A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist (VKA) or Low Molecular Weight Heparin (LMWH) in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation

Thrombosis Clinical Trial

Official title:

A Prospective, Randomized, Open Label, Multi-center Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist or LMWH in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Chronic Anticoagulation for Thromboembolism Prevention

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02981472
• Other study ID #: CV185-362
• Secondary ID: 2016-001247-39
• Status: Completed
• Phase: Phase 2
• Start date: January 19, 2017
• Est. completion date: October 18, 2021

Study information

• Verified date: September 2022
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To investigate the safety and pharmacokinetics of apixaban in children with congenital or acquired heart disease who have a need for anticoagulation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 192
• Est. completion date: October 18, 2021
• Est. primary completion date: October 18, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 28 Days to 17 Years

Eligibility

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Males and Females, 28 days to < 18 years of age, inclusive

• Congenital or acquired heart diseases requiring chronic anticoagulation for thromboprophylaxis (eg, single ventricle physiology including all 3 stages of palliation, dilated cardiomyopathy, Kawasaki disease with coronary aneurysms, and pulmonary hypertension)

• Eligible participants include those who newly start anticoagulants and those who are currently on VKA or LMWH or other anticoagulants for thromboprophylaxis

• Able to tolerate enteral medication [eg, by mouth, nasogastric tube, or gastric tube]

• Participants 28 days to < 3 months must be able to tolerate oral/nasogastric tube (NGT)/gastric tube (GT) feeds for at least 5 days prior to randomization

Exclusion Criteria:

• Recent thromboembolic events less than 6 months prior to enrollment

• Weight < 3 kg

• Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) at the time of enrollment

• Artificial heart valves and mechanical heart valves

• Known inherited bleeding disorder or coagulopathy (e.g. hemophilia, von Willebrand disease, etc.)

• Active bleeding at the time of enrollment

• Any major bleeding other than perioperative in the preceding 3 months

• Known intracranial congenital vascular malformation or tumor

• Confirmed diagnosis of a GI ulcer

• Known antiphospholipid syndrome (APS).

Other protocol defined inclusion/exclusion criteria apply

Related Conditions & MeSH terms

• Heart Diseases
• Thrombosis

Intervention

Drug:
• Apixaban
Specified dose on specified days
• Vitamin K Antagonist (VKA)
Specified dose on specified days
• Low Molecular Weight Heparin (LMWH)
Specified dose on specified days

Locations

Country	Name	City	State
Argentina	Local Institution	Caba	Buenos Aires
Australia	Local Institution - 0030	Parkville	Victoria
Austria	Local Institution - 0001	Vienna
Brazil	Local Institution - 0020	Campinas	Sao Paulo
Brazil	Local Institution - 0022	Curitiba	Parana
Brazil	Instituto De Cardiologia Do Rio Grande Do Sul	Porto Alegre	Rio Grande Do Sul
Brazil	Instituto de Pesquisa PENSI	Sao Paulo
Brazil	Universidade Federal De Sao Paulo	Sao Paulo
Canada	Local Institution - 0015	Toronto	Ontario
Finland	Local Institution - 0031	HUS
Germany	Local Institution - 0002	Freiburg
Germany	Local Institution - 0004	Hamburg
Germany	Local Institution - 0003	Muenchen
Israel	Local Institution - 0047	Petach Tikva
Israel	Local Institution - 0046	Tel Hashomer
Italy	Local Institution - 0028	Bologna
Italy	Local Institution - 0027	Milano
Italy	Local Institution - 0026	Rome	Roma
Mexico	Local Institution - 0044	Leon	Guanajuato
Mexico	Local Institution - 0016	Mexico City	Distrito Federal
Mexico	Local Institution - 0018	Mexico City	Distrito Federal
Mexico	Local Institution - 0019	Mexico City	Distrito Federal
Russian Federation	Local Institution - 0062	Ekaterinburg
Russian Federation	Local Institution	Kazan
Russian Federation	Local Institution	Kemerovo
Russian Federation	Local Institution - 0057	Novosibirsk
Spain	Local Institution - 0049	Barcelona
Spain	Local Institution	Madrid
Spain	Local Institution - 0048	Madrid
United Kingdom	Local Institution - 0042	Bristol	Somerset
United Kingdom	Local Institution - 0040	Leicester	Leicestershire
United Kingdom	Local Institution	Manchester
United States	Local Institution - 0013	Ann Arbor	Michigan
United States	Childrens Healthcare Of Atlanta	Atlanta	Georgia
United States	Children'S Hospital Colorado	Aurora	Colorado
United States	Local Institution - 0009	Boston	Massachusetts
United States	Local Institution - 0012	Charleston	South Carolina
United States	Local Institution - 0006	Cincinnati	Ohio
United States	Local Institution - 0011	Houston	Texas
United States	Local Institution - 0008	Indianapolis	Indiana
United States	Childrens Mercy Hospital	Kansas City	Missouri
United States	University Of California San Diego	La Jolla	California
United States	Childrens Hospital Of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children'S Hospital	Phoenix	Arizona
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Local Institution - 0055	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Bristol-Myers Squibb	Pediatric Heart Network, Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Brazil,  Canada,  Finland,  Germany,  Israel,  Italy,  Mexico,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events	The number of participants with adjudicated major or CRNM bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Events are adjudicated by a blinded, independent events adjudication committee (EAC).; Major bleeding satisfies one or more of the following criteria: fatal bleeding, clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS, or bleeding that requires surgical intervention in an operating suite, including interventional radiology.; CRNM bleeding satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition or bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room.	From first dose to 2 days after last dose (Up to approximately 12 months)
Secondary	The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death	The number of participants with thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, pulmonary embolism (PE), stroke, other arterial or venous thromboembolic events, etc.) and thromboembolic event-related death detected by imaging or clinical diagnosis.; Death and thromboembolic events are adjudicated by a blinded, independent events adjudication committee (EAC)	From randomization to 2 days after last dose (Up to approximately 12 months)
Secondary	The Number of Participants With Adjudicated Major Bleeding	The number of participants with adjudicated major bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC).; Major bleeding is defined as bleeding that satisfies one or more of the following criteria: fatal bleeding; clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period; bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; bleeding that requires surgical intervention in an operating suite, including interventional radiology	From first dose to 2 days after last dose (Up to approximately 12 months)
Secondary	The Number of Participants With Adjudicated CRNM Bleeding	The number of participants with adjudicated clinically relevant non-major (CRNM) bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. CRNM bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC).; CRNM bleeding is defined as bleeding that satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition; bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room	From first dose to 2 days after last dose (Up to approximately 12 months)
Secondary	The Number of Participants With All Adjudicated Bleeding	The number of participants with all adjudicated bleeding events	From first dose to 2 days after last dose (Up to approximately 12 months)
Secondary	The Number of Participants With Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding	The number of participants with drug discontinuation due to adverse effects, intolerability, or bleeding.	From first dose to 2 days after last dose (Up to approximately 12 months)
Secondary	The Number of Participant Deaths in the Study	The number of participant deaths in the study.	From first dose to 2 days after last dose (Up to approximately 12 months)
Secondary	Maximum Observed Concentration (Cmax)		From first dose up to 6 months after first dose
Secondary	Trough Observed Concentration (Cmin)		From first dose up to 6 months after first dose
Secondary	Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU))		From first dose up to 6 months after first dose
Secondary	Time of Maximum Observed Concentration (Tmax)		From first dose up to 6 months after first dose
Secondary	Anti-FXa Activity	Anti-FXa Activity was measured to assess participant plasma apixaban levels.; 125 participants received at least one dose of apixaban and had anti-FXa samples collected that contributed measurements to at least one of the timepoints below.	From first dose up to 6 months after first dose
Secondary	Chromogenic FX Assay (Apparent FX Level)	Chromogenic FX was measured to assess (apparent) FX levels in participants and inhibition of FXa by apixaban.; 125 participants received at least one dose of apixaban and had chromogenic FX assay samples collected that contributed measurements to at least one of the timepoints below.	From first dose up to 6 months after first dose
Secondary	The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL)	Subjects' quality of life was measured using the PedsQL instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses.; PedsQL consists of 23 items scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or for the child report for younger children ages 5-7, a 3-point Likert scale: 0 (Not at all), 2 (Sometimes), and 4 (A lot).; Scores are reverse scored and transformed to a 0-100 scale as follows: 0=100, 1=75, 3=25, 4=0. Higher scores indicate a better HRQOL and/or lower problems.	from randomization up to 12 months after randomization
Secondary	Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score	Subjects' quality of life was measured using the KIDCLOT instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses.; KIDCLOT Parent inventory uses a 5 point Likert scale from 1 (N/A), 2 (Never), 3 (Rarely), 4 ( Now and then), 5 (Often). Child inventory uses a 4 point Likert scale 1 (N/A), 2 (Never), 3 (Now and then), 5 (Always). Values are scores as follows 1=0, 2=1, 3=2, 4=3, 5=4. Score interpretation is 0 to 100 percent IMPACT of anticoagulation on a child's life therefore, higher scores indicates a more negative effect.	from randomization up to 12 months after randomization

External Links

•   BMS Clinical Trial Information
•   BMS Clinical Trial Patient Recruiting
•   FDA Safety Alerts and Recalls