Publications by authors named "Lingfeng Yang"

34 Publications

Real-world homologous recombination repair mutation testing in metastatic castration-resistant prostate cancer in the USA, Europe and Japan.

Future Oncol 2022 Jan 19. Epub 2022 Jan 19.

Merck & Co., Inc., Kenilworth, NJ, USA.

To assess homologous recombination repair mutation (HRRm) testing patterns in metastatic castration-resistant prostate cancer. A point-in-time, international survey conducted January-August 2020. Three-quarters of physicians (oncologists, urologists, specialist surgeons) globally reported access to genetic/genomic testing and just over half were HRRm testers. Surveyed physicians reported HRRm testing and positivity rates for 1913 patients, which were 18.1% and 33.7%, respectively. Of patients tested (n = 347), the most common HRR genes tested were (91.6%) and (47.3%). Overall testing rates were low, with physicians mostly testing patients they considered higher risk. Increased awareness and education are needed to encourage broader testing, to understand familial risk and to identify patients with worse outcomes or those eligible for life-prolonging treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2021-1113DOI Listing
January 2022

N-terminal pro-B-type natriuretic peptide testing patterns in patients with heart failure with reduced ejection fraction.

ESC Heart Fail 2022 Feb 16;9(1):87-99. Epub 2021 Dec 16.

Merck & Co., Inc., Kenilworth, NJ, USA.

Aims: The N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a commonly used biomarker in heart failure for diagnosis and prognostication. We aimed to determine the prevalence of NT-proBNP testing, distribution of NT-proBNP concentrations, and factors associated with receiving an NT-proBNP test in patients with heart failure with reduced ejection fraction (HFrEF), including the subset with a worsening heart failure event (WHFE).

Methods And Results: This was a retrospective cohort study using two US databases: (i) the de-identified Humana Research Database between January 2015 and December 2018 and (ii) the Veradigm PINNACLE Registry between July 2013 and September 2017. We included adult patients with a confirmed diagnosis of HFrEF. In each data source, a subgroup of patients with a WHFE was identified, where a WHFE was defined as a heart failure-related hospitalization or receipt of intravenous diuretics. Bivariate and multivariate analyses were conducted to assess factors associated with receiving NT-proBNP testing. In Cohort 1 (n = 249 238), 9.2% of patients with HFrEF and 10.8% of patients with a WHFE received NT-proBNP testing. When restricted to patients with at least one laboratory claim, 11.3% of patients with HFrEF and 13.2% of those with a WHFE received NT-proBNP testing. In Cohort 2 (n = 91 444), 2.3% of patients with HFrEF were tested. Median (inter-quartile range) NT-proBNP concentrations among patients with HFrEF were 1399 (423-4087) pg/mL in Cohort 1 and 394 (142-688) pg/mL in Cohort 2. Median (inter-quartile range) NT-proBNP concentrations in the subset of patients with a WHFE in each cohort were 2209 (740-5894) and 464 (174-783) pg/mL, respectively. In Cohort 1, 13.4% of all HFrEF patients receiving NT-proBNP testing and 18.9% of patients with a WHFE had NT-proBNP values >8000 pg/mL; in Cohort 2, these percentages were 1.0% and 2.5%, respectively.

Conclusions: In US clinical practice, NT-proBNP testing was not frequently performed in patients with HFrEF. NT-proBNP concentrations varied across data sources and subpopulations within HFrEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ehf2.13749DOI Listing
February 2022

Single Dose of SHR-1222, a Sclerostin Monoclonal Antibody, in Healthy Men and Postmenopausal Women With Low Bone Mass: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation, Phase I Study.

Front Pharmacol 2021 20;12:770073. Epub 2021 Oct 20.

National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.

SHR-1222 is a humanized monoclonal antibody targeting sclerostin and has the potential to promote bone formation and reduce bone resorption. This study was aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1222 in healthy men and postmenopausal women with low bone mass (BMD). It was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Subjects received SHR-1222 at 50, 100, 200, 300, and 400 mg sequentially or matching placebo subcutaneously. Totally, 50 subjects with low BMD were enrolled and randomly assigned; 10 received placebo and 40 received SHR-1222 (50 mg, n = 4; 100, 200, 300, or 400 mg, n = 9). The most common adverse events that occurred at least 10% higher in subjects with SHR-1222 treatment than those with placebo were decreased blood calcium, blood urine present, increased blood cholesterol, electrocardiogram T wave abnormal, urinary tract infection, increased blood pressure diastolic, and positive bacterial test. All the above adverse events were mild in severity and well resolved except one of increased blood cholesterol in a subject lost to follow-up. The serum SHR-1222 concentration increased in a dose-dependent manner. Administration of SHR-1222 upregulated the bone-formation markers N-terminal propeptide of type 1 procollagen, osteocalcin, and bone-specific alkaline phosphatase, while downregulated the bone-resorption marker β-C-telopeptide. The BMD at the lumbar spine notably rose after a single dose of SHR-1222. The largest increase occurred in the 400 mg cohort (3.8, 6.7, and 6.1% on day 29, 57, and 85, respectively; compared with 1.4, 0.8, and 1.0% in the placebo group). Although 10.0% of subjects receiving SHR-1222 tested positive for anti-SHR-1222 antibodies, no obvious effects of antibody formation were found on pharmacokinetics. Overall, SHR-1222 was well tolerated at doses from 50 to 400 mg and is a promising new remedy for osteoporosis. http://www.clinicaltrials.gov, NCT03870100.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.770073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564351PMC
October 2021

Using Deep Learning to Identify High-Risk Patients with Heart Failure with Reduced Ejection Fraction.

J Health Econ Outcomes Res 2021 29;8(2):6-13. Epub 2021 Jul 29.

Merck & Co., Inc., Kenilworth, NJ, USA.

Deep Learning (DL) has not been well-established as a method to identify high-risk patients among patients with heart failure (HF). This study aimed to use DL models to predict hospitalizations, worsening HF events, and 30-day and 90-day readmissions in patients with heart failure with reduced ejection fraction (HFrEF). We analyzed the data of adult HFrEF patients from the IBM® MarketScan® Commercial and Medicare Supplement databases between January 1, 2015 and December 31, 2017. A sequential model architecture based on bi-directional long short-term memory (Bi-LSTM) layers was utilized. For DL models to predict HF hospitalizations and worsening HF events, we utilized two study designs: with and without a buffer window. For comparison, we also tested multiple traditional machine learning models including logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost). Model performance was assessed by area under the curve (AUC) values, precision, and recall on an independent testing dataset. A total of 47 498 HFrEF patients were included; 9427 with at least one HF hospitalization. The best AUCs of DL models without a buffer window in predicting HF hospitalizations and worsening HF events in the total patient cohort were 0.977 and 0.972; with a 7-day buffer window the best AUCs were 0.573 and 0.608, respectively. The best AUCs in predicting 30- and 90-day readmissions in all adult patients were 0.597 and 0.614, respectively. An AUC of 0.861 was attained for prediction of 90-day readmission in patients aged 18-64. For all outcomes assessed, the DL approach outperformed traditional machine learning models. The DL approach can automate feature engineering during the model learning, which can increase the clinical applicability and lead to comparable or better model performance. However, the lack of granular clinical data, and sample size and imbalance issues may have limited the model's performance. A DL approach using Bi-LSTM was shown to be a feasible and useful tool to predict HF-related outcomes. This study can help inform the future development and deployment of predictive tools to identify high-risk HFrEF patients and ultimately facilitate targeted interventions in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.36469/jheor.2021.25753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322198PMC
July 2021

Beyond Frontline Therapy with Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer: A Real-World US Study.

Clin Genitourin Cancer 2021 Dec 10;19(6):480-490. Epub 2021 Jul 10.

Merck & Co., Inc., Kenilworth.

Background: Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting.

Methods: Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013-03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis.

Results: Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively.

Conclusions: This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2021.07.009DOI Listing
December 2021

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors.

Adv Ther 2021 08 19;38(8):4520-4540. Epub 2021 Jul 19.

Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.

Introduction: Therapeutic options for metastatic castration-resistant prostate cancer (mCRPC) patients are continuously advancing. We described mCRPC treatment patterns in the US from 2013 to 2019.

Methods: Patients with a confirmed mCRPC diagnosis and adenocarcinoma histology were included in the US Flatiron Health Electronic Health Record-derived de-identified database. Treatment patterns [including treatment per lines of therapies (LOTs), LOT sequences, and time on treatment] and overall survival (OS) have been described in mCRPC settings.

Results: Of 5213 patients (mean age: 72.6 years), 4374 (83.9%) were treated with ≥ 1 LOT post-mCRPC diagnosis (among those with ≥ 1 LOT, 55.3%, 29.5%, 14.7%, and 6.7% had ≥ 2, 3, 4, and 5 LOTs, respectively). In first line (1L), the main treatment class was next-generation hormonal agents (NHA; 62.5% of patients with ≥ 1 LOT), while the shortest and longest time on 1L were observed for chemotherapy (median 2.8 months) and NHA (median 5.1 months), respectively. The most common LOT sequences were NHA → NHA (29.4% of patients with ≥ 2 LOTs) and NHA → NHA → chemotherapy (16.7% of patients with ≥ 3 LOTs). In Kaplan-Meier analyses, the median OS was 19.4, 14.6, and 11.1 months post-1L, 2L, and 3L start, respectively. Patients who moved rapidly through LOTs had an increased risk of death.

Conclusions: NHA were widely used as 1L therapy in mCRPC patients from 2013 to 2019, but time on 1L NHA treatment was on average < 6 months. While NHA → NHA was the most observed 1L → 2L LOT sequence, a plethora of other LOT sequences were observed. OS was poor, highlighting an unmet need for life-prolonging treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12325-021-01823-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342357PMC
August 2021

Representativeness of the VICTORIA Trial Population in Clinical Practice: Analysis of the PINNACLE Registry.

J Card Fail 2021 12 13;27(12):1374-1381. Epub 2021 Jul 13.

Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina.

Background: In the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, vericiguat reduced the risk of mortality due to cardiovascular problems and of hospitalization due to heart failure (HF) among patients with HF with reduced ejection fraction (HFrEF) and recent worsening HF events (WHFEs). The representativeness of the VICTORIA population of patients with WHFE in clinical practice is unknown.

Methods And Results: Patients with HF and ejection fraction <45% were identified in the Practice Innovation And Clinical Excellence (PINNACLE) registry and were stratified by the occurrence of WHFEs. Characteristics and outcomes of patients in the PINNACLE registry with and without WHFEs were compared to the VICTORIA population. Of the 14,180 PINNACLE patients identified with HFrEF, 26.5% had had a WHFE. The VICTORIA population was similar to PINNACLE patients with WHFEs in mean age (67.3 vs 66.7), ejection fraction (28.9% vs 28.3%), body mass index (26.8 vs 27.6), and comorbidity burden. The rate of hospitalization because of HF at 1 year was 29.6% in the placebo group of VICTORIA, compared to 35.8% in PINNACLE patients with WHFEs and 13.3% in patients without WHFEs.

Conclusions: The PINNACLE patients with WHFEs meeting the VICTORIA definition resembled the VICTORIA population in characteristics and outcomes, suggesting that VICTORIA's population may be generalizable to patients with WHFEs in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cardfail.2021.06.019DOI Listing
December 2021

Secondary metformin monotherapy failure in individuals with type 2 diabetes mellitus.

BMJ Open Diabetes Res Care 2021 06;9(1)

Ochsner Diabetes Clinical Research Unit, Ochsner Health System, New Orleans, Louisiana, USA.

Introduction: To assess secondary metformin monotherapy (MM) failure in a real-world type 2 diabetes mellitus (T2DM) cohort.

Research Design And Methods: Using the IQVIA Electronic Medical Record (formerly GE Centricity) database, adults with T2DM who initiated MM between January 1, 2012 and June 30, 2016 and achieved glycemic control (hemoglobin A1c (HbA1c) <7% (53 mmol/mol); index date) were analyzed. Secondary MM failure was defined in two ways: loss of glycemic control (HbA1c ≥7% (53 mmol/mol)) and treatment change (addition or switch of antihyperglycemic agent). Multivariable logistic regression models assessed the association between secondary MM failure and sociodemographic and clinical factors.

Results: The analysis included 4775 patients initiating MM. 32.9% and 19.2% experienced secondary MM failure at 24 months measured as loss of glycemic control and treatment change, respectively. Multivariable logistic regression found that women (OR=1.3, 95% CI 1.1 to 1.5) compared with men, lower Charlson Comorbidity Index (CCI) (OR=0.89, 95% CI 0.86 to 0.93), and lower baseline HbA1c (OR=0.93, 95% CI 0.88 to 0.98) were associated with increased likelihood of loss of glycemic control. Lower CCI was associated with increased likelihood of treatment change (OR=0.78, 95% CI 0.75 to 0.82).

Conclusions: The observed frequency of secondary MM failure underscores the importance of the American Diabetes Association's recommendation for glycemic monitoring of at least every 6 months so that timely therapeutic adjustments can be made.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjdrc-2021-002127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230991PMC
June 2021

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study.

Int J Clin Pharmacol Ther 2021 Aug;59(8):578-584

Objective: Clozapine is the most effective therapy for schizophrenia. This study compared the bioequivalence of a generic formulation of clozapine (ChangZhou Pharmaceutical Factory Co. Ltd. Jiangsu, China) to the brand name formulation (Clozaril, HLS Therapeutics, Inc., Philadelphia, PA, USA) after multiple doses in Chinese schizophrenic patients.

Materials And Methods: This was a randomized, open-label, multiple-dose, 2-way crossover study in which patients with schizophrenia received the generic clozapine or Clozaril 100 mg twice daily for 10 days before crossing over to the alternate formulation for the next 10 days. Blood samples were collected at regular intervals during each treatment period, and plasma concentration of clozapine was determined by high-performance liquid chromatography.

Results: 26 patients were enrolled, of whom 24 completed the study and were included in the steady-state analyses. The mean AUC was 6,003.29 h×ng/mL for generic clozapine and 6,347.53 h×ng/mL for Clozaril. The mean C was 698.52 ng/mL for generic clozapine and 739.75 ng/mL for Clozaril. The ratio of the adjusted geometric means and its 90% CI of the ratios for AUC was 96.24% (89.60 - 103.36%), and for C was 95.90% (88.91 - 103.44%). A total of 66 adverse events were reported by 22 (84.62%) subjects. Among them, 34 occurred in 17 (65.38%) patients during dosing of generic clozapine, and 32 occurred in 16 (61.54%) patients during dosing of brand-name clozapine.

Conclusion: The result demonstrated that the generic clozapine was bioequivalent to brand-name clozapine (Clozaril). This would provide physicians with reassurance that patients who receive the studied generic clozapine will achieve similar plasma drug concentrations to those of brand-name clozapine (Clozaril).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5414/CP203864DOI Listing
August 2021

Factors associated with switching from sulphonylureas to dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in the United States.

Diabetes Obes Metab 2021 10 6;23(10):2251-2260. Epub 2021 Jul 6.

Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Aims: Studies examining the prevalence of and factors associated with switching from sulphonylureas (SUs) to dipeptidyl peptidase 4 (DPP-4) inhibitors in real-world settings are lacking. We assessed the factors associated with switching from SUs to DPP-4 inhibitors in the United States.

Materials And Methods: This retrospective cohort study was conducted using the Optum Clinformatics® Data Mart (2009-2018). Adults with type 2 diabetes and newly prescribed at least two SUs were included and were followed for 2 years after the initiation of SU (index date). We compared the characteristics of those who switched from SUs to DPP-4 inhibitors (only; no additional antidiabetic drugs) with those who continued with SUs (without adding other antidiabetic drugs) using multivariate logistic regression. Multinomial regression analyses were also conducted to assess the factors associated with switching to different drug classes versus continuation with SUs.

Results: In a sample of 119 107 new SU users, 2.2% (2633) switched to DPP-4 inhibitors, 3.8% (4542) switched to antidiabetic drugs other than DPP-4 inhibitors, 68.3% (81 394) discontinued SUs but did not switch to another antidiabetic drug, 12.9% (15 345) continued with SUs and added other antidiabetic drugs, and 12.8% (15 193) continued with SUs only. Multivariate logistic regression showed that those who had significantly higher likelihood of switching were younger, female [vs. males; adjusted odds ratio (AOR) = 0.70], and living in the south; had previous use of DPP-4 inhibitors (AOR = 1.71); were not using antidiabetic drugs at baseline; had more baseline diabetes-related emergency room visits (AOR = 1.13), depression (AOR = 1.34), post-index hypoglycaemia (AOR = 2.20), and an earlier index year; and were glyburide users (vs. glimepiride users; AOR = 1.29).

Conclusions: The discontinuation rate for SUs is high. Factors associated with switching from SUs to DPP-4 inhibitors included age, sex, geographic region, baseline antidiabetic drug use, type of SU, baseline diabetes-related emergency room visits, hypoglycaemia and depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14466DOI Listing
October 2021

Treatment patterns and clinical outcomes among patients <65 years with a worsening heart failure event.

Eur J Heart Fail 2021 08 17;23(8):1334-1342. Epub 2021 Jun 17.

Merck & Co., Inc, Kenilworth, NJ, USA.

Aims: Data regarding patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) following a worsening HF event (WHFE) are largely driven by findings from elderly patients. Younger patients are not well studied. The aim of this study was to evaluate treatment patterns and clinical outcomes in commercially insured chronic HFrEF patients <65 years old during 1-year periods before and after a WHFE.

Methods And Results: A retrospective claims analysis was performed using the IBM® MarketScan® Commercial Database on HFrEF patients aged <65 years during the year before and after a WHFE, defined as HF hospitalization or outpatient intravenous diuretic use. Treatment patterns, rehospitalizations, health care resource utilization, and costs were assessed. A total of 4460 HFrEF patients with WHFE were included. Guideline-recommended HF therapy was initially underutilized, increased pre-WHFE, and peaked 0-3 months post-WHFE. The proportions of patients using dual and triple therapy were 31.5% and 9.8% pre-WHFE, 41.5% and 17.4% 0-3 months post-WHFE, and 34.6% and 13.9% 10-12 months post-WHFE, respectively. Within 30 and 90 days after a WHFE, 12% and 23% of patients had HF-related and 16% and 30% had all-cause rehospitalizations, respectively. HF-related and all-cause hospitalizations and outpatient visits peaked 0-3 months post-WHFE, whereas emergency department visits peaked 0-3 months pre-WHFE.

Conclusions: Use of HF medications increased pre-WHFE but decreased post-WHFE, despite recurrent hospitalizations. These findings suggest that age and insurance status may not totally explain the suboptimal treatment of HFrEF patients before and after a WHFE. Reasons for these trends need further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.2252DOI Listing
August 2021

Real-world genetic testing patterns in metastatic castration-resistant prostate cancer.

Future Oncol 2021 Aug 28;17(22):2907-2921. Epub 2021 Apr 28.

Merck & Co., Inc., Kenilworth, NJ 07033, USA.

To assess the patterns of genetic testing for homologous recombination repair mutations in patients with metastatic castration-resistant prostate cancer (mCRPC) pre-PARP inhibitors approval. mCRPC patients were selected in an oncology electronic medical records database. Patterns and predictors of testing for , , ,  and gene alterations were assessed. Of 5213 mCRPC patients, 674 (13%) had a documented genetic test. The number of tested patients increased from 1 in 2013 to 313 in 2018 (out of 3161 and 3010 clinically active patients, respectively). Receiving care in an academic oncology center (versus a community-based center) strongly predicted genetic testing (hazard ratio = 2.41). The use of and access to genetic testing pre-PARP inhibitor approval was suboptimal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2021-0153DOI Listing
August 2021

Systemic therapy, survival and end-of-life costs for metastatic triple-negative breast cancer: retrospective SEER-Medicare study of women age ≥65 years.

Future Oncol 2021 Jul 25;17(20):2581-2592. Epub 2021 Mar 25.

MRL, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

To analyze therapy for metastatic triple-negative breast cancer (mTNBC), factors contributing to survival and costs. Using 2010-2016 SEER-Medicare data, we identified women (≥65 years) with mTNBC. Of 302 eligible patients, 152 (50%) received systemic therapy. In multivariable regression analyses, only age <75 years was associated with therapy receipt (odds ratio: 2.91; 95% CI: 1.79-4.74); and only systemic therapy significantly reduced risk of death (hazard ratio: 0.34; 95% CI: 0.26-0.44). Median overall survival was 13.4 (95% CI: 11.3-15.1) vs 3.3 months (95% CI: 2.7-3.9) in therapy vs no-therapy cohorts. Mean per-patient-per-month costs <30 days before end-of-life/follow-up were $14,100 and $15,600 (2019 USD), respectively. Poor outcomes and high costs indicate need for more effective mTNBC therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2021-0019DOI Listing
July 2021

Real-World Adherence and Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists Therapy in Type 2 Diabetes Mellitus Patients in the United States.

Patient Prefer Adherence 2020 27;14:2337-2345. Epub 2020 Nov 27.

Center for Observational and Real-World Evidence, Merck & Co., Inc, Kenilworth, NJ, 07033, USA.

Aim: To assess adherence and discontinuation of injectable glucagon-like peptide-1 receptor agonists (GLP-1 RA) at 12 and 24 months among adult type 2 diabetes mellitus (T2DM) patients in the United States initiating GLP-1 RA using the administrative claims-based database, Optum Clinformatics Data Mart 7.1.

Methods: A retrospective study was conducted from 01/2009 to 12/2017. Patients were required to be continuously enrolled for 12 months prior to their first GLP-1 RA prescription. Proportion of days covered (PDC) from prescription claims ≥0.80 defined adherence. Discontinuation was defined as a ≥90-day gap from the last date of GLP-1 RA supply to the first date of subsequent prescription claim.

Results: A total of 4791 T2DM patients had ≥1 and 3907 had ≥2 GLP-1 RA prescription claims. 50.9% and 47.4% of patients were adherent at 12 and 24 months, respectively. Adherence was significantly higher among patients on weekly vs daily doses (p<0.001). Median time to discontinuation was 13 months. The discontinuation rate was 47.7% and 70.1% at 12 and 24 months, respectively, with differences at 24 months for age and dosing frequency (p<0.001 for both).

Conclusion: Over half of T2DM patients initiating GLP-1 RA were non-adherent and the majority (70.1%) discontinued therapy by 24 months. Reasons for non-adherence and discontinuation merit further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PPA.S277676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708309PMC
November 2020

Early triple-negative breast cancer in women aged ≥65: retrospective study of outcomes, resource use and costs, 2010-2016.

Future Oncol 2021 Mar 2;17(9):1039-1054. Epub 2020 Dec 2.

MRL, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

To examine real-world treatment patterns and outcomes in neoadjuvant and adjuvant settings for early-stage triple-negative breast cancer (TNBC). Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients (≥65 years) with newly diagnosed stage II/III TNBC in 2010-2015 who had surgery plus neoadjuvant and/or adjuvant (systemic and/or radiation) therapy. Treatment, survival, healthcare resource use and costs were assessed through 2016. Of 1569 patients (>99% women), 6%/74%/20% received neoadjuvant-only/adjuvant-only/both (neo + adj) therapies, respectively. Median overall survival was 23 months/not reached (NR)/78 months, with longer survival at stage II (NR/NR/78 months) than stage III (22/43/38 months). Mean per patient per month costs were $10,620 and $17,872 in neoadjuvant and adjuvant periods. These findings provide insights into clinical and economic outcomes for early-stage TNBC in 2010-2016.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0996DOI Listing
March 2021

Level of glycemic control among US type 2 diabetes mellitus patients on dual therapy of metformin and sodium-glucose cotransporter 2 inhibitor: a retrospective database study.

Curr Med Res Opin 2020 10 11;36(10):1583-1589. Epub 2020 Sep 11.

Center for Observational and Real-World Evidence, Merck & Co., Inc, Kenilworth, NJ, USA.

Objective: To assess the level of glycemic control among type 2 diabetes patients on sodium-glucose cotransporter 2 inhibitor (SGLT2i) and metformin dual therapy.

Methods: Observational, retrospective database study in adult type 2 diabetes mellitus patients from the IQVIA Electronic Medical Record (EMR) database was conducted. The observation period was June 2015 to June 2018. Patient's earliest encounter in the observation period while on SGLT2i and metformin dual therapy served as the index date. Patients were required to have at least one HbA1c measure in the 12 months prior to the index date and be on SGLT2i and metformin dual therapy and no other antihyperglycemic treatment as of the HbA1c measurement date or any time during the 90 days prior. The associations between sociodemographic factors and clinical burden on achievement of HbA1c <8% were assessed using multivariable logistic regression with backward stepwise selection.

Results: Of 3491 patients, 2176 (62.3%) achieved HbA1c <8%, with a median distance to goal of 1.1% (IQR 0.5-2.3%) for those not at glycemic target. Mean age was 56.5 years and 52.6% were male. At baseline, 28.3% of patients had established cardiovascular disease/chronic kidney disease, and of those 63.8% had HbA1c <8%. African American patients had lower odds of attaining HbA1c <8% when compared with white patients [OR 0.69], while older patients had marginally higher odds [OR 1.01].

Conclusion: Approximately 3 out of 5 patients on metformin and SGLT2i dual therapy achieved HbA1c <8%, with African Americans having a lower likelihood of achieving this glycemic goal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03007995.2020.1816945DOI Listing
October 2020

Clinical and Economic Burden of Chronic Heart Failure and Reduced Ejection Fraction Following a Worsening Heart Failure Event.

Adv Ther 2020 09 6;37(9):4015-4032. Epub 2020 Aug 6.

Merck & Co., Inc., Kenilworth, NJ, USA.

Introduction: A worsening heart failure event (WHFE) is defined as progressively escalating heart failure signs/symptoms requiring intravenous diuretic treatment or hospitalization. No studies have compared the burden of chronic heart failure with reduced ejection fraction (HFrEF) following a WHFE versus stable disease to inform healthcare decision makers.

Methods: A retrospective study using the IBM MarketScan Commercial Database included patients younger than 65 years of age with HFrEF (one inpatient or two outpatient claims of systolic HF or one outpatient claim of systolic HF plus one outpatient claim of any HF). The first claim for HFrEF during 2016 was the index date. Patients were followed for the first 12 months after the index date (the worsening assessment period) to identify a WHFE, and for an additional 12 months or until the end of continuous enrollment (the post-worsening assessment period). Mean per patient per month (PPPM) health care resource use (HCRU) and costs were compared between patients following a WHFE and stable patients during the two periods using generalized linear models adjusting for patient characteristics.

Results: Of 16,646 patients with chronic HFrEF, 26.8% developed a WHFE. Adjusted all-cause hospitalizations (0.16 vs. 0.02 PPPM, P < 0.0001), outpatient visits (3.54 vs. 2.73 PPPM, P < 0.0001), and emergency department visits (0.25 vs. 0.06 PPPM, P < 0.0001) were higher in patients following a WHFE than stable patients during the worsening assessment period. Similar differences in HCRU were observed between the two cohorts during the post-worsening assessment period. Mean total adjusted cost of care PPPM was $8657 in patients with HFrEF following a WHFE versus $2195 in stable patients during the worsening assessment period, and $6809 versus $2849, respectively, during the post-worsening assessment period.

Conclusion: HCRU and costs were significantly greater in patients with chronic HFrEF following a WHFE compared to those who remained stable, suggesting an unmet need to improve clinical and economic outcomes among these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12325-020-01456-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444407PMC
September 2020

Factors associated with the discontinuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) after initiation of insulin.

Curr Med Res Opin 2020 03 23;36(3):377-386. Epub 2019 Dec 23.

Merck & Co., Inc., Kenilworth, NJ, USA.

Type 2 diabetes (T2D) is a prevalent health problem. Oral agents, with the exception of metformin, are often discontinued with the initiation of insulin. The objective was to understand the proportion of patients discontinuing dipeptidyl peptidase-4 inhibitors (DPP-4is) and the reasons for the decision to discontinue. A retrospective study using a health claims database investigated discontinuation of DPP-4i in adult patients on a dual therapy of metformin and DPP-4i who initiated insulin ( = 3391). An online survey administered to 406 physicians in the US examined reasons for discontinuation. Physicians surveyed included endocrinologists (34.5%), general practitioners (32.5%), internal medicine specialists (30.5%), and diabetologists (2.5%), treating a monthly average of 154 patients. Among patients treated with metformin and DPP-4is who were newly prescribed insulin, 33.3 and 57.3% discontinued DPP-4i therapy within 3 and 12 months, respectively. Patients who discontinued DPP-4i therapy had higher out-of-pocket costs and a greater proportion of renal and liver disease. Top 3 responses for discontinuation included adverse events/tolerability issues (58.9%), lack of efficacy/treatment goals not being met (55.4%) and additional cost of DPP-4i with insulin (48.5%). Top 3 responses for continuing DPP-4i included meeting treatment goals (70.7%), using a lower dose of insulin (65.3%) and good tolerability (48.0%). Physician characteristics, such as physician specialty, age, gender and location impacted to some extent the reasons for treatment decisions. A large proportion of patients discontinue DPP-4is in the real world when initiating insulin. The impact of physician characteristics in treatment decisions highlights the need for enhanced physician training and support as new clinical data emerges and therapy options are available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03007995.2019.1698416DOI Listing
March 2020

Long-term training in diabetes-related knowledge, attitudes, and self-reported practice among diabetes liaison nurses.

J Int Med Res 2020 Feb 29;48(2):300060519882838. Epub 2019 Oct 29.

Diabetes Center, Department of Endocrinology, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Key Laboratory of Diabetes Immunology, Ministry of Education, Changsha, Hunan, China.

Objective: We aimed to investigate whether long-term regular training of diabetes liaison nurses (DLNs) could improve their diabetes-related knowledge, attitudes, and self-reported practice.

Methods: We enrolled 45 diabetes liaison nurses (DLNs) and 45 non-specialist nurses (controls). DLNs received 11 days of qualifying training, followed by regular theory classes and practice sessions for 4 years. All nurses were administered a questionnaire assessing demographic characteristics, knowledge about diabetes mellitus (DM), attitudes toward DM, and DM management practices, before and after the 4-year DLN training period.

Results: At baseline, there were no significant differences between the DLN and control groups for sex, age, educational level, nurse title/grade, work experience, hospital department, or questionnaire scores. At 4 years, the DLN group had a higher overall questionnaire score and higher scores for knowledge about DM, attitudes toward DM, and DM management practices, as compared with baseline scores.

Conclusion: Long-term regular training provided by a multidisciplinary diabetes care team can improve the knowledge, attitudes, and self-reported practice levels of DLNs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0300060519882838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873921PMC
February 2020

Prevalence of Established Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus in the UK.

Diabetes Ther 2019 Dec 4;10(6):2131-2137. Epub 2019 Oct 4.

Center for Observational and Real-World Evidence, Merck & Co., Inc., Kenilworth, NJ, USA.

Introduction: The results of recently completed cardiovascular outcomes trials in patients with type 2 diabetes mellitus (T2DM) suggest that sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide (GLP) 1 receptor agonists have enhanced cardioprotective properties in patients with established cardiovascular disease (eCVD), but to a lesser degree in those without eCVD. SGLT2 inhibitors appear to be particularly beneficial in patients with heart failure. As recent data for the UK are lacking, we undertook to identify the percentage of T2DM patients with eCVD and heart failure in the UK.

Methods: This was a retrospective cohort study that utilized the Clinical Practice Research Datalink (CPRD) database in the UK. We included de-identified adult patients with T2DM with at least one encounter in the CPRD database between 1 January 2018 and 31 December 2018 in the analysis and extracted the full health records of these patients. eCVD was defined as myocardial infarction, stroke, unstable angina pectoris, coronary artery disease and peripheral artery disease. We further assessed the number of patients with heart failure.

Results: From the total of 148,803 patients with T2DM analyzed (53% were male; mean age was 65 years), 52,601 (35.4%) suffered from eCVD and 8650 (5.8%) suffered from heart failure (73.7% of patients with heart failure overlap with those with atherothrombotic eCVD). Glycated hemoglobin levels of < 7% were attained by 49.5% of patients (with eCVD, 49.7%; without eCVD, 49.3%) (p < 0.001).

Conclusion: Approximately one-third of patients with T2DM in the UK have concomitant CVD.

Funding: Merck Sharp & Dohme Corp., a subsidiary Merck & Co., Inc., Kenilworth, NJ, USA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13300-019-00698-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848348PMC
December 2019

A survey on glycemic control rate of type 2 diabetes mellitus with different therapies and patients' satisfaction in China.

Patient Prefer Adherence 2019 31;13:1303-1310. Epub 2019 Jul 31.

Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, People's Republic of China.

Aim: To compare the blood glucose control of patients with type 2 diabetes mellitus (T2DM) with different treatment methods, oral hypoglycemic agents (OHA) monotherapy, insulin injection and combined therapy (OHA + insulin injection) and evaluate their satisfaction with the medical care.

Methods: A total of 1512 T2DM patients were assessed, to compare the effects of different treatment methods on glycemic control in T2DM patients, the influencing factors of patients' satisfaction with medical care measures and their relationship with glycemic control. Fasting plasma glucose (FPG), 2 hrs postprandial plasma glucose (2hPG) and HbA1c were measured as the standard of the glycemic control. Satisfaction was defined using the simplified version of DAWN of chronic disease care patient scale (PACIC - DSF).

Results: In this study, the FPG compliance rate, 2hPG compliance rate and HbA1c compliance rate were 25.5%, 22.7% and 19.5%, respectively. The differences in the glycemic control compliance rates of different treatment methods were not statistically significant. The total score of PACIC - DSF was 34.54±11.65(>0.05), and the influencing factors included fast blood glucose (FBG) and 2hPG, 2hPG and PACIC - DSF were negatively correlated.

Conclusions: The T2DM glycemic control rate in China is currently low. From the score of the PACIC - DSF, there is no significant difference in general satisfaction with medical care measures in different treatments. What is more, education level, occupation and exercise of patients with type 2 diabetes had influence on PACIC - DSF score. Different treatment methods have no influence on the glycemic control of patients with T2DM. FPG value and the 2hPG value are negative correlation with the satisfaction of patients in medical care measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PPA.S198908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682321PMC
July 2019

Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study.

J Immunother Cancer 2018 10 22;6(1):109. Epub 2018 Oct 22.

Department of Internal Medicine, UT Southwestern - Kidney Cancer Program, Dallas, TX, 75390, USA.

Background: Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.

Methods: Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.

Results: Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.

Conclusions: The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.

Trial Registration: Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40425-018-0420-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196426PMC
October 2018

Outcomes at 7 years post-transplant in black vs nonblack kidney transplant recipients administered belatacept or cyclosporine in BENEFIT and BENEFIT-EXT.

Clin Transplant 2018 04 14;32(4):e13225. Epub 2018 Mar 14.

Department of Surgery, Emory University Transplant Center, Atlanta, GA, USA.

Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to belatacept more intense-based, belatacept less intense-based, or cyclosporine-based immunosuppression. At year 7, belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); belatacept was associated with similar graft survival vs cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for belatacept-treated vs cyclosporine-treated patients. Seven-year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1 to 84 using a repeated-measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT-EXT, respectively, were black. Time to death or graft loss was similar in blacks and nonblacks. For both subgroups, estimated mean GFR increased over 7 years for belatacept, but declined for cyclosporine. Outcomes were similar in belatacept-treated black and nonblack patients. Due to the small number of black patients, these results must be interpreted with caution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ctr.13225DOI Listing
April 2018

Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial.

Curr HIV Res 2017 ;15(3):216-224

Gilead Sciences, Inc., Foster City, CA, United States.

Objectives: Cobicistat (COBI) enhances atazanavir (ATV) pharmacokinetic parameters similarly to ritonavir (RTV) in both healthy volunteers and HIV-infected adults. Primary efficacy and safety outcomes of this Phase 3, international, randomized, double-blind, double-dummy, active- controlled trial in HIV-1-infected treatment-naïve adults (GS-US-216-0114/NCT01108510) demonstrated that ATV+COBI was non-inferior to ATV+RTV, each in combination with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF), at Weeks 48 and 144, with high rates of virologic success for both regimens (85.2% and 87.4%, respectively, at Week 48; and 72.1% and 74.1% at Week 144), and with comparable safety and tolerability. Here, we describe virologic response and treatment discontinuation by a wider range of subgroups than previously presented.

Methods: Subgroup analyses by baseline CD4 count (≤200, 201-350, >350 cells/mm3), baseline HIV-1 RNA level (≤100,000, >100,000 copies/mL), race, sex, and age (<40, ≥40 years) evaluated ATV+COBI versus ATV+RTV univariate odds ratios (ORs) for virologic success (viral load <50 copies/mL, intention-to-treat US Food and Drug Administration Snapshot algorithm) and discontinuation due to adverse events (AEs) at Weeks 48 and 144. Of 692 patients randomized, 344 received ATV+COBI and 348 ATV+RTV.

Results: ATV+COBI versus ATV+RTV ORs for virologic success did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.90; 95% confidence interval [CI]: 0.64, 1.26) or within subgroups, except in females, for whom ATV+COBI was favored at Week 144 (OR 2.36; 95% CI: 1.02, 5.47). However, there were more discontinuations due to withdrawal of consent and pregnancies in females receiving ATV+RTV versus ATV+COBI. ORs for discontinuation due to AEs did not significantly differ by regimen overall at Weeks 48 and 144 (OR 0.98; 95% CI: 0.61, 1.58) or within subgroups.

Conclusion: These findings indicate that both ATV+COBI and ATV+RTV, each with FTC/TDF, are effective and well-tolerated treatment options across a wide demographic range of HIV-infected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1570162X14666161021102728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543662PMC
March 2018

Pharmacokinetics and Tolerability of Single-Ascending Doses of Desvenlafaxine Administered to Children and Adolescents with Major Depressive Disorder.

J Child Adolesc Psychopharmacol 2016 12 18;26(10):909-921. Epub 2016 Jul 18.

2 Pfizer Inc, Collegeville , Pennsylvania.

Objective: To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory.

Methods: The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R).

Results: In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents.

Conclusions: Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cap.2016.0009DOI Listing
December 2016

Long-term safety and tolerability of bapineuzumab in patients with Alzheimer's disease in two phase 3 extension studies.

Alzheimers Res Ther 2016 Jun 23;8(1):24. Epub 2016 Jun 23.

Pfizer Inc., 235 East 42nd Street, New York, NY, 10017, USA.

Background: Immunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer's disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols.

Methods: The long-term safety and tolerability of intravenous-administered bapineuzumab in patients with AD was evaluated in apolipoprotein E ε4 allele noncarriers (Study 3002, extension of Study 3000) and apolipoprotein E ε4 allele carriers (Study 3003, extension of Study 3001). Those receiving bapineuzumab in the parent study were continued at the same dose; if receiving placebo, patients began bapineuzumab. Bapineuzumab doses were 0.5 mg/kg in both studies and also 1.0 mg/kg in the noncarrier study. Clinical efficacy of bapineuzumab was also assessed in exploratory analyses.

Results: Because of lack of efficacy in two other phase 3 trials, the parent protocols were stopped early. As a result, Studies 3002 and 3003 were also terminated. In total, 492 and 202 patients were enrolled in Studies 3003 and 3002, respectively. In apolipoprotein E ε4 carriers (Study 3003), treatment-emergent adverse events occurred in 70.7% of the patients who originally received placebo and 66.9% of those who originally received bapineuzumab. In noncarriers, treatment-emergent adverse events occurred in 82.1% and 67.6% of patients who received placebo + bapineuzumab 0.5 mg/kg and placebo + bapineuzumab 1.0 mg/kg, respectively, and in 72.7% and 64.3% of those who received bapineuzumab + bapineuzumab 0.5 mg/kg and 1.0 mg/kg, respectively. Amyloid-related imaging abnormalities with edema or effusions were the main bapineuzumab-associated adverse events in both studies, occurring in approximately 11% of placebo + bapineuzumab and 4% of bapineuzumab + bapineuzumab groups overall. Exploratory analyses of clinical efficacy were not significantly different between groups in either study.

Conclusions: In these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trials.

Trial Registration: Noncarriers (Study 3002): ClinicalTrials.gov NCT00996918 . Registered 14 October 2009. Carriers (Study 3003): ClinicalTrials.gov NCT00998764 . Registered 16 October 2009.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-016-0193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918115PMC
June 2016

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

Alzheimers Res Ther 2016 May 12;8(1):18. Epub 2016 May 12.

Pfizer Inc., 500 Arcola Road, Collegeville, PA, 19426, USA.

Background: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD).

Methods: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale and the Disability Assessment for Dementia.

Results: A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event.

Conclusions: These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed.

Trial Registration: Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810 ; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143 ; registered 2 May 2008.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-016-0189-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866415PMC
May 2016

Safety and tolerability of desvenlafaxine in children and adolescents with major depressive disorder.

J Child Adolesc Psychopharmacol 2014 May 10;24(4):201-9. Epub 2014 Mar 10.

1 Johns Hopkins University , Baltimore, Maryland.

Objective: The purpose of this study was to assess long-term safety and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) in children and adolescents with major depressive disorder (MDD).

Methods: An 8 week, multicenter, open-label, fixed-dose study of children (ages 7-11 years) and adolescents (ages 12-17 years) with MDD was followed by a 6 month, flexible-dose extension study. Patients were administered desvenlafaxine 10-100 mg/day (children) or 25-200 mg/day (adolescents) for a total of 8 months. Treatment-emergent adverse events (AEs), withdrawals because of AEs, laboratory tests, vital signs, and the Columbia Suicide-Severity Rating Scale (C-SSRS) were collected. Eight month safety results from the lead-in plus extension studies are reported for extension study participants, using lead-in study day -1 as baseline.

Results: Forty patients were enrolled in both studies (20 children; 20 adolescents). Of those, four children and three adolescents withdrew because of AEs. Treatment-emergent AEs reported by three or more patients were upper abdominal pain (15%) and headache (15%) in children, and somnolence (30%), nausea (20%), upper abdominal pain (15%), and headache (15%) in adolescents. Negativism (oppositional behavior) in a child was the single serious AE reported. No deaths occurred during the lead-in or extension studies. Mean pulse rates demonstrated statistically significant increases from lead-in study baseline to final evaluation (children, +5.2 bpm; adolescents, +5.9 bpm; p≤0.05). No statistically significant change in blood pressure was observed at final evaluation. Two adolescents (0 children) reported suicidal ideation on the C-SSRS at screening assessment and during the lead-in and/or extension trials; one adolescent reported suicidal ideation after screening only.

Conclusions: Long-term (8 month) treatment with desvenlafaxine was generally safe and well tolerated in depressed children and adolescents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cap.2012.0126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026302PMC
May 2014

Draft genome sequence of the Tibetan antelope.

Nat Commun 2013 ;4:1858

Key Laboratory for High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai 810001, China.

The Tibetan antelope (Pantholops hodgsonii) is endemic to the extremely inhospitable high-altitude environment of the Qinghai-Tibetan Plateau, a region that has a low partial pressure of oxygen and high ultraviolet radiation. Here we generate a draft genome of this artiodactyl and use it to detect the potential genetic bases of highland adaptation. Compared with other plain-dwelling mammals, the genome of the Tibetan antelope shows signals of adaptive evolution and gene-family expansion in genes associated with energy metabolism and oxygen transmission. Both the highland American pika, and the Tibetan antelope have signals of positive selection for genes involved in DNA repair and the production of ATPase. Genes associated with hypoxia seem to have experienced convergent evolution. Thus, our study suggests that common genetic mechanisms might have been utilized to enable high-altitude adaptation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms2860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674232PMC
December 2013
-->