Clinical trial NCT03545893
Conditions: Abortion Second Trimester
Sponsor: University of Pennsylvania
Start date: 2018-06-19; Completion date: 2019-02-07
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare maximum pain scores between patients seeking induced abortion and requiring cervical preparation with osmotic dilators. Patients will be randomized to receive prescription for ibuprofen alone or to receive prescription for ibuprofen + oxycodone for overnight pain management after cervical preparation with osmotic dilators. Data collected in-person and through a text-messaging platform.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Ibuprofen 600 mg intervention 2: OxyCODONE 5 Mg Oral Tablet
Intervention descriptions: intervention 1: Ibuprofen 600mg prescription, to be taken 1 tablet as needed every 6 hours for pain. intervention 2: Oxycodone 5mg Oral Tablet prescription, to be taken 1-2 tablets as needed every 6 hours for pain.

Protocol documents:
Prot_SAP_000.pdf: 
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A PILOT RANDOMIZED TRIAL OF OPIODS VERSUS NONOPIOIDS 
FOR PAIN CONTROL AFTER OSMOTIC DILATOR PLACEMENT FOR 
ABORTION CARE  
 
 
 
Principal Investigator  
Courtney A. Schreiber, MD, MPH 
Division of Family Planning, Obstetrics and Gynecology 
1000 Courtyard, 3400 Spruce St. Philadelphia, PA 19104 
215-615-0381 
267-586-8358 
Courtney.Schreiber@uphs.upenn.edu 
 
Funding Sponsor 
 
Society of Family Planning  
255 South 17th Street  
Suite 2709  
Philadelphia, PA 19103 
866-584-6758 
 
 
Protocol Number 
 
 
829723 
 
NCT# 
NCT03545893 
 
 
Initial version 
5/9/18  
Amended 
[Date] 
Amended 
[Date] 


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Table of Contents 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 5 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 5 
2 
STUDY OBJECTIVES ......................................................................................................................... 6 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 7 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 7 
3.1 
GENERAL DESIGN .......................................................................................................................... 7 
3.2 
ALLOCATION TO INTERVENTIONAL GROUP ....................................................................................... 7 
3.3 
STUDY MEASURES ......................................................................................................................... 7 
3.4 
STUDY ENDPOINTS......................................................................................................................... 7 
3.4.1 
Primary Study Endpoint ........................................................................................................... 7 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 8 
4.1 
DURATION OF STUDY PARTICIPATION .............................................................................................. 8 
4.2 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 8 
4.3 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.4 
EXCLUSION CRITERIA ..................................................................................................................... 9 
4.5 
SUBJECT RECRUITMENT ................................................................................................................. 9 
4.6 
VULNERABLE POPULATIONS: .......................................................................................................... 9 
5 
STUDY PROCEDURES ....................................................................................................................... 9 
5.1 ............................................................................................................................................................. 9 
5.2 
SCREENING ................................................................................................................................. 11 
5.3 
STUDY INTERVENTION .................................................................................................................. 11 
5.3.1 
Visit 2 ..................................................................................................................................... 12 
5.4 
SUBJECT WITHDRAWAL ................................................................................................................ 12 
5.4.1 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 12 
6 
STATISTICAL PLAN ......................................................................................................................... 12 
6.1 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 12 
6.2 
STATISTICAL METHODS ................................................................................................................ 12 
6.2.1 
Baseline Data ........................................................................................................................ 13 
6.2.2 
Analysis of Primary Outcome of Interest ............................................................................... 13 
6.2.3 
Interim Analysis (only if applicable) ....................................................................................... 13 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 13 
7.1.1 
Adverse Events ..................................................................................................................... 13 
7.1.2 
Data and Safety Monitoring Plan........................................................................................... 15 
THE PRINCIPAL INVESTIGATOR WILL BE RESPONSIBLE FOR THE DATA MONITORING AND 
SAFETY OF SUBJECTS. ........................................................................................................................... 15 
8 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 15 
8.1 
CONFIDENTIALITY ......................................................................................................................... 15 
8.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 16 
8.3 
RECORDS RETENTION .................................................................................................................. 16 
RESEARCH DATA WILL BE COLLECTED BY RESEARCH STAFF AND STORED IN STUDY-
SPECIFIC FILES KEPT IN A LOCKED AREA IN ONE OF THE RESEARCH LOCATIONS DURING THE 
ACTIVE PHASE OF THE STUDY.  ANY ELECTRONIC DATA WILL BE KEPT ON CONTROLLED 


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ACCESS DEPARTMENTAL SHARED DRIVES, OR IN A SECURED DATABASE ON REDCAP. ONLY 
THE PI AND STUDY STAFF LISTED WILL HAVE ACCESS TO DATA WITH PATIENT IDENTIFIERS. 
THERE SHOULD NOT BE A NEED TO TRANSMIT DATA FILES CONTAINING PHI FOR THIS STUDY.  
AT THE CONCLUSION OF THE STUDY DATA WILL BE RETAINED ON SITE IN THE SAME 
SECURED MANNER FOR A MINIMUM OF TWO YEARS, AND MAY BE TRANSFERRED TO A LONG-
TERM STORAGE FACILITY (IRON MOUNTAIN) THEREAFTER.  THERE IS NO CURRENT PLAN TO 
DESTROY THE IDENTIFIABLE INFORMATION. ..................................................................................... 16 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 16 
9.1 
STUDY MONITORING PLAN ............................................................................................................ 16 
9.2 
AUDITING AND INSPECTING ........................................................................................................... 16 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 16 
10.1 
RISKS .......................................................................................................................................... 17 
10.2 
BENEFITS .................................................................................................................................... 17 
10.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... 17 
11 
STUDY FINANCES ............................................................................................................................ 17 
11.1 
FUNDING SOURCE ........................................................................................................................ 17 
11.2 
CONFLICT OF INTEREST ................................................................................................................ 17 
11.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 17 
12 
PUBLICATION PLAN ........................................................................................................................ 18 
13 
REFERENCES ................................................................................................................................... 18 
14 
ATTACHMENTS ................................................................................................................................ 19 
 


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Study Summary 
 
Title 
A Pilot Randomized Trial of Opioids versus Nonopioids for Pain Control After 
Osmotic Dilator Placement in Abortion Care  
Short Title 
OPTION: Overnight Pain Treatment: Investigation Opioids vs. Nonopioids 
IRB Number 
829723 
Methodology 
Randomized Controlled Trial; Pilot 
Study Duration 
May 2018- March 2019  
Study Center(s) 
PEACE Center (Hospital of the University of Pennsylvania) 
3400 Spruce Street, 1000 Courtyard 
Philadelphia, PA 19104 
 
PEACE Center (Penn Medicine Washington Square / Pennsylvania Hospital) 
800 Walnut Street 
Philadelphia, PA 19107 
  
Objectives 
Primary: To compare maximum pain scores between patients seeking induced 
abortion and requiring cervical preparation with osmotic dilators, randomized to 
receive prescription for ibuprofen alone and those randomized to receive 
prescription for ibuprofen + oxycodone for overnight pain management after 
cervical preparation with osmotic dilators 
 
Number of Subjects 
70  
Main 
Inclusion 
and 
Exclusion Criteria 
Inclusion: English-speaking women, 18 years or older, access to cell phone 
with text-messaging capability, receiving cervical preparation for induced 
abortion, and able to complete baseline survey on smartphone/tablet at 
screening visit. 
  
Exclusion: History of opioid or alcohol abuse, contraindications or allergy to 
ibuprofen, contraindications or allergy to opioid medications, seeking uterine 
evacuation for premature preterm rupture of membranes or advanced cervical 
dilation or intrauterine fetal demise.  
Intervention  
 
Comparison of prescription of 4 tablets of 600 mg ibuprofen, one tablet every 6 
hours as needed for pain to the above ibuprofen + Oxycodone (8 tablets of 
5mg) one tablet every 6 hours as needed for pain, for pain control following 
osmotic dilators placement.    


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Statistical 
Methodology 
Demographic and perioperative characteristics between groups will be 
compared using a Chi-square test for proportions, or Fisher’s exact test for 
small numbers as appropriate. 
 
The primary outcome for analysis will be maximum pain score. We will 
compare the median pain score reported at various intervals in the ibuprofen 
alone arm, compared to the oxycodone+ibuprofen arm using the Wilcoxon 
rank-sum test.  NRS pain scores will be used.  
 
Analysis of changes in pain scores from baseline at the time of dilator 
placement, 2hr and 6hr post-dilator pain scores will be analyzed by group as 
well using the Wilcoxon rank-sum test. 
Data 
and 
Safety 
Monitoring Plan  
The Principal Investigator will be responsible for the data monitoring and safety 
of subjects.  
 
Background and Study Rationale 
 
This study will be conducted in full accordance with all applicable University of Pennsylvania Research 
Policies and Procedures and all applicable Federal and state laws and regulations including Introduction 
 
Introduction 
The United States is in the throes of an opioid epidemic1. The rise in prescription opioid-associated 
morbidity and mortality2 contributes to this public health crisis3. Unused prescribed opioids are 
problematic, as the surplus of pills facilitates misuse, diversion and long-term dependence. Identifying 
patients who are unlikely to use most of their prescribed opioid medications could enable clinicians to 
safely prescribe fewer pills after surgery4.  
 
Dilation and evacuation is the most common technique used for second-trimester abortion. Pre-operative 
dilation of the cervix with the use of osmotic dilators decreases the risk of complications, and evidence-
based research supports their use. Dilators remain in place for hours, often overnight, and expand; hence 
many women require overnight analgesia. Prescribing patterns are variable: women may or may not 
receive opioids for pain control, and this variability is provider dependent. Clinical data to inform best 
practices in this area are lacking.  
 
We propose a pilot randomized trial to compare prescription for ibuprofen alone with ibuprofen + 
oxycodone for overnight analgesia, among women receiving osmotic dilators for second trimester 
abortion care. We will use a text messaging platform to record real-time pain scores, and collect 
information regarding the timing and type of therapies used between dilator insertion and evacuation 
procedure. The primary outcome will be to compare maximum pain scores between groups.  
 
1.1 
Background and Relevant Literature  
After pain was coined “the fifth vital sign” in the 1990s, the sale of prescription opioids in the United States 
has quadrupled5. The pendulum has now swung to the other direction with the realization that opioid 
exposure places individuals at risk for long-term opioid use and abuse. Even opioid-naïve surgical 
patients, who are appropriately prescribed opioids for short-term use to treat post-procedural pain, are at 
risk of opioid dependency6. However, in the postoperative period, notably after minor surgical procedures, 
many patients do not take the prescribed opioids7. 


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Women appear to be particularly susceptible to opioid abuse. In 2015, 1.2 million women were diagnosed 
with opioid misuse compared 0.9 million men8. Among women, opioid overdose deaths have risen five-
fold from 1999-20101. A recent study, evaluating post-cesarean section pain control, showed that there 
are opportunities to modify opioid exposure9. Like Cesarean section, dilation and evacuation (D&E) is a 
common procedure during which women may be exposed to opioids10,11.  Overnight cervical preparation 
with osmotic dilators such as Laminaria or Dilapan-S is standard practice because of the associated 
decrease in surgical complications12,13,14. Women typically rate the pain of osmotic dilator insertion as 
moderate to severe15, and pain can persist beyond the time of placement. Osmotic dilators exert radial 
pressure against the cervical stoma and cause the release of prostaglandins. This endogenous 
prostaglandin release can cause myometrial contractility, ultimately leading to uterine ischemia and 
pain16.  
 
Most providers prescribe medications for overnight analgesia, but evidence-based practices have not 
been established. An informal survey conducted among Society of Family Planning members showed 
that prescribing patterns vary from ibuprofen alone to opioids such as acetaminophen/codeine (T#3), 
oxycodone or hydrocodone +/− acetaminophen, or tramadol for outpatient analgesia after osmotic dilator 
placement (unpublished data).  
 
Evidence from randomized trials has demonstrated that non-steroidal anti-inflammatory agents (NSAIDs), 
such as ibuprofen, are effective in treatment of pain resulting from prostaglandin release in the setting of 
dysmenorrhea17. NSAIDs may be sufficient (non-inferior to narcotics) for post-dilator pain, but this 
question has not been tested.  
 
To our knowledge, no published studies have been conducted to specifically evaluate use of oxycodone 
for post-osmotic dilator pain control in patients receiving osmotic dilators for cervical preparation. 
Recently, Soon et al demonstrated the reduction in pain scores, and improved patient satisfaction, in 
those who received paracervical block for analgesia during laminaria insertion2. Because our thorough 
literature search did not uncover published data on the expected difference of mean pain scores or 
standard deviation in the post-osmotic dilator population, we chose our standard deviation from studies 
assessing similar outcomes in similar populations. The study by Renner et al18, which evaluated pain 
scores in first trimester abortion, along with the study by Akers et al19, which assessed pain scores at the 
time of and following intrauterine device placement, established a standard deviation of 30mm for pain 
scores in gynecologic care. Other studies have demonstrated a strong correlation of the Numerical Rating 
Scale (NRS) and VAS, and that it may be a more appropriate instrument for acute pain20. In the literature, 
a difference of 1.3 in the NRS has been considered clinically meaningful, within specific subsets. There 
have been recent studies that compare various analgesics for acute pain. A study by Chang et al, 
assessed patients who presented to the ED with acute extremity pain21. Patients were randomized to 
single dose treatment with ibuprofen and acetaminophen or with 3 different opioid and acetaminophen 
combination analgesics. NRS pain scores were used in this study. There was no statistically significant or 
clinically important reduction in pain scores with the use of opioids 
 
 
2 
Study Objectives 
Our primary aim is to compare maximum pain scores between women randomized to receive ibuprofen 
alone to those randomized to receive ibuprofen + oxycodone in the setting of osmotic dilator placement 
for dilation and evacuation. Given the prevalence of abortion and the susceptibility of young women to 
opioid addiction, the ultimate goal is to reduce unnecessary exposure to opioids while ensuring effective 
pain management. This study will allow us to obtain preliminary estimates of maximum overnight pain 
scores among women receiving osmotic dilators who are randomized to one of two different analgesic 
options, ibuprofen or ibuprofen + oxycodone. Our overarching goal is to improve the care and safety of 
women requiring abortion procedures.  
 
 
 


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2.1 
Primary Objective 
To compare maximum pain scores between patients seeking induced abortion and requiring cervical 
preparation with osmotic dilators, randomized to receive prescription for 4 tablets 600 mg ibuprofen alone 
and those randomized to receive prescription for 4 tablets 600 mg ibuprofen + 8 tablets 5 mg oxycodone 
for overnight pain management after cervical preparation with osmotic dilators.  
 
We hypothesize that such a trial is feasible, that 50% of our eligible patients will be willing to enroll.  We 
will compute point estimates of the mean, median, and standard deviation for maximum pain scores 
among women randomized to use ibuprofen alone, and of women randomized to ibuprofen + oxycodone, 
to provide pilot data for future clinical trials.   
3 
Investigational Plan  
3.1 
General Design 
We propose a pilot randomized trial, in which 70 eligible women who are receiving cervical preparation 
with osmotic dilators will be randomized to one of two arms: 1) prescription for ibuprofen alone or 2) 
prescription for ibuprofen + prescription for oxycodone. All patients are offered oral ibuprofen 600 mg to 
take prior to their procedure as standard of care, and will receive a paracervical block at the time of dilator 
placement. Additionally, all study participants will receive standardized counseling regarding pain 
management. Randomization will occur after dilator placement. Women randomized to arm 1 will receive 
a prescription for 4 tablets of 600 mg of ibuprofen. They will be instructed to take 600 mg ibuprofen, 1 
tablet, every 6 hours, as needed for pain.  Those randomized to arm 2 will receive a prescription for 4 
tablets of 600 mg ibuprofen and a prescription for 8 tablets of oxycodone. Patients will be instructed to 
use oxycodone as an adjunctive medication, when ibuprofen was not sufficient in controlling pain. They 
will be told to take 1-2 tablets every 6 hours as needed for moderate to severe pain. As we expect 
participants to have dilators in for approximately 24 hours +/- 6 hours, we will prescribe 8 tablets, as this 
is commensurate with clinical practice.  
3.2 
Allocation to Interventional Group  
The randomization scheme will be generated using www.randomization.com, and assignment will be 
performed using the randomization module in REDCap. A research assistant who will not be involved in 
opening the envelopes will ensure allocation concealment by placing study assignments in sequentially 
numbered, opaque, sealed envelopes. We will use block randomization with unequal block sizes of 4 and 
6 to balance the number of participants in each group, given our small planned sample size. 
3.3 
Study Measures 
 
We will use a Numerical Rating Scale (NRS 0-10) to measure pain scores in both arms at baseline 
(before osmotic dilator placement, at the time of the baseline questionnaire), immediately after osmotic 
dilator placement, and at arrival at preoperative holding area.  
 
NRS scores will additionally be collected via text message at 2 hours and 6 hours after osmotic dilator 
placement. This study will allow us to document the feasibility of obtaining pain score data remotely using 
a text-messaging platform. A survey assessing pain, acceptability, and adequacy of pain control will be 
administered in the pre-operative holding area (Appendix F). The primary outcome will be maximum pain 
score during the study period.  
3.4 
Study Endpoints  
3.4.1 
Primary Study Endpoint 
The primary outcome measure is maximum NRS as measured by subtracting baseline pain score, from 
maximum pain score. The pain scores are collected at baseline, immediately after dilator placement, 2 


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and 6 hours post-dilator placement and in the pre-operatively holding area. Maximum scores at any of 
these collection points will be the primary outcome in both arms.  
 
Given onset of action of ibuprofen to be 30-60 minutes, with a maximum effect at 120 to 240 hours, and 
the onset of action of oxycodone to be 15-30 minutes, with peak effect at 30-60 min there was not a 
discrete time point that we felt to be concordant. Rather, a short interval pain score (2 hours), and score 
at potential maximum dilation (6 hours) will be used. We will use a text-messaging platform with 
automated prompts to collect real-time overnight pain scores.  
 
Additional measures including medications taken, or interventions used, timing and dose of medications, 
number of tablets used will also be collected through a final questionnaire in the preoperative holding.  
 
Procedural variables such as length of time dilators were in place and the number of dilators placed will 
also be collected.  
4 
Study Population and Duration of Participation  
4.1 
Duration of Study Participation  
Enrollment for the study will occur between June 2018 and November 2018. The Pennsylvania Abortion 
Laws (Pennsylvania Abortion Control Act) require patients receive specific information, and sign consents 
regarding termination of pregnancy at least 24 hours prior to the start of an abortion procedure. Patients 
traditionally have consultation appointments that include procedural consents, and an ultrasound to 
establish gestational age, prior to the placement of osmotic dilators. Eligible patients will be identified 
research staff, who will then approach the patient at their consultation visit prior to osmotic dilator 
placement and offer participation in the study. Following this, those patients who have consented would 
return for follow-up the day prior to the procedure for osmotic dilator placement. Pain scores (NRS; 0-10) 
will be collected at the dilator visit. The patients will be followed overnight via the text-messaging platform, 
and ultimately followed up until the procedure in the operating room. The final questionnaire will be 
administered in the pre-operative holding. Once this is complete their study participation has ended. Total 
duration of participation is approximately 24 hours.  
4.2 
Total Number of Subjects and Sites  
All women aged 18 or older, presenting for second-trimester abortion care, and desiring surgical 
management with uterine evacuation who require cervical preparation at the PEACE clinic will be 
approached for the study. Informed consent will be obtained for participation in the study. All 70 patients 
will be enrolled at Penn.  
 
The Hospital of the University of Pennsylvania is the primary referral center for medically complex 
patients needing abortion care in the greater Philadelphia area. We see an increase in our volume 
annually, and we performed 300 second trimester D&Es in FY17. Ninety-five percent of these patients 
receive osmotic dilators the day before surgery. We anticipate being able to screen at least 140 women 
within a 6-month period, and enroll 70. We have a second practice at Penn Medicine Washington Square 
(Pennsylvania Hospital) with the same practice patterns that we will also utilize for recruitment. 
 
4.3 
Inclusion Criteria 
English-speaking women  
18 years or older  
Access to cell phone with text-messaging capability/data 
Receiving cervical preparation for induced abortion 
Able to complete baseline survey on smartphone/tablet at screening visit 
 
 


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4.4 
Exclusion Criteria 
History of opioid or alcohol abuse 
Contraindications or allergy to ibuprofen 
Contraindications or allergy opioid medications 
Seeking uterine evacuation for premature preterm rupture of membranes or advanced cervical 
dilation or intrauterine fetal demise  
 
 
4.5 
Subject Recruitment  
All women aged 18 or older, presenting for second-trimester abortion care, and desiring surgical 
management with uterine evacuation who require cervical preparation at the PEACE clinic will be 
approached for the study. PEACE: Family Planning and Pregnancy Loss services clinic at Penn 
Medicine. We are a referral center for medically complex patients needing abortion care in the greater 
Philadelphia area. No advertising for this study will take place. Eligible patients will be identified research 
staff, who will then approach the patient at their consultation visit prior to osmotic dilator placement and 
offer participation in the study. Informed consent will be obtained for participation in the study by research 
staff 
4.6 
Vulnerable Populations:  
This study involves pregnant women and fetuses.  
The patient will be approached for study consents after clinical procedural consents have been signed. 
While individuals delegated on this study may be responsible for obtaining clinical consent for the 
patient’s pregnancy termination, the person approaching and obtaining consent for study participation will 
be a different individual than the person who obtains the clinical consent. 
 
If any Penn affiliates are approached for study participation, they will be informed that their decision of 
whether to participate in this study will in no way impact their standing with the institution.  
5 
Study Procedures  
 
5.1 
 
Study Phase 
Screening/Visit1 
Visit 2/Dilator 
Text-
messaging 
Visit 3/ 
Procedure 
Day 
Informed Consent/Assent 
X 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
Vital Signs: BP, HR, RR 
X 
X 
 
X 
Height and Weight 
X 
 
 
 
Data Collection Form 
X 
 
 
 
Baseline Questionnaire 
X 
 
 
 
Prior/Concomitant Medications 
X 
 
X 
X 
Clinical Laboratory Evaluation 
X 
 
 
 


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Ultrasound 
X 
 
 
 
Text-messaging Questionnaire 
 
 
X 
 
Final Questionnaire  
 
 
 
X 
NRS 
X 
X 
X 
X 
VAS 
X 
X 
 
X 
Adverse Event / Unanticipated 
Problems Assessment 
 
 
 
X 
 
 
Does your study use MRI? (CAMRIS is the appropriate contact for all studies involving MRIs) 
 Yes  
 
 No (If No, no CAMRIS review needed) 
 
Check of all that apply: 
 1.5T MRI 
 3T MRI 
 7TMRI 
 
Does the MRI use investigational sequences and/ or coils? 
(See Experimental Device Clause) 
  
 Yes  
 
 No              
 Unsure (if unsure be sure to contact CAMRIS)  
 
Does your study include pregnant women? 
(See Pregnancy Clause and Justification) 
  
 Yes  
 
 No 
 
Does the MRI require the use of Contrast Agents? 
(See Contrast Risks) 
 
 Yes  
 
 No 
 
Does your study involve the exposure to radiation, radiotracers and/or radiological imaging modalities?  
 
 Yes  
 
 No (If No, no RRSC review is needed)  
 
Will any of the radiation exposure result from procedures that are or could be performed solely as a result 
of a subject’s participation in the research protocol? 
 Yes  
 
 No  
 
The following are examples of procedures involving ionizing radiation:  
(Review appendix 15.3 and appendix 15.5)  
 
 
X-rays (examples: CT scan, chest x-ray, hand/wrist x-ray, abdomen x-ray, DEXA, pQCT, 
Fluoroscopy/Angiography) 
 
Nuclear Medicine scans (examples:  FDG-PET, PET/CT, Tc-99m, SPECT, MUGA, bone 
scan) 
 
If you are unsure please contact Will Davidson in EHRS (wed@ehrs.upenn.edu). 
 
 
 


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Ultrasound  
 Yes  
 
 No 
 
If yes, there is no protocol specific language to include but please contact Susan Schultz at: 
susan.schultz@uphs.upenn.edu 
 
Will your study be using CT Scans? (CACTIS is the appropriate contact for studies involving CT scans)  
 Yes  
 
 No 
 
 
Studies involving Nuclear Medicine: Will subjects be undergoing any of the following procedures specific 
to research: 
 MUGA 
 
(See Nuclear Medicine-Muga Scan) 
 PET/CT Scan 
 
(See PET/CT Scan) 
 Bone /DXA 
 
(See Bone Scan) 
 
Check off all of the following procedures that will be performed in your research- each option you select 
will link to the template language document:  
 Apheresis/plasma exchange  
 Leukapheresis  
 Bone Marrow Biopsy or Aspirate  
 Use of AP clinical specimens  
 Biopsies- check those which apply  
 Blood draw  
 
5.2 
Screening  
 
Screening/Visit 1 
 
Informed Consent 
 
Eligibility/Admission form  
 
Medical Record Review- Data Collection Form (Age, Insurance status, gestational age, BMI) 
 
Baseline Questionnaire (Race, Education, Marital status, Income, parity, prior surgical abortion) 
 
Vital Signs (Blood pressure, heart rate)  
 
Lab tests (Urine Protein/creatinine, urine glucose, type and screen, complete blood count)  
 
Physical Exam (Height, Weight)  
 
Ultrasound confirmation of gestational age   
 
NRS pain score –collected in Baseline questionnaire  
 
 
 
  
 
 
5.3 
Study Intervention  
 
Visit 2/ Dilators 
 
Dilator placement  
 
Randomization 
 
Data collection form (No. dilators placed, type and size of dilators, length of dilators in place)   
 
NRS pain score –Recorded in Data Collection Form  


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Text-messaging 
 
Text Messaging Questionnaire (NRS to be collected)  
 
Visit 3/Procedure Day  
 
Final Questionnaire (NRS to be recorded)  
 
5.3.1 
Visit 2 
5.4 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  Patients will be 
discontinued if there is a failure to place osmotic dilators for any reason.  Reasons for failure may include 
change of decision to terminate pregnancy, decision by provider to not place osmotic dilators, or technical 
inability to place dilators secondary to anatomy (fibroids, etc.). It will be documented whether or not each 
subject completes the study. 
5.4.1 
Data Collection and Follow-up for Withdrawn Subjects 
If a patient withdraws or is discontinued, data that has been collected prior to withdrawal or 
discontinuation will still be included in applicable statistical analyses.  They will not be included in any 
analyses that require collection of pain scores.  
6 
Statistical Plan 
6.1 
Sample Size and Power Determination 
As this is a pilot study, our sample size is a convenience sample. We will recruit 70 participants as part of 
this convenience sample. There has been literature to support a pilot trial sample size of 70 participants in 
order to reduce the imprecision around the estimate of the standard deviation22. Based upon our clinical 
volume we anticipate that it will be feasible to recruit 70 participants within a 6-month time period. Below 
are the possible effect size calculations, based on varying standard deviations, that we will demonstrate 
with n=70. The effect size quantifies the magnitude of the difference between the two study groups.  
 
SD 
N  
Beta  
Effect size  
1.0 
35 (per arm)  
0.2 
0.68 
1.5 
35 (per arm) 
0.2 
1.02 
2.0 
35 (per arm) 
0.2 
1.36 
2.5 
35 (per arm)  
0.2 
1.70 
 
Given our high show-rate for abortion after dilator placement, we anticipate high retention rate, and ability 
to obtain maximum pain scores in all of the randomized participants.  
 
Our primary analysis will be intention-to-treat analyses, although a per-protocol analysis will also be 
performed. Given that there are no published data on pain scores in the post-dilator time period, our study 
will be a crucial first step for optimizing the pain management and safety of these women. 
 
6.2 
Statistical Methods 
Data analysis will be performed in Stata by the primary investigator in consultation with professional 
statisticians. Demographic and perioperative characteristics between groups will be compared using a 
Chi-square test for proportions, or Fisher’s exact test for small numbers as appropriate. The primary 
outcome for analysis will be maximum pain scores. We will compare the maximum median pain score 
reported in the ibuprofen alone arm, compared to the oxycodone+ibuprofen arm using the Wilcoxon rank-


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sum test. Analysis of changes in pain scores from baseline at the time of dilator placement, 2hr and 6hr 
post-dilator pain scores will be analyzed by group as well using the Wilcoxon rank-sum test. Additionally, 
analysis based on pain medication actually used, ibuprofen versus oxycodone will be performed. Sub-
group analyses will be conducted similarly. We plan to perform subgroup analyses by gestational age 
(completed weeks), parity, number of dilators placed, BMI and by certain maternal demographic 
characteristics.  
 
Control of Bias and Confounding  
Given the side-effect profile of oxycodone, true participant blinding is not possible. Although we had 
considered the use of a placebo, and the strength of a placebo-controlled design, we have chosen to 
utilize a more “real-world” study design. However, in this study the research staff conducting the 
questionnaires and obtaining pain scores will be blinded to the intervention. By blinding the outcome 
assessor, we limit the potential for treatment effect estimates to be exaggerated. It also reduces bias in 
the way the questionnaires are asked, and primary outcome data collection is obtained. 
6.2.1 
Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive statistics.  
6.2.2 
Analysis of Primary Outcome of Interest 
The primary outcome for analysis will be maximum pain scores, computed as the difference between 
baseline pain score and the participates maximum reported pain score. We will compare the median pain 
score reported at pre-operative holding in the ibuprofen alone arm, compared to the oxycodone+ibuprofen 
arm using the Wilcoxon rank-sum test.  
 
6.2.3 
Interim Analysis (only if applicable) 
Not applicable.  
 
7 
Safety and Adverse Events 
The safety of the medications used within this study is well established. The side effects that are known 
are listed below. We will be asking participants in the final questionnaire detailing which, if any, side 
effects they experienced.  
 
7.1.1 
Adverse Events 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Not all events that would traditionally be defined as AEs will be collected 
by the sponsor for this trial. 
 
There are a number of expected side effects related to the medications being used in this study: 
 
Ibuprofen  
Mechanism of action: reversibly inhibits cyclooxygenase-1 and 2 (Cox 1 and 2), which results in 
decreased formation of prostaglandin precursors 
 
Onset of action: 30-60 minutes 
Peak effect: 120 to 240 hours 
Duration of effect: 6 to 8 hours 
Half-life: 2 hours  
 


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Adverse reactions: edema (1-3%), dizziness (3-9%), headache (1-3%), nervousness (1-3%), skin rash (3-
9%), pruritis (1-3%), fluid retention (1-3%), epigastric pain (3-9%), heartburn (3-9%), nausea (3-9%), 
abdominal pain (1-3%), constipation (1-3%), decreased appetite (1-3%), diarrhea (1-3%), dyspepsia (1-
3%), flatulence (1-3%), vomiting (1-3%) 
 
Oxycodone 
Mechanism of action: binds to opiate receptors in the CNS, causing inhibition of ascending pain 
pathways, altering the perception of and response to pain; produces generalized CNS depression  
 
Onset of action: 15-30 minutes 
Peak effect: 30-60 minutes  
Duration of effect: 3 to 6 hours  
Half-life: 3.2 to 4 hours  
 
Adverse reactions: drowsiness (23%), dizziness (9-13%), nausea (15-23%), constipation (23%), vomiting 
(12-13%), fever (1-11%), edema (1%), orthostatic hypotension (1-5%), anxiety (1-5%), confusion (1-5%), 
dysphoria (1-5%), nervousness (1-5%), twitching (1-5%), agitation (<1%), depression (<1%), diaphoresis 
(5%), diarrhea (1-6%), anorexia (1-5%), dyspepsia (1-5%), gastritis (1-5%), hiccups (1-5%), weakness (1-
6%), dyspnea (1-5%) 
 
All adverse events will be collected, recorded, and assessed locally by the investigator or her designee. 
Only events that are determined to be both unexpected and related to the study will be entered into the 
electronic CRF and report to the local IRB (as described below).  
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 
 
results in persistent or significant disability or incapacity 
 
a congenital anomaly or birth defect 
 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. 
 
Adverse Event Reporting Instructions 
The Principal Investigator will evaluate women who experience a SAE as necessary until the event is 
resolved. Adverse events that are both serious and unexpected will be reported to the IRB per their local 
reporting requirements. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up. For this study, initiation 
will be at the time of randomization, and the study treatment follow-up is completed at the time of the 
surgical procedure, once the osmotic dilators are removed.  
 
Post-study Adverse Event 


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All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study. The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol. Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for 
an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition. Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
 
Recording of Adverse Events 
At each contact with the subject, the investigator or designee must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events should be 
recorded immediately in the study documents. 
 
All adverse events occurring during the study period must be recorded. The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause. Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
 
7.1.2 
Data and Safety Monitoring Plan 
The Principal Investigator will be responsible for the data monitoring and safety of subjects. 
 
8 
Study Administration, Data Handling and Record Keeping 
8.1 
Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 
What protected health information (PHI) will be collected from subjects in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
The program being used for the study text messages is Twilio. Twilio is a third-party application with the 
capability to integrate and directly feed data into REDCap. All study data will be maintained behind the 
UPHS firewall and in a password-protected encrypted REDCap database. Any paper research records 
will be collected by research staff and stored in study-specific files kept in a locked area in one of the 
research locations during the active phase of the study.  Any electronic data will be kept on controlled 
access Departmental shared drives, or in a secured database on REDCap. Only the PI and study staff 
will have access to data with patient identifiers. There should not be a need to transmit data files 
containing PHI for this study.  At the conclusion of the study data will be retained on site in the same 
secured manner for a minimum of two years, and may be transferred to a long-term storage facility (Iron 
Mountain) thereafter.  There is no current plan to destroy the identifiable information. 
8.2 
Data Collection and Management  
Data will be entered into a password protected REDCap database accessible only by study staff.  Trained 
research staff will enter the data.  Cleaning will occur throughout the data collection period and again after 
completion by the study staff.   
 
8.3 
Records Retention 
Research data will be collected by research staff and stored in study-specific files kept in a locked area in 
one of the research locations during the active phase of the study.  Any electronic data will be kept on 
controlled access Departmental shared drives, or in a secured database on REDCap. Only the PI and 
study staff listed will have access to data with patient identifiers. There should not be a need to transmit 
data files containing PHI for this study.  At the conclusion of the study data will be retained on site in the 
same secured manner for a minimum of two years, and may be transferred to a long-term storage facility 
(Iron Mountain) thereafter.  There is no current plan to destroy the identifiable information.  
9 
Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
The primary investigator will be responsible for ensuring the ongoing quality and integrity of the research 
study. The PI will annually complete PICA for monitoring at the time of continuing review. 
 
9.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related.  The investigator will ensure the capability for inspections of applicable study-related facilities 
. 
10 Ethical Considerations 
We will obtain IRB approval prior to beginning recruitment for the study.  Any protocol amendments will 
be submitted to the IRB prior to implementation.  We will additionally comply with all HHS regulations as 
outlined in 45CFR46 Subparts.  


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10.1 
Risks 
 
The risks included known side effects of the study medications, which are established and noted in the 
above section on safety. There is a potential risk of inadequate pain control in those randomized to 
ibuprofen alone. However, participants, will have access to on-call physician line with the capability of 
additional “rescue” prescription availability on an as needed basis. There are no reproductive risks to 
participating in the study.  
10.2 
Benefits 
Participants are not expected to get direct benefits from being in the study. Anticipated benefits to future 
women include a better understanding of pain control while osmotic dilators are in place. Furthermore, the 
study may change pain management options for patients, that rather than being practice-based would be 
evidence-based.  
10.3 
Risk Benefit Assessment 
This study is of minimal risk.  
 
Informed Consent Process / HIPAA Authorization  
All subjects for this study will be provided a consent form describing this study providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a subject, using the IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The subject, or legally acceptable surrogate, must sign the consent 
form, and the investigator-designated research professional obtaining the consent. Subjects will be 
consented by the study Principal Investigator, or appropriate designee. Potential subjects will review the 
consent form in detail with the person designated to consent (either PI or CRC) and have the ability to 
take the consent home for further review.  
 
11 Study Finances 
11.1 
Funding Source 
 
This study is financed through a grant from the Society for Family Planning. 
 
11.2 
Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
11.3 
Subject Stipends or Payments 
For time and the inconvenience related to participation in this study, the participants will be paid for each 
study procedure completed using a Greenphire ClinCard. The payment will be approved and loaded onto 
the debit card following each completed study visit.  If a patient is screened for the study and is not 
eligible to enroll, she will be paid for the screening visit if it is completed. No additional financial 
compensation will be provided.  
 
Visit Type 
Compensation 
Screening/Visit 1 
$25 
Text Questionnaire at Hour 2  
$25 


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Text Questionnaire at Hour 6 
$25 
Procedure Day/Visit 3 
$25 
 
A total of $100 will be distributed for completing all desired questionnaires.  
12 Publication Plan 
This is a single institution study and we do not anticipate any barriers to publication. Results will be 
disseminated via a publication(s) in a peer-reviewed journal  
13 References 
1. Centers for Disease Control and Prevention. Adult use of Prescription Opioid Pain Medications. 
MMWR 2008; 59: 153-157.  
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14.  Fox MC, Krajewski CM. Cervical preparation for second-trimester surgical abortion  
 prior to 20 weeks’ gestation: SFP Guideline #2013-4. Contraception 2014; 89:75-84. 
15.  Mercier RJ, Liberty A. Intrauterine lidocaine for pain control during laminaria insertion:  
 a randomized controlled trial. Contraception 2014; 90:594-600.  
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Gynecology 1978;130(7):833-847. 
17. Marjoribanks J, Ayeleke RO, Farquhar C, Proctor M. Nonsteroidal anti-inflammatory drugs for 
dysmenorrhoea. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2015.  
18. Renner R-M, Edelman AB, Nichols MD, Jensen JT, Lim JY, Bednarek PH. Refining paracervical 
block techniques for pain control in first trimester surgical abortion: a randomized controlled 
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20. Bijur PE, Clarke TL, Gallagher  JE. Validation of a verbally administered numerical rating scale of 
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38(17): 1661-1667.   
 
14 Attachments 
Information will be entered directly into a REDCap database. Please see attachments for study 
questionnaires, ICFs, etc.