Clinical trial NCT03669081
Conditions: Pain, Postoperative
Keywords: live kidney donor donor nephrectomy
Sponsor: University of Utah
Start date: 2016-09-20; Completion date: 2018-09-30
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators will assess how the use of toradol and pregabalin affects return to bowel function and see if there is a difference in length of hospital stay. Narcotic use can affect bowel function so the investigators hypothesize that use of Toradol will decrease delayed bowel function and aid in a patients discharge and reduction of hospital stay.

Detailed description:
Perioperative pain management is a significant challenge following surgery. Many pathways contribute to perioperative pain, including nociceptive, inflammatory, and neuropathic sources. Although opioids have long been a mainstay for perioperative analgesia, other non-opioid therapies have been increasingly used as part of a multimodal analgesic regimen to provide improved pain control while minimizing opioid-related side effects

TORADOL (ketorolac tromethamine), is a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults), management of moderately severe acute pain that requires analgesia at the opioid level.

Anecdotal evidence has shown that the use of Toradol (Ketorolac) is safe in renal surgery patients. The study team aims to further evaluate this in a pilot study specifically in the population of patient who have donated their kidney in live kidney transplants. The study team will assess how the use of toradol affects return to bowel function and see if there is a difference in length of hospital stay. Narcotic use can affect bowel function so the investigators hypothesize that use of Toradol will decrease delayed bowel function and aid in a patients discharge and reduction of hospital stay. The study team will assess differences in visual analog pain scores and total narcotic consumption, whereas secondary endpoints of urine output, serum creatinine and hemoglobin levels to assess for efficacy and safety.

Pregabalin is prescribed for neuropathic pain. In many studies, preoperative administration of pregabalin reduced postoperative morphine consumption and early postoperative pain.

There will be two arms of the study including:

Arm 1 (pure placebo group): Placebo oral preop then Saline placebo IV x 1 in the OR, then saline placebo IV every 6 hours for 7 doses.

Arm 2: Pregabalin 75mg oral preop, then Ketorolac 30 mg IV x 1 in the OR, then ketorolac 15 mg IV every 6 hours for 7 doses.

Toradol and Lyrica will be used consistent with its FDA approval in terms of dosing, route of administration, etc.

Arms: arm 1: Over-Encapsulated Pregabalin 75 mg was administered PO 30 minutes prior to operation; Ketorolac 30 mg IV x 1 was administered in the OR, followed by ketorolac 15 mg IV every 6 hours for 7 doses (or until discharge). arm 2: Identical placebo oral capsule (same size and color) was administered PO 30 minutes prior to operation; Saline placebo IV x 1 was administered in the OR, followed by saline placebo IV every 6 hours for 7 doses. Standard of care practices maintained.
Interventions: intervention 1: Ketorolac intervention 2: Pregabalin intervention 3: Placebo oral capsule intervention 4: Saline
Intervention descriptions: intervention 1: Ketorolac was administered intravenously: 30 mg in the operating room, and 15 mg every 6 hours for 7 doses post-operatively. intervention 2: Pregabalin was administered orally: 75 mg 30 minutes prior to operation. intervention 3: Placebo oral capsule was administered orally 30 minutes prior to operation. intervention 4: Saline was administered intravenously: once in the operating room, and every 6 hours for 7 doses post-operatively.

Protocol documents:
Prot_001.pdf: 
A prospective, double-blind, randomized pilot study evaluating the effects of Toradol 
and Lyrica verses placebo for pain control after donor nephrectomy  
Principal Investigator: Jeffrey Campsen, MD 
NCT03669081 
07/03/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Background and Introduction 
Perioperative pain management is a significant challenge following surgery. Many pathways contribute to perioperative pain, including nociceptive, 
inflammatory, and neuropathic sources. Although opioids have long been a mainstay for perioperative analgesia, other non-opioid therapies have 
been increasingly used as part of a multimodal analgesic regimen to provide improved pain control while minimizing opioid-related side effects 
TORADOL (ketorolac tromethamine), is a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults), 
management of moderately severe acute pain that requires analgesia at the opioid level. 
Anecdotal evidence has shown that the use of Toradol (Ketorolac) is safe in renal surgery patients (Grimsby, 2012). We aim to further evaluate this 
in a pilot study specifically in the population of patient who have donated their kidney in live kidney transplants. We will assess how the use of 
toradol affects return to bowel function and see if there is a difference in length of hospital stay. Narcotic use can affect bowel function so we 
hypothesize that use of Toradol will decrease delayed bowel function and aid in a patients discharge and reduction of hospital stay. We will assess 
differences in visual analog pain scores and total narcotic consumption, whereas secondary endpoints of urine output, serum creatinine and 
hemoglobin levels to assess for efficacy and safety.  
Pregabalin is prescribed for neuropathic pain. In many studies, preoperative administration of pregabalin reduced postoperative morphine 
consumption and early postoperative pain.  
There will be two arms of the study including: 
 Arm 1 (pure placebo group): Placebo oral preop then Saline placebo IV x 1 in the OR, then saline placebo IV every 6 hours for 7 doses. 
 Arm 2: Pregabalin 75mg oral preop, then Ketorolac 30 mg IV x 1 in the OR, then ketorolac 15 mg IV every 6 hours for 7 doses. 
Toradol and Lyrica will be used consistent with its FDA approval in terms of dosing, route of administration, etc. 
Purpose and Objectives 
The study is seeking to understand how the use of Toradol/ Lyrica in live donor nephrectomies affects: 
1) 
Reduce/ minimize narcotic use 
2) 
Return to bowel function 
3) 
Shortened hospital stay 
4) 
Ensure proper kidney function 
Study Population 
Age of Participants: 18+ 
Sample Size: 
At Utah: 
62  
All Centers: 
n/a 
Inclusion Criteria: 
Patients who are 18 years or older and able to provide informed consent and who are anticipated donating a kidney in a live donor kidney transplant. 
Both male and female patients will be included. 
Exclusion Criteria: 
Patients who are not able to provide informed consent, younger than 18, not receiving a donor nephrectomy, pregnant, lactating or nursing mothers, 
medical allergies or history that would otherwise be contraindicated for use of a nonsteroidal anti-inflammatory drug. 
Design  
Prospective Clinical Research 
Double Blind 
Placebo Controlled 


Randomized 
Study Procedures 
Recruitment/Participant Identification Process: 
Study team will identify patients who are scheduled for live donor kidney transplant- donor nephrectomies. A review of their medical record will be 
performed to look for inclusion/exclusion criteria. Patient will then be approached and have the study explained to them through the informed 
consent process. No study procedures will be initiated until informed consent is obtained.  
Informed Consent: 
Description of location(s) where consent will be obtained:  
Transplant clinic and pre-operative suite. 
Description of the consent processes(es), including the timing of consent: 
Patients will be approached before their donor nephrectomy about the study. They will have sufficient time to understand study and 
procedures as well as risks and benefits. Time for questioning will be available. They will be allowed as much time as needed for the 
decision process. A return visit before the operation can be held if necessary. 
Procedures: 
Study team will identify patients who are scheduled for live donor kidney transplant- donor nephrectomies. A review of their medical record will be 
performed to look for inclusion/exclusion criteria. A pregnancy test will be performed on eligible females. Patient will then be approached and have 
the study explained to them through the informed consent process. No study procedures will be initiated until informed consent is obtained. 
Once consented, patients will be randomized in a 1:1 manner by investigational drug pharmacy and assigned to a study arm. 
 Arm 1 (pure placebo group): Placebo oral preop then Saline placebo IV x 1 in the OR, then saline placebo IV every 6 hours for 7 doses. 
 Arm 2: Pregabalin 75mg oral preop, then Ketorolac 30 mg IV x 1 in the OR, then ketorolac 15 mg IV every 6 hours for 7 doses. 
Patients will be followed by study staff for 30 days to determine narcotic use, length of hospital stay, and return of bowel function (which is obtained 
by review of daily progress reports).  
This study will be conducted in addition to standard pain protocols for patients ie: no patients will be deprived of pain medication following surgery. 
The Transplant team develops the pain med protocol for each individual patients needs based on allergy history, former narcotic tolerance/preference 
due to side effects, etc. and in conjunction with the pain management team recommendations. Therefore, it is possible that Toradol could be given as 
part of a patients personalized pain management regime and Toradol is approved by the FDA for this group, but this study is standardizing it for all 
donor nephrectomy patients. Lyrica is typically used during a patient's anesthesia course in the operative period. However, there is no standardized 
protocol for anesthesia for a patient, it is left up to the individual anesthesiologist, so again this study would just standardize its use in this particular 
group. 
Procedures performed for research purposes only:  
Only administration of Toradol/ Lyrica vs. placebo will be non-standard of care procedures. The donor nephrectomy and subsequent care will be 
standard of care.  
This study will be conducted in addition to standard pain protocols for patients ie: no patients will be deprived of pain medication following surgery. 
The Transplant team develops the pain med protocol for each individual patients needs based on allergy history, former narcotic tolerance/preference 
due to side effects, etc. and in conjunction with the pain management team recommendations. Therefore, it is possible that Toradol could be given as 
part of a patients personalized pain management regime and Toradol is approved by the FDA for this group, but this study is standardizing it for all 
donor nephrectomy patients. Lyrica is typically used during a patient's anesthesia course in the operative period. However, there is no standardized 
protocol for anesthesia for a patient, it is left up to the individual anesthesiologist, so again this study would just standardize its use in this particular 
group. 
Statistical Methods, Data Analysis and Interpretation 
Randomization will be stratified based on whether receiving a left or right kidney during their standard of care. 


Study team is working with SDBC biostatistician for data analysis.  
Simple t-statistics and chi-squared data analysis will be performed for primay and secondary endpoints. 
Power calculation is based off of the average number of donors per year and the endpoints of kidney function and narcotic use.  
 
 

SAP_000.pdf: 
 
 
Study Design and Biostatistics Center 
Center for Clinical and Translational Science 
A prospective, double-blind, randomized pilot study evaluating the effects of 
Toradol versesplacebo for pain control after donor nephrectomy.[820] 
Principal Investigator:  Jeffrey Campsen/Eddie Martinez 
SAP Author:  Angela P. Presson 
Project Lead: Chelsea Allen 
Additional Statistician(s):  
Date:  10/31/2017 
Introduction 
This is a randomized controlled trial (RCT) comparing placebo to toradol treatment for pain control 
after donor nephrectomy. The primary outcomes of interest include narcotic use and length of stay 
(LOS), where the hypothesis is that toradol will reduce post-operative narcotic use and LOS.  The study 
was powered on the safety outcome allowing for a limited creatinine increase on post-operative day 
1.  The rationale being that regardless of toradol efficacy, if it was not safe to use then it would not be 
adopted into clinical practice.  
Investigator’s Description 
Completed pilot study now need power calculation for a prospective, double-blind, randomized pilot 
study evaluating the effects of Toradol, and Lyrica verses placebo for pain control after donor 
nephrectomy. 
 
Project Endpoints 
Paper, ASTS abstract 11/22/17 
Data 
The raw data set is at: Campsen_Jeffrey_820_toradol_rct\Data\Raw\Torpedo II Study.xlsx, the analysis 
data set is: Campsen_Jeffrey_820_toradol_rct\Data\Torpedo II Study - Recoded.xlsx.   
Exposure Variables 
The variable “group” in the analysis data set describes the exposure group, toradol versus placebo.   
Outcomes 
cr.ratio = Construct this safety outcome of fold change in creatinine within the toradol group (pre-
op/post op day 1), constructed from the variables cr.pre and cr.pod1. 


cum.me = The post-operative narcotic usage outcome in morphine equivalents (ME).  
postop.los = Hospital LOS. 
Inclusion/Exclusion 
None, all patients in the data set were included in the analysis 
Research Objectives 
1. Compare patient characteristics: age, height, weight, bmi, sex, race, operative time, side, opioid 
usage, hct pre, hct pacu, hct pod1, hct diff, hct ratio, cr pre, cr pod1, cr ratio, postop nausea, 
failed foley and postop LOS between toradol and control groups. 
2. Assess the creatinine safety outcome using a non-inferiority test that the fold change is at most 
two-fold, or alternatively for the pre-surgery creatinine group to be ≥0.5 times the post-surgery. 
Analyses 
1. For the comparison of patient characteristics, we will use the R functions developed by our 
center to implement simple statistical tests selected from the following options: 1=t.test, 
2=Wilcox, 3=Chi-square, 4=Fisher's exact, 5=Fisher's exact test with simulation, 6=Exact wilcoxon 
rank sum test.  The following table indicates our results and which test was used for which 
variable.  
 
Table 1. Summary by group.    
Variable* 
placebo (N=29) 
Toradol (N=33) 
P-value 
Test 
age - Mean (SD) 
45.1 (12.2) 
43.8 (11) 
0.68 
1 
  -Median (IQR) 
44 (35, 53) 
42 (34, 52) 
- 
- 
  -Range 
(26, 69) 
(25, 66) 
- 
- 
height - Mean (SD) 
171.6 (8.9) 
169.9 (9.4) 
0.47 
1 
  -Median (IQR) 
170.2 (166.4, 179) 
170.2 (162.6, 172.7) 
- 
- 
  -Range 
(154.9, 190.5) 
(156, 195.6) 
- 
- 
weight - Mean (SD) 
79.6 (13.3) 
77.7 (16.3) 
0.62 
1 
  -Median (IQR) 
80.3 (70.5, 88.9) 
77.4 (64.5, 88) 
- 
- 
  -Range 
(56.2, 109) 
(50.9, 123) 
- 
- 
bmi - Mean (SD) 
26.9 (3.2) 
26.6 (4.7) 
0.76 
1 
  -Median (IQR) 
27.3 (24, 28.9) 
27.5 (22.1, 30) 
- 
- 
  -Range 
(21, 33.4) 
(17.1, 34.8) 
- 
- 
sex -Female 
17 (59%) 
26 (79%) 
0.086 
3 
   Male 
12 (41%) 
7 (21%) 
- 
- 
race -American Indian and Alaska Native 
0 (0%) 
1 (3%) 
0.4 
4 
Black or African American 
0 (0%) 
1 (3%) 
- 
- 
Other 
3 (10%) 
1 (3%) 
- 
- 
White-Caucasion 
26 (90%) 
29 (91%) 
- 
- 
ethnicity -Hispanic/Latino 
2 (7%) 
2 (6%) 
>0.99 
4 
   Not Hispanic/Latino 
27 (93%) 
29 (94%) 
- 
- 
optime -Mean (SD) 
129.3 (30) 
124.7 (27.8) 
- 
- 
 -Median (IQR) 
124 (110, 135) 
116 (110, 128) 
0.33 
6 
  -Range 
(80, 200) 
(99, 245) 
- 
- 
side -Left 
20 (69%) 
25 (76%) 
0.55 
3 
   Right 
9 (31%) 
8 (24%) 
- 
- 
cum.me -Mean (SD) 
62.9 (65.2) 
31.1 (25.5) 
- 
- 
 -Median (IQR) 
45 (25, 70.8) 
27 (13, 42.3) 
0.006 
6 


Variable* 
placebo (N=29) 
Toradol (N=33) 
P-value 
Test 
  -Range 
(10.7, 343.8) 
(0.7, 111) 
- 
- 
hct.pre - Mean (SD) 
44.1 (2.8) 
43.5 (3) 
0.4 
1 
  -Median (IQR) 
44.5 (42.1, 45.6) 
43.1 (41.5, 44.8) 
- 
- 
  -Range 
(38.3, 51) 
(38.7, 50) 
- 
- 
hct.pacu - Mean (SD) 
41.8 (3.4) 
39.9 (3.2) 
0.023 
1 
  -Median (IQR) 
42.2 (39.4, 44.3) 
39.5 (38.3, 40.8) 
- 
- 
  -Range 
(34.9, 47) 
(34.4, 48.3) 
- 
- 
hct.pod1 - Mean (SD) 
39.8 (3.5) 
37.2 (2.7) 
0.002 
1 
  -Median (IQR) 
40.1 (37.5, 42.4) 
36.9 (35.9, 38.2) 
- 
- 
  -Range 
(33.6, 45.7) 
(32.6, 46.3) 
- 
- 
hct.diff - Mean (SD) 
4.3 (2.5) 
6.3 (2.1) 
0.002 
1 
  -Median (IQR) 
4.7 (2.5, 5.7) 
6.4 (5, 7.3) 
- 
- 
  -Range 
(-1.9, 9.5) 
(1.7, 12.5) 
- 
- 
hct.ratio - Mean (SD) 
1.1 (0.1) 
1.2 (0.1) 
<0.001 
1 
  -Median (IQR) 
1.1 (1.1, 1.2) 
1.2 (1.1, 1.2) 
- 
- 
  -Range 
(1, 1.3) 
(1, 1.3) 
- 
- 
cr.pre - Mean (SD) 
0.9 (0.1) 
0.8 (0.2) 
0.65 
1 
  -Median (IQR) 
0.9 (0.8, 0.9) 
0.8 (0.7, 0.9) 
- 
- 
  -Range 
(0.6, 1.1) 
(0.6, 1.2) 
- 
- 
cr.pod1 - Mean (SD) 
1.3 (0.3) 
1.3 (0.3) 
0.87 
1 
  -Median (IQR) 
1.2 (1.1, 1.5) 
1.2 (1.1, 1.4) 
- 
- 
  -Range 
(0.8, 1.9) 
(0.9, 1.9) 
- 
- 
cr.ratio - Mean (SD) 
0.7 (0.1) 
0.6 (0.1) 
0.19 
1 
  -Median (IQR) 
0.7 (0.6, 0.7) 
0.6 (0.6, 0.7) 
- 
- 
  -Range 
(0.5, 1) 
(0.5, 0.8) 
- 
- 
postop.nasea -N 
5 (17%) 
8 (24%) 
0.5 
3 
   Y 
24 (83%) 
25 (76%) 
- 
- 
failedfoley -N 
29 (100%) 
32 (97%) 
>0.99 
4 
   Y 
0 (0%) 
1 (3%) 
- 
- 
postop.los -Mean (SD) 
56.1 (16) 
50 (13.5) 
- 
- 
 -Median (IQR) 
57.3 (50.6, 66.3) 
51.5 (46.5, 56) 
0.029 
6 
  -Range 
(26.4, 82.2) 
(23.6, 81.1) 
- 
- 
 
*Missing values:  race =1, ethnicity =2, 
Test: 1=t.test, 2=Wilcox, 3=Chi-square, 4=Fisher's exact, 5=Fisher's exact test with simulation, 6=Exact 
wilcoxon rank sum test 
 
2. The safety analysis was conducted using a 1-sided t-test compared to a 0.5 fold change.  Here 
are the results: 
 
A one-sided t-test shows that the pre-surgery creatinine increase over the post-surgery measure 
ቀ
HCT Pre−OP
HCT Post−OP Day 1ቁ  within the Toradol group has a mean fold change of 0.64 (95% CI: 0.62, 0.66), which 
is over the safety level of a 0.5 fold change (because this is pre/post). The p-value for this test is less 
than 0.0001, thus the Toradol group meets the safety threshold. 
 
Power Calculation 
The primary safety outcome is defined by a creatinine increase on post-operative day 1 of at most 100% 
(ie, twice the pre surgery measure) in the toradol group.  To achieve 90% power at a 2.5% significance 
level for testing that the post-surgery creatinine increase is at most two-fold (where 1.5 fold is expected), 
or alternatively for the pre-surgery creatinine group to be ≥0.5 times the post-surgery, we need 17 subjects 
in the toradol group. This calculation was based on a non-inferiority test (one sided t-test). 
Quality Control (QC) Plans 
The analysis plan and code was reviewed by two independent statisticians.  


SDBC Information 
Please remember to acknowledge the SDBC: "This investigation was supported by the University of Utah 
Study Design and Biostatistics Center, with funding in part from the National Center for Research 
Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, 
through Grant 8UL1TR000105 (formerly UL1RR025764).". 
 
 
The University of Utah 
Study Design and Biostatistics Center 
Center for Clinical and Translational Science 
http://www.ccts.utah.edu/biostats/