A Randomized Controlled Trial of Oral Acetaminophen for Analgesic Control After Transvaginal Oocyte Retrieval
Phase: PHASE4
Conditions: Pain
Sponsor: University of Alabama at Birmingham

 
 
A Randomized Controlled Trial of Oral Acetaminophen for 
Analgesic Control After Transvaginal Oocyte Retrieval 
 
Study Protocol & Statistical Analysis Plan 
 
NCT02418182 
 
 
November 19, 2018 
 
 
Deidre D. Gunn, MD, Principal Investigator 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 
 

 
STUDY SUMMARY ...................................................................................... 
1 ..................................................................................................................... INTRODUCTION 
1.1 
BACKGROUND ..................................................................................................................................  
1.2 
PRECLINICAL DATA ..........................................................................................................................  
1.3 
CLINICAL DATA TO DATE...................................................................................................................  
2 .......................................................................................................... STUDY OBJECTIVES 
3 ..................................................................................................................... STUDY DESIGN 
3.1 
GENERAL DESIGN ............................................................................................................................  
3.2 
PRIMARY STUDY ENDPOINTS ............................................................................................................  
4 ......................................................... SUBJECT SELECTION AND WITHDRAWAL 
4.1 
INCLUSION CRITERIA ........................................................................................................................  
4.2 
EXCLUSION CRITERIA .......................................................................................................................  
4.3 
SUBJECT RECRUITMENT AND SCREENING .........................................................................................  
4.4 
EARLY WITHDRAWAL OF SUBJECTS...................................................................................................  
4.4.1 
When and How to Withdraw Subjects .......................................................................................  
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ............................................................  
5        STUDY DRUG 
6        STUDY PROCEDURES ...................................................................... 
7 ............................................................................................................ STATISTICAL PLAN 
7.1 
SAMPLE SIZE DETERMINATION ..........................................................................................................  
7.2 
STATISTICAL METHODS ....................................................................................................................  
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ...........................................................................................  
8 ............................................................................... SAFETY AND ADVERSE EVENTS 
8.1 
DEFINITIONS ....................................................................................................................................  
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................  
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .....................................  
8.6 
MEDICAL MONITORING .....................................................................................................................  
9 .......................................................... DATA HANDLING AND RECORD KEEPING 
9.1 
CONFIDENTIALITY .............................................................................................................................  
9.2 
SOURCE DOCUMENTS ......................................................................................................................  
8.3 
RECORDS RETENTION ......................................................................................................................  
10     STUDY MONITORING, AUDITING, AND INSPECTING ..................... 
10.1 
STUDY MONITORING PLAN ................................................................................................................  
10.2 
AUDITING AND INSPECTING ...............................................................................................................  
11 ...................................................................................... ETHICAL CONSIDERATIONS 
12 ............................................................................................................ STUDY FINANCES 
12.1 
FUNDING SOURCE ............................................................................................................................  
12.2 
CONFLICT OF INTEREST ....................................................................................................................  

12.3 
SUBJECT STIPENDS OR PAYMENTS ...................................................................................................  
13 ....................................................................................................... PUBLICATION PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1   INTRODUCTION 
1.1 Background 
 
The current standard of pain control during oocyte retrieval for in vitro fertilization 
(IVF) involves fentanyl, propofol, as well as oxycodone [1]. However, there exists 
little data of alternatives to narcotic medications for analgesic purposes in oocyte 
retrieval procedures. Potential for non-steroidal anti-inflammatory drugs (NSAIDSs), 
specifically ketorolac, to significantly improve pain scores in women undergoing 
oocyte retrieval has been shown previously [2]. In that study, ketorolac was 
administered immediately after oocyte retrieval procedures in addition to standard 
sedation. It was also shown that the use of these medications did not significantly 
alter pregnancy rate, live birth rate, or miscarriage rate in these patients [2]. Few 
other studies have delved into the question of anesthetics for oocyte retrievals other 
than a retrospective study that showed no significant difference in pregnancy rates 
or implantation with the use of acetaminophen and diclofenac vs. acetaminophen 
alone if given postoperatively [3]. However, pain was not measured in this study for 
either group.  
 
Acetaminophen and NSAIDs have been studied as an adjunctive treatment in a 
single prospective study with no significant differences in outcomes other than 
cumulative pain scores and reduction in use of rescue analgesia with tramadol [4]. 
Additionally, few alternatives other than narcotic medications have been studied; 
such adjuncts as EMLA cream and acupuncture have not shown a significant 
reduction in analgesic effect [5,6]. The paucity of data on analgesics used for IVF 
oocyte retrievals illustrates that more research is necessary to determine if there are 
safe and effective non-narcotic medications that can be used for this purpose. 
 
1. Kwan I, et al, Pain relief for women undergoing oocyte retrieval for assisted 
reproduction. Cochrane Database Syst Rev, 2013. 1: p. CD004829. 
2. Mesen TB, et al, The effect of ketorolac on pregnancy rates when used 
immediately after oocyte retrieval. Fertil Steril 2013. 100(3): 725-/. 
3. Akande V, Garas A, and Cahill D, The effect of diclofenac and paracetamol 
on pregnancy and implantation rates in infertile women undergoing IVF 
treatment. J Obstet Gynaecol 2006. 26(8): 785-7. 
4. Mohamad AH, et al, Parecoxib and paracetamol for pain relief following minor 
day-stay gynaecological surgery. Anaesth Intensive Care 2014. 42(1): 43-50. 
5. Piroli A, et al, Comparison of different anaesthetic methodologies for sedation 
during in vitro fertilization procedures: effects on patient physiology and 
oocyte competence. Gynecol Endocrinol, 2012. 28(10): 796-9. 
6. Gejervall AL, et al, Electro-acupuncture versus conventional analgesia: a 
comparison of pain levels during oocyte aspiration and patients’ experience 
of well-being after surgery. Hum Reprod 2005. 20(3): 728-35. 
 

1.2 Preclinical Data 
 
None 
 
1.3 Clinical Data to Date 
N/A 
 
2 
STUDY OBJECTIVES 
 
The objective of this randomized double-blinded placebo-controlled trial is to determine 
whether preoperative acetaminophen administration improves post-operative pain 
control following transvaginal cyst puncture for oocyte retrieval. We hypothesize that 
patients administered an oral dose of acetaminophen one hour before the procedure will 
have significantly lower cumulative pain scores at both 60 minutes post-procedure and 
24 hours post-procedure as compared to patients randomly assigned to placebo. 
 
3   STUDY DESIGN 
 
3.1  GENERAL DESIGN 
 
Randomized double-blinded placebo-controlled trial 
 
3.2  PRIMARY STUDY ENDPOINTS 
 
Primary outcome measures are as follows: 
1. Median of cumulative pain scores up to 60 minutes post-procedure 
2. Median of cumulative pain scores up to 24 hours post-procedure 
 
4  SUBJECT SELECTION AND WITHDRAWAL 
4.1 INCLUSION CRITERIA 
Females ages 21-45 undergoing planned TVCP for oocyte retrieval for IVF; English-
speaking 
4.2 EXCLUSION CRITERIA 
Opioid use within 24 hours prior to procedure; acetaminophen use within 24 hours prior 
to procedure; allergy to acetaminophen 
4.3 SUBJECT RECRUITMENT AND SCREENING 

Potential subjects were recruited and screened for eligiblity on the morning of the 
procedure by study personnel (staff and physicians involved in the study). 
4.4 EARLY WITHDRAWAL OF SUBJECTS 
4.4.1 WHEN AND HOW TO WITHDRAW SUBJECTS 
Subjects who consented to participate were informed that they could voluntarily 
withdraw consent for participation in the study at any time. Subjects were also 
informed that they could be removed from the study if it was determined that 
participation would be harmful to the patient’s health or if the patient did not 
follow the study rules and requirements. 
4.4.2 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS 
Median cumulative pain scores at 60 minutes post-procedure and at 24 hours 
post-procedure were compared between groups in an intent-to-treat analysis. 
 
5  STUDY DRUG 
This study involves administration of either a single 1000-mg oral dose of 
acetaminophen (administered in the form of two 500-mg tablets) or a drug placebo 
(administered in the form of two tablets, identical in appearance to the study drug). 
Administration of the study drug or placebo occurs at 60 minutes prior to the TVCP 
oocyte retrieval procedure. 
 
6   STUDY PROCEDURES 
As each patient arrives to the IVF procedure suite on their scheduled procedure date, 
study personnel will recruit and obtain informed consent from willing participants for the 
study. Also, patients will be questioned to determine whether there are any exclusion 
criteria that would preclude their participation in the study. Demographic data including 
body mass index, alcohol and tobacco use, history of prior oocyte retrieval, history of 
prior pelvic surgery, and history of chronic pelvic pain or endometriosis. The serum 
estradiol level at the time of ovulation trigger was abstracted from each participant’s 
medical record. 
Those patients who consent to participate will then have a numbered envelope from the 
Research Pharmacy Department assigned to their data collection form. The 
anesthesiologist, who is the only person not blinded to the intervention, will then open 
the envelope to reveal the patient’s group assignment. After study personnel have 
obtained a baseline pain score from the patient using a visual analog scale (VAS) 
corresponding to numbers 1 through 10. The anesthesiologist will subsequently 
administer either acetaminophen or placebo 60 minutes prior to the procedure.  

During the procedure, participants are given the usual medications administered during 
all TVCP procedures at this institution, which consist of propofol, fentanyl, and 
midazolam.  
After the procedure is completed, patients will be asked for a pain score using the VAS 
every 15 minutes for 60 minutes as per routine care in the recovery suite. Additionally, 
study personnel will document all other procedure and recovery data listed on the data 
collection form. All participants were discharged home with a prescription for 8 tablets of 
hydrocodone/acetaminophen (5 mg / 325 mg), as per clinic protocol for all patients 
undergoing TVCP procedure. 
On post-procedure day one, 24 hours post-procedure, participants will be contacted by 
phone to obtain a pain score on a scale of 1 to 10.  
 
7   STATISTICAL PLAN 
7.1 SAMPLE SIZE DETERMINATION 
Based on data from prior studies evaluating pain control after minor gynecologic 
surgery, a power analysis determined that 50 subjects in each arm are needed to detect 
a 2-point difference in median cumulative pain score at 24 hours post-procedure, with 
80% power and an alpha error 0.05.  
7.2 STATISTICAL METHODS 
Baseline characteristics will be compared between groups with student’s t-test, Mann-
Whitney U, chi-squared, or Fisher’s exact as appropriate. Median cumulative pain 
scores at 24 hours post-procedure will be compared between groups in an intent-to-
treat analysis using Mann Whitney U-test. Use of additional medications within 60 
minutes post-procedure or in the first 24 hours post-procedure will be compared using a 
chi-squared test.  
 
8  SAFETY AND ADVERSE EVENTS  
8.1 DEFINITIONS 
Adverse Events 
An adverse event is defined as “any untoward or unfavorable medical occurrence in a 
participant, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participant’s 
participation in the research, whether or not considered related to the participant’s 
participation in the research” (clinicaltrials.gov).  
 
The following categories of adverse event data will be reported as applicable: "All-
Cause Mortality," "Serious," and "Other (Not Including Serious)" adverse events. 

1. All-Cause Mortality: The occurrence of death due to any cause. 
2. Serious Adverse Events: Adverse events that result in any of the following 
outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the participant 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
3. Other (Not Including Serious) Adverse Events: Adverse events that are not 
Serious Adverse Events. 
Possible risks of acetaminophen include allergic reactions (rash, urticaria, and/or 
anaphylaxis) and, rarely, liver dysfunction. The latter is associated with doses greater 
than 4000 mg. This study will involve administration of only 1000 mg in the treatment 
group. Patients with recent acetaminophen use will be excluded. Additionally, 
participants will be counseled to avoid post-procedure acetaminophen use. 
8.2 RECORDING OF ADVERSE EVENTS  
Each participant will be followed from baseline (administration of study or placebo drug) 
to 24 hours post-procedure, and any adverse events will be recorded by study 
personnel and the principal investigator.  
As the study involves only the potential pre-procedure administration of oral 
acetaminophen (or non-active placebo), there is minimal risk for harm or discomfort to 
participants. The study group will receive two 500-mg tablets, for a total of 1000 mg of 
acetaminophen, a dose well below the threshold for toxicity. 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED 
PROBLEMS 
Any serious adverse events or other unanticipated problems will be reported 
immediately to the Institutional Review Board.  
8.4 MEDICAL MONITORING 
The study drug or placebo will be administered pre-procedure while in the preoperative 
area where the participants are already being monitored with routine vital signs prior to 
the procedure. They are then observed and monitored during the actual procedure (the 
average duration of which is 30 minutes) by the anesthesiologist providing conscious 
sedation as per routine. Additionally, one outcome measure requires a 60-minute post-
procedure assessment. Thus, in total, each participant will be directly monitored on the 
day of the procedure for at least 2.5 hours following drug administration.  

Participants will be given instructions at discharge to report any problems to the on-call 
physician. Specifically, participants will be instructed to seek medical assistance 
immediately if they experience any symptoms suggestive of liver damage, including 
dark urine, persistent nausea and/or vomiting, stomach/abdominal pain, extreme 
tiredness, or yellowing of the eyes or skin.  
Finally, the participant will be contacted by phone 24 hours post-procedure for final 
assessment of pain score and will be asked about any side effects or unanticipated 
problems. 
 
9  DATA HANDLING AND RECORD KEEPING  
9.1 CONFIDENTIALITY, 9.2 SOURCE DOCUMENTS, 9.3 RECORDS RETENTION 
A study code will be assigned to each enrolled subject. The link between samples and 
the enrollee will be stored in an encrypted database on a secure, password-protected 
server. Access to the server and database will be granted only to those personnel with 
IRB approval for this study. There will be data recorded on paper that will only be 
handled by study personnel. All paper data collection forms will be stored in the locked 
office of the principal investigator. 
 
10 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 STUDY MONITORING PLAN 
The principal investigator will review the individual data forms daily to monitor for any 
adverse events or deviations from study protocol. Any such incident will be reported to 
the Institutional Review Board immediately. 
 
11 ETHICAL CONSIDERATIONS 
Currently there are no oral pain medications given to patients prior to oocyte retrieval. 
Participants will not receive any alterations in the current medication standard of care 
but if randomized to the study group will receive an additional preoperative pain 
medication, acetaminophen. Control subjects will receive placebo which should not 
cause harm. There are no anticipated delays, withholding, or washouts for standard of 
care treatment as part of this study. If patients have used acetaminophen-containing 
products within the 24 hours prior to the oocyte retrieval procedure, they will be 
excluded from the study.  
 
12 STUDY FINANCES 

12.1 FUNDING SOURCE 
This study is not funded by any grants or outside funding. The minimal cost of 
acetaminophen and placebo will be covered by the general research fund of the UAB 
Division of Reproductive Endocrinology and Infertility. 
12.2 CONFLICT OF INTEREST 
There are no conflicts of interest among study personnel.  
12.3 SUBJECT STIPENDS OR PAYMENTS 
Subjects will not be compensated for their participation in this study.