Buccal Misoprostol Prior to Abdominal Myomectomy for Reduction of Intraoperative Blood Loss: A Randomized Placebo-Controlled Trial
Phase: PHASE4
Conditions: Fibroids
Sponsor: Northwestern University

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Buccal Misoprostol Prior to Myomectomy for Reduction of Intraoperative Blood Loss: A 
Randomized Placebo-Controlled Trial (NCT02209545) 
 
  
Principal Investigator:  
Magdy Milad MD 
Department of Obstetrics and Gynecology 
Northwestern University Feinberg School of Medicine 
250 East Superior Street, Room 05-2177 
Chicago, IL 60611 
312-472-4673 
Mmilad@nmh.org 
         
         
         
         
 
Study Drug/Study Device:   
Active: Buccal Misoprostol (Cytotec) 400mcg 
Placebo: Buccal Pyridoxine (Vitamin B6) 100mg 
  
Funding Source:          The Gerbie Professorship 
  
  
Initial version: 01/14/2019          
 
Amended: 09/09/2020        
         
         
 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1.1           Disease Background .................................................................................................... 6 
1.2           Study Agent(s)/Devices Background and Associated Known Toxicities ..................... 6 
1.3           Other Agents/Devices .................................................................................................. 7 
1.5           Correlative Studies n/a ................................................................................................. 7 
2.0           STUDY OBJECTIVES ....................................................................................7 
2.2           Secondary Objectives .................................................................................................. 7 
2.3           Exploratory Objectives  n/a .......................................................................................... 7 
2.4           Endpoints ...................................................................................................................... 7 
3.0           PATIENT ELIGIBILITY ..................................................................................7 
3.1           Inclusion Criteria ........................................................................................................... 8 
3.2           Exclusion Criteria ......................................................................................................... 8 
4.1           Treatment Dosage and Administration ......................................................................... 8 
4.2           Toxicities and Dosing Delays/Dose Modifications........................................................ 8 
4.4           Other Modalities or Procedures None. ......................................................................... 9 
4.5           Duration of Therapy ...................................................................................................... 9 
4.6           Duration of Follow Up ................................................................................................... 9 
4.8           Patient Replacement .................................................................................................... 9 
5.0           STUDY PROCEDURES .................................................................................9 
5.1           Screening/Baseline Procedures ................................................................................... 9 
5.2        Procedures During Treatment ....................................................................................... 10 
5.3      Follow-up Procedures ..................................................................................................... 10 
7.2           Adverse Event Monitoring .......................................................................................... 13 
7.3           Definitions ................................................................................................................... 13 
7.4           Steps to Determine If an Adverse Event Requires Expedited Reporting ................... 14 
7.5         Reporting Requirements for Adverse Events ............................................................... 14 
7.6           Unblinding Procedures ............................................................................................... 15 

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8.1           Agent/Device: Misoprostol .......................................................................................... 15 
11.0        STUDY MANAGEMENT ...............................................................................19 
11.1          Conflict of Interest ..................................................................................................... 19 
11.2          Registration Procedures ............................................................................................ 20 
11.3          Data Management and Monitoring/Auditing .............................................................. 20 
11.4          Adherence to the Protocol ......................................................................................... 20 
11.5          Amendments to the Protocol ..................................................................................... 21 
11.6        Record Retention ........................................................................................................ 21 
11.7        Obligations of Investigators ......................................................................................... 21 

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LIST OF ABBREVIATIONS 
EBL- Estimated Blood Loss 
Hgb- Hemoglobin 
Hct - Hematocrit 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SUMMARY 
 
Title 
Buccal misoprostol prior to either an abdominal and laparoscopic 
myomectomy for reduction of intraoperative blood loss: a 
randomized placebo-controlled trial 
Short Title 
Buccal misoprostol prior to either an abdominal and laparoscopic 
myomectomy 
Protocol Number 
STU00091259 
Phase 
IV 
Methodology 
Randomized double-blinded placebo-controlled parallel group trial 
Study Duration 
12 months 
Study Center(s) 
Prentice Women’s Hospital, Northwestern Memorial Hospital  
Objectives 
Examine efficacy of buccal misoprostol at reduction in 
intraoperative blood loss at time of either an abdominal and 
laparoscopic myomectomy 
Number of Subjects 
70 
Diagnosis and Main 
Inclusion Criteria 
Symptomatic uterine fibroids, desire to retain uterus 
Study Product(s), Dose, 
Route, Regimen 
Misoprostol 400mcg buccally 
Duration of administration 
1 hour pre-procedure – At least 4 hours post-procedure 
Reference therapy 
Placebo (100mg Vitamin B6 tablets) 
Statistical Methodology 
Power calculation indicates 35 patients per arm will detect 1 
standard deviation difference with 90% power. Fisher’s exact test 
to be used for categorical variables and T test to be used for 
continuous variables with P <.05. 
 
 
 
 
 
 
 
 

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 1.0           BACKGROUND AND RATIONALE 
1.1           Disease Background  
Leiomyomata are the most common tumors of the uterus. Though the majority of women with fibroids are 
asymptomatic, a significant portion suffer symptoms including abnormal bleeding, pain, pressure and 
abdominal distention (1). Submucosal and large intramural fibroids have also been shown to impair 
fertility. Many women seek treatment for fibroids but desire to retain their uterus, whether to preserve 
future fertility or for other personal reasons. Myomectomy is a curative treatment that allows for uterine 
preservation but can come at the risk of substantial intraoperative blood loss. 
 
Studies have assessed the utility of GnRH, vasopressin, peri-cervical tourniquet, misoprostol and 
oxytocin, among others, in reducing intraoperative blood loss (2). Findings from small randomized trials 
demonstrate significantly lower intraoperative blood loss among women who receive preoperative 
misoprostol compared to those who receive placebo (4, 6, 7). Other research fails to demonstrate a 
difference in blood loss following preoperative misoprostol (8) and cites methodologic flaws with existing 
studies (5). Additionally, no randomized controlled trial has been done in a U.S. population. A double-
blinded, randomized, placebo-controlled trial at a tertiary care center in a major U.S. city is an ideal 
setting for evaluation of this research question. 
 
The aim of this study is to assess the impact of preoperative buccal misoprostol on intraoperative blood 
loss and clinical outcomes related to blood loss (blood transfusion, protracted hospital stay). Defining the 
relationship between misoprostol and blood loss during myomectomy would provide insight into the 
mechanism of uterine contraction and hemostasis and inform optimal preoperative clinical management 
of patients undergoing this common and potentially morbid procedure. 
1.2           Study Agent(s)/Devices Background and Associated Known Toxicities 
Misoprostol is an analogue of prostaglandin E1 initially developed for treatment of NSAID induced peptic 
ulcers, which is currently used in a variety of contexts in the field of obstetrics and gynecology including in 
the FDA approved regimen for medical abortion, cervical ripening, and treatment of postpartum 
hemorrhage. In non-pregnant women, misoprostol has been widely described for use in cervical 
preparation prior to hysteroscopy, intrauterine device insertion, and endometrial biopsy. 
 
Multiple routes of administration have been studied including oral, sublingual or buccal, rectal and vaginal 
administration with peak plasma concentrations less than 30 minutes after administration via the oral or 
sublingual route. Systemic bioavailablity of sublingual misoprostol is significantly greater than with orally 
or vaginally administered misoprostol however overall plasma concentrations persist for at least 6 hours 
at higher concentrations when administered vaginally. Potent uterotonic activity is noted as a result of 
increased intracellular calcium activating myosin light-chain kinase. 
 
Adverse effects of misoprostol vary and include abnormal vaginal bleeding, lower abdominal pain and 
cramping, fever or shivering, nausea, vomiting and diarrhea with more uterine cramping and vaginal 
bleeding associated with vaginal administration (3). 
 
Prior studies evaluating misoprostol effect on intraoperative blood loss at time of either an abdominal and 
laparoscopic myomectomy have used a single dose of 400mcg misoprostol administered vaginally or 
rectally pre-procedure and have found a significant decrease in blood loss. 400mcg is the standard dose 
used for the majority of gynecologic applications and appears to be well tolerated (4-9). There are no 
additional risks to study participants adding laparoscopic surgery to this study.  

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1.3           Other Agents/Devices 
Placebo will be 100mg vitamin B6 (pyridoxine) tablets (see Section 8.2).  
 
1.4           Rationale 
Abdominal myomectomy is a common procedure that comes with risks of significant morbidity, including 
intraoperative blood loss at time of abdominal myomectomy as well as numerous postoperative 
complications including an up to 20% requirement for transfusion and 2% reported conversion to 
hysterectomy. The significant morbidity associated with this procedure has led to studies evaluating 
multiple interventions to reducing bleeding during myomectomy. A systematic review of the interventions 
to reduce blood loss at time of myomectomy found significant reductions in blood loss with use of vaginal 
misoprostol however included only one randomized controlled trial (2). Since this time, other studies have 
been done that reproduce these findings (6, 7), though sample size in these trials is small and results are 
inconsistent (8). This study would augment existing data by employing a larger sample size and double-
blinded design in a U.S. population. This study would also assess the impact of a route of misoprostol 
administration that is less invasive for patients (buccal instead of vaginal or rectal) but offers a similar 
pharmokinetic profile. Outcomes assessed include estimated blood loss, need for transfusion, prolonged 
hospitalization, change in postoperative hemoglobin level from preoperative baseline. 
1.5           Correlative Studies n/a 
2.0           STUDY OBJECTIVES 
2.1           Primary Objectives 
 
2.1.1        To determine the effect of 400mcg buccal misoprostol at least one hour pre-procedure on 
intraoperative blood loss at time of either an abdominal or laparoscopic myomectomy. 
2.2           Secondary Objectives 
  
2.2.1       To determine the effect of 400mcg buccal misoprostol at least one hour pre-procedure on the 
need for blood transfusion during or in post-operative course for either an abdominal or laparoscopic 
myomectomy 
  
2.2.2  
To determine the effect of 400mcg buccal misoprostol at least one hour pre-procedure on post-
operative fever after either an abdominal or laparoscopic myomectomy. 
  
2.2.3   To determine the incidence of adverse effects, if any, of 400mcg buccal misoprostol at least one 
hour prior to either an abdominal or laparoscopic myomectomy. 
2.3           Exploratory Objectives  n/a 
2.4           Endpoints 
Estimated blood loss as determined by anesthesia and surgeon at time of abdominal or laparoscopic 
myomectomy, difference between post-operative and pre-operative hemoglobin, post-operative 
temperature, and overall length of hospital admission. 
3.0           PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study 
treatment may not begin until a subject is registered. 

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3.1           Inclusion Criteria 
  
3.1.1      Patients presenting for either an abdominal and myomectomy with documented uterine fibroids 
on pelvic imaging (pelvic ultrasound or MRI) within in last 12 months 
  
3.1.2      Age ≥ 18 years and ≤ 50 years. 
  
3.1.3     Pre-operative hemoglobin >8 g/dl. 
   
3.1.4     Willing to have buccal administration of misoprostol or a placebo at least one hour pre-procedure. 
  
3.1.5   Ability to understand and the willingness to sign a written informed consent. 
 
3.1.6     Admissible medical/surgical history. 
  
a. Can be previously treated with Depo-Lupron, Depo-Provera, or Oral Contraceptive pills 
b.  Intraoperative use of vasopressin and uterine tourniquet is permissible 
c. Can have had prior Cesarean delivery 
3.2           Exclusion Criteria 
3.2.1   Pregnancy. All patients will be required to have a negative urine pregnancy test prior to enrollment. 
 
3.2.2.  Patients who have had a prior abdominal myomectomy. 
  
3.2.3    Post-menopausal women. 
  
3.2.4    Patients with known bleeding/clotting disorders. 
  
3.2.5    Patients with a history of gynecologic malignancy. 
 
3.2.6    History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
misoprostol. 
 
3.2.7   Any cases converted to abdominal hysterectomy orother additional elective surgical procedures 
performed at time of abdominal or laparoscopic myomectomy will be excluded from data analysis. 
  
3.2.8   Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
  
4.0           TREATMENT PLAN 
4.1           Treatment Dosage and Administration 
  
4.1.1   400mcg misoprostol or 100mg vitamin B6 placebo administered buccally at least one hour prior to 
procedure. 
  
4.2           Toxicities and Dosing Delays/Dose Modifications 
Given this is a one-time dosing, toxicities will be limited to the immediate intervention period. Any patient 
who receives treatment on this protocol will be evaluable for toxicity for the entire duration of action of this 

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medication.  
 
According to published research, serum levels of misoprostol nadir 6 hours following administration and 
the duration of pharmacologic action is considered to be only 3 hours (3,5). All patients are hospitalized 
following abdominal myomectomy and laparoscopic such that all patients will be monitored as inpatients 
for a minimum of 4 hours post-operatively.   
  
 4.3           Concomitant Medications/Treatments 
None. 
4.4           Other Modalities or Procedures 
None. 
4.5           Duration of Therapy 
Pre-operative administration of misoprostol or pyridoxine placebo. 
4.6           Duration of Follow Up 
Patients will be followed for the duration of their hospital admission following abdominal or laparoscopic 
myomectomy. Patients will be required to stay a minimum of 4 hours post-surgery. Blood will be drawn 
right before patient leaves the hospital, post operatively.  
4.7           Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 5.5 apply. The principal 
investigator will be notified of any and all patients removed from therapy and the reason for study removal 
and date the patient was removed will be documented in the Case Report Form. The patient will be 
followed-up per protocol. 
4.8           Patient Replacement 
If a patient is removed from the study, an additional patient may be enrolled and randomized to replace 
them. 
5.0           STUDY PROCEDURES 
5.1           Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after obtaining 
informed consent. Assessments performed for clinical indications (not exclusively to determine study 
eligibility) may be used for baseline values even if the studies were done before informed consent was 
obtained. 
  
All screening procedures must be performed within ninety days of registration unless otherwise stated. 
The screening procedures include: 
5.1.1      Informed Consent 
Will be obtained for all potentially eligible participants. Please see attached Informed Consent documents, 
including eConsent, which will be sent through REDCap. 
5.1.2      Medical history 
Complete medical, surgical, gynecologic and obstetrical history, medications, allergies, social and family 
history including and history of prior myomectomy and personal or family history of blood dyscrasias, 

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coagulopathy and bleeding disorders. 
5.1.3      Demographics 
Age, gender, race, ethnicity, gravidity, parity. 
5.1.4      Review subject eligibility criteria  
Refer to section 3.0. 
5.1.5      Review previous and concomitant medications 
5.1.6      Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight. 
5.1.7      Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event monitoring and reporting. 
5.1.8      Baseline Hemoglobin 
 Baseline serum hemoglobin will be determined for all patients.  
 
5.1.9      Pregnancy test (for reproductive age females) 
See section 3.1.6.1 for definition. 
5.1.10   Other 
*Note: Aside from signing of informed consent, all of the above information will be garnered from existent 
medical records. No additional physical examination, history taking or laboratory testing will be required of 
study participants. 
5.2        Procedures During Treatment 
Administration of 400mcg Misoprostol or 100mg Pyridoxine (placebo). 
5.3      Follow-up Procedures 
None.  
  
5.4           Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own request, or they may 
be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The 
reason(s) for discontinuation will be documented and may include: 
5.5.1         
Patient voluntarily withdraws from treatment (follow-up permitted); 
5.5.2         
Patient withdraws consent (termination of treatment and follow-up); 
5.5.3        
Patient is unable to comply with protocol requirements; 
5.5.4         
Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.5.5         
Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
5.5.6         
Patient becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event); 
5.5.7         
Lost to follow-up. If a research subject decides against undergoing abdominal or 
laparoscopic myomectomy and/or surgical case is cancelled after receiving misoprostol or placebo,  the 

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subject may be considered lost to follow-up.  
6.0     
Response Criteria 
Clinically-documented intraoperative blood loss.  
 
6.1   Safety/Tolerability 
All patients will be closely monitored by physician and nursing staff in the operating room and post-
operative recovery area for the full duration of action of the active medication. Misoprostol is largely 
considered a safe, well-studied medication (10). The risk profile may be even more favorable when a 
single dose of misoprostol is administered (11).  
 
The placebo medication, pyridoxine (Vitamin B6), is a safe nutritional supplement with no known side 
effects of a one-time dose. Additionally, it is absorbed in the jejunum such that absorption when buccally 
administered (12). 
7.0     
ADVERSE EVENTS 
7.1      Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or Study Agent 
Prescribing Information. The following information is taken from the FDA website (10). 
7.1.1      Contraindications 
Pregnancy, history of allergy to prostaglandins or Vitamin B6. 
7.1.2   Special Warnings and Precautions for Use 
In pregnant women, cytotec can cause birth defects, abortion or premature birth. Uterine rupture has 
been reported when cytotec has been administered to pregnant women to induce labor or to induce 
abortion beyond the 8th week of pregnancy. Patients should be advised that cytotec should not be given 
to others due to its abortifacient properties. 
Cytotec may be prescribed if the patient: 
• has had a negative serum pregnancy test within 2 weeks prior to beginning therapy. 
• is capable of complying with effective contraceptive measures. 
• has received both oral and written warnings of the hazards of misoprostol, the risk of possible 
contraception failure, and the danger to other women of childbearing potential should the drug be taken 
by mistake. 
• will begin Cytotec only on the second or third day of the next normal menstrual period. 
WARNING for off-label uses: 
For hospital use only if misoprostol were to be used for cervical ripening, induction of labor, or for the 
treatment of serious post-partum hemorrhage, which are outside of the approved indication. 
7.1.3   Interaction with other medications 
Misoprostol is a renally-cleared medication and does not affect the hepatic mixed function oxidase 
(cytochrome P-450) enzyme systems in animals. 
 
Drug interaction studies between misoprostol and several nonsteroidal anti-inflammatory drugs showed 
no effect on the kinetics of ibuprofen or diclofenac, and a 20% decrease in aspirin AUC, not thought to 
be clinically significant. Pharmacokinetic studies also showed a lack of drug interaction with antipyrine 
and propranolol when these drugs were given with misoprostol. Misoprostol given for 1 week had no 
effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours 

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apart. The serum protein binding of misoprostol acid is less than 90% and is concentration-independent in 
thetherapeutic range. 
 
7.1.4   Adverse Reactions 
The FDA reports the following possible side effects with the active medication (Misoprostol):  
 
Gastrointestinal: In subjects receiving Cytotec 400 or 800 mcg daily in clinical trials, the most frequent 
gastrointestinal adverse events were diarrhea and abdominal pain. The incidence of diarrhea at 800 mcg 
in controlled trials in patients on NSAIDs ranged from 14-40% and in all studies (over 5,000 patients) 
averaged 13%. Abdominal pain occurred in 13-20% of patients in NSAID trials and about 7% in all 
studies, but there was no consistent difference from placebo. 
 
Diarrhea was dose related and usually developed early in the course of therapy (after 13 days), usually 
was self-limiting (often resolving after 8 days), but sometimes required discontinuation of Cytotec (2% 
of the patients). Rare instances of profound diarrhea leading to severe dehydration have been reported. 
 
Patients with an underlying condition such as inflammatory bowel disease, or those in whom 
dehydration, were it to occur, would be dangerous, should be monitored carefully if Cytotec is 
prescribed. 
 
Gynecological: Women who received Cytotec during clinical trials reported the following gynecological 
disorders: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%) and 
dysmenorrhea (0.1%). Postmenopausal vaginal bleeding may be related to Cytotec administration. If it 
occurs, diagnostic workup should be undertaken to rule out gynecological pathology. Research studies in 
obstetrics and gynecology also identify possible side effects of diarrhea, fever and shivering (4,6,7). 
 
Elderly: There were no significant differences in the safety profile of Cytotec in approximately 500 ulcer 
patients who were 65 years of age or older compared with younger patients. 
 
Additional adverse events which were reported are categorized as follows: 
 
In clinical trials, the following adverse reactions were reported by more than 1% of the subjects receiving 
Cytotec and may be causally related to the drug:  nausea (3.2%), flatulence, (2.9%), headache (2.4%), 
dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%). However, there were no significant 
differences between the incidences of these events for Cytotec and placebo.  
 
Causal relationship unknown: The following adverse events were infrequently reported. Causal 
relationships between Cytotec and these events have not been established but cannot be excluded: 
Body as a whole: aches/pains, asthenia, fatigue, fever, rigors, weight changes. 
Skin: rash, dermatitis, alopecia, pallor, breast pain. 
Special senses: abnormal taste, abnormal vision, conjunctivitis, deafness, tinnitus, earache. 
Respiratory: upper respiratory tract infection, bronchitis, bronchospasm, dyspnea, pneumonia, epistaxis. 
Cardiovascular: chest pain, edema, diaphoresis, hypotension, hypertension, arrhythmia, phlebitis, 
increased cardiac enzymes, syncope. 
Gastrointestinal: GI bleeding, GI inflammation/infection, rectal disorder, abnormal hepatobiliary 
function, gingivitis, reflux, dysphagia, amylase increase. 
Hypersensitivity: anaphylaxis 
Metabolic: glycosuria, gout, increased nitrogen, increased alkaline phosphatase. 
Genitourinary: polyuria, dysuria, hematuria, urinary tract infection. 
Nervous system/Psychiatric: anxiety, change in appetite, depression, drowsiness, dizziness, thirst, 
impotence, loss of libido, sweating increase, neuropathy, neurosis, confusion. 
Musculoskeletal: arthralgia, myalgia, muscle cramps, stiffness, back pain. 
Blood/Coagulation: anemia, abnormal differential, thrombocytopenia, purpura, ESR increased. 

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7.2           Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of Subjects enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care. 
  
All patients experiencing an adverse event, regardless of its relationship to study drug/device, will be 
monitored until: 
Ø  the adverse event resolves or the symptoms or signs that constitute the adverse event return to 
baseline; 
Ø  any abnormal laboratory values have returned to baseline; 
Ø  there is a satisfactory explanation other than the study drug for the changes observed; or 
Ø  death. 
7.3           Definitions 
7.3.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an experimental intervention, whether or not related to the 
intervention. 
7.3.2 Severity of Adverse Events 
The severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly 
affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 
7.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward medical occurrence that: 
7.3.3.1         Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.3.3.2         Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it 
were more severe). 

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7.3.3.3         Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.3.3.4         Results in persistent or significant disability or incapacity. 
7.3.3.5         Is a congenital anomaly/birth defect 
7.3.3.6         Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
7.4           Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1:       
Identify the type of adverse event   
  
Step 2: Grade the adverse event 
  
Step 3: Determine whether the adverse event is related to the protocol therapy 
Attribution categories are as follows: 
-        Definite – The AE is clearly related to the study treatment. 
-        Probable – The AE is likely related to the study treatment. 
-        Possible – The AE may be related to the study treatment. 
-                   Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any event 
that occurs more than 30 days after the last dose of treatment and is attributed (possibly, probably, or 
definitely) to the agent(s) must also be reported accordingly. 
  
Step 4:          
Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as resulting from administration of the 
agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either 
the type of event or the severity of the event is not listed in: 
·    
the current known adverse events listed in the Agent Information Section of this protocol; 
·    
the drug package insert; 
·    
the current Investigator’s Brochure 
7.5         Reporting Requirements for Adverse Events 
7.5.1      Expedited Reporting 
·         The Principal Investigator must be notified within 24 hours of learning of 
any serious adverse events, regardless of attribution, occurring during the 
study or within 30 days of the last administration of the study drug. 
·         The office of Risk Management and the IRB must be notified within 10 
business days of “any unanticipated problems involving risk to subjects or others” 
(UPR/UPIRSO). 
Insert your local requirements below: 
The following events meet the definition of UPR: 

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1.     Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2.     Any serious accidental or unintentional change to the IRB-
approved protocol that alters the level of risk. 
3.     Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4.     Any new information (e.g., publication, safety monitoring report, 
updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5.     Any breach in confidentiality that may involve risk to the subject or 
others. 
6.     Any complaint of a subject that indicates an unanticipated risk or 
that cannot be resolved by the Principal Investigator. 
·         For IND/IDE trials: The FDA should be notified within 7 business days of 
any unexpected fatal or life-threatening adverse event with possible 
relationship to study drug, and 15 business days of any event that is 
considered: 1) serious, 2) unexpected, and 3) at least possibly related to 
study participation. 
7.5.2      Routine Reporting 
·         All other adverse events- such as those that are expected, or are unlikely 
or definitely not related to the study participation- are to be reported 
annually as part of regular data submission. 
7.6           Unblinding Procedures 
Unblinding to occur in the case of serious morbidity or life-threatening illness that may be reasonably 
attributable to administration of misoprostol, including but not limited to admission to the intensive care 
unit, hyperpyrexia and repeated or high-grade fevers. While the safety of the subject always comes first, it 
is still important to seriously consider if unblinding the study therapy is necessary to ensure a subject’s 
safety.  
 
7.7           Stopping Rules 
This study involves a one-time pre-operative intervention prior to a planned surgical procedure. If a 
patient develops immediate, intolerable side effects including but limited to emesis, diarrhea, or heavy 
vaginal bleeding following buccal administration of misoprostol or placebo, therapy will be discontinued.  
 
8.0           DRUG/DEVICE INFORMATION 
8.1           Agent/Device: Misoprostol 
·       Other names for the drug(s)/device: Cytotec 
  
·       Classification - type of agent/device: medication, synthetic Prostaglandin E1 analogue 
  
·       Mode of action: Production of uterine contractions 
  
·       Storage and stability: Store at or below 25°C (77°F), in a dry area. 
  

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·       Protocol dose: 400mcg 
  
·       Preparation: Tablet 
  
·       Route of administration for this study: Buccally, 200mcg on each side  
  
·       Incompatibilities: Pregnancy, history of adverse reaction to prostaglandins 
  
·       Availability: Commercially available  
  
·       Side effects: A brief summary of the adverse events most likely to occur in this study and associated 
with this agent should be inserted here. Refer the reader to the agent’s package insert or Section 7.1 
above for a comprehensive list of adverse events. 
·       Nursing implications: Ensure patient has a negative pregnancy test and confirm list of allergies prior 
to providing the medication. Day of surgery urine pregnancy testing and verbal confirmation of a patient’s 
allergies are both standard of care practices for reproductive age women undergoing surgery. 
 
8.2  
Agent/Device: Vitamin B6  
 
·       Other names for the drug(s)/device: Pyroxidine  
  
·       Classification - type of agent/device: medication, synthetic vitamin  
  
·       Mode of action: Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and 
is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with 
protein metabolism (12). 
  
·       Storage and stability: Store at or below 25°C (77°F), in a dry area. 
  
·       Protocol dose: 100mg  
  
·       Preparation: Tablet 
  
·       Route of administration for this study: Buccally,50 mg on each side  
  
·       Incompatibilities: none 
  
·       Availability: Commercially available  
  
·       Side effects: none 
 
·       Nursing implications: none  
 
8.1.1      Return and Retention of Study Drug/Device 
Active medication will be purchased on a case by case basis from NMH inpatient research pharmacy 
such that excess misoprostol is not anticipated. In the event of access active medication, this will be 
disposed per pharmacy protocol.  
  
8.1.2     
Compliance with administration will be documented by pre-operative nursing staff.  
 
9.0           CORRELATIVES/SPECIAL STUDIES 
N/A.  
 

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10.0        STATISTICAL CONSIDERATIONS  
 
10.1        Study Design/Study Endpoints 
 
This is a double blinded randomized, controlled trial of women undergoing either an abdominal and 
laparoscopic myomectomy at a single university-affiliated tertiary care center. Women ages 18-50 years 
of age with clinically documented, sonographic evidence of uterine fibroids being scheduled for abdominal 
myomectomy were eligible for inclusion. Eligible participants will be randomized to receive preoperative 
400cg buccal misoprostol or placebo on the basis of total fibroid volume, location (intramural or 
subserosal) and parity. Stratification by fibroid volume (or fibroid size) will be performed prior to 
randomization. Fibroid volume is defined as the cumulative volume of intramural and subserosal fibroids 
as measured on preoperative magnetic resonance imaging (MRI), or in the instance of patient 
contraindication to MRI, transvaginal ultrasound (TVUS). The data collection sheet (addendum) and chart 
of study variables below include definition of this variable and allow for ease of recording and tracking of 
this variable in our study database. Women with a history of gynecologic malignancy, critical anemia or 
blood dyscrasias and those with a history of prior myomectomies will be excluded.  
 
List of Study Variables to be Collected: 
Outcomes 
Type 
Definition          
Estimated blood loss 
Continuous 
Intraoperative blood loss as estimated by intra-
operative anesthesiologists and surgeons. 
% drop in Hgb 
Continuous 
Ratio of the drop in hemoglobin over the starting 
hemoglobin (Hgpost-op – Hgpre-op)/ Hgpre-op 
Duration of hospital 
stay (days) 
Continuous 
Number of days inpatient following abdominal 
myomectomy. 
Duration of procedure 
(minutes) 
Continuous 
Number of days inpatient following abdominal 
myomectomy. 
Post-op fever 
Dichotomous 
If patient has one Temperature >101.4 or two 
temperatures >100.4, then yes. 
If not then no. 
Adverse reaction to 
misoprostol 
Dichotomous 
If patient experiences vaginal bleeding, vomiting or 
diarrhea then yes. 
If not then no. 
  
Exposures 
Type 
Definition 
Pre-op Misoprostol 
Dichotomous 
If women randomized to receive misoprostol, then yes. 
If women randomized to placebo, then no. 
  
Covariates 
Type 
Definition 
Woman’s Age 
Continuous 
Female age in years at time of abdominal myomectomy 
Volume of fibroids (pre-
op) 
Continuous 
Cumulative volume of intramural and subserosal 
fibroids based on preoperative imaging 
Will be used for stratification and randomization. 

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Mass of fibroids (post-
op) 
Continuous 
Cumulative mass of intramural and subserosal fibroids 
based on pathology reports 
-Will be used to account for variability in final models. 
Pre-treatment with 
Lupron, Depo-provera, 
OCPs 
Dichotomous 
Pre-operative treatment with Lupron, Depo-provera or 
OCP’s 
Intraoperative treatment 
with vasopressin or 
tourniquet 
Dichotomous 
Use of intraoperative vasopressin or tourniquet during 
myomectomy. 
  
Other 
Type 
Definition 
Use 
Uterus size in 
weeks gestation 
Ordinal 
Uterus size in weeks gestation per pre-
operative physical exam 
Table 1 characteristic 
History of 
Gynecologic 
Malignancy 
Dichotomous 
If history of gynecologic cancer 
(uterine, ovarian or cervical cancer), 
then yes. 
If not, then no. 
Exclude if yes. 
Uterine 
Anomaly 
Dichotomous 
If septate, unicornuate or bicornuate 
uterus, then yes. 
If abnormality is less severe than 
arcuate uterus or normal then no. 
Exclude if yes. 
Prior Cesarean 
Section Cycle 
Dichotomous 
If prior Cesarean delivery, then yes. 
If no prior Cesarean delivery, then no. 
Table 1 characteristic, 
stratum-specific sub-
analyses 
Gravidity 
Count 
Number of prior pregnancies 
Table 1 population 
characteristic 
Gravid 
Dichotomous 
If number of pregnancies is 1+, then 
yes 
If number of pregnancies is 0, then no 
Table 1 characteristic, 
stratum-specific sub-
analyses 
Parity 
Count 
Number of prior pregnancies 
Table 1 population 
characteristic 
Living children 
Count 
Number of living children 
Table 1 characteristic 
Woman’s Age 
(SART 
categories) 
Categorical 
Group by age in years at abdominal 
myomectomy: 
<30 
30-34 
35-37 
38-39 
40-42 
43+ 
Table 1 population 
characteristic 
Race 
Categorical 
Group by race: White, Black/Africa-
American, Hispanic, Asian/Pacific 
Table 1 population 
characteristic 

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Islander, American Indian/Alaskan 
Native, Middle-Eastern 
 
10.2        Sample Size and Accrual 
Power calculation based on the standard deviation in published reports (5) demonstrates that enrollment 
of 25 participants per arm is necessary to detect 1 standard deviation difference with 90% power. Further, 
published results from pilot studies in this population (7) and demonstrates that enrollment of 25 
participants per arm is necessary to detect 0.5g/dL difference in hemoglobin with 90% power.  
 
Prentice Women’s Hospital of Northwestern Memorial performed over 100 abdominal myomectomies in 
2013. Across a year-long study period, we anticipate identifying a minimum of 70 patients to evaluate our 
primary hypothesis. We have increased our sample size from 50 to 70 to account for the 9 participants 
that were either consented by a non-study team member, did not get the study drug due to an error at 
pharmacy or left the hospital after surgery thus we could not obtain a POD 1 which is needed for data 
analysis. 
 
Following data collection from at least 20 participants in each arm, standard deviation calculations will be 
performed to confirm that the standard deviations in our sample population is similar. Power calculation 
will be repeated using the standard deviations in our active and placebo groups and additional 
participants will be enrolled as needed to achieve adequate power to evaluate our primary outcome of 
intraoperative blood loss. 
 
 
10.3        Data Analyses Plans 
To determine whether women who take a pre-operative dose of misoprostol experince lower blood loss 
during abdominal myomectomy compared to matched controls who take placebo, we will perform linear 
regression. We will use this model to assess for the role of numerous covariates, including gravidity, 
parity and age. Secondary outcomes of percent hemoglobin drop, duration of procedure and length of 
inpatient hospitalization will be assessed using the T test and further evaluated with multivariate-adjusted 
linear regression where appropriate. The need for post-operative blood transfusion between groups will 
be assessed with the Chi-square (Fischer’s exact) test. The role of numerous potential covariates will be 
assessed with Chi-square (Fischer’s exact) test for dichotomous variables and T test for continuous 
variables with p <0.05.  
11.0        STUDY MANAGEMENT 
11.1          Conflict of Interest 
  
None to disclosure.  All investigators will follow the University conflict of interest policy. 
 
11.2  Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol. 
  
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
         
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 

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understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB‑approved consent form. 
  
Prior to a patient’s participation in the trial, the written informed consent form will be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
 
Patients who have their pre-op appointment via telehealth calls will also be able to consent as participants 
using an eConsent form through the secure Northwestern University REDCap. They will be contacted 
during or after their pre-op appointment by the research coordinator to discuss the study. The research 
coordinator will consent the patient over the phone and leave time to answer any questions they have 
about participating in the study before sending the econsent form through REDCap.   
11.2          Registration Procedures 
N/A. 
11.3          Data Management and Monitoring/Auditing 
N/A. 
11.4          Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol. 
11.4.1   Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval. 
  
For any such emergency modification implemented, a IRB modification form must be completed within 
five (5) business days of making the change. 
11.4.2   Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal Investigator and 
the IRB. According to the IRB, a protocol deviation is any unplanned variance from an IRB approved 
protocol that: 
·      Is generally noted or recognized after it occurs 
·      Has no substantive effect on the risks to research participants 
·      Has no substantive effect on the scientific integrity of the research plan or the value of the data 
collected 
·      Did not result from willful or knowing misconduct on the part of the investigator(s). 
  
An unplanned protocol variance is considered a violation if the variance: 
·      Has harmed or increased the risk of harm to one or more research participants. 
·       Has damaged the scientific integrity of the data collected for the study. 
·      Results from willful or knowing misconduct on the part of the investigator(s). 
·      Demonstrates serious or continuing noncompliance with federal regulations, State laws, or University 
policies. 
  
If a deviation or violation occurs without prior approval from the Principal Investigator, please follow the 
guidelines below: 

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11.5          Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and documented by 
the Principal Investigator. It should also be noted that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a revised consent form might be required. 
  
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation. 
11.6        Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
  
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
  
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization (ICH) region. In all 
other cases, study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.7        Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both 
during and after study completion. 
  
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be reviewed 
by the Principal Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.0        REFERENCES 
1.  Bulun, S. (2013). Uterine Fibroids. NEJM (369: 1344-1355), DOI: 10.1056/NEJMra1209993 
2. Kongnyuy, E. J., & Wiysonge, C. S. (2011). Interventions to reduce haemorrhage during myomectomy 
for fibroids. Cochrane Database Syst Rev(11), Cd005355. doi: 
10.1002/14651858.CD005355.pub4 
3. Choksuchat, C. (2010). Clinical use of misoprostol in nonpregnant women: review article. Minim 
Invasive Gynecol, 17(4), 449-455. doi: 10.1016/j.jmig.2010.03.015 
4. Celik, H., & Sapmaz, E. (2003). Use of a single preoperative dose of misoprostol is efficacious for 
patients who undergo abdominal myomectomy. Fertil Steril, 79(5), 1207-1210. 
5. Chan, L. Y. (2004). The use of vaginal misoprostol before myomectomy. Fertil Steril, 81(4), 1160; 
author reply 1160-1161. doi: 10.1016/j.fertnstert.2004.01.010 
6. Frederick, S., Frederick, J., Fletcher, H., Reid, M., Hardie, M., & Gardner, W. (2013). A trial comparing 
the use of rectal misoprostol plus perivascular vasopressin with perivascular vasopressin alone to 
decrease myometrial bleeding at the time of abdominal myomectomy. Fertil Steril, 100(4), 1044-
1049.  
7. Kalogiannidis, I., Xiromeritis, P., Prapas, N., & Prapas, Y. (2011). Intravaginal misoprostol reduces 
intraoperative blood loss in minimally invasive myomectomy: a randomized clinical trial. Clin Exp 
Obstet Gynecol, 38(1), 46-49. 
8. Park, H., Yoon, B. S., Seong, S. J., Kim, J. Y., Shim, J. Y., & Park, C. T. (2011). Can misoprostol 
reduce blood loss in laparoscopy-assisted vaginal hysterectomy? Aust N Z J Obstet Gynaecol, 
51(3), 248-251. doi: 10.1111/j.1479-828X.2011.01304.x 
9. Shokeir, T., Shalaby, H., Nabil, H., & Barakat, R. (2013). Reducing blood loss at abdominal 
myomectomy with preoperative use of dinoprostone intravaginal suppository: a randomized 
placebo-controlled pilot study. Eur J Obstet Gynecol Reprod Biol, 166(1), 61-64. doi: 
10.1016/j.ejogrb.2012.09.014 
10. FDA. (2009, 05/05/2009). "Misoprostol (marketed as Cytotec) Drug Safety Information."   Retrieved 
01/08/2014, from 
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/

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ucm111315.htm. 
11. Goldberg, A. B., D. A. Carusi and K. R. Meckstroth (2003). "Misoprostol in gynecology." Curr Womens 
Health Rep 3(6): 475-483. 
12. National Institutes of Health, Office of Dietary Supplements (09/15/2011). “Vitamin B6: Dietary 
supplement for Health Professionals.” Retrieved 02/17/2014, from 
http://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/#h9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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 13.0        APPENDICES 
 
13.1 
Data Collection Sheet (see attached)