Amicar Pharmacokinetics of Children Having Craniofacial Surgery

October 31, 2012 updated by: Paul Stricker

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • The Children's Hospital of Philadelphia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 months to 2 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A
Group A - Low Dose
Drug: Epsilon-Aminocaproic Acid
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.
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Experimental: Group B
Group B - Intermediate Dose
Drug: Epsilon-Aminocaproic Acid
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.
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Experimental: Group C
Group C - High Dose
Drug: Epsilon-Aminocaproic Acid
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.
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Experimental: Group D
Group D - Extra Low
Drug: Epsilon-Aminocaproic Acid
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.
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid
Drug: Epsilon-Aminocaproic Acid
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
Other Names:
  • Amicar
  • 6-aminohexanoic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
pharmacokinetic parameters of EACA including clearance, AUC0-∞, half-life, and volume of distribution
Time Frame: 80 hours
80 hours

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Paul Stricker

Collaborators

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

Investigators

  • Principal Investigator: Paul Stricker, MD, Children's Hospital of Philadelphia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2009

Primary Completion (Actual)

October 1, 2011

Study Completion (Actual)

October 1, 2011

Study Registration Dates

First Submitted

June 1, 2009

First Submitted That Met QC Criteria

June 2, 2009

First Posted (Estimate)

June 3, 2009

Study Record Updates

Last Update Posted (Estimate)

November 1, 2012

Last Update Submitted That Met QC Criteria

October 31, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 08-007017

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Craniosynostosis

Clinical Trials on Epsilon-Aminocaproic Acid

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Nigeria

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe