Naum Khutoryansky

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects

The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non-plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, single-center, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy-induced bleeding model in healthy subjects. The effects of warfarin (experiment 1) and rFVIIa (5-80 microg/kg; experiment 2) were evaluated. Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 microg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1).

Absence of QTc Prolongation in a Thorough QT Study With Subcutaneous Liraglutide, a Once‐Daily Human GLP‐1 Analog for Treatment of Type 2 Diabetes

The objective of this study was to establish effects of liraglutide on the QTc interval. In this randomized, placebo‐controlled, double‐blind crossover study, 51 healthy participants were administered placebo, 0.6, 1.2, and 1.8 mg liraglutide once daily for 7 days each. Electro cardiograms were recorded periodically over 24 hours at the end of placebo and highest dosing periods. Four different models for QT correction were used: QTci, as the primary endpoint, and QTciL, QTcF, and QTcB as secondary endpoints. The upper bound of the 1‐sided 95% confidence interval for time‐matched, baseline‐corrected, placebo‐subtracted QTc intervals was <10 ms for all 4 correction methods. Moxifloxacin (400 mg) increased QTc intervals by 10.6 to 12.3 ms at 2 hours. There was no concentration‐exposure dependency on QTc interval changes by liraglutide and no QTc thresholds above 500 ms or QTc increases >60 ms. The authors conclude that liraglutide caused no clinically relevant increases in the QTc interval.

Reversal of Clopidogrel-Induced Bleeding with rFVIIa in Healthy Subjects: A Randomized, Placebo-Controlled, Double-Blind, Exploratory Study

BACKGROUND:Clopidogrel (Plavix®) therapy, although effective for minimizing risk of thrombotic events, is also associated with potential bleeding risk. Recombinant activated FVII (rFVIIa, NovoSeven®) induces hemostasis in hemophilia patients with inhibitors (alloantibodies) and has been proposed as potential treatment for mitigating clopidogrel therapy–mediated bleeding. METHODS:In this single-center, randomized, placebo-controlled, double-blind, dose-escalation, exploratory phase I trial, we assessed the safety and effects of rFVIIa in reversing clopidogrel-enhanced bleeding in an experimentally induced punch biopsy in healthy subjects. Efficacy assessments included the reversal of bleeding characteristics (bleed duration [BD], the primary end point and blood loss volume [BV] induced by punch biopsy, and thromboelastograph [TEG®] parameters) with rFVIIa or placebo after clopidogrel treatment. RESULTS:A significant number of subjects (56%) had limited response to clopidogrel (defined as ⩽30% platelet aggregation inhibition) and were discontinued from study. The remaining subjects continued and had 4 biopsies. Of 40 subjects randomized, 37 were evaluated for efficacy. Clopidogrel treatment increased BD and BV compared with the baseline biopsy. Recombinant FVIIa (10 and 20 &mgr;g/kg) significantly mitigated the clopidogrel-induced effects on BV (P = 0.007 and P = 0.001, respectively). Early trial termination limited the evaluation of effects of higher rFVIIa doses. Subgroup analyses of subjects biopsied by the same physician demonstrated significant reduction of clopidogrel-induced BD with 20 &mgr;g/kg rFVIIa (P = 0.048). Ex vivo analysis of rFVIIa demonstrated clotting dynamics presented by parameters time to clot onset (TEG®-R) and clot angle (TEG®-A) (P < 0.005). CONCLUSIONS:In this clinical study, rFVIIa (10 and 20 &mgr;g/kg) reversed the effect of clopidogrel on blood loss.

Identification of factors associated with good response to growth hormone therapy in children with short stature: results from the ANSWER Program®.

ObjectiveTo identify factors associated with growth in children on growth hormone (GH) therapy using data from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® registry.MethodsGH-naïve children with GH deficiency, multiple pituitary hormone deficiency, idiopathic short stature, Turner syndrome, or a history of small for gestational age were eligible (N = 1,002). Using a longitudinal statistical approach, predictive factors were identified in patients with GHD for change from baseline in height standard deviation score (ΔHSDS) following 2 years of treatment.ResultsGradual increases in ΔHSDS over time were observed for all diagnostic categories. Significant predictive factors of ΔHSDS, ranked by significance were: height velocity (HV) at 4 months > baseline age > baseline HSDS > baseline body mass index (BMI) SDS > baseline insulin-like growth factor I (IGF-I) SDS; gender was not significant. HV at 4 months and baseline BMI SDS were positively correlated, whereas baseline age, HSDS, and IGF-I SDS were negatively correlated with ΔHSDS.ConclusionsThese results may help guide GH therapy based on pretreatment characteristics and early growth response.

Evidence supporting an association between hypoglycemic events and depression.

Abstract Objectives: This retrospective study investigated the association between hypoglycemic events (HEs) and depression events (DEs) in patients with diabetes mellitus (type 1 and type 2). Methods: Analyzed data were from health care claims for individuals with employer-sponsored primary or Medicare supplemental insurance from the Thomson Reuters Market Scan database during the years 2008 and 2009. A baseline period (January 2008 to December 2008) was used to identify eligible patients and collect baseline clinical and demographic characteristics. Eligible patients were aged ≥18 years with diabetes (ICD-9-CM codes: 250.00, 250.01, 250.02, 250.03) who had not experienced any HEs or DEs and were not on antidepressant therapy during the baseline period. We studied the relationships between the DEs and HEs before and after adjusting for the covariates. Results: Of the 923,024 patients meeting the inclusion criteria, 22,735 (2.46%) patients had HEs (ICD-9-CM coded: 251.0, 251.1, 251.2, 250.8) and 6164 (0.67%) patients had DEs (ICD-9-CM: 311) during the evaluation period. Patients reporting HEs had 78% higher odds of experiencing depression than patients without HEs before adjusting for the covariates. Similarly, after adjusting for the covariates, data indicated that patients with HEs had higher odds of experiencing depression (OR = 1.726; 95% CI = 1.52–1.96). Similar analyses in different age categories showed that the OR monotonically increases with age regardless of whether the other covariates are included in the model. Conclusions: ICD-9-CM–coded HEs were independently associated with an increased risk of DEs in patients with diabetes, and this incidence increased with the patients’ age. Key limitations: A key limitation to this study is that only those HEs that resulted in health care provider contact and subsequent claims coding indicative of hypoglycemia were included. It is likely that many cases of mild hypoglycemia, particularly those not severe enough to warrant medical attention, were not captured in this study.