scholarly journals Adaptive Bayesian Approach to Clinical Trial Renal Impairment Biomarker Signal from Urea and Creatinine

2013 ◽  
Vol 9 (2) ◽  
pp. 156-163 ◽  
Author(s):  
Pierre-Edouard Sottas ◽  
Gordon F. Kapke ◽  
Jean-Marc Leroux
Keyword(s):  
Clinical Trial ◽  
Renal Impairment ◽  
Bayesian Approach

Bayesian Approach for Clinical Trial Safety Data Using an Ising Prior

Biometrics ◽  
2013 ◽  
Vol 69 (3) ◽  
pp. 661-672 ◽  
Author(s):  
Bradley W. McEvoy ◽  
Rajesh R. Nandy ◽  
Ram C. Tiwari
Keyword(s):  
Clinical Trial ◽  
Bayesian Approach ◽  
Safety Data

No Accumulation of Peak Anti-Xa Activity of Tinzaparin in Elderly Patients with Moderate to Severe Renal Impairment: A Substudy of IRIS Clinical Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 172-172 ◽  
Author(s):  
Virginie Siguret ◽  
Alain Leizorovicz ◽  
Eric Pautas ◽  
Isabelle Gouin-Thibault
Keyword(s):  
Infectious Disease ◽  
Clinical Trial ◽  
Molecular Weight ◽  
Renal Impairment ◽  
Elderly Patients ◽  
Creatinine Clearance ◽  
Severe Renal Impairment ◽  
Renal Elimination ◽  
Significant Difference ◽  
The Mean

Abstract Abstract 172 The “Innohep® in Renal Insufficiency Study” (IRIS) was an international, multicentre, open, randomized, parallel group clinical trial with a primary objective to compare the safety of tinzaparin and unfractionated heparin in terms of clinically relevant bleeding (CRB) in elderly patients with impaired renal function for initial treatment of acute deep vein thrombosis. In the elderly, concerns have been raised about the risk of an accumulation effect and/or overdose due to the renal elimination of low molecular weight heparins (LMWH). In a subset of centres participating in the IRIS study, we conducted a substudy in order to assess whether there was an accumulation of anti-Xa activity and whether there was any relationship between anti-Xa activity and age, weight, creatinine clearance or clinical outcomes in patients treated with tinzaparin (175 IU/kg/24h) for venous thromboembolism. Plasma anti-Xa activity was to be analysed at peak level (4–6 hours after injection) on Day 2 or Day 3 and on Day 5 or at visit S (VS: day of visit at end of SC treatment) using a chromogenic assay (Rotachrom® heparin, Diagnostica Stago®). Of the complete IRIS study population who received tinzaparin (n=268), data from 87 patients (32%) were analysed. The patient characteristics (mean age 83±5 years [75–99 years], mean creatinine clearance (Cockcroft-Gault) 40.8 mL/min (SD 11.7, range 14–59) were consistent with those of the overall population of IRIS study. Of note, 24.1% had severe renal impairment (creatinine clearance < 30 mL/min). The mean peak anti-Xa activities, which were 0.86 (SD 0.34) and 0.87 (SD 0.31) IU/mL on Day2/3 and Day5/VS, respectively, were found close to the mean 0.85 IU/mL reported in the literature in patients receiving tinzaparin at therapeutic dose. There was no correlation between the anti-Xa activity and age, weight, or creatinine clearance. There was no significant difference in the anti-Xa levels between patients with, versus those without, severe renal impairment. The mean accumulation ratio (defined as anti-Xa activity on Day5/VS divided by the anti-Xa activity on Day2/3) was 1.06 (SD 0.30, 90% CI:1.01–1.11): as the 90% CI of the accumulation did not exceed the pre-defined upper limit of 1.25, no significant accumulation was detected. The mean anti-Xa activity did not differ significantly between the 8 patients experiencing a CRB during tinzaparin treatment and the 79 who did not experience a CRB during tinzaparin treatment. Among the 8 patients who had a CRB, one had an anti-Xa activity > 2.0 IU/mL (considered above therapeutic level) whereas the seven others had anti-Xa < 1.5 IU/mL. Interestingly, we found that the mean anti-Xa activities were significantly lower in the 12 patients with infectious disease at baseline compared to the patients without infectious disease: 0.66 (SD 0.18) vs 0.8 (SD 0.35) IU/mL on Day2/3, p=0.007; 0.62 (SD 0.23) vs 0.91 (SD 0.30) IU/mL on Day5/VS, p=0.002). These numbers are small but may require further investigation. There was no statistically significant difference in anti-Xa levels when comparing patients with versus those without ongoing malignancy. In conclusion, an IRIS substudy demonstrated no accumulation of anti-Xa activity in elderly patients with moderate to severe renal impairment receiving unadjusted recommended full dose of tinzaparin and confirms previous pharmacokinetic studies in similar populations. The high proportion of higher molecular weight moieties in tinzaparin may account for reduced dependence on renal elimination of the anti-Xa activity seen in elderly patients with renal impairment. Disclosures: Siguret: Leo-Pharma: this work was supported by a grant from Leo-Pharma. Leizorovicz:GSK: Consultancy. Gouin-Thibault:Leo-Pharma: this work was supported by a grant from Leo-Pharma.

scholarly journals Adaptive Bayesian Analysis of Serum Creatinine as a Marker for Drug-Induced Renal Impairment in an Early-Phase Clinical Trial

2012 ◽  
Vol 58 (11) ◽  
pp. 1592-1596 ◽  
Author(s):  
Pierre-Edouard Sottas ◽  
Gordon F Kapke ◽  
Jean-Marc Leroux
Keyword(s):  
Clinical Trial ◽  
Renal Impairment ◽  
Serum Creatinine ◽  
Early Phase ◽  
Reference Interval ◽  
Reference Intervals ◽  
Screening Tests ◽  
Drug Induced ◽  
Individual Participant ◽  
Z Scores

BACKGROUND A concern with using creatinine for the identification of drug-induced renal impairment is that small changes in serum creatinine (SCr) that frequently are perceived as measurement bias or imprecision translate into important changes in the glomerular filtration rate. Important drug-generated changes in creatinine are difficult to detect because they are frequently observed within the reference interval. The design of a crossover drug protocol is an opportunity to use study participants as their own control to identify these small but important changes. METHODS Twenty individuals participating in a phase I clinical trial were evaluated for SCr changes beyond those expected for biological variation according to individual Z scores derived from an adaptive Bayesian model. After 2 screening tests, participants were administered either drug (n = 11) or placebo (n = 9) during the first dosing interval. A washout period followed, and drug was then administered to the group that initially received placebo, and vice versa (10 visits total per participant). RESULTS Although all creatinine values fell within the reference interval, 8 participants individually showed increased concentrations (Z scores &gt;2.33). These 8 participants were confirmed at unblinding to have received the drug in the identified dosing period, with 1 exception. CONCLUSIONS The ability to identify a drug effect on an individual-participant basis in early-phase studies permits drug developers to recognize issues early in development and rapidly engage in risk–benefit analysis. These results suggest that SCr monitoring is able to detect early kidney dysfunction when individual-based reference intervals are used.

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