Rationale and Design of a Phase IIb/III Open-Label, Multicenter Study of Dabigatran Etexilate for Venous Thromboembolism in Children: The Diversity Study

Abstract Background Venous thromboembolism (VTE) is increasing in children. The current standard of care comprises unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for at least 5 days followed by UFH, LMWH or Vitamin K antagonists (VKA) for approximately 3 months in general. All of the current options have limitations: UFH and LMWH require parenteral administration; VKA requires frequent international normalized ratio (INR) monitoring and is associated with multiple food and drug interactions. The direct thrombin inhibitor, dabigatran, which is orally administered as the prodrug, dabigatran etexilate (DE) is effective for the treatment of VTE in adults and may overcome some of the limitations associated with standard of care. Objective To describe the design of a study evaluating the appropriateness of a proposed DE dosing algorithm and assessing the safety and efficacy of DE versus standard of care in pediatric patients with VTE. Methods This open-label, randomized, parallel-group, active-controlled, multi-center, non-inferiority study (NCT01895777) will be conducted in approximately 100 sites in approximately 30 countries. Patients aged 0 to < 18 years with an imaging-confirmed diagnosis of VTE initially receiving parenteral treatment with UFH or LMWH for 5-7 days (but no more than 21 days) who are expected to require anticoagulation therapy for at least 3 months will be eligible for inclusion. Main exclusion criteria include conditions associated with an increased risk of bleeding, renal dysfunction, active infective endocarditis, mechanical or biological heart valve prosthesis, hepatic disease and anemia or thrombocytopenia. Patients will be stratified into three age groups: stratum 1 (12 to < 18 years), stratum 2 (2 to < 12 years) and stratum 3 (birth to < 2 years). Recruitment will begin in stratum 1, being subsequently escalated to strata 2 and 3, respectively based on recommendations from the Data Monitoring Committee. Patients will be randomized (2:1) to receive DE versus standard of care (LMWH or VKA). DE will be administered twice daily as capsules, pellets or an oral liquid formulation depending on patient age and the patient's ability to swallow pellets or capsules. Upon completion of a 3-month treatment period (including the initial parenteral treatment phase) patients will be followed off-study drug for any adverse events. DE will be dosed to achieve steady-state measured trough circulating plasma concentrations (≥50 and < 250 ng/mL); the initial dose required will be calculated using a nomogram, which adjusts dosing according to the age and weight of the child. Dabigatran plasma concentrations will be evaluated at all study visits (7 scheduled during treatment period); DE will be up- or down-titrated as required. Results In terms of efficacy, the study will evaluate the proportion of patients with complete thrombus resolution, freedom from recurrent VTE (including symptomatic and asymptomatic, contiguous progression or non-contiguous new thrombus, deep vein thrombosis, pulmonary and paradoxical embolism, and thrombus progression) and freedom from VTE-related mortality. With regards to safety, the key endpoint will be freedom from major bleeding events, as per International Society on thrombosis and Haemostasis (ISTH) pediatric-specific criteria. All components of the primary efficacy and key safety endpoints will be adjudicated by an independent blinded committee. Conclusion This study, one of the largest controlled pediatric studies for VTE, will provide data on the safety and efficacy of DE compared with standard of care for the treatment of VTE in children aged 0 to < 18 years. Disclosures Albisetti: Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Huang:Boehringer Ingelheim: Employment. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.

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Pharmacokinetics (PK) and Pharmacodynamics (PD), Safety and Tolerability of a Single-Dose Oral Solution of Dabigatran Etexilate Given after Standard Anticoagulant Therapy in Children from Birth to Less Than One Year Old, with Venous Thromboembolism

Blood ◽

10.1182/blood.v128.22.1441.1441 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1441-1441 ◽

Cited By ~ 3

Author(s):

Jacqueline ML Halton ◽

Anne-Caroline Picard ◽

Ruth Harper ◽

Fenglei Huang ◽

Martina Brueckmann ◽

...

Keyword(s):

Single Dose ◽

Venous Thromboembolism ◽

Plasma Concentration ◽

Treatment Period ◽

Working Group ◽

Dabigatran Etexilate ◽

Older Children ◽

Bleeding Events ◽

Expert Working Group ◽

Relationship Of

Abstract Background: Venous thromboembolism (VTE) events are more frequent in neonates than in children of other age groups. The standard of care for pediatric anticoagulation includes unfractionated or low-molecular-weight heparin, or vitamin K antagonists. However, these treatments have limitations in terms of practicality of use in infants, such as parenteral administration, frequent monitoring and drug interactions. Alternative oral agents that address these shortcomings may improve compliance, efficacy and safety. The safety and efficacy of dabigatran etexilate (DE), a direct thrombin inhibitor, are established in adults; pharmacokinetic/pharmacodynamic (PK/PD) studies indicate linear PK. There is a relationship between dabigatran plasma concentration (PK) and its PD effects, resulting in reproducible dose-dependent prolongation in clotting times with rapid onset and offset of effect, which is consistent across populations. Although phase IIa studies suggest a similar PK/PD relationship of dabigatran in children and adults, the hemostatic system in infants differs from older children and adults, which may lead to a different PK/PD effect. Objective: To demonstrate comparable PK/PD relationship of DE oral liquid formulation (OLF) between infants and older children and adults, and to assess safety and tolerability. Methods: Open-label, multicenter, single-dose, single-arm, phase IIa pediatric study. Infants aged < 1 year diagnosed with VTE who completed standard anticoagulant treatment for VTE were enrolled. Exclusion criteria included < 37 weeks gestational age at birth, weight < 3 kg, major bleed with standard anticoagulant and swallowing abnormalities. Patients received DE OLF (based on age- and weight-adjusted nomogram) and were followed up for 30 (+7) days. The primary endpoints were PK/PD related, measured at 2 hrs and 12 (±2) hrs after DE administration. The PK endpoint was plasma concentration of total dabigatran, and PD endpoints were activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and diluted thrombin time (dTT). Secondary endpoints included incidence of all bleeding events and adverse events (AEs), acceptability and tolerability. Descriptive statistics were applied to the endpoints. PK/PD relationship was analyzed using a simple linear regression model and nonlinear Emax model to confirm whether models used in previous studies were consistent with the pediatric data of this study. Results: Ten patients were screened and 8 entered the study (mean age [SD]: 89 [52] days; range: 41-169 days). Patients received a single dose of DE OLF. The geometric mean (gMean) total dabigatran plasma concentrations 2 hrs post dose (around peak concentrations) was 120 ng/mL with geometric coefficient of variation (gCV) of 62.1%, which indicated moderate variability. The gMean at 12 hrs post dosing was 60.4 ng/mL (gCV 30%), which indicated low variability. The projected steady-state dabigatran trough concentrations were largely comparable to those observed in adults with VTE (Table). A linear PK/PD relationship was observed for ECT (ECT ratio) and dTT (dTT ratio) (Figure). The relationship between total dabigatran concentration and aPTT (aPTT ratio) was nonlinear. The observed PK/PD relationships were similar to those in adult and adolescent patients with VTE, except for patients aged < 2 months, in whom a slight upward shift of aPTT of 10-20% (average) and ECT by 10-15% was observed relative to adults. There were no AEs, deaths or treatment discontinuations during the treatment period. None of the treated patients had any bleeding events or thromboembolic events during the study. One patient had a serious AE (aortic stenosis) during the post-treatment period, which was not considered treatment related by the investigator. There were no clinically relevant or unexpected laboratory findings. The majority of patients were assessed with good tolerability (six patients, 75%), and one patient each (12.5%) was evaluated with satisfactory or bad tolerability. Conclusion: In this small population of infants (aged < 1 year), DE OLF was well tolerated without any treatment-related AEs, thromboembolic or bleeding events. The observed PK/PD relationships were consistent with the established profile in adult and adolescent patients with VTE. Disclosures Halton: Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim. Picard:Boehringer Ingelheim: Employment. Harper:Boehringer Ingelheim: Employment. Huang:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Maas:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Nurmeev:Boehringer Ingelheim: Other: Investigator fees. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group.

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Dabigatran Etexilate in Children with Venous Thromboembolism: Results of the Open-Label, Phase IIb/III, Randomized Diversity Clinical Trial

Blood ◽

10.1182/blood-2020-136682 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Jacqueline Halton ◽

Leonardo R. Brandao ◽

Matteo Luciani ◽

Lisa Bomgaars ◽

Elizabeth Chalmers ◽

...

Keyword(s):

Venous Thromboembolism ◽

Major Bleeding ◽

Working Group ◽

Dabigatran Etexilate ◽

Age Groups ◽

Bleeding Events ◽

Open Label ◽

Dosing Algorithm ◽

Expert Working Group ◽

Child Friendly

Background: In children, current standard of care (SOC) with heparins or vitamin K antagonists is limited by the need for parenteral administration and frequent monitoring. Dabigatran etexilate (DE), a direct oral anticoagulant, is an effective oral treatment for venous thromboembolism (VTE) in adults and may be an effective and safe alternative to SOC for treating acute VTE in children. Aims: The DIVERSITY trial evaluated the efficacy and safety of DE versus SOC, and the appropriateness of a DE dosing algorithm, in children with VTE aged from birth to < 18 years. Methods: This was an open-label, randomized, active-controlled, multicenter, phase IIb/III trial (NCT01895777; consent obtained and ethics committee approved). Children (12 to < 18 years, 2 to < 12 years, birth to < 2 years) with an objectively confirmed VTE diagnosis and initially treated with unfractionated heparin or low-molecular-weight heparin were randomized (2:1) to DE (capsules, and child-friendly pellets and oral suspension, dosed using an age- and body-weight-adjusted dosing algorithm) or SOC, and treated for up to 3 months. The primary composite efficacy endpoint was the proportion of children with complete thrombus resolution, and freedom from recurrent VTE or VTE-related death. Safety endpoints included bleeding events and adverse events (AEs), and pharmacokinetic/pharmacodynamic (PK/PD) relationships. Results: Of 267 children in the randomized set, 35 were aged < 2 years (13 SOC, 22 DE; of these, 14 were < 6 months [3 SOC, 11 DE]), 64 were 2 to < 12 years (21 SOC, 43 DE), and 168 were 12 to < 18 years (56 SOC, 112 DE). Overall, similar proportions of children treated with SOC and DE met the composite efficacy endpoint (38/90 [42.2%] vs 81/177 [45.8%]; Mantel Hänszel-weighted difference -0.04; 90% confidence interval [CI] -0.14 to 0.07; p < 0.0001 for non-inferiority), and major bleeding events were comparable (2/90 [2.2%] and 4/176 [2.3%]; hazard ratio 0.94; 95% CI 0.17-5.16; p = 0.95). Across the three age groups (12 to < 18 years, 2 to < 12 years, birth to < 2 years), DE was comparable with SOC for the combined efficacy endpoint, which was achieved by 33.9-57.1% of children treated with SOC and 42.0-59.1% treated with DE. Similar numbers of children experienced major bleeding events, reported by between 0.0-3.6% of children treated with SOC and 1.8-4.5% treated with DE. In the overall population, the incidence of AEs in children treated with SOC and DE was 66.7% and 76.7%, respectively, and serious AEs were reported by 20.0% and 12.5% of all children, respectively. Across the three main age groups, the frequency of serious AEs was comparable for SOC and DE (reported by 19.0-23.1% and 9.1-14.4% of children, respectively). Dabigatran PK/PD relationships for three laboratory coagulation parameters (activated partial thromboplastin time [aPTT], diluted thrombin time [dTT], and ecarin clotting time [ECT]) were comparable across the three main age groups and were also similar in infants aged < 6 months (Figure). There was a linear relationship between total dabigatran plasma concentration for both dTT and ECT, and a nonlinear relationship with aPTT. These PK/PD relationships were similar to those observed in adults (data not shown). Conclusions: This randomized trial confirmed that an age- and weight-adjusted dabigatran dosing algorithm was appropriate in children aged from birth to < 18 yrs. Dabigatran, given as either capsules or child-friendly pellets or oral suspension, was comparable with SOC in terms of efficacy for acute VTE treatment across all age groups and, notably, in vulnerable children aged < 2 yrs. Disclosures Halton: Boehringer Ingelheim: Other: Member of a paediatric expert working group. Brandao:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Luciani:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Bomgaars:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Chalmers:Shire/Takeda: Honoraria; CSL Behring: Honoraria; Bristol-Myers Squibb: Honoraria; Sobi: Honoraria; Roche: Honoraria; Grifols: Honoraria; Boehringer Ingelheim: Other: Member of a paediatric expert working group. Mitchell:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Sharathkumar:Takeda: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; Kedrion: Consultancy. Svirin:Takeda: Consultancy, Other: Personal fees; CSL Behring: Consultancy, Other: Personal fees. Tartakovsky:Boehringer Ingelheim: Current Employment. Simetzberger:Boehringer Ingelheim: Current Employment. Huang:Boehringer Ingelheim: Current Employment. Sun:Boehringer Ingelheim: Current Employment. Kreuzer:Boehringer Ingelheim: Current Employment. Gropper:Boehringer Ingelheim: Current Employment. Brueckmann:Boehringer Ingelheim: Current Employment. Albisetti:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Other: Member of a paediatric expert working group. OffLabel Disclosure: dabigatran etexilate in paediatric VTE

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An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15060 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15060-e15060

Author(s):

Christopher G. C. A. Jackson ◽

Noelyn Anne Hung ◽

David Cutler ◽

Douglas Kramer ◽

Jay Zhi ◽

...

Keyword(s):

Treatment Period ◽

Dabigatran Etexilate ◽

Plasma Concentrations ◽

Metastatic Breast ◽

Healthy Male ◽

Open Label ◽

Fixed Sequence ◽

Once Daily ◽

Period 2 ◽

Sequence Study

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in < 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.

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Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children

Blood ◽

10.1182/blood.2019000998 ◽

2020 ◽

Vol 135 (7) ◽

pp. 491-504 ◽

Cited By ~ 10

Author(s):

Leonardo R. Brandão ◽

Manuela Albisetti ◽

Jacqueline Halton ◽

Lisa Bomgaars ◽

Elizabeth Chalmers ◽

...

Keyword(s):

Risk Factor ◽

Venous Thromboembolism ◽

Dabigatran Etexilate ◽

Standard Of Care ◽

Central Line ◽

Clinical Risk Factor ◽

Postthrombotic Syndrome ◽

Minor Bleeding ◽

Bleeding Events ◽

Open Label

Abstract This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

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Efficacy and Safety of Dabigatran in the Treatment and Secondary Prophylaxis of Children with Venous Thromboembolism and Thrombophilia

Blood ◽

10.1182/blood-2020-136695 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Leonardo R. Brandao ◽

Igor Tartakovsky ◽

Manuela Albisetti ◽

Lisa Bomgaars ◽

Elizabeth Chalmers ◽

...

Keyword(s):

Clinical Trials ◽

Risk Factor ◽

Working Group ◽

Dabigatran Etexilate ◽

Secondary Prophylaxis ◽

Efficacy And Safety ◽

Open Label ◽

Expert Working Group ◽

Open Label Phase ◽

Favorable Safety

Background: Thrombophilia in children is characterized by hypercoagulability and increased frequency of thrombotic events (Young G, et al. Circulation. 2008;118:1373-1378; Kenet G, et al. Circulation. 2010;121:1838-1847). Recently, phase IIb/III clinical trials in children with venous thromboembolism (VTE) have reported the non-inferiority of dabigatran etexilate (DE) versus standard of care (SOC) for the treatment of acute VTE (Albisetti M, et al. ISTH 2019, Abstract OC 57.3), and a favorable safety profile for DE in secondary VTE prevention in children with persistent VTE risk factor(s) (Brandão LR, et al. Blood. 2020;135:491-504). Aims: To perform a subgroup analysis evaluating the efficacy and safety of DE for the treatment and secondary prophylaxis of VTE in children with thrombophilia in the phase IIb/III DE clinical trials. Methods: In the open-label, phase IIb/III DIVERSITY trial (NCT01895777), children aged from birth to < 18 years (yrs) with an objectively confirmed VTE diagnosis (by imaging studies) initially treated with unfractionated heparin or low-molecular-weight heparin were randomized (2:1) to receive up to 3 months of DE or SOC. Primary composite efficacy endpoint: complete thrombus resolution and freedom from VTE recurrence, or VTE-related death. Safety endpoints included bleeding events (BEs). The open-label, phase III, secondary VTE prevention trial (NCT02197416) treated children aged from > 3 months to < 18 yrs with DE for up to 12 months or less, if the identified VTE clinical risk factor resolved. Eligible children had an objectively confirmed diagnosis of VTE treated with SOC for ≥ 3 months, or had completed DE or SOC treatment in DIVERSITY and had an unresolved clinical VTE risk factor requiring further anticoagulation. Primary endpoints included VTE recurrence and BEs. Thrombophilia status was confirmed according to the definitions used by the local experts. Results: In DIVERSITY, 23.2% of children had thrombophilia; demographics were comparable to the overall population, although they were slightly older (mean [standard deviation] age 13.2 [4.9] vs 11.1 [6.1] years in the overall population; p = 0.005). In children with thrombophilia, DE was found to be non-inferior to SOC for the primary endpoint (similar to the overall population), and more children treated with DE achieved the composite primary endpoint than with SOC (SOC 21.7% vs DE 35.9%; Mantel-Hänszel-weighted difference in rates for SOC minus DE [90% CI] −0.14 [−0.32 to 0.05]; p for non-inferiority = 0.0014), similar to the overall population (Table). Regardless of treatment, VTE recurrence appeared higher in children with thrombophilia than in the overall population, with numerically fewer VTE recurrences reported by children with thrombophilia treated with DE (7.7%) versus SOC (21.7%), although this was not significantly lower (p = 0.13). Numerical differences in residual thrombotic burden between SOC vs DE seen in the overall population appeared to be amplified in children with thrombophilia. Numerically fewer children with thrombophilia treated with DE reported thrombus progression (SOC 13.0% vs DE 5.1%) or stabilization (21.7% vs 10.3%), while more reported partial (34.8% vs 43.6%) or complete thrombus resolution (21.7% vs 35.9%). In the thrombophilia subgroup, BEs appeared to be lower in children treated with DE (SOC 26.1% vs DE 17.9%), while in the overall population BEs with SOC and DE were comparable. In the secondary VTE prevention trial, children with thrombophilia were also slightly older versus the overall population (mean [standard deviation] age 14.1 [3.6] vs 12.8 [4.6] yrs; p = 0.006). In this larger subgroup of children, rates of recurrent VTE at 12 months appeared to be higher in the thrombophilia group (2.8%) compared to the overall population (1.4%) (Table), with BEs largely comparable (27.4% and 22.5%, respectively). Conclusions: Unsurprisingly, numerically more children with thrombophilia appeared to report VTE recurrence, and in DIVERSITY thrombus progression/stabilization also seemed higher compared with the overall population. Compared with the overall populations, these subgroup analyses showed consistent results for DE in children with acute VTE and thrombophilia in the DIVERSITY trial, along with a favorable safety profile of DE for secondary VTE prevention. Disclosures Brandao: Boehringer Ingelheim: Other: Member of a paediatric expert working group. Tartakovsky:Boehringer Ingelheim: Current Employment. Albisetti:Boehringer Ingelheim: Other: Member of a paediatric expert working group; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Bomgaars:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Chalmers:CSL Behring: Honoraria; Shire/Takeda: Honoraria; Boehringer Ingelheim: Other: Member of a paediatric expert working group; Grifols: Honoraria; Roche: Honoraria; Sobi: Honoraria; Bristol-Myers Squibb: Honoraria. Mitchell:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Luciani:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Lvova:Boehringer Ingelheim: Honoraria. Simetzberger:Boehringer Ingelheim: Current Employment. Sun:Boehringer Ingelheim: Current Employment. Gergei:Boehringer Ingelheim: Current Employment. Brueckmann:Boehringer Ingelheim: Current Employment. Halton:Boehringer Ingelheim: Other: Member of a paediatric expert working group. OffLabel Disclosure: dabigatran etexilate in paediatric VTE

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Rationale and Design of a Phase III Single-Arm Multicenter Study of Dabigatran Etexilate for the Secondary Prevention of Venous Thromboembolism in Children

Blood ◽

10.1182/blood.v128.22.5028.5028 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5028-5028

Author(s):

Matteo Luciani ◽

Manuela Albisetti ◽

Ivan Manastirski ◽

Martina Brueckmann ◽

Savion Gropper ◽

...

Keyword(s):

Risk Factor ◽

Steady State ◽

Venous Thromboembolism ◽

Secondary Prevention ◽

Working Group ◽

Dabigatran Etexilate ◽

Phase Iii ◽

Clinical Risk Factor ◽

Clinical Risk ◽

Expert Working Group

Abstract Background: In children, the incidence of venous thromboembolism (VTE) is increasing and is often associated with underlying diseases such as cancer, or risk factors such as thrombophilia. Following treatment for acute VTE, thrombosis or thromboembolic events can recur particularly if a clinical risk factor for VTE persists. The efficacy and safety of the oral anticoagulant dabigatran etexilate (DE) have been demonstrated in a number of thrombosis-related indications in adults, including for secondary VTE-prevention. There are, however, potential differences between adults and children related to developmental physiology and pharmacology and therefore trials to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of DE in children are required. To date, all pediatric phase IIa studies conducted have shown a similar PK and PK/PD relationship of DE in comparison to adult studies. Objective: To describe the design of a study to evaluate the safety and PK-PD of DE for secondary prevention of VTE in children aged 0-<18 years. Methods: This phase III, open-label, single-arm, multicenter study will be conducted at ~100 sites worldwide (NCT02197416). Eligible patients will have completed a course of initial treatment for confirmed acute VTE (for ≥ 3 months) and be considered at high risk for VTE recurrence due to the remaining presence of a clinical risk factor. Approximately 100 subjects between 0-<18 years of age will be included. Treatment with DE will extend up to 12 months, or less if the clinical risk factor resolves, with a follow-up visit 28 days after the last dose. DE will be administered twice daily as capsules, pellets or oral liquid formulation, depending on subject age and their ability to swallow capsules or pellets. A dosing nomogram will be used to scale down an adult dose based on the child's age and weight. Initial doses calculated using the nomogram should achieve steady-state trough concentrations of DE of between 50 and < 250 ng/ml, a range which is assumed to result in safe and effective use of DE in this pediatric population; after about 3 days, trough dabigatran plasma concentration will be measured and DE may be titrated up or down to achieve the target steady-state trough plasma concentration. Results: Demographic and medical history data will be collected for all participants. The primary outcomes to be evaluated are instances at 6 and 12 months of image-proven VTE recurrence; major and minor bleeding, including clinically relevant non-major bleeding; and overall and thrombotic/thromboembolic mortality. All elements of the primary endpoints will be evaluated by an independent adjudication committee that will confirm or refute outcome events. The secondary outcomes are rates of post-thrombotic syndrome at 6 and 12 months; PK and PD (e.g., activated partial thromboplastin time and ecarin clotting time); and the number of DE dose adjustments required during the treatment period. Data on the acceptability of the age-appropriate drug formulation, the tolerability of the study medication, adverse events, treatment discontinuations due to an adverse event, and laboratory and clinical parameters will also be collected during the study. Safety and tolerability will be monitored by the independent Data Monitoring Committee. Conclusion: This phase III study has been designed to provide data on the safety and PK-PD of DE for the secondary prevention of VTE in children aged 0-<18 years. Disclosures Luciani: Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Mitchell:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Huang:Boehringer Ingelheim: Employment. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.

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A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in COVID-19 patients with Regular Intravenous Immunoglobulin Therapy

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab098 ◽

2021 ◽

Author(s):

Raman R S ◽

Vijaykumar Bhagwan Barge ◽

Anil Kumar Darivenula ◽

Himanshu Dandu ◽

Rakesh R Kartha ◽

...

Keyword(s):

Mechanical Ventilation ◽

Randomized Study ◽

Standard Of Care ◽

Immunoglobulin Therapy ◽

Clinical Trial Registry ◽

Open Label ◽

Intravenous Immunoglobulin Therapy ◽

Safety And Efficacy ◽

Therapeutic Benefits ◽

Wide Range

Abstract Background Currently, there is no specific drug for the treatment of COVID-19. Therapeutic benefits of intravenous immunoglobin (IVIG) have been demonstrated in wide range of diseases. The present study is conducted to evaluate the safety and efficacy of IVIG in the treatment of COVID-19 patients with moderate pneumonia. Methods An open-label, multicenter, comparative, randomized study was conducted on COVID-19 patients with moderate pneumonia. 100 eligible patients were randomized in 1:1 ratio either to receive IVIG + standard of care (SOC) or SOC. Results Duration of hospital stay was significantly shorter in IVIG group to that of SOC alone (7.7 Vs. 17.5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation in two groups were not significantly different (24% Vs. 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 Vs.18 days). There were only mild to moderate adverse events in both groups except for one patient (2%), who died in SOC. Conclusions IVIG was safe and efficacious as an adjuvant with other antiviral drugs in the treatment of COVID-19. The trial was registered under Clinical Trial Registry, India (CTRI/2020/06/026222).

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Anticoagulant dosing in renal impairment

Phlebologie ◽

10.12687/phleb2290-6-2015 ◽

2015 ◽

Vol 44 (06) ◽

pp. 316-319 ◽

Cited By ~ 2

Author(s):

S. Harder

Keyword(s):

Risk Factor ◽

Venous Thromboembolism ◽

Renal Impairment ◽

Anticoagulant Therapy ◽

Severe Renal Impairment ◽

Dabigatran Etexilate ◽

The Elderly ◽

Thrombin Inhibitor ◽

Safety And Efficacy ◽

Direct Acting

SummaryAnticoagulants are widely used for prophylaxis and treatment of venous thromboembolism in the elderly, who commonly have renal impairment and other comorbidities. Renal impairment is a risk factor for bleeding and thrombosis during anticoagulant therapy and can influence the balance between the safety and efficacy of such agents. Some anticoagulants, such as fondaparinux and the direct acting oral thrombin inhibitor dabigatran etexilate are contraindicated for use in patients with severe renal impairment (eGFR <30 ml/min). However, also the direct acting oral FXa-inhibitors rivaroxaban, edoxaban and apixaban need caution regarding dosing advice or contraindications when used in patients with renal impairment.

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INNV-10. SAFETY OF APIXABAN FOR VENOUS THROMBOEMBOLISM PREVENTION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.553 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi132-vi132

Author(s):

Alissa Thomas ◽

Heather Wright ◽

Hannah Walker ◽

Prachi Prasad ◽

Kelly Chan ◽

...

Keyword(s):

Venous Thromboembolism ◽

Standard Of Care ◽

High Risk Group ◽

Prevention Strategy ◽

Newly Diagnosed ◽

Bleeding Events ◽

Open Label ◽

Effective Prevention ◽

Vte Prophylaxis ◽

Venous Thromboembolism Prevention

Abstract Venous thromboembolism (VTE) impacts an estimated one in every three patients with malignant glioma (MG), resulting in increased morbidity and mortality. Despite the high prevalence and serious consequences of VTE, there is no outpatient standard of care prevention strategy. There have been three prospective clinical trials of VTE prophylaxis in patients with newly diagnosed MG, all of which used an injectable low molecular weight heparin (LMWH) product. We performed an open-label safety study of apixaban, a direct oral anticoagulant (DOAC), for VTE prevention in patients with newly diagnosed MG. All patients had surgery or biopsy two to twenty-one days prior to enrollment in the study. Patients were treated with apixaban 2.5 mg twice daily for up to 6 months. Peak and trough apixaban concentrations were measured at the beginning and end of treatment. Thirteen patients consented to the study and ten enrolled (2 screen-fail, 1 withdrawal). The patients have completed a mean of 4.5 cycles of apixaban (range 2 to 6, with 2 patients still undergoing treatment). There were no bleeding events while receiving apixaban. There were no hematologic or non-hematologic treatment-related adverse events. There were no VTE events observed in patients receiving apixaban. Two patients who came off treatment early due to disease progression developed VTEs after stopping prophylactic apixaban. Quality of life analysis is ongoing. In this pilot study we found that prophylactic dosing of 2.5 mg twice daily of apixaban was safe in the post-operative period for patients with newly diagnosed MG. Our preliminary results suggest that this may be a safe and effective prevention strategy for VTE prophylaxis in this high risk group of patients.

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M42. INDEPENDENT REVIEW & MONITORING IMPROVES QUALITY OF PANSS DATA IN GLOBAL CLINICAL TRIALS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.354 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S150-S150

Author(s):

Barbara Echevarria ◽

Cong Liu ◽

Selam Negash ◽

Mark Opler ◽

Patricio Molero ◽

...

Keyword(s):

Clinical Trials ◽

Data Quality ◽

Working Group ◽

Double Blind Study ◽

Open Label ◽

Rater Training ◽

Double Blind ◽

Open Label Extension ◽

Expert Working Group ◽

Independent Review

Abstract Background The Positive and Negative Syndrome Scale (PANSS) (1) is the most widely used endpoint for measuring change in schizophrenia clinical trials. A set of flags have been developed by ISCTM expert working group to identify potential scoring errors in PANSS assessments (2). Measures have been taken by sponsors (pharmaceutical industry) with the goal of increasing scoring reliability and data quality, such as the use of Independent Review (IRev). We evaluated changes in data quality when site raters stop being recorded and monitored via IRev by comparing two studies with the same cohort of raters, one with independent review and one without. Methods Data from PANSS assessments in two global multisite schizophrenia clinical trials were analyzed. We selected data from raters participating in both studies (which run concurrently for a significant period of time). Raters were rigorously trained on administration and scoring conventions and certified prior to the study through demonstration of adequate interrater reliability. In addition to these steps, raters in study A were required to audio record all PANSS assessments with a selected subset of visits being subject to IRev. PANSS assessments in study B were neither recorded nor monitored via IRev. Data quality after study completion was examined by calculating the frequency of anomalous data patterns identified as “high” (very probable or definite error) by the ISCTM Working Group in both studies. Additionally, we examined the percentage of assessments with lower than expected PANSS interview duration as captured via an eCOA platform. Results There were 9441 eCOA PANSS assessments in study A and 6178 in study B included in this analysis. The proportions of flags that represented highly probable/definite error differed significantly between the studies (9% vs 18% for Study A and B, respectively, p<.01). The most significant differences in ISCTM flags were related to overly consistent scoring patterns (27 or more items scored identically to the prior visit) occurring with higher frequency in study B. Additionally, study B also had a significantly higher frequency of assessments flagged for low interview duration (< 15 minutes) (1% vs 4% for Study A and B, respectively, p<.01). Discussion Initial rater training is necessary but not sufficient to ensure adequate data quality in schizophrenia trials. Implementation of additional in-study oversight through Independent Review or similar methods reduces the probability of data error in PANSS assessments, including the appearance of improbable rating patterns and decreased time spent interviewing study subjects. One potential limitation is that study A is a double-blind study whereas study B is an open label extension of study A.

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