scholarly journals Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis

Rheumatology ◽  
2021 ◽  
Author(s):  
Nicolino Ruperto ◽  
Hermine I Brunner ◽  
Athimalaipet V Ramanan ◽  
Gerd Horneff ◽  
Rubén Cuttica ◽  
...  
Keyword(s):  
Body Weight ◽  
Phase 1 ◽  
Phase 3 ◽  
Systemic Jia ◽  
Injection Site Reactions ◽  
Dosing Regimens ◽  
Pharmacodynamic Markers ◽  
Treatment Safety ◽  
Study Participants ◽  
Weight Groups

Abstract Objectives To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). Methods In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or <30 kg, respectively. Primary end points were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with i.v. tocilizumab (i.v.-TCZ) in sJIA and pJIA. Results Study participants were 51 sJIA patients and 52 pJIA patients aged 1–17 years who received s.c.-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. Conclusion s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279

scholarly journals Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting

2019 ◽  
Vol 84 (6) ◽  
pp. 1257-1267 ◽  
Author(s):  
Kari M. Morrissey ◽  
Mathilde Marchand ◽  
Hina Patel ◽  
Rong Zhang ◽  
Benjamin Wu ◽  
...  
Keyword(s):  
Body Weight ◽  
Response Rate ◽  
Phase 1 ◽  
Objective Response ◽  
Safety Data ◽  
Comparable Efficacy ◽  
Small Cell Lung ◽  
Phase 3 ◽  
Exposure Response ◽  
Dosing Regimens

Abstract Purpose To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. Methods ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. Results No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. Conclusion Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.

scholarly journals PSVI-21 Interactive effects of Zn sources, Cu sources and phytase on growth performance in nursery pigs

2019 ◽  
Vol 97 (Supplement_2) ◽  
pp. 212-213
Author(s):  
Ping Ren ◽  
Joe Cushing ◽  
Karen Wedekind ◽  
Mercedes Vazquez-Anon
Keyword(s):  
Body Weight ◽  
Growth Performance ◽  
Feed Efficiency ◽  
Phase 1 ◽  
Interactive Effects ◽  
Phase 2 ◽  
Initial Body Weight ◽  
Phase 3 ◽  
Nursery Pigs ◽  
Dietary Treatments

Abstract This study investigated the interactive effects of Zn sources, Cu sources and phytase on growth performance in nursery pigs. A total of 288 weaning barrows (BW = 5.71 ± 0.81 kg), blocked by initial body weight, were randomly allotted to 1 of 8 dietary treatments, with 9 pens per treatment and 4 pigs per pen. The 8 dietary treatments were arranged in 2 × 2 × 2 factorial design, with 2 Zn sources [2000 ppm Zn from ZnO during phase 1 (d 1 to 14) and 2 (d 15 to 28), and 100 ppm Zn from ZnO during phase 3 (d 29 to 42); 100 ppm Zn from Zn methionine hydroxy analogue chelate (Zn-MHAC, MINTREX® Zn, Novus International Inc., St. Charles, MO) during phase 1 to 3], 2 Cu sources [150 ppm Cu from CuSO4 or Cu-MHAC (MINTREX® Cu) during phase 1, and 80 ppm Cu from CuSO4 or Cu-MHAC during phase 2 and 3], and 2 phytase inclusion levels (0, 500 FTU/kg). Results showed that there were no differences (P > 0.10) between ZnO and Zn-MHAC groups in terms of growth performance during the entire nursery period. Compared with CuSO4, Cu-MHAC tended to increase ADG (P = 0.07) and G:F (P = 0.08) during the entire nursery period. There tended to be an interaction (P = 0.09) between Cu sources and phytase on G:F during phase 2. Specifically, without phytase supplementation, there was no difference (P = 0.63) on G:F during phase 2 between Cu-MHAC and CuSO4, whereas with phytase supplementation, Cu-MHAC increased G:F during phase 2 (P = 0.05) compared with CuSO4. In conclusion, Zn-MHAC supplementation at 100 ppm could replace pharmacological level of ZnO without affecting growth performance. Cu-MHAC could improve growth performance compared with CuSO4. Cu-MHAC exerted synergistic effect with phytase on improving feed efficiency.

Sperm DNA 5-mC and RNA m 6A methylation are differently affected during periods of body weight losses and body weight gain of young and mature breeding bulls

2021 ◽  
Author(s):  
F H Moura ◽  
A Macias-Franco ◽  
C A P Bello ◽  
E C Archilia ◽  
I M Batalha ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Body Weight ◽  
Nutritional Status ◽  
Sperm Count ◽  
Phase 1 ◽  
Phase 2 ◽  
Phase 3 ◽  
Progressive Motility ◽  
Scrotal Circumference ◽  
Sperm Volume

Abstract Aiming to characterize the effects of nutritional status on epigenetic markers, such as DNA 5-mC methylation and RNA m 6A methylation, of bovine sperm, twelve Angus × Hereford crossbred breeding bulls were submitted to nutritional changes for a period of 180 days: no change in BW (Phase 1 = 12 d); BW loss (Phase 2 = 78 d); and BW gain (Phase 3 = 90 d) in a repeated measures design. Animals were fed Beardless wheat (Triticum aestivum) hay and mineral mix. Statistical analyses were performed using SAS 9.4 (SAS Inst., Cary, NC). Higher levels of RNA m 6A (P = 0.004) and DNA methylation (P = 0.007) of spermatic cells were observed at Phase 2 compared with Phase 1. In Phase 3, sperm RNA m 6A methylation levels continued to be higher (P = 0.004), whereas the DNA of sperm cells was similar (P = 0.426) compared with the Phase 1. Growing bulls had a tendency (P = 0.109) of higher RNA m 6A methylation levels than mature bulls. Phase 2 altered scrotal circumference (P < 0.001), sperm volume (P = 0.007), sperm total motility (P = 0.004), sperm progressive motility (P = 0.004), total sperm count (P = 0.049), normal sperm (P < 0.001), abnormal sperm (P < 0.001), primary sperm defects (P = 0.039), and secondary sperm defects (P < 0.001). In Phase 3, bulls had scrotal circumference, sperm volume, sperm motility, sperm progressive motility, total sperm count, normal and abnormal spermatozoa, and primary and secondary spermatozoa defects similar to Phase 1 (P > 0.05). Serum concentrations of insulin-like growth factor-1 (IGF-1) and leptin decreased during Phase 2 (P = 0.010) while no differences (P > 0.05) were detected between Phase 3 and 1; growing bulls tended (P = 0.102) to present higher leptin levels than mature bulls. Specific for mature bulls, DNA methylation was positively correlated with leptin concentration (0.569, P = 0.021). Whereas for young bulls, DNA methylation was positively correlated with abnormal spermatozoa (0.824, P = 0.006), primary spermatozoa defect (0.711, P = 0.032), secondary spermatozoa defect (0.661, P = 0.052), and negatively correlated with normal spermatozoa (−0.824, P = 0.006), total sperm count (−0.702, P = 0.035), and sperm concentration (−0.846, P = 0.004). There was no significant correlation (P > 0.05) between RNA m 6A and hormones and semen traits. In conclusion, the nutritional status of breeding bulls alters epigenetic markers, such as DNA methylation and RNA m 6A methylation, in sperm, and the impact of change seems to be age-dependent. These markers may serve as biomarkers of sperm quality and fertility of bulls in the future. Detrimental effects on sperm production and seminal quality are observed at periods and places when and where environmental and nutritional limitations are a year-round reality and may carry hidden players that may influence a lifetime of underperformance.

scholarly journals Strategy to blend leftover finisher feed to nursery pigs in a wean-to-finish production system1

2018 ◽  
Vol 3 (1) ◽  
pp. 408-418
Author(s):  
Fangzhou Wu ◽  
Kyle F Coble ◽  
Chad W Hastad ◽  
Mike D Tokach ◽  
Jason C Woodworth ◽  
...  
Keyword(s):  
Body Weight ◽  
Phase 1 ◽  
Average Daily Gain ◽  
Phase Changes ◽  
Dose Titration ◽  
Phase 2 ◽  
Growth Responses ◽  
Phase 3 ◽  
Final Body Weight ◽  
Nursery Pigs

Abstract In wean-to-finish pig production, leftover finisher feed from the previous group is commonly blended with nursery diets as weanling pigs enter the facility. Two experiments were conducted to evaluate feeding the last finisher diet to nursery pigs. The timing (phase) and dose were evaluated. Each experiment used 1,260 pigs from two commercial research rooms with 21 pigs per pen and 30 pens per room (15 pens per treatment). Pigs were fed commercial nursery diets in a five-phase feeding program, and phase changes were based on a feed budget. In experiment 1, pens of pigs (initially 5.83 kg) were blocked by body weight, gender, and room and allotted to one of four treatments. Treatments included standard nursery diets throughout (control) or standard diets with 2.5 kg/pig of the last finisher feed blended at the beginning of phase 2, 3, or 4. Growth responses during the intermediate periods were promptly decreased (P < 0.05) once the finisher feed was introduced regardless of phase in which it was blended. However, during the overall nursery period, blending the finisher diet into phase 2 decreased (P < 0.05) average daily gain (ADG) and average daily feed intake (ADFI), but did not affect gain:feed ratio (G:F), compared with control pigs or those that had blended diet in phase 4 with blending of phase 3 diet intermediate. In experiment 2, weaned pigs were fed common phase 1 and 2 diets before the start of the experiment. At the beginning of phase 3, pens of pigs (initially 10.6 kg) were blocked by body weight and room and allotted to one of four treatments. Treatments consisted of a dose-titration of blending increasing amounts of finisher feed (0, 1.25, 2.50, and 3.75 kg/pig) into the phase 3 nursery diet. Overall, blending increasing amounts of the last finisher feed with phase 3 nursery diet decreased ADG (linear, P = 0.050) and tended to decrease (linear, P < 0.07) ADFI and final body weight. However, there was no evidence for difference in overall G:F. In conclusion, blending finisher feed into the early nursery diets decreased overall ADG and ADFI; however, pigs greater than 11 kg had improved ability to compensate for the negative effects of blending the last finisher feed on overall growth performance. Nevertheless, increasing the amounts of finisher feed fed to 11-kg pigs from 0 to 3.75 kg/pig resulted in a linear decrease in overall ADG and ADFI. Economic analysis indicated no change in income-over-feed-cost due to the timing and dose of blending finisher feed into nursery diets.

PENERAPAN MODEL QUANTUM LEARNING UNTUK MENINGKATKAN HASIL BELAJAR AUTOCAD SISWA KELAS X TEKNIK PEMESINAN SMK NEGERI 1 STABAT

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Abdul Hasan Saragih
Keyword(s):  
Positive Response ◽  
Phase 1 ◽  
First Grade ◽  
Learning Model ◽  
Second Phase ◽  
Phase 2 ◽  
Phase 3 ◽  
The Third ◽  
Third Phase ◽  
Quantum Learning

This classroom research was conducted on the autocad instructions to the first grade of mechinary class of SMK Negeri 1 Stabat aiming at : (1) improving the student’ archievementon autocad instructional to the student of mechinary architecture class of SMK Negeri 1 Stabat, (2) applying Quantum Learning Model to the students of mechinary class of SMK Negeri 1 Stabat, arising the positive response to autocad subject by applying Quantum Learning Model of the students of mechinary class of SMK Negeri 1 Stabat. The result shows that (1) by applying quantum learning model, the students’ achievement improves significantly. The improvement ofthe achievement of the 34 students is very satisfactory; on the first phase, 27 students passed (70.59%), 10 students failed (29.41%). On the second phase 27 students (79.41%) passed and 7 students (20.59%) failed. On the third phase 30 students (88.24%) passed and 4 students (11.76%) failed. The application of quantum learning model in SMK Negeri 1 Stabat proved satisfying. This was visible from the activeness of the students from phase 1 to 3. The activeness average of the students was 74.31% on phase 1,81.35% on phase 2, and 83.63% on phase 3. (3) The application of the quantum learning model on teaching autocad was very positively welcome by the students of mechinary class of SMK Negeri 1 Stabat. On phase 1 the improvement was 81.53% . It improved to 86.15% on phase 3. Therefore, The improvement ofstudent’ response can be categorized good.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals How to improve emergency care to adults discharged within 24 hours? Acute Care planning in Emergency departments (The ACE study): a protocol of a participatory design study

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e041743
Author(s):  
Christina Østervang ◽  
Annmarie Touborg Lassen ◽  
Charlotte Myhre Jensen ◽  
Elisabeth Coyne ◽  
Karin Brochstedt Dieperink
Keyword(s):  
Patient Outcomes ◽  
Participatory Design ◽  
Hospital Admissions ◽  
Phase 1 ◽  
Family Needs ◽  
Focus Group Interviews ◽  
Phase 3 ◽  
Ace Study ◽  
Group Interviews ◽  
Improve Patient

IntroductionThe development of acute symptoms or changes in diseases led to feelings of fear and vulnerability and the need for health professional support. Therefore, the care provided in the acute medical and surgical areas of the emergency department (ED) is highly important as it influences the confidence of patients and families in managing everyday life after discharge. There is an increase in short-episode (<24 hours) hospital admissions, related to demographic changes and a focus on outpatient care. Clear discharge information and inclusion in treatment decisions increase the patient’s and family’s ability to understand and manage health needs after discharge, reduces the risk of readmission. This study aims to identify the needs for ED care and develop a solution to improve outcomes of patients discharged within 24 hours of admission.Methods and analysisThe study comprises the three phases of a participatory design (PD). Phase 1 aims to understand and identify patient and family needs when discharged within 24 hours of admission. A qualitative observational study will be conducted in two different EDs, followed by 20 joint interviews with patients and their families. Four focus group interviews with healthcare professionals will provide understanding of the short pathways. Findings from phase 1 will inform phase 2, which aims to develop a solution to improve patient outcomes. Three workshops gathering relevant stakeholders are arranged in the design plus development of a solution with specific outcomes. The solution will be implemented and tested in phase 3. Here we report the study protocol of phase 1 and 2.Ethics and disseminationThe study is registered with the Danish Data Protection Agency (19/22672). Approval of the project has been granted by the Regional Committees on Health Research Ethics for Southern Denmark (S-20192000–111). Findings will be published in suitable international journals and disseminated through conferences.

scholarly journals PSVI-3 Dietary supplementation with coated omega-3 fatty acids has positive effects on growth performance and nutrients digestibility in weaned pigs

2020 ◽  
Vol 98 (Supplement_3) ◽  
pp. 196-197
Author(s):  
Woo Jung Seok ◽  
Je min Ahn ◽  
Jing Hu ◽  
Dexin Dang ◽  
Yanjiao Li ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Growth Performance ◽  
Phase 1 ◽  
Dietary Supplementation ◽  
Basal Diet ◽  
Phase 2 ◽  
Omega 3 ◽  
Phase 3 ◽  
Linear Effect ◽  
Weaning Pigs

Abstract The objective of this study was to evaluate the effects of dietary supplementation of coated omega-3 fatty acid (n-3 CFA) by corn cob power silica on performance of weaning pigs. A total of 200 weaned pigs [(Landrace x Yorkshire) x Duroc, average initial body weight at 6.97 ± 1.22 kg] were randomly assigned to four experimental treatments in a 6-week experiment in 3 phases as follows: CON, basal diet; 2) 0.3CFA, CON + phase 1(0.3% n-3CFA), phase 2(0.2% n-3CFA), phase 3(0.1% n-3CFA); 3) 0.6CFA, CON + phase 1(0.6% n-3CFA), phase 2(0.4% n-3CFA), phase 3(0.2% n-3CFA); 4) 0.9CFA, CON + phase 1(0.9% n-3CFA), phase 2(0.6% n-3CFA), phase 3 (0.3% n-3CFA). Each treatment had 10 replicates with 5 pigs (three gilts and two barrows) per replicate. The data were analyzed using the GLM procedure of SAS as a randomized complete block design. Pen served as the experimental unit. Linear, quadratic and cubic polynomial contrasts were used to examine effect of dietary treatment with coated n-3FA in the basal diet. Variability in the data was expressed as the standard error of means and P&lt; 0.05 was considered to statistically significant. Increasing the level of n-3CFA in the diet linearly increased ADG and G/F of pigs (Table 1). Increasing the level of n-3CFA showed a linear increment in the digestibility of DM (83.59, 84.38, 85.13, 85.89 %) whereas nitrogen digestibility (81.79, 82.38, 82.96, 83.64 %) showed a trend (linear effect, p=0.0594) at the end of experiment. The fecal lactobacillus count was increased (7.22, 7.27, 7.33, 7.35 log10cfu/g) with the increase in the supplemental level of n-3CFA (linear effect; p&lt; 0.05). However, there were no differences in the concentration of serum haptoglobin, or fecal E. coli, Clostridium and Salmonella counts despite the increase in n-3CFA levels in the diet. Supplementation of the diet with coated n-3 fatty acids positively affected growth performance and digestibility of dry matter and nitrogen, and enhanced the count of lactobacillus in weaning pigs.

scholarly journals Body Mass, Physical Activity and Eating Habits Changes during the First COVID-19 Pandemic Lockdown in Poland

2021 ◽  
Vol 18 (11) ◽  
pp. 5682
Author(s):  
Hubert Dobrowolski ◽  
Dariusz Włodarek
Keyword(s):  
Physical Activity ◽  
Body Weight ◽  
Body Mass ◽  
Social Life ◽  
Eating Habits ◽  
High Energy ◽  
High Energy Density ◽  
Average Weight ◽  
Study Participants ◽  
The Impact

The outbreak of the COVID-19 pandemic caused a number of changes in social life around the world. In response to the growing number of infections, some countries have introduced restrictions that may have resulted in the change of the lifestyle. The aim of our study was to investigate the impact of the lockdown on body weight, physical activity and some eating habits of the society. The survey involving 183 people was conducted using a proprietary questionnaire. The mean age of the study participants was 33 ± 11 and mean height 169 ± 8 cm. An average increase in body weight was observed in 49.18% by 0.63 ± 3.7 kg which was the result of a decrease in physical activity and an increase in food consumption. We also observed a decrease in PAL from 1.64 ± 0.15 to 1.58 ± 0.13 and changes in the amount of food and individual groups of products consumption, including alcohol. Among the study participants who did not lose body mass, there was an average weight gain of 2.25 ± 2.5 kg. In conclusion, an increase of weight was shown in about half of the respondents in the study group which was associated with a decrease in physical activity and an increase in the consumption of total food and high energy density products.

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