Clinical trial NCT03558555
Conditions: Inguinal Hernia
Keywords: Acetaminophen Tylenol Intravenous versus oral
Sponsor: Yan Lai
Start date: 2017-12-08; Completion date: 2018-12-30
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There is limited research on the clinical outcome differences between intravenous (IV) acetaminophen versus oral (PO) acetaminophen. With the costs of intravenous acetaminophen sometimes being almost 100 times the cost of PO acetaminophen, it is not only important fiscally but also clinically to differentiate the benefits of IV vs PO acetaminophen. The proposed research study is to determine the clinical advantages of IV vs PO acetaminophen during the post-operative recovery time for ambulatory surgery patients by analyzing differences in time to first opioid delivery, pain scores, and patient satisfaction.

Detailed description:
In previous literature it has been shown that compared to placebo, IV acetaminophen can improve postoperative pain scores and reduce opioid requirements. In addition, IV acetaminophen has several pharmacokinetic properties that may be beneficial when compared to acetaminophen. IV acetaminophen has been shown to achieve a more rapid and higher maximum plasma concentration as well as higher cerebrospinal fluid concentrations. Comparative effectiveness trials of IV vs PO administration have not conclusively demonstrated improved clinical outcomes despite the proposed pharmacokinetic benefits. More research needs to be conducted to determine possible clinical advantages.

Arms: arm 1: Patients who are randomized to have oral acetaminophen will take oral acetaminophen preoperatively and receive saline intraoperatively. arm 2: Patients randomized to IV acetaminophen will receive IV acetaminophen after induction of general anesthesia and will take placebo pills preoperatively.
Interventions: intervention 1: Acetaminophen IV Soln intervention 2: Oral Acetaminophen intervention 3: Placebo Pills intervention 4: Saline
Intervention descriptions: intervention 1: 1000mg of IV acetaminophen intervention 2: oral acetaminophen 975mg pills intervention 3: placebo match to acetaminophen intervention 4: Intravenous saline

Protocol documents:
Prot_SAP_000.pdf: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral Acetaminophen in
Ambulatory Surgery
Dr. Yan Lai
NCT03558555
Document Date: Dec 2, 2019


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
1 
Revised 9/2/14 
HRP-503 PROTOCOL TEMPLATE  
 
Brief Summary of Research (250-400 words):  
There is limited research on the outcome differences between two different routes of 
administration for acetaminophen (brand name Tylenol).  Acetaminophen can be administered to 
humans in various forms before or during surgery, with injections into human veins (intravenous 
or IV) or taken orally by mouth (or Per Os or PO) forms being the most common. There are 
alleged reported differences with onset, duration, cost, metabolism seen with different forms of 
administration but little is substantiated by literature or clinical evidence.  With the costs of 
injection of acetaminophen through human blood vessels or veins (IV) sometimes being almost 
100 times the cost of intake by mouth (PO), it is not only important fiscally but also clinically to 
differentiate the benefits of IV versus PO acetaminophen. The proposed research study is to 
determine the advantages of IV vs PO acetaminophen during the post-operative recovery time for 
ambulatory surgery patients by analyzing differences in time to first opioid delivery, pain scores, 
and patient satisfaction. This will not affect the subject’s cost of participation since both forms of 
acetaminophen is currently administered to most eligible ambulatory surgical patients as part of 
perioperative protocol. The medications used are both part of standard of care and no extra cost 
will be incurred by the research study. 
 
1) Objectives 
Research Question:   
Are there clinical benefits of IV vs PO acetaminophen in the post-operative period in 
ambulatory surgery patients?  
The objective of this study is to determine the clinical advantage of IV vs PO 
acetaminophen. 
 
2) Background 
In previous literature it has been shown that compared to placebo, IV acetaminophen can improve 
postoperative pain scores and reduce opioid requirements (Remy C, et al. Effects of acetaminophen on 
morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. 
Br J Anaesth 2005;94(4):505-13). 
In addition, IV acetaminophen has several pharmacokinetic properties that may be beneficial when 
compared to PO acetaminophen. IV acetaminophen has been shown to achieve a more rapid and higher 
maximum plasma concentration as well as higher cerebrospinal fluid concentrations. Comparative 
effectiveness trials of IV vs PO administration have not conclusively demonstrated improved clinical 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
2 
Revised 9/2/14 
outcomes despite the proposed pharmacokinetic benefits (Jibriil F, et al. Intravenous versus oral 
acetaminophen for pain: Systematic review of current evidence to support clinical decision making. 
Canadian Journal of Hospital Pharmacy 2015:68(3)238-47). More research needs to be conducted to 
determine possible clinical advantages of PO acetaminophen when compared to IV acetaminophen. 
 
3) Setting of the Human Research 
The research study will take place at Mount Sinai West hospital and Mount Sinai St. Luke’s hospitals. 
The site PI is Yan Lai, MD. 
 
4) Resources Available to Conduct the Human Research 
For n=100, the feasibility of recruitment is easily manageable. With the HIPAA waiver requested, the 
surgeon will provide the investigators (all three of whom are physicians within the Dept of 
Anesthesiology) with information of eligible patients. Subjects will be called by the Dept of 
Anesthesiology when their surgery is scheduled, and they will be told about the study then. After the 
operating room schedule has been reviewed for potential participants in the study the contact information 
will be obtained through  the surgeon’s office. A member of the research team will then contact the 
patient and notify him/her of the study. The staff members on this protocol are all employees of Mount 
Sinai and will either be a resident or attending physicians that are included on the IRB protocol. There are 
three primary members of the research personnel: The study team plans to obtain the placebo directly 
from pharmacy. The study team team is working directly with pharmacy for the supply required to 
conduct the human research. Since the use of IV APAP is not restricted within the Dept of 
Anesthesiology, it is frequently used for patients intraoperatively. If there is any objection to allowing IV 
APAP being removed from the pyxis for the patients the Dept of Anesthesiology has volunteered to cover 
the costs associated with using IV APAP to obtain the data. 
 
Yan Lai, MD, MPH – Roles for Dr. Lai in this study include serving as primary investigator 
responsible for study design and planning, data collection, subject recruitment, manuscript writing 
and preparation, data analysis, safety monitoring, and responding to adverse events and/or 
complications. He is certified in PPHS/IRB protocols, all Citi/IRB required training in human 
subject protection, and has prior clinical research experience. He is also a board certified 
anesthesiologist and assistant professor of anesthesiology with the Icahn School of Medicine and 
the Mount Sinai Health System. 
Poonam Pai, MD – Roles for Dr. Pai include serving as primary research coordinator involved in 
data collection, subject recruitment, manuscript writing and preparation, data analysis, safety 
monitoring, and responding to adverse events and/or complications.  She has completed all of her 
required CITI training to be IRB certified and has experience in clinical research. In addition she 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
3 
Revised 9/2/14 
has been a resident physician in anesthesiology with the Icahn School of Medicine in good 
standing for the previous three years going on her fourth. 
Brittany Reardon, MD - Roles for Dr. Reardon include serving as research assistant involved in 
data collection, subject recruitment, manuscript writing and preparation, data analysis, safety 
monitoring, and responding to adverse events and/or complications.  She has completed his CITI 
training to be IRB certified and has experience in clinical research. In addition, she has been a 
resident physician in anesthesiology with the Icahn School of Medicine in good standing for the 
previous year going on her second.  
There are institutional processes to ensure that all persons assisting with the protocol will be well 
informed.  The research personnel will conduct regular meetings and department email updates to review 
the results and safety data of the study.  The research personnel will initiate the formation of a safety 
monitoring board for adverse effects, complications, or complaints from patient subjects. 
 
5) Study Design 
a) Recruitment Methods 
Potential subjects will be ambulatory surgery patients at Mount Sinai West and St. Luke’s hospitals. 
Patients who are listed as ambulatory surgery patients that meet inclusion and exclusion criterion will be 
selected. With the HIPAA waiver requested, the surgeon will provide the investigators (all three of whom 
are physicians within the Dept of Anesthesiology) with information of eligible patients. Subjects will be 
called by the Dept of Anesthesiology when their surgery is scheduled, and they will be told about the 
study then.  All patients will be provided with copies of the IRB protocol and consent if they wish to have 
it. Send a copy of the consent form in a secured e-mail to the potential subject. The e-mail will be 
secured by entering in [SECURE] in the e-mail subject line. Once recruited the blinding assessments will 
be done by the study team. 
 
b) Inclusion and Exclusion Criteria 
Inclusion criteria include: ASA scores I-III, ambulatory surgery patients, ages 18-75, 
surgeries requiring general anesthesia  
Exclusion: Patients with contraindications to acetaminophen (history of end organ liver 
dysfunction), known allergy to acetaminophen, emergency surgery, patients who were not 
fasted, patients who cannot tolerate PO, surgery anticipated to last longer than 3 hours or 
requiring re-dose of acetaminophen, pregnancy, weight less than 50kg, chronic daily 
narcotic use, patients who’s anesthetic plan requires regional anesthesia, patient refusal to 
participate or do not have capacity to provide consent. 
(NOTE: You may not include members of vulnerable populations as subjects in your 
research unless you indicate this in your inclusion criteria.). 
c) Number of Subjects 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
4 
Revised 9/2/14 
We intend to have an n=100. Based on a confidence level of 95% with a Z score of 1.96, 
standard deviation of .5 and a confidence interval of 10% our sample size should be 96. 
For ease of statistical calculations we rounded up to 100 patients. Based on previous 
literature pertaining to acetaminophen usage, we found studies included anywhere from 46 
to 105 patients which is consistent with our calculations.  
 
ss = 
Z 2 * (p) * (1-p) 
c 2 
 
Where: 
Z = Z value (1.96 for 95% confidence level)  
p = percentage picking a choice, expressed as decimal (.5 used for sample size needed) 
c = confidence interval, expressed as decimal  (e.g., .01= ±1) 
 
Sample size= [(1.96^2)(.5)(.5)]/(.1^2)=96 subjects 
For effect size, we expect a Cohens d medium effect of 0.5. The estimate for sample sizes 
was obtained by using the first set of pain scores obtained in the PACU. 
d) Study Timelines 
 
The subject’s participation will be from time of enrollment in the pre-operative period until the 
24 hour post discharge from the hospital. Estimated date of enrollment completion will be 
when n=100 (1-2 months.) Estimate date for study completion will be June 2017. 
e) Endpoints 
 
The primary endpoints will be PACU pain scores (arrival, 1 hour, and discharge), time 
to first narcotic use, and total narcotic use in PACU. 
Secondary endpoints will be PACU LOS, patient reported total narcotic use post-
discharge, and patient satisfaction. 
f) Procedures Involved in the Human Research 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
5 
Revised 9/2/14 
This will be a prospective randomized observational study. All patients will be randomized 
to receive either pre-operative PO acetaminophen or IV acetaminophen intraoperatively. 
Patients will not be at additional risk and all standards of care will be met. A standard dose 
of PO Acetaminophen 975mg (3 pills) will be given to all patients about 15 minutes prior 
to entering the operating room. A standard dose of IV Acetaminophen 1000mg will be 
given to all patients after standard induction doses. Randomization will be performed with 
a computing software. All patients who are randomized to have IV acetaminophen will 
take placebo pills preoperatively to standardize all patients and blind patients to treatment. 
Due to the pharmacologic absorption differences between the PO and IV forms the PO 
form will be given when the patient is evaluated in the holding area about 15 minutes prior 
to entering the OR. Because the IV form of a medication in general has a faster onset it is 
given at a later time in the operating room and not in the holding area.  
 
According to pharmacokinetic literature on IV and PO acetaminophen, the maximal 
plasma effect of IV acetaminophen is 15 minutes after administration and 45 minutes for 
PO administration. We will attempt to standardize the effects of PO vs IV by giving IV 
APAP 30 minutes after the other group receives the PO APAP. For example, if the PO 
group receives PO APAP 15 minutes prior to going into OR, then the IV APAP group will 
receive the IV APAP 15 minutes after they are in the OR, which allows for a difference of 
30 minutes between the two groups. This allows for the peak effect of the IV and PO to 
coincide. 
 
We do not intend on giving any other preoperative oral medications to patients, however 
all patients will have intra-venous access prior to entering the operating room. The subject 
will meet his/her anesthesia provider on the day of their surgery. The pain score will be on 
PACU arrival, 1 hour after PACU arrival, and at discharge from PACU. Should the patient 
experience post operative pain the patient will receive additional opioid medications. The 
time to first opioid medication administration after arrival to PACU and the total of 
amount of opioid medications administered will be recorded. If the subject no longer 
wishes to take part in the trial at any point no further data will be recorded. Additional 
acetaminophen can be administered four hours after the first dose of IV or PO 
acetaminophen. Opiod medication may also be given if needed for pain. 
 
Oral acetaminophen is given prior to surgery since it cannot be given intra-operatively 
while the patient is under general anesthesia. The decision was made to given intravenous 
acetaminophen after induction so the absorption profile of oral vs intravenous will be 
similar. Giving the intravenous acetaminophen upon induction of anesthesia will also 
allow for the shortest time between the administration of the two drugs. 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
6 
Revised 9/2/14 
Ambulatory surgeries usually consist of minor procedures such as hysteroscopies, hernia 
repairs, cystoscopies and laparoscopic procedures such as cholecystectomy and ovarian 
cystectomy. Due to the relatively minor incisions required in these types of procedures 
patients tolerate being discharged without significant pain. All patients will receive general 
anesthesia with either laryngeal mask airway (LMA) or endotracheal intubation.  
 
The patients pain scores will be assessed by the Post-Anesthesia Care Unit (PACU) nurses 
at arrival, 1 hour after and at discharge from PACU as part of routine patient care by 
PACU nurses. Intraoperative care of the patient will be provided by an anesthesia team 
member who is a part of the Mount Sinai System. The anesthesia provider will be aware of 
the randomization of the patient. 
 
Standard post-operative orders will be written for patients during their time in the PACU. 
Orders include oxycodone, fentanyl and hydromorphone. Acetaminophen can only be re-
administered after four hours from first dose. 
 
g) Specimen Banking 
No specimen will be needed for the study. 
h) Data Management and Confidentiality 
The information included in the data will be medical record number, age, gender, ASA class, type 
of surgery, type of acetaminophen used, pain score assessments, time to first narcotic, total 
narcotic use and satisfaction/pain 24 hours after discharge from PACU. Only the research 
personnel will have access to the data. Only the research personnel will have knowledge of which 
method of acetaminophen subjects will be receiving. The data will be stored as hard copy files and 
on a secure spreadsheet. The research personnel is responsible for the receipt of the data. The PI 
will keep the hard copies secure and any electronic data will be encrypted. No personal identifiers 
will be used. The data will undergo statistical analysis 
i) Provisions to Monitor the Data to Ensure the Safety of Subjects 
Part I: Elements of a Data and Safety Monitoring Plan 
 
MSSM Principal Monitor: 
Indicate whether this person is the PI, a Team Member, or is Independent: 
Last Name: Lai 
First Name: Yan 
Academic Title: Attending Physician, Assistant Professor 
Department: Anesthesiology 
Mailing Address: Mount Sinai West 1000 10th Avenue, New York, NY 10019 
Phone: 212-523-6915 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
7 
Revised 9/2/14 
Fax:  
E-mail: ylai@chpnet.org 
 
MSSM Additional Monitor: 
Indicate whether this person is the PI, a Team Member, or is Independent: 
Last Name: Pai 
First Name: Poonam 
Academic Title: Research Personnel, Physician 
Department: Anesthesiology 
Mailing Address: Mount Sinai West 1000 10th Avenue, New York, NY 10019 
Phone: 212-523-6915 
E-mail: Poonam.PaiBantwalHebbalasankatte@mountsinai.org 
 
 
The principal monitor is a board certified anesthesiologist thus minimizing the risk to the subjects and 
further optimizing their health and wellbeing. Adverse events are unlikely (potential side effects of 
acetaminophen use) and will be monitored as a standard of care everyone receives regardless of 
participation in the study. The safety and data information will be reviewed on a daily basis until the 
desired sample size is achieved. All temporary and/or permanent suspensions will be reported.  
 
j) Withdrawal of Subjects 
Patients may withdraw from the study at any given time by contacting any member of the 
research study group. Data will not be collected on patients who wish to withdraw. Patient 
do not need to withdraw consent in writing. 
6) Risks to Subjects 
Acetaminophen is a commonly used over the counter medication with minimal foreseeable 
risks when used at the recommended dosages. As with any medication, there is a 
possibility of an allergic reaction. There is a risk of liver damage with acetaminophen use 
regardless of the route. There is no risk of grogginess. There is no risk of pain or bruising 
with IV acetaminophen administration. When given either PO acetaminophen or placebo 
the subject will be given a small amount water. Although oral intake prior to surgery can 
increase risk of aspiration, the minimal amount of water given will not increase the risk of 
aspiration should an LMA or endotracheal breathing tube be required for the surgery. Oral 
medications are routinely given immediately prior to many procedures to help with 
analgesia intra- and post-operatively.  
7) Provisions for Research Related Harm/Injury 
If you are injured or made sick from taking part in this research study, medical care will be provided. 
Generally, this care will be billed to you or your insurance in the ordinary manner and you will be 
responsible for all treatment costs not covered by your insurance, including deductibles, co-payments 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
8 
Revised 9/2/14 
and coinsurance.  This does not prevent you from seeking payment for injury related to malpractice or 
negligence. Contact the investigator for more information. 
 
8) Potential Benefits to Subjects 
It is important to know that you may not get any benefit from taking part in this research.  Others may 
not benefit either. However, possible benefits may be improved knowledge about how the different 
forms of acetaminophen affect pain control.  
9) Provisions to Protect the Privacy Interests of Subjects 
Patients will be appropriately educated about the research study. Any questions or 
concerns they have will be adequately addressed and patients will have the option to 
decline participation. Patients will be given as much time as they need to review the 
consent form. The study personnel will be approaching the subjects. Privacy will be 
maintained by not including any identifiers such as names or addresses in the data 
collected.  
10) 
Economic Impact on Subjects 
Patients will not incur any additional cost for participating in the study. The medications 
used are part of a standard anesthetic regimen that will be billed to subject’s insurance as 
bundled standard of anesthesia care.  The cost of the procedure is overall unaffected.  The 
cost of Acetaminophen IV will be provided by the Dept of Anesthesiology.  
 
11) 
Payments to Subjects 
Patients will not be be reimbursed for their participation. 
12) 
Consent Process 
Both the HRP-090 (SOP) Informed Consent Process for Research and the HRP-091 (SOP) Written 
Documentation of Consent will be followed by the study team. These documents are both available at 
http://icahn.mssm.edu/research/resources/program-for-the-protection-
of-human-subjects/irb-members-palette. 
13) 
Process to Document Consent in Writing 
The patients will receive a paper copy of the IRB approved consent packet and will sign in 
the designated areas to confirm consent of participation.  They will have the option of have 
a copy of the consent and may ask for a personal copy of the consent.  
14) 
Vulnerable Populations 
Indicate specifically whether you will include (target) or exclude each of the following 
populations: 
Include 
Exclude 
Vulnerable Population Type 


 
Protocol Name: 
Comparative Efficacy of Intravenous Acetaminophen vs. Oral 
Acetaminophen in Ambulatory Surgery 
Principal Investigator:  
Yan Lai, M.D., M.P.H 
Primary Contact 
Name/Contact Info: 
Brittany Reardon  
Brittany.reardon@mountsinai.org  848-203-2169 
Date Revised: 
December 2, 2018 
Study Number: 
HSM 16-01057 and GCO 16-1763 
 
9 
Revised 9/2/14 
 
x 
Adults unable to consent 
 
x 
Individuals who are not yet adults (e.g. infants, children, teenagers) 
 
x 
Wards of the State (e.g. foster children) 
 
x 
Pregnant women 
 
x 
Prisoners 
 
15) 
Multi-Site Human Research (Coordinating Center) 
This study will be performed within the Mount Sinai West and St. Luke’s Hospitals. No 
additional centers will be involved. 
16) 
Community-Based Participatory Research 
This does not apply to our study. 
17) 
Sharing of Results with Subjects 
Results will not be shared with the patients since the study will take time to complete.  
Patients can request results if they contact the PI by writing. 
18) 
External IRB Review History 
This does not apply to our study. 
19) 
Control of Drugs, Biologics, or Devices 
 
Acetaminophen IV and PO are stored within the Pyxis drug storage system at Mount Sinai West and St. 
Luke’s.