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Amicar Pharmacokinetics of Children Having Craniofacial Surgery

Primary Purpose

Craniosynostosis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Epsilon-Aminocaproic Acid

About this trial

This is an interventional treatment trial for Craniosynostosis focused on measuring craniofacial surgery, pharmacokinetics, cranial vault abnormalities, homologous blood products, wide scalp dissections, transfusion requirements

Eligibility Criteria

2 Months - 24 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Males or females of every race and ethnicity ages 2 months- 24 months
Diagnosis - Craniosynostosis (including syndromic craniosynostosis)
Surgical procedure - Pediatric patients undergoing craniofacial reconstruction procedures involving a craniotomy
Written informed parent/guardian consent

Exclusion Criteria:

Children with known or suspected hypersensitivity reaction to epsilon-aminocaproic acid
Subjects who do not have a parent or legal guardian who speaks English
Presence of a known coagulation abnormality
Presence of hematuria
Presence of a preoperative coagulation test abnormality (PT or PTT outside of normal range)
Known history of a coagulation disorder in either parent. Children in whom this history is not available (e.g., adopted children) will be eligible for study inclusion.
History of abnormal renal function
Serum creatinine or blood urea nitrogen (BUN) value outside of normal range (collected within 30 days of proposed EACA administration)
Initial intra-operative serum creatinine or BUN value outside of normal range
Children undergoing strip craniectomy for sagittal craniosynostosis
Presence of a preexisting neurologic deficit, seizure disorder, or other neurologic disorder
History of congenital cardiac disease (does not include patent ductus arteriosis, patent foramen ovale, or spontaneously closed muscular ventricular septal defect)
Children having other surgical procedures performed in addition to craniofacial reconstruction surgery
Preoperative laboratory abnormalities that indicate clinically significant hematologic disease (collected within 30 days of proposed EACA administration):
Hemoglobin < 9 gm/dL Platelet count < 100,000/mm3
Any investigational drug use within 30 days prior to proposed EACA administration.
Wards are not eligible for study
Children who have been previously enrolled in this study may not be enrolled again.

Sites / Locations

The Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Group A

Group B

Group C

Group D

Arm Description

Group A - Low Dose

Group B - Intermediate Dose

Group C - High Dose

Group D - Extra Low

Outcomes

Primary Outcome Measures

pharmacokinetic parameters of EACA including clearance, AUC0-∞, half-life, and volume of distribution

Secondary Outcome Measures

Volume of homologous blood (mL/kg) transfused postoperatively

Volume of homologous blood (mL/kg) transfused intraoperatively

Safety and tolerability of EACA based on the occurrence of Adverse Events

Potentially defining a Maximum Tolerated Dose (MTD) for EACA in the stated population

Full Information

NCT ID

NCT00912119

First Posted

June 1, 2009

Last Updated

October 31, 2012

Sponsor

Paul Stricker

Collaborators

Children's Anesthesiology Associates, Ltd., Thomas B. and Jeannette E. Laws McCabe Fund Pilot Award

1. Study Identification

Unique Protocol Identification Number

NCT00912119

Brief Title

Amicar Pharmacokinetics of Children Having Craniofacial Surgery

Official Title

Pharmacokinetics of Epsilon-Aminocaproic Acid in Children Undergoing Craniofacial Reconstruction Surgery

Study Type

Interventional

2. Study Status

Record Verification Date

October 2012

Overall Recruitment Status

Completed

Study Start Date

May 2009 (undefined)

Primary Completion Date

October 2011 (Actual)

Study Completion Date

October 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Paul Stricker

Collaborators

Children's Anesthesiology Associates, Ltd., Thomas B. and Jeannette E. Laws McCabe Fund Pilot Award

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Craniofacial reconstruction surgery involves a surgical approach to the craniofacial region to repair cranial vault and facial deformities. The surgery is extensive, often requiring wide scalp dissections and multiple osteotomies and has been associated with significant morbidity. Some of the most severe and commonly seen problems are associated with the rate and extent of blood loss. Efforts to minimize surgical bleeding may translate to reduced transfusion requirements and a lessening of associated risks Epsilon-aminocaproic acid (EACA), an inhibitor of fibrinolysis, reduces transfusion requirements in children undergoing procedures on cardiopulmonary bypass (CPB), as well as in older children undergoing spinal surgery for scoliosis (1-6). Before controlled studies to assess efficacy of EACA in a craniofacial surgical population can be done, appropriate pharmacokinetic (PK) data are needed to determine the optimal dosing strategy. PK data exist for EACA in children undergoing operations on CPB and hypothermia. The aim of this study is to determine the pharmacokinetics of EACA in infants and children undergoing craniofacial reconstruction procedures.

Detailed Description

Craniosynostosis is the condition in which there is premature fusion of one or more of these sutures between the bones of the skull. Craniosynostosis limits the ability of the cranial vault to expand to accommodate the rapidly growing brain in infancy and early childhood. Deformation of skull shape results as cranial vault expansion occurs in areas of the skull that have not abnormally fused. Left uncorrected, craniosynostosis may adversely impact neurologic and psychosocial development. In some cases, increased intracranial pressure may also result. Craniofacial (CF) reconstruction procedures to treat craniosynostosis are undertaken in young children to improve appearance, prevent functional disturbances, and enhance psychosocial development. Optimal surgical results are achieved when these procedures are performed in infancy. These procedures are extensive, often requiring wide scalp dissections and multiple osteotomies and have been associated with significant morbidity. Reported complications include massive blood loss, intraoperative cardiac arrest, transfusion reactions, venous air embolism, hypotension, coagulopathy, bradycardia, postoperative seizures, surgical site infections, facial swelling, and unplanned postoperative mechanical ventilation (7-13). Many of the most severe and commonly seen problems are associated with the rate and extent of blood loss. Intraoperatively, the presence of hyperfibrinolysis has been demonstrated in children undergoing CF reconstruction procedures (8,14), although the extent of its contribution to bleeding is unclear. Epsilon-aminocaproic acid (EACA), another inhibitor of fibrinolysis, is an attractive alternative. EACA is a synthetic lysine analog that blocks the lysine binding sites on plasminogen, resulting in antifibrinolytic activity through inhibition of plasmin formation. We have chosen to study EACA in this population.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Craniosynostosis

Keywords

craniofacial surgery, pharmacokinetics, cranial vault abnormalities, homologous blood products, wide scalp dissections, transfusion requirements

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Experimental

Arm Description

Group A - Low Dose

Arm Title

Group B

Arm Type

Experimental

Arm Description

Group B - Intermediate Dose

Arm Title

Group C

Arm Type

Experimental

Arm Description

Group C - High Dose

Arm Title

Group D

Arm Type

Experimental

Arm Description

Group D - Extra Low

Intervention Type

Drug

Intervention Name(s)

Epsilon-Aminocaproic Acid

Other Intervention Name(s)

Amicar, 6-aminohexanoic acid

Intervention Description

Group C (high dose) will receive a loading dose of EACA of 100 mg/kg over ten minutes followed by a continuous EACA infusion at 40 mg/kg/hr, which will be continued until the end of surgery.

Intervention Type

Drug

Intervention Name(s)

Epsilon-Aminocaproic Acid

Other Intervention Name(s)

Amicar, 6-aminohexanoic acid

Intervention Description

Group A (low dose) will receive a loading dose of EACA of 25 mg/kg over ten minutes followed by a continuous EACA infusion at 10 mg/kg/hr, which will be continued until the end of surgery

Intervention Type

Drug

Intervention Name(s)

Epsilon-Aminocaproic Acid

Other Intervention Name(s)

Amicar, 6-aminohexanoic acid

Intervention Description

Group B (intermediate dose) will receive a loading dose of EACA of 50 mg/kg over ten minutes followed by a continuous EACA infusion at 20 mg/kg/hr, which will be continued until the end of surgery

Intervention Type

Drug

Intervention Name(s)

Epsilon-Aminocaproic Acid

Other Intervention Name(s)

Amicar, 6-aminohexanoic acid

Intervention Description

Group D (extra low dose) will receive a loading dose of EACA of 12.5 mg/kg over ten minutes followed by a continuous EACA infusion at 5 mg/kg/hr, which will be continued until the end of surgery

Primary Outcome Measure Information:

Title

pharmacokinetic parameters of EACA including clearance, AUC0-∞, half-life, and volume of distribution

Time Frame

80 hours

Secondary Outcome Measure Information:

Title

Volume of homologous blood (mL/kg) transfused postoperatively

Time Frame

72 hours

Title

Volume of homologous blood (mL/kg) transfused intraoperatively

Time Frame

6 hours

Title

Safety and tolerability of EACA based on the occurrence of Adverse Events

Time Frame

720 hours

Title

Potentially defining a Maximum Tolerated Dose (MTD) for EACA in the stated population

Time Frame

6 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Months

Maximum Age & Unit of Time

24 Months

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Males or females of every race and ethnicity ages 2 months- 24 months Diagnosis - Craniosynostosis (including syndromic craniosynostosis) Surgical procedure - Pediatric patients undergoing craniofacial reconstruction procedures involving a craniotomy Written informed parent/guardian consent Exclusion Criteria: Children with known or suspected hypersensitivity reaction to epsilon-aminocaproic acid Subjects who do not have a parent or legal guardian who speaks English Presence of a known coagulation abnormality Presence of hematuria Presence of a preoperative coagulation test abnormality (PT or PTT outside of normal range) Known history of a coagulation disorder in either parent. Children in whom this history is not available (e.g., adopted children) will be eligible for study inclusion. History of abnormal renal function Serum creatinine or blood urea nitrogen (BUN) value outside of normal range (collected within 30 days of proposed EACA administration) Initial intra-operative serum creatinine or BUN value outside of normal range Children undergoing strip craniectomy for sagittal craniosynostosis Presence of a preexisting neurologic deficit, seizure disorder, or other neurologic disorder History of congenital cardiac disease (does not include patent ductus arteriosis, patent foramen ovale, or spontaneously closed muscular ventricular septal defect) Children having other surgical procedures performed in addition to craniofacial reconstruction surgery Preoperative laboratory abnormalities that indicate clinically significant hematologic disease (collected within 30 days of proposed EACA administration): Hemoglobin < 9 gm/dL Platelet count < 100,000/mm3 Any investigational drug use within 30 days prior to proposed EACA administration. Wards are not eligible for study Children who have been previously enrolled in this study may not be enrolled again.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paul Stricker, MD

Organizational Affiliation

Children's Hospital of Philadelphia

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

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Amicar Pharmacokinetics of Children Having Craniofacial Surgery

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