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Amicar Pharmacokinetics of Children Having Craniofacial Surgery

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

Tracking Information
First Submitted Date  ICMJE June 1, 2009
First Posted Date  ICMJE June 3, 2009
Last Update Posted Date November 1, 2012
Study Start Date  ICMJE May 2009
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History Complete list of historical versions of study NCT00912119 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Amicar Pharmacokinetics of Children Having Craniofacial Surgery
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Craniosynostosis
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 3, 2012)
18
Original Estimated Enrollment  ICMJE
 (submitted: June 2, 2009)
24
Actual Study Completion Date  ICMJE October 2011
Actual Primary Completion Date October 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Months to 24 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00912119
Other Study ID Numbers  ICMJE 08-007017
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Paul Stricker, Children's Hospital of Philadelphia
Study Sponsor  ICMJE Paul Stricker
Collaborators  ICMJE
  • Children's Anesthesiology Associates, Ltd.
  • Thomas B. and Jeannette E. Laws McCabe Fund Pilot Award
Investigators  ICMJE
Principal Investigator: Paul Stricker, MD Children's Hospital of Philadelphia
PRS Account Children's Hospital of Philadelphia
Verification Date October 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP