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Ketorolac in Postoperative Infants: Pharmacokinetics and Safety

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ClinicalTrials.gov Identifier: NCT01260883
Recruitment Status : Completed
First Posted : December 15, 2010
Results First Posted : August 8, 2012
Last Update Posted : June 13, 2013
Sponsor:
Collaborator:
University of Washington
Information provided by (Responsible Party):
Anne M. Lynn, Seattle Children's Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Care Provider, Investigator);   Primary Purpose: Treatment
Condition Postoperative Pain in Infants
Interventions Drug: Ketorolac Tromethamine 1 mg/kg
Drug: Ketorolac Tromethamine 0.5 mg/kg
Drug: Placebo
Enrollment 77
Recruitment Details Infants less than 18 months of age, having surgery requiring inpatient admission, from 2001 through 2008, with normal renal and liver function, not on chronic medication , not prematurely born, were selected.
Pre-assignment Details If screening lab studies (blood urea nitrogen [BUN], creatinine, liver transaminase concentrations, urinalysis) were abnormal infants were excluded. If postoperative concerns precluded blood sampling or if sampling intravenous (iv) catheters did not function, infants were excluded.Of 77 infants screened, 51 infants started study
Arm/Group Title Ketorolac 1 mg/kg Intravenous Ketorolac 0.5 mg/kg Intravenous Dextrose 5% in Water (D5W)
Hide Arm/Group Description intravenous infusion over 10 minutes intravenous infusion over 10 minutes intravenous infusion over 10 minutes
Period Title: Overall Study
Started 22 11 18
Completed 22 11 18
Not Completed 0 0 0
Arm/Group Title Ketorolac 1 mg/kg Intravenous Ketorolac 0.5 mg/kg Intravenous Dextrose 5% in Water (D5W) Total
Hide Arm/Group Description intravenous infusion over 10 minutes intravenous infusion over 10 minutes intravenous infusion over 10 minutes Total of all reporting groups
Overall Number of Baseline Participants 22 11 18 51
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 11 participants 18 participants 51 participants
<=18 years
22
 100.0%
11
 100.0%
18
 100.0%
51
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 22 participants 11 participants 18 participants 51 participants
8.9  (3.8) 9.4  (4.2) 9  (3.8) 9.1  (3.9)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 11 participants 18 participants 51 participants
Female
12
  54.5%
6
  54.5%
8
  44.4%
26
  51.0%
Male
10
  45.5%
5
  45.5%
10
  55.6%
25
  49.0%
[1]
Measure Description: while 77 infants were enrolled, exclusions during screening or lack of intravenous access precluding blood sampling eliminated 26 infants. Gender data was not collected for infants not randomized to receive drug or placebo.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 22 participants 11 participants 18 participants 51 participants
22 11 18 51
1.Primary Outcome
Title Clearance of S-ketorolac and R+ Ketorolac in 2-6 Month Old Infants Following Surgery
Hide Description stereo-isomer specific clearance determined by population-based pharmacokinetic analysis (NONMEM)
Time Frame 24 hours following surgery
Hide Outcome Measure Data
Hide Analysis Population Description
of 25 infants aged 2-6 months enrolled, 11 were excluded. 8 received drug, 6 received placebo; this is a subset of the 77 enrolled infants (aged 2-18 months) of whom 51 completed the study. Infants receiving drug at 0.5 or 1 mg/kg were reported together, since no difference in drug handling was seen.
Arm/Group Title S- Ketorolac Clearance R+ Ketorolac Clearance Placebo
Hide Arm/Group Description:
stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration, analyzed by NONMEM population pharmacokinetic methodology
stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
stereo-specific ketorolac isomer concentrations from blood samples collected for 12 hours after ketorolac intravenous administration,analyzed by population pharmacokinetic analysis (NONMEM)
Overall Number of Participants Analyzed 8 8 0
Mean (Standard Error)
Unit of Measure: ml/min
30.7  (22.8) 6.5  (2.2)
2.Primary Outcome
Title Central Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants
Hide Description stereo-specific ketorolac analysis using population-based analysis (NONMEM)for ketorolac given intravenously 24 hours after surgery in 2-6 month old infants
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
infants enrolled but did not complete protocol if abnormal laboratory studies or intravenous catheters were not functioning prior to study drug infusion. Of 77 enrolled, 51 completed study; of the 33 given ketorolac,8 were aged 2-6 months. Doses of 0.5 or 1 mg/kg were handled similarly so reported together.
Arm/Group Title S- Ketorolac Volume Distribution, Central R+ Ketorolac Volume Distribution, Central Placebo
Hide Arm/Group Description:
stereo-specific ketorolac analysis by NONMEM
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
Overall Number of Participants Analyzed 8 8 0
Mean (Standard Error)
Unit of Measure: ml
1480  (920) 992  (440)
3.Primary Outcome
Title Peripheral Volume of Distribution for S- and R+ Ketorolac in 2-6 Month Old Infants
Hide Description peripheral volume of distribution for ketorolac stereo-isomers determined by population kinetic analysis (NONMEM)
Time Frame 24 hours post surgery
Hide Outcome Measure Data
Hide Analysis Population Description
25 infants aged 2-6 months enrolled; 11 excluded for no sampling intravenous access. 8 infants received drug, 6 received placebo. No difference in analysis of doses of 0.5 or 1 mg/kg so reported together.
Arm/Group Title S- Ketorolac Volume Distribution, Peripheral R+ Ketorolac Volume Distribution, Peripheral Placebo
Hide Arm/Group Description:
stereo-specific ketorolac analysis by NONMEM
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
Overall Number of Participants Analyzed 8 8 0
Mean (Standard Deviation)
Unit of Measure: ml
341  (342) 658  (207)
4.Primary Outcome
Title Half-life of S- and R+ Ketorolac in 2-6 Month Old Infants
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
total infants enrolled was 77; 26 were excluded before study procedures began. Of 51 infants completing the study, 8 infants aged 2-6 months received drug.No difference in analysis at doses of 0.5 or 1 mg/kg so reported together.
Arm/Group Title S- Ketorolac Half-life R+ Ketorolac Half-life Placebo
Hide Arm/Group Description:
stereo-specific ketorolac analysis by NONMEM
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
Overall Number of Participants Analyzed 8 8 0
Mean (Standard Error)
Unit of Measure: min
67  (33) 197  (82)
5.Primary Outcome
Title Clearance of S- and R+ Ketorolac in 6-18 Month Old Infants
Hide Description stereo-specific ketorolac clearance by population-based analysis (NONMEM)
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
52 infants aged 6-18 months enrolled; 15 excluded for abnormal laboratory results or intravenous sampling catheters that did not allow sampling. 25 infants aged 6-18 months received ketorolac, 12 received placebo. Doses of 0.5 or 1 mg/kg reported together since no difference found in handling.
Arm/Group Title S- Ketorolac Clearance R+ Ketorolac Clearance Placebo
Hide Arm/Group Description:
stereo-specific ketorolac analysis by NONMEM
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
Overall Number of Participants Analyzed 25 25 0
Mean (Standard Error)
Unit of Measure: ml/min
45.3  (12.1) 7.52  (9.3)
6.Primary Outcome
Title Volume of Distribution for Ketorolac Isomers in 6-18 Month Old Infants
Hide Description population-based kinetic analysis of ketorolac isomers following intravenous infusion in infants after surgery
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
of 52 enrolled infants aged 6-18 months, 37 completed the study. Of these, 25 received drug, 12 placebo.Doses of 0.5 or 1 mg/kg showed no difference in handling so reported together.
Arm/Group Title S- Ketorolac Volume Distribution Central R+ Ketorolac Volume Distribution Central Placebo
Hide Arm/Group Description:
stereo-specific ketorolac analysis by NONMEM
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
Overall Number of Participants Analyzed 25 25 0
Mean (Standard Error)
Unit of Measure: ml
2320  (14.6) 1200  (13.6)
7.Primary Outcome
Title Ketorolac Stereo-isomer Volume of Distribution Peripheral in 6-18 Month Old Infants
Hide Description population-based analysis of ketorolac stereo-isomers
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac, 12 received placebo. Drug handling not different at doses of 0.5 or 1 mg/kg so reported together.
Arm/Group Title S- Ketorolac Volume Distribution, Peripheral R+ Ketorolac Volume Distribution, Peripheral Placebo
Hide Arm/Group Description:
stereo-specific ketorolac analysis by NONMEM
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
stereo-specific ketorolac analyzed by population kinetic (NONMEM)
Overall Number of Participants Analyzed 25 25 0
Mean (Standard Error)
Unit of Measure: ml
224  (86) 828  (13)
8.Primary Outcome
Title Half-life of Ketorolac Stereo-isomers in 6-18 Month Old Infants After Surgery
Hide Description noncompartmental pharmacokinetic analysis of ketorolac stereo-isomers after intravenous infusion in postoperative infants
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
52 infants of the 77 total were aged 6-18 months. 15 were excluded for abnormal laboratory values at screening or for lack of access to draw blood samples. 25 received drug, 12 placebo.Doses 0.5 or 1 mg/kg reported together since no difference in analysis.
Arm/Group Title S- Ketorolac Half-life R+ Ketorolac Half-life Placebo
Hide Arm/Group Description:
noncompartmental ketorolac analysis
noncompartmental analysis of stereo-isomers of ketorolac
noncompartmental analysis of stereo-isomers of ketorolac
Overall Number of Participants Analyzed 25 25 0
Mean (Standard Deviation)
Unit of Measure: min
50.1  (42) 238  (48)
9.Secondary Outcome
Title Morphine Use in 2-6 Month Old Infants Given Ketorolac or Placebo Following Surgery
Hide Description total morphine given intravenously in the 12 hours following receiving intravenous ketorolac or placebo
Time Frame first day after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
25 infants enrolled but 11 excluded. 8 received ketorolac, 6 placebo. total morphine given over 12 hours following infusion collected
Arm/Group Title Ketorolac 1 or 0.5 mg/kg Placebo
Hide Arm/Group Description:
infants receiving active drug intravenously after surgery
infants receiving placebo infusion intravenously after surgery
Overall Number of Participants Analyzed 8 6
Mean (Standard Deviation)
Unit of Measure: mg/kg
0.12  (0.28) 0.08  (0.12)
10.Secondary Outcome
Title Percent Time With Room Air Oximetry Saturations Under 90% in 2-6 Month Infants
Hide Description continuous oximetry monitoring of room air saturation was collected for 12 hours after intravenous infusion of ketorolac or placebo
Time Frame 12 hours after ketorolac or placebo infusion
Hide Outcome Measure Data
Hide Analysis Population Description
25 infants aged 2-6 months enrolled; 11 excluded. 8 received ketorolac, 6 placebo
Arm/Group Title Ketorolac 1 or 0.5 mg/kg Placebo
Hide Arm/Group Description:
infants given ketorolac intravenously after surgery
infants given placebo intravenously after surgery
Overall Number of Participants Analyzed 8 6
Median (Full Range)
Unit of Measure: percentage of time in 12 h after drug
NA [1] 
(2.1 to 7.3)
NA [1] 
(1.9 to 5.1)
[1]
Median not calculated due to small sample size
11.Secondary Outcome
Title Total Morphine Use in 6-18 Month Old Infants After Ketorolac or Placebo Intravenous Infusion After Surgery
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac and 12 received placebo infusion after surgery
Arm/Group Title Ketorolac 1 or 0.5 mg/kg Placebo Infusion
Hide Arm/Group Description:
infants receiving ketorolac infusion after surgery
infants receiving placebo infusion after surgery
Overall Number of Participants Analyzed 25 12
Mean (Standard Deviation)
Unit of Measure: mg/kg
1.8  (1.5) 2.2  (1.4)
12.Secondary Outcome
Title Oximetry Saturation Under 90% After Ketorolac or Placebo Infusion in 6-18 Month Old Infants
Time Frame 24 hours after surgery
Hide Outcome Measure Data
Hide Analysis Population Description
52 infants aged 6-18 months enrolled; 15 excluded. 25 received ketorolac, 12 received placebo
Arm/Group Title Ketorolac 1 or 0.5 mg/kg Placebo Infusion
Hide Arm/Group Description:
infants receiving ketorolac after surgery
infants receiving placebo infusion after surgery
Overall Number of Participants Analyzed 25 12
Mean (Standard Deviation)
Unit of Measure: per cent time of 12 hours
0.8  (0.8) 1  (1)
Time Frame 24 hours following surgery, monitoring for oximetry, blood loss, renal and liver function tests were done after drug infusion (active drug or placebo)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Ketorolac 1 mg/kg Intravenous Ketorolac 0.5 mg/kg Intravenous Dextrose 5% in Water (D5W)
Hide Arm/Group Description intravenous infusion over 10 minutes intravenous infusion over 10 minutes intravenous infusion over 10 minutes
All-Cause Mortality
Ketorolac 1 mg/kg Intravenous Ketorolac 0.5 mg/kg Intravenous Dextrose 5% in Water (D5W)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Ketorolac 1 mg/kg Intravenous Ketorolac 0.5 mg/kg Intravenous Dextrose 5% in Water (D5W)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/22 (0.00%)   0/11 (0.00%)   0/18 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Ketorolac 1 mg/kg Intravenous Ketorolac 0.5 mg/kg Intravenous Dextrose 5% in Water (D5W)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/22 (0.00%)   0/11 (0.00%)   0/18 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Anne Lynn MD
Organization: Seattle Children's Hospital
Phone: 206 987-2518
Responsible Party: Anne M. Lynn, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT01260883     History of Changes
Obsolete Identifiers: NCT00014716
Other Study ID Numbers: IND 59883
First Submitted: December 9, 2010
First Posted: December 15, 2010
Results First Submitted: July 20, 2011
Results First Posted: August 8, 2012
Last Update Posted: June 13, 2013