Ball S.,Lilly Research Laboratories |
Ball S.,Indiana University |
Marangell L.B.,Lilly Research Laboratories |
Marangell L.B.,University of Texas Health Science Center at Houston |
And 2 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2013
Background: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and anxiety, but has not been examined systematically in generalized anxiety disorder (GAD). The objective of this study was to examine the relationship between baseline BDNF level and treatment response in patients with GAD. Methods: Patients (N= 168) were from China, met criteria for DSM-IV GAD, had a Hospital Anxiety and Depression Rating Anxiety (HADS-A) subscale score ≥. 10, and a Sheehan Disability Scale (SDS) global functioning total score ≥. 12 at baseline. Study design was double-blind therapy for 15. weeks with duloxetine 60-120. mg or placebo. Efficacy measures included the HADS-A and Hamilton Anxiety Rating Scale (HAMA) total score. Change from baseline to endpoint for BDNF by treatment group was analyzed using ANCOVA models with baseline BDNF level as a covariate. Results: No significant association was found between baseline plasma BDNF levels and anxiety illness severity. Patients who received duloxetine (n= 88) had a significantly greater mean increase in plasma BDNF level (957.80. picograms/ml) compared with patients who received placebo (n = 80; 469.93. pg/mL) (P= 007). Patients who met response and remission criteria (with either treatment) had greater mean increases in BDNF at endpoint from baseline (P≤. 05) but when compared with nonresponders and nonremitters, respectively, the differences in mean increase were not statistically significant between groups. Conclusions: BDNF levels significantly increased with duloxetine treatment for GAD, but response and remission outcomes were not clearly related to an increase in plasma BDNF level. © 2013.
Buse J.B.,University of North Carolina at Chapel Hill |
Nauck M.,Diabeteszentrum Bad Lauterberg |
Forst T.,Institute for Clinical Research and Development |
Sheu W.H.-H.,Taichung Veterans General Hospital |
And 9 more authors.
The Lancet | Year: 2013
Background Glucagon-like peptide-1 receptor agonists exenatide and liraglutide have been shown to improve glycaemic control and reduce bodyweight in patients with type 2 diabetes. We compared the efficacy and safety of exenatide once weekly with liraglutide once daily in patients with type 2 diabetes. Methods We did a 26 week, open-label, randomised, parallel-group study at 105 sites in 19 countries between Jan 11, 2010, and Jan 17, 2011. Patients aged 18 years or older with type 2 diabetes treated with lifestyle modification and oral antihyperglycaemic drugs were randomly assigned (1:1), via a computer-generated randomisation sequence with a voice response system, to receive injections of once-daily liraglutide (1·8 mg) or once-weekly exenatide (2 mg). Participants and investigators were not masked to treatment assignment. The primary endpoint was change in glycated haemoglobin (HbA 1c) from baseline to week 26. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01029886. Findings Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA 1c was greater in patients in the liraglutide group (-1·48%, SE 0·05; n=386) than in those in the exenatide group (-1·28%, 0·05; 390) with the treatment difference (0·21%, 95% CI 0·08-0·33) not meeting predefined non-inferiority criteria (upper limit of CI <0·25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events. Interpretation Both once daily liraglutide and once weekly exenatide led to improvements in glycaemic control, with greater reductions noted with liraglutide. These findings, plus differences in injection frequency and tolerability, could inform therapeutic decisions for treatment of patients with type 2 diabetes.
Perlis R.H.,Massachusetts General Hospital |
Fijal B.,Eli Lilly and Company |
Dharia S.,PharmaNet i3 |
Houston J.P.,Lilly United States LLC |
Houston J.P.,Indiana University
Pharmacogenomics Journal | Year: 2013
We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60-120 mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P≤0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression-Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin- releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response. © 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13.
Copher R.,OptumInsight |
Cerulli A.,Novartis |
Watkins A.,OptumInsight |
Laura Monsalvo M.,PharmaNet i3
Journal of Medical Economics | Year: 2012
Objectives: To describe treatment patterns and healthcare burden among individuals with suspected pulmonary arterial hypertension (PAH), as identified through a practice guideline-based healthcare claims algorithm. Methods: Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified. Given the lack of an ICD-9 code for PAH, an algorithm was developed requiring: (1) ≥1 claim for PAH medication (index date); (2) ≥1 claim with a pulmonary hypertension diagnosis code in the 6-month pre-index period (baseline) or within 90 days post-index; (3) a right heart catheterization or pulmonary hypertension-related inpatient stay during baseline or within 90 days post-index; and (4) continuous health plan enrollment for 6 months pre-index and ≥6 months post-index. Patients with PAH-specific medications during baseline were excluded. Treatment patterns, healthcare utilization, and costs were assessed during the period ending with the earlier of health plan disenrollment or 31 December 2008. Results: Among the 521 included patients, 69% were female. Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan), and 12.7% of all patients augmented their therapy by the end of the observation period. The medication possession ratio was 0.96 each for ambrisentan (SD=0.04), bosentan (SD=0.04), and sildenafil (SD=0.05). Overall, 72.6% of patients discontinued therapy with a mean of 149 (SD=170) days until discontinuation. A mean (SD) of 2.14 (1.82) all-cause office and 1.64 (1.98) outpatient visits occurred per patient per month. Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs. The guideline-based algorithm may not have perfectly captured patients with PAH. Conclusions: Patients with suspected PAH were likely to initiate treatment with oral monotherapy, had high compliance rates, and received close ambulatory follow-up. PAH-related costs constituted the majority of all-cause healthcare costs. © 2012 Informa UK Ltd.
Burton T.,Health Economics and Outcomes Research |
Le Nestour E.,PharmaNet i3 |
Bancroft T.,Health Economics and Outcomes Research |
Pituitary | Year: 2013
Acromegaly is a rare, chronic, and debilitating disease that results from excessive growth hormone production. Clinically, this disease is associated with enlargement of soft tissue, excessive skeletal growth, and increased risk of cardiovascular disease. Acromegaly is often diagnosed late, when a wide range of comorbidities may already be present. First-line therapy for acromegaly is typically surgery; but a number of highly-specific pharmacological agents have recently enabled a more aggressive medical management of acromegaly. Since surgical cure of acromegaly is low for macroadenomas, medical control of active acromegaly is an important component of treatment. There are no published US data currently available regarding real-world rates of comorbidities and treatment patterns among patients with acromegaly. This retrospective study examined the comorbidities and treatment patterns of 949 health plan enrollees, who had acromegaly diagnosis and/or procedure codes in an administrative claims database from July 1, 2002 through June 30, 2010. Acromegaly was associated with high rates of hypertension and diabetes along with a number of other comorbidities. The incidence of comorbidities was highest among patients with acromegaly-related treatment, which may have resulted, in part, from inadequate disease management and/or poor disease control. Unexpectedly, 55 % of patients identified with acromegaly received no treatment for acromegaly (i.e., surgery, radiotherapy, and medication) and only 28 % received a medication treatment during the observation period. However, some patients may have received a curative surgery prior to the observation period, which may have reduced the use of other acromegaly-related treatments during the study period. Of those treated with medications, the most common first medications were octreotide, cabergoline, and bromocriptine. Given the high incidence of serious comorbidities associated with active acromegaly, earlier diagnosis and treatment, along with appropriate follow-up care, may potentially avoid the life-long consequences of uncontrolled disease. © 2012 The Author(s).
Diamant M.,Diabetes Center |
Van Gaal L.,University of Antwerp |
Stranks S.,Southern Adelaide Diabetes and Endocrine Services |
Guerci B.,University of Lorraine |
And 4 more authors.
Diabetes Care | Year: 2012
OBJECTIVE - We recently reported that after 26 weeks, exenatide once weekly (EQW) resulted in superior A1C reduction, reduced hypoglycemia, and progressive weight loss compared with daily insulin glargine (IG) in patients with type 2 diabetes who were taking metformin alone or with sulfonylurea. This 84-week extension study assessed the long-term safety and efficacy of EQW versus IG. RESEARCH DESIGN AND METHODS - This multicenter, open-label, randomized, two-arm, parallel trial assessed change in A1C, proportions of patients achieving A1C <7.0 and ≤6.5%, body weight, incidence of hypoglycemia, and overall safety. RESULTS - Of 415 patients who completed 26 weeks, 390 (194 EQW and 196 IG patients) entered the extension study. At 84 weeks, A1C decreased from baseline (8.3%) by -1.2% for EQW vs. -1.0% for IG (P = 0.029). The proportions of patients who achieved end point A1C targets <7.0 and ≤6.5% were 44.6% for EQW patients vs. 36.8% for IG patients (P = 0.084) and 31.3% for EQW patients vs. 20.2% for IG patients (P = 0.009), respectively. Patients taking EQW lost 2.1 kg of body weight, whereas those taking IG gained 2.4 kg (P < 0.001). Among patients taking metformin plus sulfonylurea, the incidence of minor hypoglycemia was 24% for EQW patients vs. 54% for IG patients (P < 0.001); among patients taking metformin alone, it was 8% for EQW patients vs. 32% for IG patients (P < 0.001). Among adverse events occurring in ≥5% of patients, diarrhea and nausea occurred more frequently (P < 0.05) in the EQW group than in the IG group (12 vs. 6% and 15 vs. 1%, respectively). CONCLUSIONS - After 84 weeks, patients treated with EQW continued to experience better glycemic control with sustained overall weight loss and a lower risk of hypoglycemia than patients treated with IG. © 2012 by the American Diabetes Association.
Leonardi C.,Saint Louis University |
Matheson R.,Oregon Medical Research Center |
Zachariae C.,Copenhagen University |
Cameron G.,Eli Lilly and Company |
And 4 more authors.
New England Journal of Medicine | Year: 2012
BACKGROUND: Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17A (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY2439821), a humanized anti-interleukin-17 monoclonal antibody, for psoriasis treatment. METHODS: In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 90% or by 100%. RESULTS: At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose) - 150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%) - than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. CONCLUSIONS: Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.) Copyright © 2012 Massachusetts Medical Society.
Muram D.,Eli Lilly and Company |
Melby T.,PharmaNet i3 |
Alles Kingshill E.,Eli Lilly and Company
Current Medical Research and Opinion | Year: 2012
Objective: Axiron* (testosterone topical solution 2) is an approved topical testosterone replacement therapy applied to the axilla. The axilla is a novel application site for testosterone replacement therapy, with differences in skin structure and exposure that could impact the type and/or severity of skin reactions observed with testosterone topical solution 2. We therefore present a detailed description of data from a pivotal clinical trial regarding the incidence, time of onset, duration, and severity of patient-reported skin reactions as well as visual assessments made by investigators and rated using Draize scoring. *Axiron is a trademark of Eli Lilly and Company, Indianapolis, IN, USA. Methods: Data were analyzed from a multinational, open-label, clinical study in which a 2 testosterone topical solution was applied to the axilla in hypogonadal men. The primary study was for 120 days (N155) with a 60-day extension that evaluated skin safety (N71). At each visit investigators asked patients about adverse skin reactions (including those occurring between study visits); visually assessed the application site; and graded observed instances of erythema or edema using Draize scoring (rated from 0 to 4). Results: Application-site irritation following study drug application was the most commonly reported event (n12 patients) and was generally mild (n11; moderate, n1) in severity. Application-site irritation did not increase in severity over time and led to only one discontinuation. Erythema was the second most common patient-reported skin reaction (n10 patients) and was also generally mild (n9; moderate, n1). Draize scoring rated all directly observed cases of erythema as grade 1 (very slight, 6 patients) or grade 2 (well-defined, two patients), and identified two instances of erythema not reported by patients. Erythema was typically transient, and in most cases resolved without interruption of therapy. Three cases of edema were reported by patients, and two of these were also identified by visual inspection; all cases of edema occurred in conjunction with erythema. Two cases of acne (facial, shoulders) and one of folliculitis (scalp) were also reported. Conclusions: Skin reactions were observed in a minority of patients, were mild or at most moderate in severity, and seldom led to discontinuation. © 2012 Informa UK Ltd All rights reserved.
Danielsson B.R.,Pharmanet I3
Methods in Molecular Biology | Year: 2013
Although demonstration of some degree of maternal toxicity is required in regulatory developmental toxicology studies, marked maternal toxicity may be a confounding factor in data interpretation. Reduction in maternal body weight gain is the far most frequently used endpoint of toxicity, but alternative endpoints, like organ toxicity or exaggerated pharmacological response, can also be taken into consideration. The following conclusions are based on literature data and discussions at maternal toxicity workshops attended by representatives from regulatory agencies, academia, and industry: (1) Available results do not support that maternal toxicity (defined as clinical signs, decreased body weight gain or absolute body weight loss of up to 15% in rats or 7% in rabbits) can be used to explain the occurrence of major malformations. (2) There is clear evidence that substantial reductions in maternal weight gain (or absolute weight loss) are linked with other manifestations of developmental toxicity. Among these can be mentioned decreased fetal weight, and skeletal anomalies (e.g., wavy ribs) in rats and decreased fetal weights, post implantation loss, abortions, and some skeletal anomalies in rabbits. (3) There are several examples of misinterpretation among companies, where it was incorrectly expected that regulatory authorities would not label chemicals/drugs as "teratogens/developmental toxicants" because embryo fetal adverse effects were only observed at doses also causing signs of maternal toxicity. (4) Similarly, even if mechanistic studies indicate that a substance causes developmental toxicity via exaggerated pharmacological effects in the mother, such a mechanism does not automatically negate the observed fetal adverse effects. From a regulatory perspective, an observed developmental toxic finding is considered to be of potential human relevance (even if it is mediated via maternal pharmacological effects or occur at doses causing signs of maternal toxicity) unless the company can provide appropriate mechanistic and/or other convincing evidence to the contrary. © 2013 Springer Science+Business Media, LLC.
Verpoort K.,Gemeinschaftspraxis fur Hamatologie Onkologie |
Mohler T.M.,PharmaNet i3
Therapeutic Advances in Medical Oncology | Year: 2012
Objectives: Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. Biosimilar G-CSF is now approved for use, based on comparable efficacy, safety and quality with the originator product. Methods: We conducted a retrospective review of patients charts following the switch from originator G-CSF (Neupogen®) to biosimilar G-CSF (Zarzio®/Filgrastim Hexal®) in a large community oncology practice. A total of 77 consecutive patients with cancer who received biosimilar G-CSF were reviewed, as were 25 patients who received originator G-CSF at the same centre. Results: The median age of patients in the biosimilar G-CSF cohort was 67 years (range 20-83). In this cohort 48% had chemotherapy with a febrile neutropenia risk of <20%. Biosimilar G-CSF was given as primary prophylaxis in 52% and as secondary prophylaxis in 48% of patients. Age and febrile neutropenia in medical history or in previous chemotherapy were factors that triggered the use of G-CSF in patients with a febrile neutropenia risk of >20%. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in five patients (6.5%) and discontinuation in two patients (2.5%). No unexpected safety findings were observed. Patient characteristics were generally similar in the originator G-CSF cohort. Only 24% of patients had a febrile neutropenia risk <20% and 36% received primary prophylactic G-CSF. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in two patients (8%) and discontinuation in two patients (8%). Conclusions: Biosimilar G-CSF was effective and prevented dose reductions/discontinuation in the majority of patients. Biosimilar G-CSF was considered clinically comparable to its reference product. © The Author(s), 2012.