Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study.

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

Pharmacokinetics and safety of ticagrelor in infants and toddlers with sickle cell disease aged <24 months.

Inhibition of platelet activation may reduce vaso-occlusion rates in patients with sickle cell disease (SCD). In the HESTIA4 (NCT03492931) study, 21 children with SCD received a single oral dose of the antiplatelet agent ticagrelor (0.1 mg/kg <6 months; 0.2 mg/kg ≥6 to <24 months). All patients had measurable ticagrelor plasma concentrations. Ticagrelor and active metabolite (AR-C124910XX) exposure were comparable across all groups (<6 months, ≥6 to <12 months and ≥12 to <24 months). Ticagrelor was well tolerated. Palatability was generally acceptable. These data will be used to enable dose selection for further investigations of ticagrelor efficacy and safety in children with SCD.

Scandcleft Project Trial 2-Comparison of Speech Outcome in 1- and 2-Stage Palatal Closure in 5-Year-Olds With UCLP.

OBJECTIVE: To investigate in-depth speech results in the Scandcleft Trial 2 with comparisons between surgical protocols and centers and with benchmarks from peers without cleft palate. DESIGN: A prospective randomized clinical trial. SETTING: Two Swedish and one Finnish Cleft Palate center. PARTICIPANTS: One hundred twelve participants were 5-years-old born with unilateral cleft lip and palate randomized to either lip repair and soft palate closure at 4 months and hard palate closure at 12 months or lip repair at 3 to 4 months (Arm A), or a closure of both the soft and hard palate at 12 months (Arm C). MAIN OUTCOME MEASURES: A composite measure dichotomized into velopharyngeal competency (VPC) or velopharyngeal incompetency (VPI), overall assessment of velopharyngeal function (VPC-Rate), percentage of consonants correct (PCC score), and consonant errors. In addition, number of speech therapy visits, average hearing thresholds, and secondary surgeries were documented to assess burden of treatment. RESULTS: Across the trial, 53.5% demonstrated VPC and 46.5% VPI with no significant differences between arms or centers. In total, 27% reached age-appropriate PCC scores with no statistically significant difference between the arms. The Finnish center had significantly higher PCC scores, the Swedish centers had higher percentages of oral consonant errors. Number of speech therapy visits was significantly higher in the Finnish center. CONCLUSION: At age 5, poor speech outcomes with some differences between participating centers were seen but could not be attributed to surgical protocol. As one center had very few participants, the results from that center should be interpreted with caution.

A dose-ranging study of ticagrelor in children aged 3-17 years with sickle cell disease: A 2-part phase 2 study.

Antiplatelet treatment is a potential therapeutic approach for sickle cell disease (SCD). Ticagrelor inhibits platelet aggregation and is approved for adults with acute coronary syndrome and following myocardial infarction. HESTIA1 (NCT02214121) was a 2-part, phase 2 dose-finding study generating ticagrelor exposure, platelet inhibition, and safety data in children with SCD (3-17 years). In part A (n = 45), patients received 2 ticagrelor single doses, 0.125-2.25 mg/kg (washout ≥7 days), then 7 days of twice-daily (bid) dosing with 0.125, 0.563, or 0.75 mg/kg. In the 4-week blinded Part B extension (optional), patients received ticagrelor (0.125, 0.563, or 0.75 mg/kg bid; n = 16) or placebo (n = 7). Platelet reactivity decreased from baseline to 2 hours postdosing, and returned to near baseline after 6 hours postdosing. Dose-dependent platelet inhibition was seen with ticagrelor; mean relative P2Y12 reaction unit inhibition 2 hours after a single dose ranged from 6% (0.125 mg/kg) to 73% (2.25 mg/kg). Ticagrelor plasma exposure increased approximately dose proportionally. No patients experienced a hemorrhagic event during treatment. No differences were seen between groups in pain ratings and analgesic use during Part B. Ticagrelor was well tolerated with no safety concerns, no discontinuations due to adverse events (AEs), and reported AEs were mainly due to SCD. In conclusion, a dose-exposure-response relationship for ticagrelor was demonstrated in children with SCD for the first time. These data are important for future pediatric studies of the efficacy and safety of ticagrelor in SCD.

Inverse Correlation between the Atrial Fibrillatory Rate and the Ventricular Repolarization Time: Observations at Baseline and after an Intravenous Infusion of a Combined Potassium and Sodium Current Blocker.

BACKGROUND: The atrial fibrillatory rate (AFR) and the ventricular rate and repolarization (QTcF) were studied at baseline and under the influence of the combined potassium and sodium current blocker AZD7009. METHODS: Ninety-two patients with atrial fibrillation (AF) were randomized to an intravenous infusion of AZD7009 or placebo. The atrial fibrillatory activity in lead V1 was extracted using spatiotemporal QRST cancellation. The exponential decay (ED) characterized the degree of atrial signal organization. RESULTS: The mean (SD) AFR at baseline was 396  ±  57 (range 253-584) and 410 ± 33 (range 363-469) bpm in patients randomized to AZD7009 and placebo, respectively. The AFR decreased within the first minutes of the AZD7009 infusion and reached its minimum of 235 ± 34 bpm after 18 minutes. On placebo, the AFR was unchanged. On AZD7009, the ED decreased from 1.2 ± 0.3 to reach its lowest level at 0.7 ± 0.2 after 14 minutes. The ventricular rate did not change significantly over time. The AFR was statistically significantly related to the ventricular repolarization at baseline, the QTcF being longer at lower AFR values, and this relationship remained during and after AZD7009. In the full multivariate linear regression model, including age, sex, left ventricular ejection fraction, QRS duration, heart rate, QTcF, AF episode duration, AF history duration, and right atrial or left atrial size, only QTcF and age were statistically significantly correlated with the AFR. The correlation remained when the uncorrected QT interval was used. CONCLUSIONS: The QTcF was inversely correlated with AFR, both at baseline and during administration of AZD7009. The AFR was not correlated with the ventricular rate.

Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans.

AIMS: We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF). METHODS AND RESULTS: The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P<0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period. CONCLUSION: Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.

Rapid slowing of the atrial fibrillatory rate after administration of AZD7009 predicts conversion of atrial fibrillation.

BACKGROUND: Effects on the atrial fibrillatory rate (AFR) were studied during infusion with the combined potassium and sodium channel blocker AZD7009. METHODS AND RESULTS: Patients with persistent atrial fibrillation (AF) were randomized to AZD7009 or placebo. Thirty-five patients converted to sinus rhythm (SR) and were matched to 35 non-converters. The mean AFR before conversion was 231 fibrillations per minute (fpm), having decreased by 41%; in non-converters, it was 296 fpm at the end of infusion, having decreased by 26%. The rate of decrease was greater in converters at 5 min, -88 vs. -66 fpm (p=0.02), and at 10 min, -133 vs. -111 fpm (p=0.048). The AFR-SD and the exponential decay decreased. A small left atrial area was the only baseline predictor of conversion to SR. CONCLUSIONS: AZD7009 produced a significantly more rapid decrease of the AFR in converters than in non-converters, but the AFR at baseline was not predictive of conversion.

Assessment of ventricular repolarization variability with the DeltaT50 method improves identification of patients with congenital long QT syndromes.

BACKGROUND: We analyzed ventricular repolarization variability in genotyped long QT syndrome (LQTS) patients and in healthy volunteers (HV). METHOD: The deltaT50, that is, the temporal variability of ventricular repolarization at 50% of the T-wave downslope, was analyzed every 15th minute on 175 and 390 Holter electrocardiogram (ECG) recordings from HV and genotyped LQTS patients, respectively. The average deltaT50 and QTcF were calculated in each subject. RESULTS: DeltaT50 was 2.26 ± 0.71 ms (mean ± SD) in the HV and 5.74 ± 2.30 ms in the LQTS population (P < 0.0001). The sensitivity and specificity of QTcF (cutoff value 450 ms) to discriminate between the LQTS patients and the HV were 51.5% and 98.9%, and for deltaT50 (cutoff value 3 ms) 93.9% and 88.6%, respectively. The combination of both variables improved the diagnosis of the LQTS patients even further. Subgroups of LQTS patients at higher risk of cardiac events (with LQTS3, JLN, QTc > 500 ms or symptoms) had higher deltaT50 than subgroups at lower risk (with LQTS1, QTc < 450 ms or without symptoms). The variation in deltaT50 between day and night was concordant with the risk of symptoms; patients with LQTS1 had higher deltaT50 in the daytime and patients with LQTS3 had higher deltaT50 during the night. CONCLUSION: DeltaT50 more accurately distinguished between LQTS patients and HV than QTcF and was higher in LQTS patients with a higher risk of cardiac events. DeltaT50 can be used together with QTcF to improve the diagnosis in patients with the LQTS phenotype and tentatively also be of value for risk assessment in such patients.

Decrease of the atrial fibrillatory rate, increased organization of the atrial rhythm and termination of atrial fibrillation by AZD7009.

BACKGROUND: The atrial fibrillatory rate (AFR), on AZD7009 as compared to placebo, was investigated as a potential biomarker for electrophysiological effect in early antiarrhythmic drug development. METHODS: Patients with permanent AF received infusions of AZD7009 and placebo in an exploratory two-way, single-blind, randomized cross-over study. The ECG was continuously recorded, and following QRST cancellation the AFR, its standard deviation (SD), the exponential decay and the atrial electrogram amplitude were determined as 3-min averages. RESULTS: The mean AFR rapidly decreased by 43% from baseline (394 ± 38 to 225 ± 61 fibrillations/min, p=0.0003) on AZD7009, but not on placebo. The SD of the AFR and the exponential decay decreased in parallel. In 2 of 8 patients, termination of AF occurred after the AFR had decreased by 58% and 53%, respectively. CONCLUSIONS: The AFR may potentially serve as a biomarker of electrophysiological effects in early evaluation of rhythm control agents.

Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously.

AIM: AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR). METHODS AND RESULTS: Patients with AF episodes of duration 3 h to 3 months were randomized in a 3:1 ratio to receive a maximum 30 min intravenous infusion of AZD1305 or matching placebo. The primary efficacy endpoint was the proportion of patients converting within 90 min of the start of infusion, after which patients who had not converted were to undergo direct current (DC) cardioversion. Four ascending AZD1305 dose groups were assigned sequentially, with dose rates of 50, 100, 130, and 180 mg/h. A total of 171 patients were randomized. Pharmacological conversion was achieved in 0 of 43 patients (0%) in the placebo group, and in 2 of 26 (8%; P= 0.14 vs. placebo), 8 of 45 (18%; P= 0.006), 17 of 45 (38%; P< 0.001), and 6 of 12 patients (50%; P< 0.001) in AZD1305 dose groups 1-4, respectively. Maximum QTcF (QT interval corrected according to Fridericia's formula) generally increased dose-dependently up to a plateau, although there was wide variation between patients. Two patients experienced torsade de pointes (TdP): one patient without symptoms in dose group 3, and one patient requiring DC defibrillation in dose group 4. Both patients recovered without sequelae. CONCLUSIONS: AZD1305 was effective in converting AF to SR, but was associated with QT prolongation and TdP. The benefit-risk profile was judged as unfavourable and the AZD1305 development programme was discontinued. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov identifier NCT00915356.

DeltaT50--a new method to assess temporal ventricular repolarization variability.

BACKGROUND: Increased beat-to-beat variability in cardiac repolarization time is a tentative risk marker of drug-induced torsades de pointes. We developed a new, automatic method based on the temporal variability of the T-wave down slope to assess this variability. METHOD AND RESULTS: Leads V(1) to V(6) of resting electrocardiograms were recorded in 42 healthy subjects (18-68 years, 22 men). The temporal variability at 50% of the T-wave down slope, deltaT50 (1.5 ± 0.41 milliseconds; range, 0.86-2.66 milliseconds), was measured with an accuracy of 1 millisecond on at least 9 pairs of electrocardiogram complexes with a signal-to-noise ratio more than 10 and changes in the R-R interval less than 150 milliseconds. The correlation between repeated measurements of deltaT50 was high. DeltaT50 was measured without corrections for age, sex, heart rate, T-wave amplitude, signal-to-noise ratio, R-R variability, and QTcF because none of these factors explained more than 4% of the within-subject deltaT50 variability. CONCLUSION: The beat-to-beat repolarization variability was measured with high fidelity with the deltaT50 method and was a robust measure in healthy volunteers.

A randomized invasive cardiac electrophysiology study of the combined ion channel blocker AZD1305 in patients after catheter ablation of atrial flutter.

BACKGROUND: This study assessed the cardiac electrophysiological and hemodynamic effects of an intravenous infusion of the combined ion channel blocker AZD1305. METHODS: After successful ablation of atrial flutter, patients were randomized to receive placebo (n = 12) or AZD1305 (n = 38) in 4 ascending dose groups. Electrophysiological and hemodynamic measurements were performed before and commencing 20 minutes after start of infusion. RESULTS: Left atrial effective refractory period increased dose and the primary outcome measure increased dose and plasma concentration dependently, with a mean increase of 55 milliseconds in dose group 3. There was a corresponding increase in right atrial effective refractory period of 84 milliseconds. The right ventricular effective refractory period and the paced QT interval also increased dose and concentration dependently, by 59 and 70 milliseconds, respectively, in dose group 3. There were indications of moderate increases of atrial, atrioventricular nodal, and ventricular conduction times. No consistent changes in intracardiac pressures were observed, but there was a small transient decrease in systolic blood pressure. Adverse events were consistent with the study population and procedure, and there were no signs of proarrhythmia despite marked delay in ventricular repolarization in some individuals. CONCLUSIONS: AZD1305 shows electrophysiological characteristics indicative of potential antiarrhythmic efficacy in atrial fibrillation.

Prediction of drug-related morphological changes of the T wave.

OBJECTIVES: To describe the characteristics of patients presenting with morphological T wave changes that lead to measurement difficulties, and to identify possible predictors of such changes at baseline and early after start of treatment. DESIGN: ECGs from 145 patients receiving a combined potassium and sodium channel blocking agent for conversion of atrial fibrillation (AF), underwent semiautomatic analysis in a digitalized high-precision analysis program. In 15 patients, one or more ECGs were identified as difficult to interpret due to morphological T wave changes. They were compared with the 130 patients without such changes. RESULTS: A history of cardiac failure (p=0.027), a smaller left atrial area (p=0.010) and a longer QT(tang) minus QT(top) interval (p<0.001) at baseline was significantly more frequent as compared to the controls. Identified patients also had somewhat longer baseline QT interval duration (median QT(cB) 432 vs. 408 ms, N.S.) and a larger proportion of them were females (47% vs. 27%, N.S.). After start of infusion the QT(cB) became significantly longer in identified patients than in controls (p=0.012). CONCLUSIONS: Independent predictors of subsequent morphological changes were found at baseline and shortly after start of treatment, and may be of use to identify individuals with a reduced repolarization reserve.

Effects of a selective glucocorticoid receptor modulator (AZD9567) versus prednisolone in healthy volunteers: two phase 1, single-blind, randomised controlled trials.

BACKGROUND: Glucocorticoids are highly effective and widely used anti-inflammatory drugs, but their use is limited by serious side-effects, including glucocorticoid-induced hyperglycaemia and diabetes. AZD9567 is a non-steroidal, selective glucocorticoid receptor modulator that aims to reduce side-effects. We aimed to assess the safety, tolerability, and pharmacokinetics of AZD9567 in healthy volunteers. METHODS: Two phase 1 clinical studies were done. First, a randomised, placebo-controlled, single-blind, single-ascending dose study was done in healthy men who received single oral doses of AZD9567 2 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 125 mg, or 155 mg, or prednisolone 60 mg (n=8 per dose group, randomly assigned [6:2] to receive active drug or placebo). Second, a randomised, active-controlled, single-blind, multiple-ascending dose study was done, in which men and women received oral AZD9567 or prednisolone once daily for 5 days. One cohort of volunteers with prediabetes received AZD9567 10 mg (n=7) or prednisolone 20 mg (n=2). All other cohorts comprised healthy volunteers, receiving AZD9567 20 mg, 40 mg, 80 mg, or 125 mg (n=7 per dose group), or prednisolone 5 mg (n=13), 20 mg (n=16), or 40 mg (n=13). Participants and study centre staff were masked to treatment assignment for each cohort, although data were unmasked for safety review between cohorts. The primary outcome of the single-ascending dose study was the safety, tolerability, and pharmacokinetics of single ascending doses of AZD9567; for the multiple-ascending dose study it was the safety and tolerability of AZD9567 following multiple ascending doses. As a secondary outcome, effects on glycaemic control were ascertained with oral glucose tolerance tests (OGTTs) done at baseline and on day 1 of the single-ascending dose study, and at baseline and on day 4 of the multiple-ascending dose study. These trials are registered at ClinicalTrials.gov, NCT02512575 and NCT02760316. FINDINGS: In the single-ascending dose study, between Nov 18, 2015, and Sept 26, 2016, 72 healthy white men were enrolled, and all completed the study. In the multiple-ascending dose study, between May 2, 2016, and Sept 13, 2017, 77 predominantly white male volunteers (including nine individuals with prediabetes and eight women) were enrolled and 75 completed the study. All doses of AZD9567 and prednisolone were well tolerated, with no serious adverse events or events suggesting adrenal insufficiency. In the single-ascending dose study, nine adverse events of mild intensity were reported (five with AZD9567 and four with placebo); no adverse event was reported by more than one person. In the multiple-ascending dose study, 44 adverse events of mild or moderate intensity were reported (18 with AZD9567 and 26 with prednisolone). The most common were headache and micturition. Apparent clearance, volume of distribution, and half-life of AZD9567 were consistent across doses and for single versus repeated dosing. In the multiple-ascending dose study, OGTTs showed no significant difference with AZD9567 doses up to 80 mg compared with prednisolone 5 mg in glucose area under the curve from 0 h to 4 h post-OGTT (AUC0-4h) from baseline to day 4; the increase in glucose AUC0-4h from baseline to day 4 was significantly lower with all AZD9567 doses versus prednisolone 20 mg (AZD9567 20 mg p<0·0001, 40 mg p=0·0001, 80 mg p=0·0001, and 125 mg p=0·0237). INTERPRETATION: AZD9567 appears to be safe and well tolerated in healthy, predominantly white male volunteers and shows promising initial evidence for improved post-prandial glucose control. Studies of longer duration, with a greater proportion of women and other ethnic groups, and in patients requiring anti-inflammatory treatment are needed to characterise the clinical efficacy and safety profile of AZD9567. FUNDING: AstraZeneca.

Rapid conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009.

This randomized, double-blind trial compared cardioversion rates between AZD7009 infusion (15-minute 3.25 mg/min, 15-minute 4.4 mg/min, or 30-minute 3.25 mg/min) and placebo infusion (15 or 30 minutes) in patients with atrial fibrillation (AF) scheduled for DC cardioversion. One hundred sixty-eight patients were randomized, 167 received study treatment, and 159 were included in perprotocol analyses. The mean duration of current AF episode was 47 days (range, 0.8-92). In the AZD7009 30-minute 3.25 mg/min group, 21 of 42 patients converted within 90 minutes, compared with 7 of 39, 7 of 36, and 0 of 42 patients in the 15-minute 3.25 mg/min, 15-minute 4.4 mg/min, and combined placebo groups, respectively. Patients not converted within 90 minutes underwent DC cardioversion. In patients with AF episodes

The nasal alar elevator: a new device that may reduce the need for primary operation of the nose in patients with cleft lip.

To improve the shape of the cleft lip nose preoperatively, we have developed the nasal alar elevator. This has been used routinely since 1996 on all our cleft lip patients who have an asymmetrical nose, from the first week after birth until the date of primary lip surgery. We present our 11-year-long experience of using the device on patients born with complete, unilateral cleft lip. In this study 56 children, born between 1996 and 2006 inclusive, with complete unilateral cleft lip, had preoperative treatment with the elevator. During this 11-year period, continuous evaluation during the preoperative period, and its effects on the cleft lip nose, were evaluated, both preoperatively and postoperatively. Our results show that the preoperative use of the device has led to less need for primary nasal surgery. Instead of having to have a primary rhinoplasty (McComb) together with a lip plasty, as a routine, now only about 30% of the patients need primary surgical correction of the nose. If nasal correction is needed, a rather limited undermining of skin over the ala on the cleft side will often be sufficient. The use of a nasal elevator reduces both the length and the extent of the primary intervention, without compromising the final result.

Population Pharmacokinetics/Pharmacodynamics of Ticagrelor in Children with Sickle Cell Disease.

BACKGROUND AND OBJECTIVE: Ticagrelor, a reversible P2Y12 platelet inhibitor, is under investigation as a sickle cell disease (SCD) therapy in children. HESTIA1 (NCT02214121) was the first ticagrelor study generating pharmacokinetic (PK), pharmacodynamic (PD, P2Y12 reactivity units [PRU]), and safety data in 45 pediatric SCD patients. Population PK and PK/PD relationships for ticagrelor were quantified using a PK approach. METHODS: An adult population PK model was refined to describe ticagrelor and AR-C124910XX (active metabolite) plasma concentration and time data over a wide range of single/repeated ticagrelor doses (0.125-2.25 mg/kg). Population PK/PD modeling was used to describe the time course and extent of platelet inhibition. Demographic covariate relationships were investigated. RESULTS: The final population PK model adequately described ticagrelor and AR-C124910XX plasma concentrations over time. An allometric body weight relationship between ticagrelor and AR-C124910XX clearances and volumes of distribution was used. Significant covariates for ticagrelor were sex (relative bioavailability) and cholecystectomy (central volume of distribution). Estimated oral clearances (35 kg patient; median bodyweight) were 22.8 L/h (ticagrelor) and 9.97 L/h (AR-C124910XX). The final population PK/PD model well-described the time course and extent of platelet inhibition. Estimated baseline PRU was 283, maximum PRU effect was fixed at 1, and the ticagrelor concentration for half-maximum PRU effect was 233 nmol/L. CONCLUSIONS: These analyses offer the first quantitative characterization of the dose-exposure-response relationship for ticagrelor in pediatric SCD patients. This model-based approach may be used to inform dose selection and design of subsequent studies that aim to define ticagrelor safety and efficacy in pediatric SCD patients.

Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor.

BACKGROUND AND OBJECTIVE: Ticagrelor is a P2Y12 receptor inhibitor approved as an antiplatelet drug for patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also being investigated for the reduction of vaso-occlusive crises in pediatric patients with sickle cell disease. A pediatric formulation suitable for this age range was developed; the development strategy is described. Primary objectives were determining the relative bioavailability of ticagrelor pediatric tablets and granules for oral suspension to the adult immediate-release tablet, and the pediatric tablets taken whole and dispersed/suspended in water to the granules for oral suspension. Bioequivalence between the pediatric tablet taken whole or suspended in water was also assessed. Secondary objectives were comparing the formulations' safety and tolerability. METHODS: We conducted a randomized, four-period, cross-over, single-dose study. Pharmacokinetic parameters were assessed for ticagrelor and its active metabolite AR-C124910XX. Bioequivalence was concluded if the 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration-time curve ratios were contained completely within the 80.00-125.00% limits for ticagrelor/AR-C124910XX. RESULTS: Forty-four healthy adults (95% white; 57% male) were included. Similar bioavailability of ticagrelor (and AR-C124910XX) was demonstrated for all comparisons tested. Ticagrelor pediatric tablets taken whole were bioequivalent to pediatric tablets suspended in water. The plasma concentration-time profiles for ticagrelor and AR-C124910XX were similar, showing rapid ticagrelor absorption and AR-C124910XX formation. All formulations were well tolerated. CONCLUSION: Similar bioavailability of a new pediatric dispersible tablet formulation of ticagrelor for use across a wide age range of pediatric patients was demonstrated compared with other oral ticagrelor formulations. CLINICALTRIALS. GOV IDENTIFIER: NCT03126695. EUDRACT: 2017-000371-93.

Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3).

BACKGROUND: An unmet need for therapies exists to reduce sickle cell disease (SCD) complications in pediatric patients. Activated platelets contribute to the formation of cellular aggregates during sickling and vaso-occlusive crises (VOCs). Ticagrelor is an oral, direct-acting, and reversible adenosine diphosphate P2Y12 receptor antagonist that inhibits platelet activation and aggregation. Although ticagrelor was well tolerated in two phase 2 studies in children and young adults with SCD, larger and longer-term treatment studies are needed to assess ticagrelor's efficacy to reduce VOCs. HESTIA3 will evaluate the efficacy, safety, and tolerability of ticagrelor versus placebo over a minimum of 1 year (maximum 2 years) in pediatric patients with SCD. METHODS: Approximately 180 patients (aged ≥ 2 to <18 years) with SCD (≥ 2 VOCs in the prior year) from 18 countries will be randomized 1:1 to ticagrelor or placebo. Primary endpoint: number of VOCs (a composite endpoint of painful crises and/or acute chest syndrome); key secondary endpoints: hospitalizations, pain intensity and analgesic use during VOCs, acceptability of formulation, and health-related quality of life. The weight-based doses of ticagrelor are set by modeling and simulation. Platelet inhibition data, measured by the vasodilator-stimulated phosphoprotein assay, will be collected for exploratory purposes. CONCLUSIONS: HESTIA3 aims to demonstrate that using greater target platelet inhibition than previous studies on SCD, ticagrelor will decrease the frequency of VOC in pediatric patients. Trial Identifier: NCT03615924; EudraCT2017-002421-38.

Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies.

BACKGROUND: Fibrinogen and prothrombin have been suggested to become rate limiting in trauma associated coagulopathy. Administration of fibrinogen is now recommended, however, the importance of prothrombin to patient outcome is unknown. METHODS: We have utilized two trauma patient databases (database 1 n = 358 and database 2 n = 331) to investigate the relationship of plasma prothrombin concentration on clinical outcome and coagulation status. Database 1 has been used to assess the relationship of plasma prothrombin to administered packed red blood cells (PRBC), clinical outcome and coagulation biomarkers (Prothrombin Time (PT), ROTEM EXTEM Coagulation Time (CT) and Maximum Clot Firmness (MCF)). ROC analyses have been performed to investigate the ability of admission coagulation biomarkers to predict low prothrombin concentration (database 1), massive transfusion and 24 h mortality (database 1 and 2). The importance of prothrombin was further investigated in vitro by PT and ROTEM assays in the presence of a prothrombin neutralizing monoclonal antibody and following step-wise dilution. RESULTS: Patients who survived the first 24 h had higher admission prothrombin levels compared to those who died (94 vs.67 IU/dL). Patients with lower transfusion requirements within the first 24 h (≤10 units of PRBCs) also had higher admission prothrombin levels compared to patients with massive transfusion demands (>10 units of PRBCs) (95 vs.62 IU/dL). Admission PT, in comparison to admission ROTEM EXTEM CT and MCF, was found to be a better predictor of prothrombin concentration <60 IU/dL (AUC 0.94 in database 1), of massive transfusion (AUC 0.92 and 0.81 in database 1 and 2 respectively) and 24 h mortality (AUC 0.90 and 0.78 in database 1 and 2, respectively). In vitro experiments supported a critical role for prothrombin in coagulation and demonstrated that PT and ROTEM EXTEM CT are sensitive methods to measure low prothrombin concentration. DISCUSSION: Our analyses suggest that prothrombin concentration at admission is predictive of mortality and transfusion and indicates that prothrombin and fibrinogen are rate limiting in coagulopathy. CONCLUSIONS: Admission PT is predictive of low prothrombin concentration and clinical outcome. PT could therefore be used as a surrogate for prothrombin concentration and further evaluation of point-of-care devices for faster PT analysis is warranted.