Amicar Pharmacokinetics of Children Having Craniofacial Surgery

• ClinicalTrials.gov Identifier: NCT00912119
• Recruitment Status: Completed
• First Posted: June 3, 2009
• Last Update Posted: November 1, 2012
• Sponsor: Paul Stricker
• 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

Tracking Information

• First Submitted Date: June 1, 2009
• First Posted Date: June 3, 2009
• Last Update Posted Date: November 1, 2012
• Study Start Date: May 2009
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 2, 2009): pharmacokinetic parameters of EACA including clearance, AUC0-∞, half-life, and volume of distribution [ Time Frame: 80 hours ]
• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT00912119 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 2, 2009)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Amicar Pharmacokinetics of Children Having Craniofacial Surgery
• Official Title: Pharmacokinetics of Epsilon-Aminocaproic Acid in Children Undergoing Craniofacial Reconstruction Surgery

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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Craniosynostosis

Intervention

• 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

Study Arms

• Experimental: Group A
  Group A - Low Dose
  Intervention: Drug: Epsilon-Aminocaproic Acid
• Experimental: Group B
  Group B - Intermediate Dose
  Intervention: Drug: Epsilon-Aminocaproic Acid
• Experimental: Group C
  Group C - High Dose
  Intervention: Drug: Epsilon-Aminocaproic Acid
• Experimental: Group D
  Group D - Extra Low
  Intervention: Drug: Epsilon-Aminocaproic Acid

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 3, 2012): 18
• Original Estimated Enrollment (submitted: June 2, 2009): 24
• Actual Study Completion Date: October 2011
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Months to 24 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00912119
• Other Study ID Numbers: 08-007017
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Paul Stricker, Children's Hospital of Philadelphia
• 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

• PRS Account: Children's Hospital of Philadelphia
• Verification Date: October 2012