Amicar Pharmacokinetics of Children Having Craniofacial Surgery

This study has been completed.
Sponsor:
Collaborators:
Children's Anesthesiology Associates, Ltd.
Thomas B. and Jeannette E. Laws McCabe Fund Pilot Award
Information provided by (Responsible Party):
Paul Stricker, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT00912119
First received: June 1, 2009
Last updated: October 31, 2012
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Craniosynostosis
Drug: Epsilon-Aminocaproic Acid
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Epsilon-Aminocaproic Acid in Children Undergoing Craniofacial Reconstruction Surgery

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • pharmacokinetic parameters of EACA including clearance, AUC0-∞, half-life, and volume of distribution [ Time Frame: 80 hours ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Volume of homologous blood (mL/kg) transfused postoperatively [ Time Frame: 72 hours ] [ Designated as safety issue: Yes ]
  • Volume of homologous blood (mL/kg) transfused intraoperatively [ Time Frame: 6 hours ] [ Designated as safety issue: Yes ]
  • Safety and tolerability of EACA based on the occurrence of Adverse Events [ Time Frame: 720 hours ] [ Designated as safety issue: Yes ]
  • Potentially defining a Maximum Tolerated Dose (MTD) for EACA in the stated population [ Time Frame: 6 hours ] [ Designated as safety issue: Yes ]

Enrollment: 18
Study Start Date: May 2009
Study Completion Date: October 2011
Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
Group A - Low Dose
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
Experimental: Group B
Group B - Intermediate Dose
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
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
Experimental: Group D
Group D - Extra Low
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

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.

  Eligibility

Ages Eligible for Study:   2 Months to 24 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00912119

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Paul Stricker
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
  More Information

No publications provided

Responsible Party: Paul Stricker, Assistant Professor for the University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT00912119     History of Changes
Other Study ID Numbers: 08-007017
Study First Received: June 1, 2009
Last Updated: October 31, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Hospital of Philadelphia:
craniofacial surgery
pharmacokinetics
cranial vault abnormalities
homologous blood products
wide scalp dissections
transfusion requirements

Additional relevant MeSH terms:
Craniosynostoses
Synostosis
Dysostoses
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Plagiocephaly
Congenital Abnormalities
Aminocaproic Acid
Antifibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hemostatics
Coagulants
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2014