Previous Monotherapy Research Articles

Stimulation of spermatogenesis by combined therapy with follicle-stimulating hormone and chorionic gonadotropin for azoospermia and infertility in cases of previous ineffective monotherapy with chorionic gonadotropin and antiestrogen

Often there is a need of application of the methods of treatment, directed on increase in quantity of spermatozoa in an ejaculate. In the research efficiency of the combined therapy by preparation follicle-stimulating hormone was estimated and a chorionic gonadotrophin in cases of the previous inefficiency monotherapy a chorionic gonadotrophin and an anti-estrogen. The efficiency of treatment concerning an oligoteratozoospermiya made 65 %. Positive changes of morphology of spermatozoa included improvement of condensation of a chromatin and decrease of the degrading forms. At the same time this treatment was safe and didn»t lead to development of side effects.

Amlodipine/valsartan single pill combination therapy in Chinese patients not controlled on previous monotherapy.

The majority of hypertensive patients requires combination therapy to reach target blood pressure (BP), usually a value <140/90 mmHg (1,2). On the basis of data available from published hypertension treatment trials, a rule of thumb has recently been proposed whereby approximately a third or less of unselected hypertensive patients will have their BP controlled with a single agent while two third need at least two drugs (3).

Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes.

To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes. We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug-naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. β-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated. Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved β-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion. In patients with type 2 diabetes, imeglimin improves β-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials.

Cardiovascular safety of two bronchodilators' fixed-dose combination: indacaterol and glycopyrronium.

Combination therapy with anticholinergics and β2-agonists should be used in COPD patients after failure of previous monotherapy with one of these drugs. Synergistic effect of both mechanisms of bronchodilation can maximize the efficacy of separately administered drugs. The effectiveness of the combination of LABA and LAMA is already confirmed, nevertheless the question about the safety profile of this therapy is still remaining, particularly with regard to the cardiovascular system. The paper discusses the overall safety profile of the combined preparation compare to placebo as well as the active comparators, especially the cardiovascular safety of fixed-dose formulation. Based on the data it has been demonstrated, that the combination of two ultra-long-acting bronchodilators with different complementary mechanisms of action increases the effectiveness of COPD therapy without affecting the safety.

Blood Pressure Response to Zofenopril or Irbesartan Each Combined with Hydrochlorothiazide in High-Risk Hypertensives Uncontrolled by Monotherapy: A Randomized, Double-Blind, Controlled, Parallel Group, Noninferiority Trial

In this randomized, double-blind, controlled, parallel group study (ZENITH), 434 essential hypertensives with additional cardiovascular risk factors, uncontrolled by a previous monotherapy, were treated for 18 weeks with zofenopril 30 or 60 mg plus hydrochlorothiazide (HCTZ) 12.5 mg or irbesartan 150 or 300 mg plus HCTZ. Rate of office blood pressure (BP) response (zofenopril: 68% versus irbesartan: 70%; p = 0.778) and 24-hour BP response (zofenopril: 85% versus irbesartan: 84%; p = 0.781) was similar between the two treatment groups. Cardiac and renal damage was equally reduced by both treatments, whereas the rate of carotid plaque regression was significantly larger with zofenopril. In conclusion, uncontrolled monotherapy treated hypertensives effectively respond to a combination of zofenopril or irbesartan plus a thiazide diuretic, in terms of either BP response or target organ damage progression.

The effect of combined treatment of bevacizumab and triamcinolone for diabetic macular edema refractory to previous intravitreal mono-injections.

The purpose of this study is to evaluate the efficiency of combined treatment of bevacizumab and triamcinolone in refractory diffuse DME (DDME). Twenty-five pseudophakic eyes with DDME refractory to previous successive intravitreal bevacizumab (IVB, 1.25 and 2.5 mg/0.1 ml) and triamcinolone (IVT, 4 mg and 10 mg/0.1 ml) injections were included. The average number of injections was two (1-4). The mean best corrected visual acuity (BCVA) was 0.8 (0.3-1.5) logMAR before enrollment, 0.6 (0.0-1.5) logMAR at 6 months and 0.6 (0-1.8) logMAR at 12 months (p = 0.0001, p = 0.003). The median central macular thickness (CMT) of all the eyes was 575 (502-1049) µm at baseline, 370 (179-983) µm at 6 months, and 410 (198-929) µm at 12 months (p = 0.0001; p = 0.0001). At 6 months, the VA of 13 (52 %) patients was stabilized (± 0.2 logMAR of initial BCVA) and 12 (48 %) patients showed visual improvement (>0.2 logMAR). At 12 months, 10 (40 %) patients had stabilized vision, 13 (52 %) showed visual improvement and 2 (8 %) showed visual loss. At 6 months, 18 (72 %) patients showed anatomic stabilization (a decrease of 10 % to 50 % in initial CMT) and 7 (28 %) anatomical success (a decrease in CMT more than 50 % or ≤250 µm at final visit). At 12 months, 13 (52 %) patients showed anatomic stabilization, 10 (40 %) anatomic success, and 2 (8 %) anatomical failure (decrease in CMT less than 10 %). The combined application of IVB and triamcinolone may improve vision and decrease CMT in severe DDME cases refractory to previous monotherapies.

Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR.

The blood pressure (BP) of most patients on antihypertensive monotherapy or bitherapy remains uncontrolled. Our study evaluated the efficacy of triple therapy with perindopril, amlodipine, and indapamide sustained release (SR) in patients with uncontrolled hypertension on previous antihypertensive therapy. This 4-month, multicenter, prospective, observational, open-label study included patients switched from previous antihypertensive therapy to triple therapy with perindopril, amlodipine, and indapamide SR. The main outcome was change in office BP from baseline to 4 months, as well as changes in 24-h ambulatory BP monitoring (ABPM) parameters in a subgroup of patients. Age was 62.8 ± 11.3 years in 6,088 patients (55 % were male). Office BP at baseline was 158.1 ± 13.0/92.6 ± 8.8 mmHg. By 4 months, office BP decreased by 26.7 ± 13.3/12.9 ± 9.4 mmHg (p < 0.001). ABPM was performed in 62 patients. In these patients, 24-h systolic BP decreased (from 138.7 ± 12.5 to 125.5 ± 12.8 mmHg), as did 24-h diastolic BP (from 77.5 ± 11.4 to 70.4 ± 8.7 mmHg) (both p < 0.0001). Heart rate remained unchanged. In patients previously on renin-angiotensin-aldosterone system (RAAS) inhibitor/amlodipine, 24-h ambulatory systolic and diastolic BP decreased from 136.9 ± 12.8 to 125.4 ± 13.3 mmHg (p = 0.0003) and from 76.3 ± 12.6 to 70.2 ± 9.5 mmHg (p = 0.0005). In those previously on RAAS inhibitor/hydrochlorothiazide, 24-h ambulatory systolic and diastolic BP decreased from 137.8 ± 12.7 to 122.7 ± 15.4 mmHg (p = 0.0039) and from 73.6 ± 9.4 to 65.7 ± 7.3 mmHg (p = 0.002). Most (74 and 80 %, respectively) patients reached target ABPM values (<130/80 mmHg). A triple combination of perindopril, amlodipine, and indapamide SR controlled BP effectively in hypertensive patients uncontrolled by previous antihypertensive monotherapy or bitherapy, including RAAS inhibitor/amlodipine or RAAS inhibitor/hydrochlorothiazide combinations.

Abstract 656: Efficacy and Safety of Valsartan/Amlodipine Single-Pill Combination in Chinese Elderly Hypertensive Patients with Chronic Kidney Disease: Subgroup analysis of the CHINA STATUS II study

Objective: To evaluate the efficacy and safety of Valsartan/Amlodipine SPC in a sub-group analysis of elderly hypertensive patients (aged ≥65 years) with Chronic Kidney Disease (CKD) treated for 8 weeks in the CHINA STATUS II study. Methods: This post-hoc analysis was conducted in 3297 hypertensive elderly patients from CHINA STATUS II study(CSII), whose blood pressure (BP) was not controlled by monotherapy . 116 patients had CKD (aged 75.5±6.8 years) while 3181 were without CKD (aged 74.4±6.3 years). All patients in CSII received Valsartan/Amlodipine 80/5 mg SPC for 8 weeks. The patients did not achieve BP control at the end of 4 weeks (BP≥ 130/80 mmHg for patients with diabetes or CKD and≥140/90 mmHg for others), an additional antihypertensive agent added. T -test and chi-square test were used for statistical analysis. Results: After valsartan/amlodipine SPC treatment for 8 weeks, mean sitting systolic blood pressure (MSBP) decreased, 25.4±13.3 mmHg and 28.3±12.5 mmHg from baseline in patients with and without CKD, respectively. Mean sitting diastolic blood pressure (MSDP) was reduced by10.4±9.3 mmHg and 13.5±9.5 mmHg from baseline in patients with and without CKD, respectively. 17.2%patients with CKD achieved their BP target of &lt;130/80 mmHg and 77.8% non-CKD patients achieved their BP goal, &lt;140/90 mmHg. The incidence of adverse events was 0.9% in patients without CKD, while none were reported in patients with CKD. Two serious adverse events (SAEs), which were not drug-related, occurred in non-CKD patients and no SAE was reported in CKD patients. 100% of the patients with CKD and 99.2% of patients without CKD rated the tolerance to therapy as ‘good’ or ‘very good’, respectively. Conclusions: Valsartan/amlodipine SPC showed good safety and tolerance in hypertensive patients aged ≥65 with CKD whose BP was uncontrolled by previous monotherapy. Lower proportion of elderly patients with CKD achieved the strict BP target compared to elderly patients without CKD. In view of the limitation of this being a post-hoc analysis, the reason for the observed low BP control rate in elderly patients with CKD needs further analysis and research.

The Influence of Previous Antipsychotic Polypharmacy Versus Monotherapy on the Effectiveness of Antipsychotic after Switching to Paliperidone Extended-release

ObjectiveAlthough antipsychotic polypharmacy is widely used in the pharmacotherapy of schizophrenia, its effectiveness is controversial. In particular, clinicians tend to avoid switching to monotherapy in patients who have been prescribed polypharmacy. In the present study, the authors investigate whether there is difference in time to discontinuation of antipsychotics between patients on previous monotherapy or polypharmacy.MethodsPooled analysis was conducted on two 24-week, multicenter, open-label, non-comparative studies that were originally designed to investigate the effectiveness of switching to paliperidone extended-release (ER) in patients with schizophrenia. Patients were divided into two groups according to previously prescribed antipsychotics, that is, to a polypharmacy group or a monotherapy group. The primary outcome measure was time to discontinuation of paliperidone ER. In addition, the authors sought to identify clinical variables that influence time to discontinuation.ResultsBefore switching to paliperidone ER, 535 of 673 (79.5%) patients were prescribed antipsychotic monotherapy, and the remaining 138 (20.5%) patients were prescribed antipsychotic polypharmacy. No significant differences in time to discontinuation of paliperidone ER were observed between the polypharmacy and monotherapy groups. Personal and social performance scale score was the only factor found to influence time to discontinuation of paliperidone ER. No differences in psychopathology or adverse effects were found between the monotherapy and polypharmacy groups.ConclusionOur results suggest that number of antipsychotics prescribed before switching to monotherapy does not influence clinical prognosis in patients with schizophrenia.

Cost-Effectiveness Analysis of Adding Low Dose Ribavirin to Peginterferon Alfa-2a for Treatment of Chronic Hepatitis C Infected Thalassemia Major Patients in Iran

BackgroundThe prevalence of hepatitis C in Iran is 1% and 18% in general population and thalassemia patients respectively. The cost effectiveness analysis of adding Ribavirin to Peginterferon alfa-2a (PEG IFN alfa-2a) as a combination treatment strategy of chronic hepatitis C in thalassemia patients in comparison with monotherapy could help clinicians and policy makers to provide the best treatment for the patients.ObjectivesIn this study we aimed to assess whether adding Ribavirin to PEG IFN alfa-2a is a cost effective strategy in different genotypes and different subgroups of 280 patients with chronic hepatitis C infection from the perspective of society in Iranian setting.Patients and MethodsA cost effectiveness analysis including all costs and outcomes of treatments for chronic hepatitis C infected thalassemia major patients was conducted. We constructed a decision tree of treatment course in which a hypothetical cohort of 100 patients received “PEG IFN alfa-2a” or “Peg IFN alfa-2a plus Ribavirin.” The cost analysis was based on cost data for 2008 and we used 9300 Iranian Rials (IR Rial) as exchange rate declared by the Iranian Central Bank on that time to calculating costs by US Dollar (USD). To evaluate whether a strategy is cost effective, one time and three times of GDP per capita were used as threshold based on recommendation of the World Health Organization.ResultsThe Incremental Cost Effectiveness Ratio (ICER) for combination therapy in genotype-1 and genotypes non-1 subgroups was 2,673 and 19,211 US dollars (USD) per one Sustain Virological Response (SVR), respectively. In low viral load and high viral load subgroups, the ICER was 5,233 and 14,976 USD per SVR, respectively. The calculated ICER for combination therapy in subgroup of patients with previously resistant to monotherapy was 13,006 USD per SVR. Combination therapy in previously resistant patients to combination therapy was a dominant strategy.ConclusionsAdding low dose of Ribavirin to PEG IFN alfa-2a for treatment of chronic hepatitis C patients with genotype-1 was “highly cost effective” and in patients with low viral load and in previous monotherapy resistant patients was “cost effective.”

AB0517 Tocilizumab monotherapy in the clinical practice: Retrospective analysis of a cohort of patients with active rheumatoid arthritis in catalonia, spain

BackgroundNew data indicates that Tocilizumab (TCZ) plus Methotrexate (MTX) does not have superior clinical efficacy to TCZ alone.ObjectivesTo evaluate demographic and clinical features of a cohort of patients with rheumatoid...

The effects of liver impairment on the pharmacokinetics of brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases

Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function. Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses). Twenty-four patients participated in the study. After a single brivanib alaninate dose, brivanib exposure was comparable between Groups A, B, and D. Area under the concentration-time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history. Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend brivanib use in this population.

Abstract PR11: Enhanced in vivo persistence and therapeutic activity of combined transferred polyclonal melanoma-reactive CTL generated in presence of IL-21 and anti-CTLA4.

Abstract Monotherapy with a blocking human anti-CTLA4 mAb achieves disease control in 20-28% of patients (pts), but failure to benefit in the remaining patients may reflect inadequate induction and/or expansion of melanoma reactive T cells following CTLA4 blockade. We have been exploring a combined biologic strategy involving the adoptive transfer of melanoma-reactive CD8+ cytotoxic T lymphocytes (CTL) with concurrent administration of anti-CTLA4 as a means to enhance and broaden the anti-tumor effect of the transferred CTL. Autologous melanoma-specific CTL were generated by stimulating CTL lines in the presence of the γc-chain cytokine Interleukin-21 (IL-21), which programs responding antigen-specific cells to retain characteristics of central memory T cells (Tcm). Responding cells were sorted for binding of a peptide-MHC (pMHC) multimer to obtain a purified tumor-reactive polyclonal product. We report on 7 pts with bulky, therapy-resistant melanoma who received 1010/m2 polyclonal IL-21-derived CTL lines targeting MART1. The infusions were preceded by intravenous cyclophosphamide 300 mg/m2 and followed by low-dose subcutaneous IL-2 (250,000 IU/m2 BID) x 14 days to promote in vivo expansion and survival. Anti-CTLA4 (ipilimumab) was administered at 3mg/kg every three weeks for four doses, starting on the day after the CTL infusion. The treatment was well tolerated, with no unexpected or serious (grade ≥3) related toxicities. 5/7 evaluable pts exhibited stable disease (SD) or partial responses (PR) by RECIST 1.1 criteria at 6 weeks, and 4/6 exhibited SD at 12 weeks. One pt who had failed previous ipilimumab monotherapy and prior CTL therapy targeting MART1 without CTLA4 blockade had a noteworthy response to the current protocol. He had SD at 12 weeks, then experienced a delayed objective response with 66% reduction in tumor mass at 28+ weeks. Persistence of the infused CTL at frequencies &amp;gt;2x baseline levels was documented at 6 weeks (6/6 evaluable pts) and 12 weeks (4/4 evaluable pts), whereas such levels of persistence beyond 6 weeks was previously typically observed in only 15-20% of pts in previous studies. The cells infused into each pt expressed moderate/detectable levels of CD28 prior to infusions, but analysis of persisting CTL detected by specific multimer binding in vivo in responding pts revealed progressively higher expression of CD28, consistent with enhanced CD28:CD80/86 interactions in the presence of CTLA4 blockade providing survival advantages. Additionally, infused multimer+ T cells continued to proliferate (multimer+ cells expressed Ki-67), secreted multiple cytokines (IFNγ, TNFα and IL-2) in response to cognate antigen, and acquired phenotypic characteristics of Tcm (including expression of CD27, CD127, CD62L and CCR7) within 12 weeks of observation after infusion. Most significantly, all pts who had clinical benefit (prolonged SD or PR) developed de novo anti-tumor responses (epitope spreading) to non-targeted antigens (NY-ESO-1, Tyrosinase, gp100 and MAGE A3) within 12 weeks, potentially reflecting release of tumor antigens following tumor lysis by the infused CTL in a pro-inflammatory, pro-immunogenic context induced by concurrent anti-CTLA4 blockade. Our preliminary results suggest that treatment with polyclonal, melanoma-targeting CTL generated in the presence of IL-21 and combined with ipilimumab is safe. Blockade of CTLA4 may enhance the activity/persistence of the infused melanoma-specific T cells in vivo. Additionally, CTL-induced tumor cell lysis in the presence of CTLA4 blockade may promote induction of anti-tumor responses to non-targeted antigens, enhancing the biologic activity of the combined regimen. This abstract is also presented as Poster A14. Citation Format: Aude G. Chapuis, John A. Thompson, Kim A. Margolin, David Byrd, Shailender Bhatia, Sylvia M. Lee, Ivy P. Lai, Ilana M. Roberts, Heather L. Sloan, Philip D. Greenberg, Cassian Yee. Enhanced in vivo persistence and therapeutic activity of combined transferred polyclonal melanoma-reactive CTL generated in presence of IL-21 and anti-CTLA4. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR11.

A Prognostic Score System for Survival in Secondary AML: Review of 1073 Patients Observed At MDACC

AbstractAbstract 131▪▪This icon denotes a clinically relevant abstract BackgroundSecondary Acute Myeloid Leukemia (sAML) is associated with prior treatment for other malignancies, particularly chemotherapy (Chemo) or radiation therapy (RT), and characterized by very bad prognosis due to high-risk features and poor clinical outcomes. Patients and MethodsWe identified 1073 patients (pts) at MDACC since March 1976 to Sept. 2011 with sAML, who were diagnosed with 1 (n=943), 2 (n=117), or 3 (n=12) Prior Malignancies (PM). Pts' characteristics, including age; type of PM; number and treatments for PM; and characteristics at sAML diagnosis such as % bone marrow and blood blasts, WBC, hemoglobin, platelet and neutrophil count, FAB, and karyotype were analyzed and correlated with survival outcome. A prognostic score for survival was developed using significant variables identified in multivariable analysis (MVA). ResultsMedian time to sAML was 64 months (mo) and 46 (p=0.000) for pts with 1 or >1 PM, respectively; longer for pts with untreated PM (62 vs 27, mo p=.008) and correlated with type of PM (p=0.001) and previous monotherapy (Surgery vs RT vs Chemo, p=.006). Median age at sAML was 66 years; 54% (n=574) were male; and pts had 1, 2 or 3 PM in 88, 11 and 1% cases, respectively. All FAB categories were represented. Median baseline characteristics at sAML were as follows: HGB 9 g/dL (2.6–17.5), PLT 49K/μL (1–1,518), WBC 4K/μL (.02–367.2), ANC 890/μL (0–84100), blood blasts 8% (0–99), and bone marrow blasts 40% (0–99). Type of prior malignancy reflected prior treatment: breast (21%), hematological (20%), prostate (14%), and skin (10%) were the most represented as 1st malignancies; 728 underwent prior surgery, 468 received prior RT, and 563 pts received prior Chemo alone or in combination, 40 pts were untreated for their PM. For pts with sAML who had only undergone prior surgery (n=310), favorable-, intermediate-, and poor-risk karyotype was reported for 9, 49, and 32%, respectively. Pts with sAML previously treated with RT only (n=72) had favorable-, intermediate-, and poor-risk karyotype in 8, 56, and 24% cases, respectively. Those who had previously received only Chemo (n=124) had favorable-, intermediate-, and poor-risk karyotype in 6, 21, and 57% cases, respectively. Univariable (UVA) and MVA analysis for survival are shown in the Table.We identified 3 survival risk-categories (Figure) according to a sum total score in which a point was given for each of the following significant variables identified in the MVA: PM Treatment (other than surgery), Age ≥60, Plt <50, Hgb <10, WBC ≥10, blood blasts >20%, and Kayotype int; 2 points was given for bad Karyotype. The estimated median OS was 58.6 (19.4, NA) mos for Group 1 (0–1 points), 13.9 (12.1, 16.2) mos for Group 2 (2–4 points), and 4.8 (4.1, 5.72) mos for Group 3 (5–8 points). ConclusionPatients diagnosed with sAML are high-risk for poor survival. Characteristics independently associated with short survival were identified and a prognostic score system was developed. Unfavorable karyotype remains a major factor associated with short survival. Validation of this model will come from prospective studies and additional insights should come from gene sequencing studies. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Long‐term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2‐year results from the LEAD‐2 study

To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2 years in patients with type 2 diabetes. In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n = 1091) were randomized (2 : 2 : 2 : 1: 2) to liraglutide (0.6, 1.2 or 1.8 mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80 years old with HbA1c 7.0-11.0% (previous monotherapy ≥3 months), or 7.0-10.0% (previous combination therapy ≥3 months), and body mass index ≤40 kg/m(2) . Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. HbA1c decreased significantly with liraglutide (0.4% with 0.6 mg, 0.6% with 1.2 and 1.8 mg) versus 0.3% increase with metformin monotherapy (p < 0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9 kg with 0.6, 1.2 and 1.8 mg, respectively) compared to weight gain (0.7 kg) with glimepiride (p < 0.0001). Weight loss with liraglutide 1.2 and 1.8 mg was significantly greater than with metformin monotherapy (1.8 kg; p = 0.0185 and p = 0.0378 for 1.2 and 1.8 mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p < 0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia.

Efficacy and tolerability of fixed-dose amlodipine/olmesartan medoxomil with or without hydrochlorothiazide in Hispanic and non-Hispanic patients whose blood pressure is uncontrolled on antihypertensive monotherapy

Objectives:This is a prespecified subgroup analysis in Hispanic and non-Hispanic patients of a study that evaluated blood pressure (BP) control with fixed-dose amlodipine/olmesartan medoxomil (AML/OM)-based therapy in patients whose condition was uncontrolled on prior monotherapy.Methods:In this prospective, open-label, dose-titration study, patients with uncontrolled BP after at least 1 month of antihypertensive monotherapy were switched to fixed-dose AML/OM 5/20 mg. Patients were uptitrated to AML/OM 5/40 and 10/40 mg, with uptitration to AML/OM + hydrochlorothiazide 10/40 + 12.5 mg and 10/40 + 25 mg to achieve target BP. The primary efficacy endpoint was the cumulative proportion of patients achieving seated cuff systolic BP (SeSBP) less than 140 mmHg (<130 mmHg in patients with diabetes mellitus) at 12 weeks. Secondary endpoints included SeBP goal rates, ambulatory BP (ABP) target rates, and mean change from baseline in seated cuff BP (SeBP) and ABP at weeks 12 and 20.Results:Mean baseline BP was similar in Hispanics (153.6/92.8 mmHg; n = 105) and non-Hispanics (153.7/91.8 mmHg; n = 894). At 12 weeks, 72.0% of Hispanics and 76.3% of non-Hispanics achieved the primary endpoint. At week 12, goal rates for cumulative SeBP (<140/90 mmHg or <130/80 mmHg in patients with diabetes) were 69.0% and 71.5% in Hispanic and non-Hispanic patients, respectively. Mean change in SeBP in Hispanics ranged from −15.3/−7.3 mmHg for AML/OM 5/20 mg to −23.2/−13.8 mmHg for AML/OM 10/40 mg + hydrochlorothiazide 25 mg, and in non-Hispanics from −14.1/−7.8 mmHg to −25.4/−13.7 mmHg (all p < 0.0001 versus baseline). A majority of patients achieved mean 24 h, daytime, and nighttime ABP targets in both subgroups. Greater proportions of Hispanics achieved ABP targets versus non-Hispanics at week 12; however, this trend was reversed at week 20. Treatment was well tolerated.Conclusions:Switching to a fixed-dose combination of AML/OM ± hydrochlorothiazide provided significant BP lowering and effectively controlled BP in a large proportion of Hispanic and non-Hispanic patients with hypertension uncontrolled on previous monotherapy.

Factors associated with outcome of secondary MDS and AML: Review of 2,182 patients at MDACC.

6603 Background: Secondary acute myeloid leukemia (sAML) and myelodysplastic syndromes (sMDS) have been associated with prior treatment for other malignancies, particularly chemotherapy, and associated with high-risk features and poor clinical outcomes. Methods: We identified 2,182 patients (pts) (57% male) diagnosed with AML (n=1,073; all FAB/WHO represented) or MDS (n=1,109; 984 MDS, 125 MDS/MPD, all WHO represented) and who had 1 (n=1,907), 2 (n=239), or 3 (n=36) prior malignancies (PM). Pt characteristics and outcomes were analyzed. Results: The median age was 67 yrs. Prior hematological neoplasms (25%), breast (16%), prostate (16%), skin (9%) were most common. The prior malignancy reflected prior treatment, 1,252 pts underwent surgery, 939 received radiation, and 1,211 received chemotherapy alone or in combination; 124 were untreated. Types of prior malignancy and prior treatment associated with AML and MDS will be presented. Median time to AML/MDS was 64 months (mo) and 46 mo (p=0.000) for pts with 1 or &gt;1 PM, respectively, and correlated with type of PM (p=0.000) and previous monotherapy (surgery vs RT vs chemo) (p=0.020). For both AML and MDS, the incidence of poor-risk cytogenetics was nearly twice for pts who received prior chemotherapy compared to those who underwent surgery or radiation alone. Factors associated with survival in secondary AML and MDS are reported in the table. Conclusions: In conclusion, outcomes for pts with secondary AML and MDS are poor, especially for pts treated with prior chemotherapy. Type of prior malignancy and treatment are correlated with outcomes. Furthermore, greater number of prior malignancies correlates with inferior outcomes. [Table: see text]

Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI treatment

This study evaluated the efficacy of adjunctive pregabalin versus placebo for treatment of patients with generalized anxiety disorder (GAD) who had not optimally responded to previous or prospective monotherapies. This was a phase 3, randomized, double-blind, placebo-controlled study. Patients diagnosed with GAD who had a historical and current lack of response to pharmacotherapy [Hamilton Anxiety Rating Scale (HAM-A) of ≥ 22 at screening] were randomized to adjunctive treatment with either pregabalin (150-600 mg/day) or placebo. The primary outcome measure was the change in HAM-A total scores after 8 weeks of combination treatment. Adverse events were regularly monitored. Randomized patients (N=356) were treated with pregabalin (n=180) or placebo (n=176). Mean baseline HAM-A scores were 20.7 and 21.4, respectively. After treatment, the mean change in HAM-A was significantly greater for pregabalin compared with placebo (-7.6 vs. -6.4, respectively; P<0.05). HAM-A responder rates (≥ 50% reduction) were significantly higher for pregabalin (47.5%) versus placebo (35.2%; P=0.0145). The time-to-sustained response favored pregabalin over placebo (P=0.014). Adverse events were consistent with previous studies and discontinuations were infrequent for pregabalin (4.4%) and placebo (2.3%). The study was discontinued early after an interim analysis. The results indicate that adjunctive pregabalin is an efficacious therapy for patients with GAD who experience an inadequate response to established treatments.

Abstract LB-136: IL-21-derived melanoma-reactive CTL combined with anti-CTLA4 persist, acquire central memory characteristics, and mediate tumor regression in patients with metastatic melanoma

Abstract Adoptive transfer of melanoma-reactive CD8+ T Cells (CTL) has demonstrated antitumor activity that may be enhanced by prolonging survival of transferred T cells in vivo. CTLA4 is up-regulated on activated T cells and when engaged to its B7-ligand, delivers inhibitory signals that impede TCR signaling, IL-2 transcription, and T cell proliferation. Human anti-CTLA4 monotherapy benefits about 25% of patients (pts), but most pts likely lack a sufficiently high frequency of pre-existing melanoma-reactive T cells susceptible to CTLA4 blockade and fail to respond. We propose a combined biologic strategy involving the adoptive transfer of melanoma-reactive CTL with concurrent administration of anti-CTLA4 as a means of enhancing the in vivo CTL survival and anti-tumor effect. Autologous polyclonal CTL were generated by multimer sorting and expanding melanoma-specific CTL lines to increase the probability of infusing cells derived from central memory (Tcm), as such cells were shown to exhibit prolonged persistence and superior replicative potential in murine and non-human primate models. Ex-vivo cultures were supplemented with the γc-chain cytokine Interleukin-21 (IL-21), which has been demonstrated to promote effector CTL helper-independence and to arrest differentiation at a Tcm stage. To date, 6 pts with bulky, therapy-resistant progressive melanoma were infused with 1010/m2 polyclonal IL-21-derived CTL targeting MART1. The infusions were preceded by intravenous cyclophosphamide 300mg/m2 and followed by low-dose subcutaneous IL-2 (250,000 IU/m2 BID) x 14 days. Anti CTLA4 (ipilimumab) 3mg/kg was started on the day after the CTL infusion. Side effects included fevers and chills starting 1-2 hours post-CTL infusion and moderately erythematous maculo-papular skin rashes in all 6 patients. No unexpected or serious (grade ≥3) toxicity was observed. Persistence of the infused CTL to frequencies &amp;gt;2x baseline levels was documented at 6 weeks (5/5 evaluable pts) and 12 weeks (4/4 pts). 3/5 and 2/3 evaluable pts experienced stable disease by RECIST 1.1 criteria at 6 and 12 weeks respectively. One patient had a delayed response with 25% reduction in tumor mass at 12 weeks after having failed previous ipilimumab monotherapy and prior CTL therapy without CTLA4 blockade. Tracking of infused multimer+ CTL in vivo revealed acquisition of both phenotypic (CD27, CD28, CD127, CD62L and CCR7) and functional (secretion of IL-2 in response to cognate antigen) characteristics of Tcm within 12 weeks. Our preliminary results suggest polyclonal IL-21-stimulated CTL targeting melanoma in combination with Ipilmumab is safe and promotes persistent anti-tumor responses such that CTL are poised for enhanced therapeutic activity in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-136. doi:1538-7445.AM2012-LB-136

Combined Antimuscarinics for Treatment of Neurogenic Overactive Bladder

Antimuscarinic drugs are the first line pharmacotherapy for overactive bladder, but they are not always effective to achieve complete continence. Nevertheless in some patients urodynamic investigations reveal insufficient effects with continuing incontinence events even with dose optimization. The aim of this study is to evaluate the effect of association of Oxybutynin chloride, Trospium chloride and Solifenacin succinate administered orally for a minimum of 12 weeks in subjects with suprasacral spinal cord injury with urge-incontinence, urodynamic–proven neurogenic detrusor overactivity dysfunction and detrusor-external sphincter dyssynergia to improve level of continence, reduce the risks of urologic complications and enhance QOL. This study was a randomized, double blind, controlled, balanced-parallel-groups investigation of orally administed Oxybutynin in addition to Trospium chloride in the first group and Oxybutynin in addition to Solifenacin in the other group. A total of 12 patients with neurogenic detrusor overactivity and clean intermittent catheterization were allocated into two treatment groups: 5 mg tablet of Oxibutinin and 20 mg tablet of Trospium Chloride were administered respectively 3 times a day and 4 times a day in the first group (Group A). 5 mg tablet of Oxibutinin and 10 mg tablet of Solifenacin were administered respective 3 times a day and once daily in the second group (Group B). In both group of patients we found a significant decrease in incontinence episodes, with an improvement of bladder compliance, bladder capacity and volume voided. Side effects were higher in patients of group B, but in generally well tolerated. In conclusion, a combined antimuscarinic treatment might be a right option for patients affected by neurogenic bladder refractory to previous antimuscarinic monotherapy, and might slow down or delay other more invasive treatments.