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Glen Ridge, NJ, United States

I3 Research

Glen Ridge, NJ, United States

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Carpenter D.J.,Glaxosmithkline | Fong R.,Glaxosmithkline | Kraus J.E.,Glaxosmithkline | Davies J.T.,Glaxosmithkline | And 3 more authors.
Journal of Clinical Psychiatry | Year: 2011

Objective: This meta-analysis of placebo-controlled paroxetine trials examines suicidality incidence in adults, focusing on disorder and age as potential risk factors. The findings are put in context with an efficacy meta-analysis of the same trial datasets. Data Sources: GlaxoSmithKline paroxetine clinical trial database(s). Study Selection: All double-blind, randomized, placebo-controlled, parallel-group studies of paroxetine therapy in adults enrolling at least 30 patients total were included in the analysis. The dataset comprised 14,911 patients from 61 trials. Data Extraction: Possible cases of suicidality were identified and blindly categorized by an expert panel, using methodology previously used by the US Food and Drug Administration. Incidences of suicidal behavior (preparatory act, suicide attempt, or completed suicide) and any suicidality (suicidal behavior or ideation) were compared between paroxetine and placebo. Efficacy assessments were based on standard depression rating scales (eg, Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale) and Clinical Global Impressions Improvement scale (CGI-I) scores. Results: In the primary dataset, ie, all disorders combined, there were no significant differences between paroxetine and placebo for overall suicidality (suicidal behavior or ideation: n/n = 83/8,958 [0.93%] vs n/n = 65/5,953 [1.09%], respectively; OR = 0.9 [95% CI, 0.7-1.3]; P = .649) or for suicidal behavior specifically (n/n = 50/8,958 [0.56%] vs n/n = 40/5,953 [0.67%], respectively; OR = 1.2 [95% CI, 0.8-1.9]; P = .483). However, in patients with major depressive disorder (MDD), a greater incidence of suicidal behavior occurred in paroxetine-treated patients than in placebo-treated patients (n/n = 11/3,455 [0.32%] vs n/n = 1/1,978 [0.05%], respectively; OR = 6.7 [95% CI, 1.1-149.4]; P = .058). Across all indications, a higher incidence of suicidal behavior occurred in paroxetine-treated versus placebo-treated adults aged 18 to 24 years (n/n = 17/776 [2.19%] vs n/n = 5/542 [0.92%], respectively; OR = 2.4 [95% CI, 0.9-7.3]). In older age groups, no increase in suicidality was observed. Efficacy was demonstrated in all disorders evaluated, including MDD. Conclusions: Across all disorders, overall suicidality incidence was similar between paroxetine and placebo. However, a higher frequency of suicidal behavior occurred with paroxetine in MDD, which was largely explained by the higher incidence in young adults. These data support the efficacy of paroxetine therapy; however, they also highlight the need for careful monitoring of suicidality during antidepressant therapy, particularly in younger adults. © Copyright 2011 Physicians Postgraduate Press, Inc.


Gomez H.L.,National Institute of Neoplastic Diseases INEN | Philco M.,Alberto Sabogal Solguren National Hospital | Pimentel P.,Alberto Sabogal Solguren National Hospital | Kiyan M.,I3 Research | And 7 more authors.
Anti-Cancer Drugs | Year: 2012

The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10mg/m2 (n=3), 12mg/m2 (n=6), and 14mg/m2 (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12mg/m2 and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Chastek B.J.,I3 Innovus | Oleen-Burkey M.,Teva Pharmaceuticals | Lopez-Bresnahan M.V.,I3 Research
Journal of Medical Economics | Year: 2010

Objective: Relapse is a common measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objective of this study was to test the content validity of an operational algorithm for detecting relapse in claims data. Methods: A claims-based relapse detection algorithm was tested by comparing its detection rate over a 1-year period with relapses identified based on medical chart review. According to the algorithm, MS patients in a US healthcare claims database who had either (1) a primary claim for MS during hospitalization or (2) a corticosteroid claim following a MS-related outpatient visit were designated as having a relapse. Patient charts were examined for explicit indication of relapse or care suggestive of relapse. Positive and negative predictive values were calculated. Results: Medical charts were reviewed for 300 MS patients, half of whom had a relapse according to the algorithm. The claims-based criteria correctly classified 67.3 of patients with relapses (positive predictive value) and 70.0 of patients without relapses (negative predictive value; kappa 0.373: p<0.001). Alternative algorithms did not improve on the predictive value of the operational algorithm. Limitations of the algorithm include lack of differentiation between relapsing-remitting MS and other types, and that it does not incorporate measures of function and disability. Conclusions: The claims-based algorithm appeared to successfully detect moderate-to-severe MS relapse. This validated definition can be applied to future claims-based MS studies. © 2010 Informa UK Ltd All rights reserved.


Klein B.,Montpellier University Hospital Center | Klein B.,French Institute of Health and Medical Research | Klein B.,Montpellier University | Seckinger A.,University of Heidelberg | And 3 more authors.
Recent Results in Cancer Research | Year: 2011

This chapter focuses on two aspects of myeloma pathogenesis: (1) chromosomal aberrations and resulting changes in gene and protein expression with a special focus on growth and survival factors of malignant (and normal) plasma cells and (2) the remodeling of the bone marrow microenvironment induced by accumulating myeloma cells. We begin this chapter with a discussion of normal plasma cell generation, their survival, and a novel class of inhibitory factors. This is crucial for the understanding of multiple myeloma, as several abilities attributed to malignant plasma cells are already present in their normal counterpart, especially the production of survival factors and interaction with the bone marrow microenvironment (niche). The chapter closes with a new model of pathogenesis of myeloma. © 2011 Springer-Verlag.


Fogel R.B.,Merck And Co. | Rosario N.,Federal University of Paraná | Aristizabal G.,Institute Enfermedades Respiratorias del Nino | Loeys T.,Merck And Co. | And 4 more authors.
Annals of Allergy, Asthma and Immunology | Year: 2010

Objectives: To evaluate the effect of montelukast, 5 mg, or inhaled salmeterol, 50 μg, added to inhaled fluticasone in reducing the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) after a standardized exercise challenge and response to rescue bronchodilation with albuterol in children aged 6 to 14 years with persistent asthma and exercise-induced bronchoconstriction (EIB). Methods: Randomized, double-blind, double-dummy, multicenter, 2-period, 4-week, crossover study conducted between December 22, 2005 and November 14, 2008 at 30 centers in Europe, Asia, Mexico, and South America. Patients with asthma receiving inhaled corticosteroids demonstrated an FEV1 of 70% or higher of the predicted value and EIB (defined as a decrease in FEV1 ≥15% compared with preexercise baseline FEV1 on 2 occasions before randomization). Standardized exercise challenges were performed at baseline (prerandomization) and at the end of each active treatment period. Results: Of 154 patients randomized, 145 completed the study. Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), mean area under the curve for the first 20 minutes after exercise (116.0%·min vs 168.8%·min; P = .006), and median time to recovery (6.0 vs 11.1 minutes; P = .04). Response to albuterol rescue after exercise challenge was significantly greater (P<.001) with montelukast. Montelukast and salmeterol were generally well tolerated. Conclusions: Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment. © 2010 American College of Allergy, Asthma & Immunology.


Ayzenberg I.,Ruhr University Bochum | Bornke C.,Ruhr University Bochum | Tonnes C.,Ruhr University Bochum | Ziebarth W.,Ruhr University Bochum | And 2 more authors.
Journal of Clinical Neuroscience | Year: 2012

We present a 77-year-old previously well patient with facial asymmetry and progressive weakness of the lower extremities. An initial MRI revealed slight contrast enhancement of the meninges. Three consecutive cerebrospinal fluid examinations demonstrated low glucose concentration, marked elevation of total protein and moderate pleocytosis. No tumor cells, fungi, acid-fast bacilli or mycobacterial DNA were found. The patient's level of consciousness deteriorated dramatically, and follow-up MRI showed widespread extensive cortical hyperintensities. The lesions showed restricted diffusion on diffusion-weighted images as well as low values on the corresponding apparent diffusion coefficient maps, the changes consistent with diffuse cytotoxic edema. Neuropathological examination findings were of leptomeningeal carcinomatosis (LMC) with diffuse continuous infiltration of the cerebral cortex, cerebellum and spinal cord. The autopsy revealed a subcentimetre adenocarcinoma of the lung. To our knowledge, this is the first report demonstrating extensive cortical involvement in adenocarcinomatous LMC. © 2012 Elsevier Ltd. All rights reserved.


Perlis R.H.,Harvard University | Adams D.H.,Eli Lilly and Company | Fijal B.,Lilly United States LLC | Sutton V.K.,Eli Lilly and Company | And 4 more authors.
Journal of Clinical Psychiatry | Year: 2010

Objective: To evaluate common genetic variations for association with symptomatic improvement in bipolar I depression following treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine. Method: Symptom improvement was assessed in 88 OFC-treated and 85 lamotrigine-treated white patients with bipolar I depression in the 7-week acute period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or 12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The original study was conducted from November 2003 to August 2004. Single nucleotide polymorphisms (SNPs) were genotyped in a set of 19 candidate genes corresponding to known sites of activity for olanzapine and fluoxetine or previously associated with antidepressant or antipsychotic response. Primary outcome was the reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score as assessed by the difference by genotype from baseline to week 7 from a mixed-effects repeated measures analysis with terms for visit, genotype, genotype-by-visit interaction, and baseline MADRS score as a covariate. Results: SNPs within the dopamine D3 receptor and histamine H1 receptor (HRH1) genes were significantly associated with response to OFC. SNPs within the dopamine D2 receptor, HRH1, dopamine β-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes were significantly associated with response to lamotrigine. Conclusions: SNPs in specific candidate genes were associated with symptomatic improvement in a treatment-specific fashion. These results suggest the importance of dopaminergic effects in the treatment of patients with bipolar I depression and the potential utility of genotyping in selection of pharmacologic treatments for bipolar depression. © Copyright 2009 Physicians Postgraduate Press, Inc.


Cantrell R.A.,Eli Lilly and Company | Alatorre C.I.,Eli Lilly and Company | Davis E.J.,I3 Innovus | Zarotsky V.,I3 Innovus | And 6 more authors.
Diabetes, Obesity and Metabolism | Year: 2010

The response to treatment for type 2 diabetes typically varies among individuals within a study population. This variation is known as heterogeneity of treatment response. We conducted a comprehensive literature review to identify factors that account for heterogeneity of treatment response in patients treated for type 2 diabetes. Three databases (PubMed, EMBASE and Cochrane Library) were searched for articles published in the last 10 years describing investigations of factors associated with treatment response and outcomes among people with type 2 diabetes receiving pharmacological treatment. Of the 43 articles extracted and summarized, 35 (81%) discussed clinical factors, 31 (72%) described sociodemographic factors and 17 (40%) reported on comorbidity or behavioural factors. Clinical factors identified included baseline glycated hemoglobin A1c or fasting plasma glucose (FPG) levels, insulin response or sensitivity, C-peptide, body composition, adipose tissue proteins, lipid profile, plasma albumin levels and duration of disease or insulin treatment. Other factors identified included age, sex, race, socioeconomic status and comorbidities. This review identified the following research gaps: use of multiple definitions for response, few patient-reported measures and lack of evidence regarding whether factors were associated with treatment response for only specific medications or across pharmacological therapies. Furthermore, identification of factors associated with type 2 diabetes treatment response was generally a secondary objective in the research reviewed. Understanding which patient subgroups are more likely to respond to treatment and identifying factors associated with response may result in targeted treatment decisions and alter the interpretation of efficacy or effectiveness of results. In conclusion, accounting for these factors in clinical trials and when making clinical treatment decisions may improve therapy selection and individual patient outcomes. © 2010 Eli Lilly and Company.


Pollack M.,Astrazeneca | Chastek B.,I3 Innovus | Williams S.A.,Astrazeneca | Moran J.,I3 Research
Journal of Clinical Outcomes Management | Year: 2010

• Objective: To evaluate the impact of treatment complexity on adherence and subsequent glycemic control among patients with type 2 diabetes mellitus. • Methods: This was a retrospective evaluation of patients enrolled in a national health plan during the period 2000 to 2007. Patients diagnosed with diabetes, naive to oral antidiabetic agents (OADs), and not using insulin were included. A treatment complexity score was assigned based on treatment characteristics. First-year adherence was calculated as a medication possession ratio (MPR) weighted by duration of OAD treatment. HbA1c values were obtained for those with available laboratory data. Multivariate analyses were conducted, controlling for patient demographics, baseline HbA1c, and comorbidities. • Results: A total of 94,860 patients were identified, 16,198 with HbA1c values. Mean age was 52.6 years; 78% initiated monotherapy, 20% initiated dual therapy, and the remaining 2% were on 3 or more therapies. Mean treatment complexity score was 3.33 (range, 0-14), with 29%, 57%, and 14% in low-, medium-, and high-complexity categories. Mean 1-year adherence was 58%, 51%, and 43% for low-, medium-, and high-complexity treatments, respectively. Probability of adherence (MPR ≥ 80%) was significantly lower for medium- and high-complexity versus low-complexity regimens in all multivariate analyses (P < 0.05). More patients with low-complexity regimens were at or below the HbA1c goal (< 7%) during the baseline and follow-up periods. The probability of reaching and maintaining goal was significantly higher for adherent patients (P< 0.01). • Conclusion: Treatment complexity has negative effects on adherence and glycemic control. Appropriate choice of therapy based on each individual's need may overcome these limitations.


Kingery L.,I3 Research | Martin M.L.,Health Research Associates | Naegeli A.N.,Eli Lilly and Company | Khan S.,Eli Lilly and Company | Viktrup L.,Eli Lilly and Company
International Journal of Clinical Practice | Year: 2012

Aims: The objective of this qualitative interview study was to assess the content validity of the Benign Prostatic Hyperplasia Impact Index (BII) in a sample of men with signs and symptoms of Benign Prostatic Obstruction believed to be caused by benign prostatic hyperplasia (BPH lower urinary tract symptoms/BPH-LUTS) using concept elicitation (CE) and cognitive interviewing (CI) methods. Methods: Fifty men with BPH-LUTS participated in the study; 27 completed CE interviews and 23 completed cognitive interviews. Results: Patient's average age was 69 years with a mean duration of BPH-LUTS of 6.5 years. IPSS scores ranged from 8 to 33 (higher scores indicating greater symptom severity). Overall, the most frequent symptoms (prevalence of ≥ 75%) reported spontaneously or after further explanation were awakening from sleep, increased daytime voiding (frequency), urgent desire to void (urgency), slow stream, and feeling of incomplete bladder emptying. Symptoms primarily recognized in response to follow up probe questions with a prevalence of ≥ 40% included terminal dribble, splitting of urinary stream, intermittent stream, straining and post-micturition dribble. Especially bothersome [> 5 on the numerical rating scale (NRS) of 0-10] and frequent symptoms included urgency and awakening at night to void. Discomfort or pain while urinating and post-micturition dribble were equally bothersome though less frequent. Five BPH symptom-related impact themes were identified: coping, daily responsibilities, emotion, lifestyle and relationships, and sleep. Conclusions: The BII was found to be easily understood, does capture clinically relevant BPH impacts related to urinary trouble and problems, and does capture most of the important symptom-related impacts as described by participants in this study. © 2012 Blackwell Publishing Ltd.

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