Clinical trial NCT03365622
Conditions: Nephrectomy
Sponsor: University of Rochester
Start date: 2018-08-08; Completion date: 2024-04-10
Enrollment: 214 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to determine whether intravenous acetaminophen compared to enteric acetaminophen offers increased efficacy in patients who are scheduled for laparoscopic donor nephrectomy and for patients scheduled for robot-assisted, laparoscopic nephrectomy for cancer at the University of Rochester Medical Center. The standard surgical and post-operative care, including post-operative pain management will not be altered.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: acetaminophen intervention 2: Acetaminophen intervention 3: Placebos intervention 4: Placebo Oral Tablet
Intervention descriptions: intervention 1: Active Intravenous doses will consist of a single 1,000mg/100 ml IV dose with contents of commercial vials transferred to an empty sterile IV bag. intervention 2: 500mg acetaminophen tablet ,2 capsules oral every six hours for 24 hours intervention 3: Placebo Intravenous doses will consist of 100ml of normal saline transferred to an empty sterile IV bag. intervention 4: Placebo, opaque capsules that have been filled with inert powder (lactose USP), 2 capsules oral every six hours for 24 hours

Protocol documents:
Prot_SAP_000.pdf: 
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Efficacy of IV Acetaminophen Versus Oral 
Acetaminophen 
 
Study Protocol and Statistical Analysis 
 
NCT03365622 
 
Date: 1-13-2023 
 


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Randomized, Double-Blind Clinical Study Evaluating Efficacy of Intravenous versus 
Enteric Acetaminophen in Donor Nephrectomy and Robot-Assisted, Laparoscopic 
Nephrectomy. 
Principal Investigator:  Joseph Dooley, MD  
1. 
 BACKGROUND, PURPOSE and OBJECTIVES OF THE STUDY  
1.1 
Background:  
Obtaining effective postoperative analgesia following major surgery can be difficult. Nonnarcotic 
regimens have been applied to specific procedures to improve outcomes. Intravenous 
acetaminophen may be more efficacious for the management of postoperative pain than oral 
acetaminophen.    
There is not a large body of literature addressing this subject.  A literature search was done 
through Miner Library through PubMed and Embase using the following strategies:  “Infusions, 
Intravenous” [Mesh] OR “Administration, Intravenous” [Mesh] OR “Injections, Intravenous” 
[Mesh] AND “administration, oral AND elective surgery AND acetaminophen” yielded only 12.  
Of those, only two were relevant.  One study compared plasma levels following IV or oral 
administration of acetaminophen.  Another study was similar to our proposed trial but compared 
IV versus oral tramadol. 
A search through Clinicaltrials,gov showed that several groups (12 trials) are studying this topic 
(comparing IV versus oral acetaminophen) but are studying different populations (laparoscopic 
cholecystectomy, hip fracture, total hip replacement, total knee replacement, lumbar 
discectomy, cesarean section).  Of these, only 4 are double blind. 
In summary, we feel that the proposed study will add knowledge to the field. 
1.2.  
Purpose of the Study:  
The aim of this study is to compare pain control for oral and intravenous acetaminophen for 
post-operative pain control in patients who undergo either (1) donor nephrectomy, or (2) 
nephrectomy for cancer.  Many clinicians believe that intravenous acetaminophen is superior to 
enteral acetaminophen for the management of perioperative pain. However, the intravenous 
formulation of acetaminophen is six-hundred times more expensive than the enteral form. To 
date, there is no empiric evidence that IV acetaminophen provides superior pain relief than PO 
acetaminophen which could be used to justify the higher cost of the IV formulation. Our 
objective is to conduct a pragmatic RCT to determine whether IV acetaminophen provides 
superior pain control compared to PO acetaminophen in the setting of routine clinical practice.  
Patients undergoing laparoscopic donor nephrectomies or robot-assisted donor nephrectomies 
were chosen to be included in this study for the following reasons: 
1. These two procedures are associated with similar levels of surgical stress and tissue 
trauma. 


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2. Patients undergoing these procedures are not treated with NSAIDs due to the 
nephrotoxic risk of NSAIDs to the remaining kidney. 
3. These patients are at minimal risk for post-operative ileus and are thus able to take 
enteral medications in the immediate post-operative period. 
4. The surgical procedures are generally well under 6 hours duration enabling patients to 
take enteral medications 6 hours after the initial pre-operative dose. 
1.3.  
Primary Objective.  
The primary objective of this study is to compare pain control for oral and intravenous 
acetaminophen for post-operative pain control. The primary outcome is the total opiate 
dose used from the study start (when the first dose of acetaminophen is administered in 
the pre-anesthesia holding area) to 24 hours post-operatively (in morphine equivalents).   
This will include opiates administered intra-operatively. 
1.4.  
Secondary Objectives.    
The secondary outcomes are:  
1. Average surgical pain intensity on a 0-10 numeric rating scale (NRS) administered 
between 20 and 24 hours post-operatively. 
2. Average surgical pain intensity on a 0-10 numeric rating scale (NRS) administered 
between 1 and 2 hours post-operatively. 
3. Inspiratory capacity at the time of pain intensity assessments (between 1-2 hours 
postoperatively and between 20-24 hours post-operatively).  The inspiratory capacity will 
be presented as a percentage of the subject’s baseline (pre-operative) inspiratory 
capacity 
4. Dynamic pain score with incentive spirometer use taken during pain intensity 
assessments at 1-2 hours and 20-24 hours post-operatively. 
5. Surgical pain score on a 0-10 numeric rating scale (NRA) obtained during the 20-24 hour 
assessment.  
6. Time to first narcotic use post-operatively.  
7. Incidence of nausea post-operatively 
8. Time to discharge from post-anesthesia care unit 
9. Time to hospital discharge 
2. 
CHARACTERISTICS OF THE RESEARCH POPULATION  
2.1.  
Number of subjects.   
We will enroll 265 subjects. 
2.2  
Sex of Subjects.  
We will enroll both males and females. The sex of the subjects will represent the sex distribution 
of the patients who have donor nephrectomies or robot-assisted laparoscopic nephrectomies.  


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2.3.  
Age of Subjects.  
We will enroll subjects 18 years of age and older.   
2.4.  
Racial and Ethnic Origin.  
Subjects will be enrolled without racial or ethnic restrictions. We expect enrolled subjects to 
represent the racial/ethnic composition of the patients at the URMC.  
2.5.  
Inclusion Criteria. The subject must:   
1. Be at least 18 years old 
2. Be scheduled for donor nephrectomy or robot-assisted or laparoscopic nephrectomy 
for cancer at URMC 
3. Have cognitive ability to verbally rate their pain on the Numeric Rating Scale (NRS). 
   
2.6.  
Exclusion Criteria.  The subject must not: 
1. Age younger than 18 years old or older than 90 years old 
2. Pregnancy (Pre-operative pregnancy test is routinely performed for all elective 
operating room cases)   
3. Weight less than 50 kg (lowest weight for safe dosing of 1000mg of acetaminophen) 
4. Epidural use 
5. Known liver disease (i.e. cirrhosis, liver failure). 
6. Patient unable to take enteral medications (i.e. cannot swallow pills, have a feeding 
tube, or are on TPN). However, patients who become NPO postoperatively due to 
ileus, persistent nausea and vomiting will be included in the analysis. These results 
will be evaluated using intention-to-treat analysis.  
7. Previous adverse reaction to acetaminophen 
2.7.  
Vulnerable Subjects.  
This study design excludes many vulnerable subjects, including children, pregnant women, and 
subjects with impaired cognition (who cannot provide accurate and consistent reports of their 
pain scores). Other potentially vulnerable subjects, such as employees, or the elderly, may enter 
the study; those who do will be afforded the same protections from risk as subjects not 
considered specifically vulnerable, and all subjects will be treated and monitored according to 
the same protocols and by the same personnel. Prisoners will not be included in the study given 
limitations in access prior to surgery and additional screening required for this population.  
3. 
METHODS AND PROCEDURES  
3.1  
Overview. 
This is a single center, randomized, double blinded study (pre, peri and post-operative days) 
clinical trial. Subjects will be randomized to receive:  1.) IV acetaminophen and placebo pills or 
2) placebo IV (normal saline) and PO acetaminophen. It is expected that this trial will take 
approximately 1-2 years to complete. 


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3.1.2 Study medication pharmacokinetics 
3.1.2.1 Intravenous and Enteric Acetaminophen.   
Physical description – Capsules, Tablets, Gel, Liquid, Suspension, Solution 
Pharmacodynamics –  
Onset of action: Oral: <1 hour. 
IV: Analgesia: 5 to 10 minutes; Peak effect: IV analgesic: 1 hour Antipyretic: 
within 30 minutes 
  
Absorption – Primarily absorbed in small intestine (rate of absorption dependent on 
gastric emptying; minimal absorption from stomach. Absorption varies by dosage 
form. 
Distribution – 1 L/kg at therapeutic doses.   
Time to peak, serum: Oral: Immediate release: 10 to 60 minutes.  IV: 15 minutes 
  
Metabolism – At normal therapeutic dosages, there is primarily hepatic metabolism 
to sulfate and glucuronide conjugates; a small amount is metabolized by  
CYP2E1 to a highly reactive intermediate, N-acetyl-p-benzoquinone imine 
(NAPQ1), which is conjugated rapidly with glutathione and inactivated to nontoxic 
cysteine and mercapturic acid conjugates.  
Excretion – Urine (<5%; 60-80% as glucuronide metabolites; 20% to 30% as 
sulphate metabolites; ~8% cysteine and mercapturic acid metabolites. 
Half-life elimination: Prolonged following toxic doses. 
Adolescents: ~3 hours (range: 2 to 4 hours) 
Adults: ~2 hours (range: 2 to 3 hours); may be slightly prolonged in severe renal 
insufficiency (CrCl<30mL/minute): 2 to 5.3 hours 
Common side effects— 
Oral, Rectal:  
Dermatologic: skin rash.  
Endocrine & metabolic: decreased serum bicarbonate, decreased serum 
calcium, decreased serum sodium, hyperchloremia, hyperuricemia, increased 
serum glucose. 
Genitourinary: Nephrotoxicity (with chronic overdose) 
Hematologic & Oncologic: Anemia, leukopenia, neutropenia, pancytopenia 
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin 
Hypersensitivity: rare 
Renal: Hyperammonemia, renal disease (analgesic) 
IV: >10%: Gastrointestional: Nausea (adults 34%), vomiting (adults 15%) 1% 
to 10%:  
Cardiovascular: hypertension, hypotension, peripheral edema, tachycardia 
Central nervous system: headache (adults 10%), insomnia (adults 7%), anxiety, 
fatigue, trismus 


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Dermatologic: Pruritus, skin rash 
Endocrine & metabolic: hypervolemia, hypoalbuninemia, hypokalemia,  
hypomagnesemia, hypophosphatemia 
Gastrointestinal: Constipation, abdominal pain, diarrhea 
Genitourinary: Olguria 
Hematologic & oncologic: Anemia 
Hepatic: Increased serum transaminases 
Local: Infusion site reaction (pain) 
Neuromuscular & skeletal: Limb pain, muscle spasm 
Ophthalmic: Periorbital edema 
Respiratory: Atelectasis, abnormal breath sounds, dyspnea, hypoxia, pleural 
effusion, pulmonary edema, stridor, wheezing 
All formulation: <1% (Limited to important or life-threatening): Anaphylaxis, 
hepatic injury (dose-related), hypersensitivity reaction, severe dermatological 
reaction (acute generalized exanthematous pustulosis, Stevens-Johnson 
syndrome, toxic epidermal necrolysis. 
(https://www.uptodate.com/contents/acetaminophen-
paracetamoldruginformation?source=preview&search=acetaminophen&anchor=
F129376#F1 29376) 
Active blinded acetaminophen capsules will consist of a single 500mg acetaminophen tablet 
over-encapsulated into a size 00 colored, opaque capsule which is then backfilled with inert 
powder (lactose USP) 
Each 1,000mg dose to consist of 2 x 500mg blinded capsules (sig: take 2 capsules POq6h) 
Active Acetaminophen IV doses will consist of a single 1,000mg/100 ml IV dose with contents of 
commercial vials transferred to an empty sterile IV bag. 
3.1.2.2. Placebo IV      
Placebo IV doses will consist of 100ml of normal saline transferred to an empty sterile IV bag. 
3.1.2.3. Placebo PO tablets    
Placebo oral doses will be the same size 00 colored, opaque capsules that have been filled with 
inert powder (lactose USP) 
3.1.3 Treatment protocol.  
This single site randomized double blind study will include a Screening Visit, Surgical Day (Pre 
and intra-operative dosing) and continued follow-up study interventions through Post-Operative 
Day 1. 
3.1.3.1 Blinding procedures. The research pharmacist will establish the blinding code 
sequence and maintain this independent of any research staff that have direct 
interactions with study subjects.  After consent has been signed, on surgical day, the 
research pharmacist will dispense blinded IV and PO study medication to be dispensed 


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to study subjects in the pre-operative suite. Subsequent dosing of subjects’ blinded 
medication will be dispensed from the inpatient Pyxis system.  All blinded study 
medication will be labelled as required.  
3.1.3.2 The University of Rochester Medical Research Pharmacist will be overseeing the 
randomization scheme incorporating blocks of 8 for study medication versus placebo.  
The randomization scheme code will only be available to research pharmacy staff and 
kept in a locked office. The Research Pharmacist will send a sealed envelope with 
unblinding information if needed for clinical safety information.  This sealed  
envelope will be kept in a locked cabinet in the clinical research locked office which will  
only be available to Principal and Sub-Investigators if needed for subject safety. 
3.1.3.3 Data Collection  
Subject demographics: 
1. Encrypted patient identifier 
2. Encrypted regional anesthesia attending provider 
3. Age  
4. Sex 
5. Race and ethnicity 
Subject clinical characteristics: 
6. Height and weight 
7. BMI 
8. Medical Comorbidities  
9. Patients’ current pre-surgical opioid use  
10. Diagnosis 
Characteristics of acetaminophen use: 
11. Pre-surgical procedure use of acetaminophen (oral or IV) including   dosing 
12. Post-surgical procedure use of acetaminophen (oral or IV) including dosing 
Outcomes: 
13. Total opiate dose used from the study start (when the first dose of 
acetaminophen is administered in the pre-anesthesia holding area) to 24 
hours post-operatively in morphine equivalents. 
14. Average surgical pain intensity on a 0-10 numeric rating scale (NRS) 
administered between 20 and 24 hours post-operatively. 
15. Average surgical pain intensity on a 0-10 numeric rating scale (NRS) 
administered between 1 and 2 hours post-operatively. 
16. Pain Intensity at 20-24 hour assessment prior to incentive spirometry use. 
17. Inspiratory capacity at the time of pain intensity assessments (between 1-2 
hours post-operatively and between 20-24 hours post-operatively.  The 
inspiratory capacity will be recorded in milliliters (nearest 250 ml mark on the 


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incentive spirometer) and as a percentage of the subject’s baseline 
(preoperative) inspiratory capacity. 
18. Dynamic pain (NRS) with incentive spirometer use. 
19. Post-procedure adjuvant analgesic use (other than opioids and 
acetaminophen; for example, neuromodulators, muscle relaxants, and 
NSAIDS) 
20. Incidence of nausea 
21. Any side effects related to use of acetaminophen22. Length of time from 
PACU arrival to discharge. 
23. Number of days to discharge from hospital 
3.1.4. Drug packaging and labeling.  
All study medications will be supplied to the investigators by the University of Rochester 
Investigational Drug Service (UR-IDS). Enteral acetaminophen and IV acetaminophen will be 
purchased. Oral and intravenous placebo will be provided by the UR-IDS.  
Preparation of placebo IV and PO acetaminophen, packaging, labeling, distribution, and 
randomization of study medications will be completed by the UR-IDS, and labels on each study 
medication will include the following information: 
1. Protocol number 
2. Medication identification 
3. Tablet or patch content number 
4. Storage instructions 
5. Cautionary statement, “For investigational use only” 
3.1.5. Storage.  
The principal investigator will ensure that the study medications are stored and dispensed in 
accordance with FDA regulations concerning the storage and administration of investigational 
drugs. All study medications will be stored at room temperature and will be protected from any 
extremes of temperature, light, and humidity. All drug supplies must be kept under locked 
conditions with access limited to those authorized by the principal investigator. 
3.1.6. Dispensing of medications to study subjects.  
Study investigators will initiate an Epic Investigational Study Medication order.  Subjects will 
then be dispensed the randomized study medication just prior to surgery and every 6 hours 
thereafter for the subsequent 24 hours (total of 5 doses) by surgical nursing and medical staff.  
Study medication will be dispensed to the inpatient unit and kept in the Pyxis system with all 
appropriate subject information for staff dispensing at appropriate timeframes.  
3.1.7. Drug accountability.  
The principal investigator and UR research pharmacist will maintain accurate records of all study 
medication. Current dispensing records will be maintained, including the date and amount of 
medication dispensed per study subject. All unused and returned study drug not required by 


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applicable federal and state regulations to be held by the clinical facility must be destroyed in 
accordance with applicable federal and state regulations or be returned to the UR-IDS 
immediately after the study is completed. 
3.1.8. Study evaluations and procedures.  
3.1.8.1 Baseline; Pre-Surgical Anesthesia Assessment  
- 
Study rationale, inclusion and exclusion criteria, and procedures will be described in 
lay terms to potential subject. 
- 
If subject is interested in participating, obtain written informed consent and copy 
given to subject.   
- 
Pre-anesthesia evaluation will be conducted per standard of care (SOC).   
- 
Incentive Spirometer instructions and baseline measure will be obtained by a study         
investigator.   
3.1.8.2 Surgical Day & Post-Operative Day 1 
- 
Research staff review inclusion/ exclusion criteria 
- 
Per Epic order set, research pharmacist dispenses blinded study medication of 
1000mg acetaminophen (IV acetaminophen/ PO placebo or IV placebo/PO 
acetaminophen) for administration prior to transfer to operating room 
- 
Note: per Standard of Care at University of Rochester Medical Center, the Epic 
ordering system will flag any potential order for additional acetaminophen to notify 
the provider of this duplication of therapy 
- 
Blinded study medication administered every 6 hours for 24 hours post-surgery  
- 
Standard of care for all pre-operative, intra-operative, and post-operative care to be 
maintained including usual post-operative IV opioid medications ordered. 
3.1.9 Measures 
3.1.9.1 Recruitment: Subjects will be referred by surgical providers.  An informational 
letter and a copy of the consent form will be given to the potential subject by surgical 
providers or by Peri-operative Evaluation Center (PEC) staff outlining general 
information regarding this clinical study.  
If the subject is interested in getting more information, they can contact the U of R  
Anesthesia research line at 585-273-5199 and a study coordinator will return their call.     
The informed consent may also l be reviewed and questions answered at the 
PeriOperative Medicine Clinic appointment by PEC staff who are approved study staff, 
or on the day of surgery by a study investigator. 
3.1.9.2 Demographic and clinical variables. Basic demographic information and clinical 
variables (ie diagnosis, medical comorbidities) will be obtained from the medical record 
as charted by surgical and nursing attendants during the standard of care for pre-, intra-, 
and post-operative treatment.  See Appendix 1 data collection sheet. 


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3.1.9.3 Total opiate administered: The total amount of opiate administered from the time 
of the study start (administration of IV or oral acetaminophen) to 24 hours 
postoperatively will be recorded and converted to morphine equivalents. 
3.1.9.4 Pain intensity. The standard of care pain rating scale will be used to quantify pain 
intensity.  Subjects will be asked to rate their pain on the 11-point rating scale ranging 
from 0 (‘no pain’) to 10, (worst pain possible).  Subjects will be asked to rate their 
average surgical pain intensity on a 0-10 numeric rating scale (NRS) assessment of pain 
from the time of waking up after surgery to a point in time between 1 and 2 hours 
postoperatively.  Similarly, subjects will be asked to rate their average surgical pain 
intensity on a 0-10 numeric rating scale (NRS) assessment of pain from the time of 
waking up after surgery to a point in time between 20 and 24 hours post-operatively. 
Both nursing staff and post-surgical team will assess pain intensity as standard of care. 
3.1.9.5: Inspiratory capacity: Inspiratory capacity is measured using a Voldyne 5000 
incentive spirometer (Hudson RCI, Teleflex Medical).  Inspiratory capacity will be 
recorded pre-operatively and at the time of pain assessments (1-2 hours and 20-24 
hours post-operatively).  Inspiratory capacity will be recorded to the nearest 250 cc mark 
on the incentive spirometer.  Proper use of the incentive spirometer will be demonstrated 
to the patient in the pre-anesthesia holding area by a study investigator. Research staff 
will assist in collection of incentive spirometer data at 1-2 hours and 20-24 hours 
postsurgical time.) 
3.1.10 Adverse events and serious adverse events 
3.1.10.1 Definitions 
3.1.10.2. Adverse event (AE). An adverse event is any untoward medical occurrence in 
a patient administered a pharmaceutical product, and which does not necessarily have 
to have a causal relationship with the treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease that develops or worsens in severity during the course of the study which is 
temporally associated with the use of a treatment, whether or not considered related to 
the treatment. Adverse events may be reported by the patient, or detected by the 
investigator or other observers. For the purpose of adverse event recording, the study 
period will begin with the initiation of study procedures (including pretreatment 
procedures) and will continue to the end of the trial.  
3.1.10.3. Intensity of adverse events. The intensity or severity of adverse events will be 
graded as follows: 
Mild: Awareness of sign or symptom, but easily tolerated. Not expected to have 
a clinically significant effect on the patient’s overall health and wellbeing. Not 
likely to require medical attention. 
Moderate: Discomfort enough to cause interference with usual activity or affects 
clinical status. It may require medical intervention. 
Severe: Incapacitating or significantly affecting clinical status. Likely requires 
medical intervention and/or close follow-up. 


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3.1.10.4. Relationship to study medication. The principal investigator or a delegated sub           
investigator will be responsible for assessing relationship of AEs to study medication              
using the following definitions: 
Probable: a clinical event, including a laboratory test abnormality, in which a 
relationship to the study drug seems probable because of such factors and 
consistency with known effects of the drug, a clear temporal association with the 
use of the drug, improvement upon withdrawal of the drug, lack of alternative 
explanations for the experience, or other factors. 
Possible: a clinical event, including a laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, but which could 
not be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking. 
Unlikely: a clinical event, including a laboratory test abnormality, with a temporal 
relationship to study drug administration, which makes a causal relationship 
improbable and in which other factors suggesting an alternative etiology exist. 
Such factors include a known relationship of the adverse experience to 
concomitant medication, the patient’s disease state, or environmental factors 
including common infectious diseases. 
3.1.10.5. Serious adverse event (SAE). Any adverse drug experience occurring at any 
dose that results in any of the following outcomes: 
• 
death 
• 
life threatening complication 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
3.1.10.6. Assessment of adverse events. All adverse events that occur during the study 
period will be recorded, regardless of the severity of the event or judged relationship to 
the study drugs, and a diagnosis will be recorded whenever possible. The onset date, 
stop date, action taken with the study drugs, and outcome of each adverse event will be 
recorded. The relationship to study drug, severity, and seriousness of each adverse 
event as judged by the investigator will be recorded. In addition, subjects who 
experience an adverse event may be withdrawn from the study at any time at the 
discretion of the investigator. The subject will be monitored until the event has resolved 
or stabilized, determination of a cause unrelated to the study is made, or the subject is 
referred to the care of a local physician.  


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3.1.10.7. Reporting of adverse events. The principal investigator will report all SAEs to 
the Institutional Review Board (IRB) and to the FDA as required by applicable local and 
federal regulations. 
4.  
DATA STORAGE AND CONFIDENTIALITY   
The privacy of the subjects including their personal identity and all personal medical information 
including medical record numbers, date of birth, date of service will be maintained at all times.   
Subjects will be identified by a unique subject identification number and all data will be 
presented in aggregate reports.   
Information about study subjects will be kept confidential and managed according to the 
requirement of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Subject 
data will be entered into electronic spreadsheets.  One spreadsheet will serve as the correlation 
tool and contain the subject name, medical record number and unique study subject identifier.  
The second spreadsheet will contain the unique study subject identifier as well as all the 
variables required for the study.  The two spreadsheets will be stored as separate files, 
protected by unique passwords.  Only the investigators and key study staff will have access to 
the files and their passwords.  All the results of this research will be presented in the form of 
aggregate data. 
5.  
SAMPLE SIZE JUSTIFICATION  
The primary outcome is total opiate dose used during the study period (from the time of the 
administration of acetaminophen in the pre-anesthesia holding area to 24 hours postoperatively) 
in morphine equivalents.  We assume that the IV acetaminophen is associated with a decreased 
opiate requirement during the surgical procedure and over the 24 hours postoperatively 
compared with oral acetaminophen.  For a moderately clinically meaningful standardized 
treatment effect size of 0.4 with a significance level 0.05, a sample size of 200 achieves 80% 
power to reject the null hypothesis of no difference between the two groups in the mean values 
of total opiate dose. Assuming approximately 15% of participants will not complete the study 
after consenting (e.g., due to COVID cancellations, surgical changes, PI review or patient 
preference), we plan to enroll 265 subjects. 
6.  
DATA ANALYSIS   
All analyses of this study will be based on the principle of modified intention-to-treat (ITT).  
Patients who did not undergo surgery or who did not receive the study drug prior to surgery will 
be excluded from the analysis. 
6.1 Analysis of primary outcome:  
The primary outcome is the total opiate dose used from the study start (when the first dose of 
acetaminophen is administered in the pre-anesthesia holding area) to 24 hours post-operatively 
in morphine milligram equivalents (MME). Pain as measured by the average surgical pain 
intensity on a 0-10 numeric rating scale (NRS) administered between 20 and 24 hours 
postoperatively will be a second primary outcome, with gatekeeping used to control for 
multiplicity.  


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We anticipate some missing data in the study. Subjects who do not undergo surgery or who do 
not receive the study drug prior to undergoing surgery will be excluded from the analysis (the 
missing data here are assumed to be missing completely at random [MCAR]). For remaining 
missing data on the primary outcome, we will assume that the data are missing at random 
(MAR), which means that the missing data only depend on observed factors.  In this case, we 
will model the probability that a patient’s data are missing on the primary outcome with logistic 
regression conditional on patient demographics (age, sex, BMI), and the type of surgery (donor 
nephrectomy versus nephrectomy for cancer). For the primary analysis, inverse probability 
weighted (IPW) semiparametric linear regression analysis will be used to study the effect of 
group indicator, adjusting for, age, sex, BMI, type of surgery (donor nephrectomy versus 
nephrectomy for cancer) and block (yes vs. no). The primary analysis will be performed first for 
the total opioid dosage outcome. If the treatment effect for that analysis is positive, the similar 
analysis will be repeated for the pain score. Sensitivity analyses will be performed that do not 
include the block as a covariate because the block is often administered after the first dose of 
experimental Tylenol, although the choice to administer the block is not based on pain or 
distress or any other outcomes that are related to success of analgesia. We will also perform a 
per-protocol analysis in which only subjects who received all 5 doses of the Tylenol as indicated 
by the protocol will be included. 
Although the primary aim of this study is not to test non-inferiority, we have prespecified a 
standardized effect size of 0.3 as the smallest effect size that we would consider to be clinically 
meaningful to guide interpretation of a non-significant result on the primary outcome. Given the 
fact that IV Tylenol is more expensive, we believe that ruling out an effect size larger than 0.3 
would support a conclusion that the disadvantages do not outweigh the benefits of using IV 
Tylenol. We will use the 95% confidence intervals of the primary (opioid MME) and key 
secondary outcome (pain score) to determine whether an effect size of 0.3 can be ruled out (i.e., 
the 95% CI excludes an effect size of 0.3). This interpretation will be limited as it is not the 
primary objective of the study, but will be more likely to be an accurate conclusion given the 
prespecification of the parameters upon which to conclude the study supports a truly negative 
result rather than an inconclusive result. 
6.2 Analysis of secondary outcomes:  
Inverse probability weighted semiparametric linear regression or logistic regression method, as 
appropriate, will be used to analyze the secondary outcomes, adjusting for age, sex, BMI, type 
of surgery (donor nephrectomy versus nephrectomy for cancer), and block (yes v. no).  
6.3 The significance level is set at 0.05 for each analysis.  All analyses will be implemented with 
SAS 9.4 (SAS Institute Inc., Cary NC). 
7. 
RISK/BENEFIT ASSESSMENT  
Potential Risk.  
There are minimal risks to the subjects associated with this clinical study.  The use of 
acetaminophen is currently used pre-, intra-, and post-operatively with various surgical 
procedures.  Subjects will be excluded if they have any known co-morbidities that pose a risk 


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14 
with use of this medication (i.e., hepatic issues) or previous adverse effects from use of 
acetaminophen). 
The most common rare side effects that may occur are skin rash, shortness of breath, chest 
pain, problems with blood, headache and liver damage or failure (with chronic use). Subjects will 
be monitored throughout the post-surgical time and any potential side effects will be evaluated 
and treated as standard of care. If subjects have any concerns about potential side effects of the 
study medication subjects can discuss this with the study team. 
Potential Benefits to the Subjects.  
Subjects potentially may have improved pain control post procedure that can facilitate recovery 
time. 
Alternatives to Participation.  
Subjects can elect not to participate in this clinical study.  
Costs  
There will be no cost to research subjects to participate in this study.  All study medications will 
be covered under this research protocol.   
Payments  
Research subjects will not be paid for participating in this study. 
8. 
DATA SAFETY AND MONITORING:   
The independent Data Safety Monitoring Board (DSMB) will be composed of:  
Raymond Zollo, MD (Anesthesiology) Chair 
Richard Wissler, MD, PhD (Anesthesiology) Biostatistician 
After clinical data collection is complete for the initial 6-10 study subjects, one half of the clinical 
records completed will be randomly selected for review by the DSMB.  Subsequent DSMB 
review meetings will occur every 4-6 months dependent on study enrollment and review by 
DSMB chair throughout the course of this clinical study. 
The board will review individual subject data, including documentation of informed consent, 
information regarding any protocol deviations and all adverse events.  They will make a 
preliminary determination of the likelihood of the adverse effect being related to participation in 
the study.  Any determination that the adverse event is possibly or likely related to participation, 
or that the DSMB association of causality differs from the PI determination will be discussed with 
the PI and reported to the RSRB.  The distribution of adverse events will be compared between 
the IV acetaminophen and placebo group (statistical testing may be deferred until sufficient 
completor data is available to reduce the possibility of Type I error).   If it is determined that 
there is a statistical difference in the incidence of adverse events between groups, then 
enrollment in the study will be stopped with this reported to the RSRB. If the study is stopped by 


RSRB# 70162  
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15 
the DSMB, the Principal Investigator and the DSMB will meet to determine the advisability of 
continuing the study.   If it is determined that the risk benefit balance merits continuation of the 
study, the PI may resubmit the study for approval to the RSRB. 
Adverse events will be considered likely related to drug administration if there is a temporal 
relationship consistent with cause and effect, no other and more likely explanation for the 
adverse event, and a clear casual mechanism linking drug to effect.  Adverse events will be 
considered possibly related (ie a suspected adverse drug reaction) if there is a reasonable 
possibility that the adverse event was caused by the study drug.   
All members of the DSMB have agreed to perform in this role and have no relevant conflicts of 
interest. 
9. 
REFERENCES 
Vu, V., et al., Intravenous Acetaminophen for Postoperative Pain Management in Patients  
Undergoing Living Laparoscopic Living-Donor Nephrectomy. Ann Pharmacother, 2016. 
Chen, P.P., P.T. Chui, and T. Gin, Comparison of ondansetron and metoclopramide for the 
prevention of post-operative nausea and vomiting after major gynaecological surgery. Eur J 
Anaesthesiol, 1996. 13(5): p. 485-91. 
Steinbrook, R.A., et al., Prophylactic antiemetics for laparoscopic cholecystectomy: ondansetron 
versus droperidol plus metoclopramide. Anesth Analg, 1996. 83(5): p. 1081-3. 
Tang, J., M.F. Watcha, and P.F. White, A comparison of costs and efficacy of ondansetron and 
droperidol as prophylactic antiemetic therapy for elective outpatient gynecologic 
procedures. Anesth Analg, 1996. 83(2): p. 304-13. 

ICF_001.pdf: 
RSRB #70162 
Version Date 1-13-2023 
Page 1 of 8 
 
DEPARTMENT OF ANESTHESIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
Efficacy of IV Acetaminophen Versus Oral Acetaminophen 
 
INFORMED CONSENT FORM 
 
NCT03365622 
 
Date: 1-13-2023


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CONSENT FORM 
 
Randomized, Double-Blind Clinical Study Evaluating Efficacy of Intravenous 
versus Enteric Acetaminophen in Donor Nephrectomy and Robot-Assisted, 
Laparoscopic Nephrectomy 
 
Principal Investigator:  Joseph Dooley, MD 
 
This consent form describes a research study, what you may expect if you decide 
to take part and important information to help you make your decision.  Please 
read this form carefully. 
 
The study staff will explain this study to you.  Please ask questions about anything that 
is not clear before you agree to participate.  You may take this consent form home to 
think about and discuss with family or friends. 
 
 Being in this study is voluntary – it is your choice. 
 If you join this study, you can change your mind and stop at any time. 
 If you choose not to take part, your routine surgical care will not be changed in any 
way.   
 There are risks from participating and you should understand what these mean to 
you. 
 
Introduction 
You are being asked to take part in this study because you are scheduled for 
laparoscopic nephrectomy procedure (removal of your kidney).  
 
Purpose of Study 
Adequate pain control after surgery is important in your recovery.  The purpose of this 
research study is to evaluate whether acetaminophen (also known as Tylenol), given by 
mouth (oral) or injected into your vein (intravenous), is more effective in controlling your 
pain after surgery.  The use of acetaminophen will be in addition to the narcotic pain 
medications that your provider may prescribe for you during your hospitalization.  
 
This study is being conducted by Dr. Joseph Dooley at the University of Rochester’s 
Department of Anesthesiology. 
 


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Description of Study Procedures 
No study related procedures will start until after you have had all of your questions 
answered and signed this informed consent form. Your pre-anesthesia evaluation will 
be conducted per standard of care, in preparation for your upcoming surgery.  
 
If you decide to take part in this study, you will be randomly assigned, like flipping a 
coin, to either receive:  
 
1) intravenous (IV) acetaminophen and placebo oral pills; 
  
 
 
 
OR  
2) placebo IV solution and oral acetaminophen medications. 
  
A placebo is a substance that looks like the study drug but doesn’t include any active 
ingredients. 
 
The study medication will be given to you prior to your surgery and every six hours for 
the first 24 hours after surgery.  
 
Neither you nor your doctors will know which treatment you are assigned to.  If there is 
an emergency, the study team will be able to find out quickly which group you were 
assigned to.  
  
In the recovery room and when transferred to a surgical inpatient unit, you will be asked 
to rate your surgical pain level and begin use of an incentive spirometer (a device used 
to keep your lungs healthy after surgery) per standard of care. You will be asked to rate 
your pain level before and after you use the incentive spirometer.  
 
As needed, you will be able to receive other non-acetaminophen pain medications as 
ordered by your surgical team as standard post-surgical care. 
 
Study staff will collect information from your medical record about your surgery, 
anesthesia, and post-operative care as it pertains to this research study.  
 
Information about your study participation and study results may be included in your 
electronic health record. If you have concerns about this or to obtain more detail, you 
should discuss this with the study team.  
 
Number of Subjects 
Approximately 265 subjects will take part in this study. 
 
Duration of the Study 
Your participation in the study will last until 1day (24 hours) after your surgery.  


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Risks of Participation   
Acetaminophen (Tylenol) is currently used pre-, intra-, and post-operatively with various 
surgical procedures.  The most common side effects are nausea, rash and headache.  
Rare but serious side effects that may occur are severe skin rash, shortness of breath, 
chest pain, low red cell or platelet cell count and acute liver damage or failure. You will 
be monitored throughout the post-surgical time and any potential side effects will be 
evaluated and treated as standard of care. If you have any concerns about potential 
side effects of the study medication please discuss this with the study team. 
 
Because this study involves collecting personal, identifiable information about you, there 
is a potential for invasion of privacy or breach in confidentiality.  To minimize this risk, 
we will assign you a study number instead of labeling the information we collect from 
you with your name [or medical record number].  All of the information we collect will be 
stored in a secure manner and only study team members will have access to it. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this 
website at any time. 
 
The study team may be notified if you receive other health care services at URMC or its 
Affiliates (e.g., visit to the emergency room). In addition, the following individuals may 
know you participated in research and may see results of testing conducted for this 
study: 
• Staff at the University of Rochester Medical Center and its Affiliates (e.g., Strong 
Memorial Hospital, Highland Hospital, URMC primary care, specialist physician 
offices) who have a reason to access your electronic health record.  
• Health care providers who are involved in your care at a facility that is not part fo 
the University of Rochester Medical Center and its Affiliates and who have 
reason to access your electronic health record. 
• Individuals who request a copy of information from your health record for 
activities such as treatment or payment (e.g., medical insurance companies, 
worker’s compensation).  
 
Benefits of Participation  
You might not benefit from being in this research study.  The potential benefit to you 
might be improved pain control post operatively. 
 
Costs  


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There will be no cost to you to participate in this study.  All study medications will be 
covered under this research protocol.   
 
Payments  
You will not be paid for participating in this study. 
 
Compensation for Injury  
If you are directly injured by the drug being studied, or by medical procedures needed 
because of this study, and you receive medical care for the injury, you may need to pay 
for that care.  You will be reimbursed for reasonable and necessary medical costs for 
such care, but you might not be reimbursed for care covered and paid for by a third 
party like your health insurance provider, or costs such as required co-payments or 
deductibles related to that coverage.  No other funds have been set aside to pay for 
such things as lost wages or expenses due to a current underlying illness or condition. 
 
If your research injury is paid for by the University, we will collect your name, date of 
birth, gender, and Medicare Health Insurance Claim Number or Social Security Number 
to determine your Medicare status. This information will be used only in accordance with 
the law. If you are a Medicare beneficiary, information about the study you are in, and 
any payments made related to your injury, will be reported to the Centers for Medicare 
& Medicaid Services (CMS), in accordance with CMS requirements.  This information 
will not be used for any other purpose. 
 
Confidentiality of Records and Authorization to Use and Disclose Information for 
Research Purposes  
 
The University of Rochester makes every effort to keep the information collected from you 
private.  In order to do so, we will not collect personally identifying information for analysis 
and will assign you a unique patient identifier, like a numbered code. In order to collect 
data from your medical record, only study personnel who are trained to do human subject 
research will access this information. All study information will be stored in a password 
protected location. Sometimes, however, researchers need to share information that may 
identify you with people that work for the University, regulators or the study sponsor.   
 
If you have never received a copy of the University of Rochester Medical Center (URMC) 
and Affiliates Notice of Privacy Practices, please ask the investigator for one.  
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Research records 
• Records about phone calls made as part of this research 


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• Records about your study visits 
• Past and present medical records related to the study    
 
Who may use and give out information about you? 
• The study doctor and the study staff 
• URMC and Affiliates 
 
Your information may be given to:  
• The Department of Health and Human Services 
• The University of Rochester  
• The U.S. Food and Drug Administration (FDA) may also need to inspect study 
records at some point during the study or even after it has been completed.  In the 
event that this should occur, every effort will be made to keep identifying 
information about you private.  
 
Why will this information be used and/or given to others? 
• To do the research  
• To study the results  
• To see if the research was done correctly   
 
If the results of this study are made public, information that identifies you will not be 
used. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over. 
 
How long will this permission be valid? 
This permission will last indefinitely.  
 
May I cancel my permission to use and disclose information? 
Yes. You may cancel your permission to use and disclose your health information at 
any time.  You do this by sending written notice to the study doctor.  Upon receiving the 
written notice, the study team will no longer use or disclose your health information and 
you will not be able to stay in this study.  Information that has already been gathered 
may need to be used and given to others for the validity of the study.   
 
May I withdraw from the study? 


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Yes. If you withdraw your permission to be in the study, no new health information 
identifying you will be gathered after that date.  Information that has already been 
gathered may still be used and given to others.   
 
Is my health information protected after it has been given to others? 
No. There is a risk that your information will be given to others without your permission. 
 
Future Use of Information/Samples  
Your information collected as part of this research will not be distributed or used for 
future research studies. 
 
Return of Research Results 
In general, we will not give you any individual results from your participation in the 
study. If we find something of urgent medical importance to you, we will inform you, 
although we expect that this will be a very rare occurrence. 
 
Contact Persons 
For more information concerning this research or if you feel that your participation has 
resulted in any research related injury, emotional or physical discomfort, please contact:  
Joseph Dooley, MD at (585) 275-2141. 
 
Please contact the University of Rochester Research Subjects Review Board at 265 
Crittenden Blvd., CU 420628, Rochester, NY 14642, Telephone (585) 276-0005 or 
(877) 449-4441 for the following reasons: 
 
• 
You wish to talk to someone other than the research staff about your rights as 
a research subject; 
• 
To voice concerns about the research; 
• 
To provide input concerning the research process; 
• 
In the event the study staff could not be reached. 
 
Voluntary Participation 
 
Taking part in this study is voluntary.  You are free not to take part or to withdraw at any 
time, for whatever reason.  No matter what decision you make, there will be no penalty 
or loss of benefit to which you are entitled.  In the event that you do withdraw from this 
study, the information you have already provided will be kept in a confidential manner. 
******************************************************************************************* 
SIGNATURES/DATES 
 


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After reading and discussing the information in this consent form you should 
understand: 
• 
Why this study is being done; 
• 
What will happen during the study; 
• 
Any possible risks and benefits to you; 
• 
Other options you may have instead of being in the study;  
• 
How your personal information will be protected; 
• 
What to do if you have problems or questions about this study. 
 
Subject Consent 
 
I have read (or have had read to me) the contents of this consent form and have been 
encouraged to ask questions.  I have received answers to my questions.  I agree to 
participate in this study.  I have received (or will receive) a signed copy of this form for 
my records and future reference. 
 
 
 
 
 
 
 
 
 
Subject Name (Printed by Subject) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Subject 
 
 
 
 
 
Date 
 
 
 
 
___________ 
 
 
 
    
 
Person Obtaining Consent 
 
I have read this form to the subject and/or the subject has read this form.  I will provide 
the subject with a signed copy of this consent form.  An explanation of the research was 
given and questions from the subject were solicited and answered to the subject’s 
satisfaction.  In my judgment, the subject has demonstrated comprehension of the 
information.  I have given the subject adequate opportunity to read the consent before 
signing. 
 
 
 
 
 
 
 
 
 
Name and Title (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent  
 
 
Date