NCT00689104.