Amicar Pharmacokinetics of Children Having Craniofacial Surgery

Phase 1

Completed

• Conditions: Craniosynostosis
• Interventions: Drug: Epsilon-Aminocaproic Acid

• Registration Number: NCT00912119
• Lead Sponsor: Paul Stricker

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.

Study Timeline

• Study Start: 2009-05
• Study First Submitted: 2009-06-01
• Study First Submitted QC: 2009-06-02
• Study First Posted: 2009-06-03
• Primary Completion: 2011-10
• Study Completion: 2011-10
• Status Verified: 2012-10
• Last Update Submitted: 2012-10-31
• Last Update Posted: 2012-11-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

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

Exclusion Criteria

1. Children with known or suspected hypersensitivity reaction to epsilon-aminocaproic acid

2. Subjects who do not have a parent or legal guardian who speaks English

3. Presence of a known coagulation abnormality

4. Presence of hematuria

5. Presence of a preoperative coagulation test abnormality (PT or PTT outside of normal range)

6. 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.

7. History of abnormal renal function

8. Serum creatinine or blood urea nitrogen (BUN) value outside of normal range (collected within 30 days of proposed EACA administration)

9. Initial intra-operative serum creatinine or BUN value outside of normal range

10. Children undergoing strip craniectomy for sagittal craniosynostosis

11. Presence of a preexisting neurologic deficit, seizure disorder, or other neurologic disorder

12. History of congenital cardiac disease (does not include patent ductus arteriosis, patent foramen ovale, or spontaneously closed muscular ventricular septal defect)

13. Children having other surgical procedures performed in addition to craniofacial reconstruction surgery

14. 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

15. Any investigational drug use within 30 days prior to proposed EACA administration.

16. Wards are not eligible for study

17. Children who have been previously enrolled in this study may not be enrolled again.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Group B	Epsilon-Aminocaproic Acid	Group B - Intermediate Dose
Group A	Epsilon-Aminocaproic Acid	Group A - Low Dose
Group C	Epsilon-Aminocaproic Acid	Group C - High Dose
Group D	Epsilon-Aminocaproic Acid	Group D - Extra Low

Primary Outcome Measures

Name	Time	Method
pharmacokinetic parameters of EACA including clearance, AUC0-∞, half-life, and volume of distribution	80 hours

Secondary Outcome Measures

Name	Time	Method
Volume of homologous blood (mL/kg) transfused postoperatively	72 hours
Safety and tolerability of EACA based on the occurrence of Adverse Events	720 hours
Volume of homologous blood (mL/kg) transfused intraoperatively	6 hours
Potentially defining a Maximum Tolerated Dose (MTD) for EACA in the stated population	6 hours

Trial Locations

Locations (1)

The Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States