scholarly journals Comparison of inulin clearance with 2-h creatinine clearance in Japanese pediatric patients with renal disease: open-label phase 3 study of inulin

2021 ◽  
Author(s):  
Osamu Uemura ◽  
Kenji Ishikura ◽  
Koichi Kamei ◽  
Riku Hamada ◽  
Masaki Yamamoto ◽  
...  
Keyword(s):  
Renal Disease ◽  
Creatinine Clearance ◽  
Primary Endpoint ◽  
Pediatric Patients ◽  
Pediatric Nephrology ◽  
Inulin Clearance ◽  
Clearance Ratio ◽  
Open Label ◽  
Maintenance Rate ◽  
Starting Point

Abstract Background There is no approved dosage and administration of inulin for children. Therefore, we measured inulin clearance (Cin) in pediatric patients with renal disease using the pediatric dosage and administration formulated by the Japanese Society for Pediatric Nephrology, and compared Cin with creatinine clearance (Ccr) measured at the same time. We examined to what degree Ccr overestimates Cin, using the clearance ratio (Ccr/Cin), and confirmed the safety of inulin in pediatric patients. Methods Pediatric renal disease patients aged 18 years or younger were enrolled. Inulin (1.0 g/dL) was administered intravenously at a priming rate of 8 mL/kg/hr (max 300 mL/hr) for 30 min. Next, patients received inulin at a maintenance rate of 0.7 × eGFR mL/min/1.73 m2 × body surface area (max 100 mL/hr) for 120 min. With the time the maintenance rate was initiated as a starting point, blood was collected at 30 and 90 min, while urine was collected twice at 60-min intervals. The primary endpoint was the ratio of Ccr to Cin (Ccr/Cin). Results Inulin was administered to 60 pediatric patients with renal disease; 1 patient was discontinued and 59 completed. The primary endpoint, Ccr/Cin, was 1.78 ± 0.52 (mean ± standard deviation). Regarding safety, five adverse events were observed in four patients (6.7%); all were non-serious. No adverse reactions were observed in this study. Conclusions The results in this study on the dosage and administration of inulin showed that inulin can safely and accurately determine GFR in pediatric patients with renal disease. ClinicalTrials.gov identifier NCT03345316.

Stop-flow analysis of creatinine excretion in the dog

1962 ◽  
Vol 203 (6) ◽  
pp. 980-984 ◽  
Author(s):  
Robert E. Swanson ◽  
Ali A. Hakim
Keyword(s):  
Creatinine Clearance ◽  
Competitive Inhibition ◽  
Flow Analysis ◽  
High Plasma ◽  
Free Flow ◽  
Inulin Clearance ◽  
Plasma Creatinine ◽  
Clearance Ratio ◽  
Creatinine Concentration ◽  
Stop Flow

Urinary excretion patterns of creatinine and inulin under stop-flow conditions in male mongrel dogs were compared. Evidence for a weak creatinine secretory mechanism at the proximal tubule level include the following: 1) Exogenous creatinine in the stop-flow samples appears prior to inulin when both are injected midway during a 10-min ureteral clamping period. 2) The ratio of creatinine/inulin U/P values (creatinine clearance ratio) shows a peak and a distribution coextensive with PAH/inulin clearance ratios. 3) Self-depression of the peak stop-flow creatinine clearance ratio was obtained at high plasma creatinine concentrations. 4) High plasma p-aminohippuric acid levels depressed the free-flow and peak stop-flow creatinine clearance ratios and, conversely, high plasma creatinine concentration depressed free-flow and peak stop-flow PAH clearance ratios (competitive inhibition). 5) Probenecid reduced free-flow and peak stop-flow creatinine clearance ratios (creatinine secretory mechanism blocked). The mean free-flow creatinine/inulin clearance ratios in 44 clearance periods was 1.2±0.1 (sd), compared to the peak stop-flow ratio of 1.8±0.4 (sd) (N = 20) at plasma creatinine concentrations less than 20 mg/100 ml.

scholarly journals Intestinal microbiota in pediatric patients with end stage renal disease: a Midwest Pediatric Nephrology Consortium study

Microbiome ◽  
2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Janice Crespo-Salgado ◽  
V. Matti Vehaskari ◽  
Tyrus Stewart ◽  
Michael Ferris ◽  
Qiang Zhang ◽  
...  
Keyword(s):  
Renal Disease ◽  
Intestinal Microbiota ◽  
End Stage Renal Disease ◽  
Pediatric Patients ◽  
Pediatric Nephrology ◽  
Stage Renal Disease ◽  
End Stage

CTNI-24. A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Susan Chi ◽  
Antony Hsieh ◽  
Megan Foley ◽  
Hongliang Shi ◽  
Preethi Swamy ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Targeted Therapies ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Treatment Options ◽  
Objective Response ◽  
Germ Cell Tumors ◽  
Cns Tumors ◽  
Activation Loop ◽  
Open Label

Abstract Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; response rates are only ~15% with targeted therapies. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT alterations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) alterations. H3K27M gliomas are dependent on PDGFRA signaling and patients have an overall survival of ~1 year. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M gliomas. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 < 2 nM), and PDGFRA activation-loop (D842V) mutants (IC50 = 0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for CNS antitumor activity. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of this 2-part phase 1/2, multicenter, open-label study are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to < 18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M gliomas and no alternative treatment options. Part 1 will enroll ≥ 6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥ 25 patients at the recommended avapritinib dose from Part 1; primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.

scholarly journals Single-arm, open-label, multicentre first in human study to evaluate the safety and performance of dural sealant patch in reducing CSF leakage following elective cranial surgery: the ENCASE trial

BMJ Open ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. e049098
Author(s):  
Tristan Van Doormaal ◽  
Menno R Germans ◽  
Mariska Sie ◽  
Bart Brouwers ◽  
Andrew Carlson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Endpoint ◽  
User Satisfaction ◽  
Neurosurgical Procedures ◽  
Open Label ◽  
Cranial Surgery ◽  
Dural Closure ◽  
Handling Characteristics ◽  
Csf Leakage ◽  
And Performance

ObjectiveThe dural sealant patch (DSP) is designed for watertight dural closure after cranial surgery. The goal of this study is to assess, for the first time, safety and performance of the DSP as a means of reducing cerebrospinal fluid (CSF) leakage in patients undergoing elective cranial intradural surgery with a dural closure procedure.DesignFirst in human, open-label, single-arm, multicentre study with 360-day (12 months) follow-up.SettingThree large tertiary reference neurosurgical centres, two in the Netherlands and one in Switzerland.ParticipantsForty patients undergoing elective cranial neurosurgical procedures, stratified into 34 supratentorial and six infratentorial trepanations.InterventionEach patient received one DSP after cranial surgery and closure of the dura mater with sutures.Outcome measuresPrimary composite endpoint was occurrence of one of the following events: postoperative percutaneous CSF leakage, intraoperative leakage at 20 cm H2O positive end-expiratory pressure or postoperative wound infection. Overall success was defined as achieving the primary endpoint in no more than two patients. Secondary endpoints were device-related serious adverse events or adverse events (AEs), pseudomeningocele and thickness of dura+DSP. Additional endpoints were reoperation in 30 days and user satisfaction.ResultsNo patients met the primary endpoint. No device-related (serious) AEs were observed. There were two incidences of self-limiting pseudomeningocele as confirmed on MRI. Thickness of dura and DSP were (mean±SD) 3.5 mm±2.0 at day 7 and 2.1 mm±1.2 at day 90. No patients were reoperated within 30 days. Users reported a satisfactory design and intuitive application.ConclusionsDSP, later officially named Liqoseal, is a safe and potentially efficacious device for reducing CSF leakage after intracranial surgery, with favourable clinical handling characteristics. A randomised controlled trial is needed to assess Liqoseal efficacy against the best current practice for reducing postoperative CSF leakage.Trial registration numberNCT03566602.

scholarly journals LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii375
Author(s):  
Eric Bouffet ◽  
James A Whitlock ◽  
Christopher Moertel ◽  
Birgit Geoerger ◽  
Isabelle Aerts ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Pediatric Patients ◽  
Objective Response ◽  
Safety Data ◽  
Dose Finding ◽  
Combination Group ◽  
Clinical Activity ◽  
Low Grade ◽  
Open Label ◽  
Independent Review

Abstract BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (<18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.

scholarly journals Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Linda T. Vahdat ◽  
Peter Schmid ◽  
Andres Forero-Torres ◽  
Kimberly Blackwell ◽  
Melinda L. Telli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Primary Endpoint ◽  
Triple Negative ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Common Grade ◽  
Open Label Phase ◽  
Grade 3

AbstractThe METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

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